Prognostic Impact of Dysnatremia in COVID-19 Pneumonia: Risk Stratification of Hospitalized Patients (preprint)

Background Severe dysnatremia is associated with poor prognosis and worse outcome and therefore needs more attention to unravel its relation with poor prognosis in patients admitted with coronavirus disease 2019 (COVID-19). Aim of our study was to determine varying degree of dysnatremia among hospitalized COVID-19 patients and identify the clinical outcome associated with it.Method This is a retrospective record analysis study done on the hospitalized COVID-19 patients in Guwahati Neurological Research Centre Medical, North Guwahati. For every included patient, his or her medical records were extracted from a standardized electronic medical record collection system and scrutinised anonymously.Results COVID-19 positive participants were divided into four categories like, dysnatremic (serum sodium > 146 or < 134 mmol/L), hypernatremic (> 146 mmol/L), hyponatremic (< 134 mmol/L) and eunatremic (134 ‒ 146 mmol/L). Total 37.9% of the included COVID-19 participants exhibited dysnatremia compared to only 20% of the patients from the control group demonstrating a significant difference (p = 0.02). Hypernatremia was significantly high (p = 0.01) compared to hyponatremia among COVID-19 positive participants (27.7% vs 12.3%) and also turned out to be relatively severe with significantly high ICU admittance (p < 0.0001) and mortality rate (p = 0.01). Magnitude of dysnatremic patients showing aberration in the circulatory level of the other laboratory parameters was significantly high to that of eunatremic group with high fatality rate among hypernatremic. Both hyper and hyponatremic group demonstrated significantly high SOFA score but increased mortality risk, based on CURB 65 score and 2.35 fold increased probability of death was observed in hypernatremic group.Conclusion Dysnatremia, with special mention to hypernatremia, is associated with increased casualty rate, aberrant laboratory parameters and ICU admittance. This highlights the significance of considering dysnatremia as a predictive outcome marker and thus directs a correct path for appropriate management of COVID-19 patients.

Xenosialylation: Role in SARS/CoV-2 Post-infectious and Post-vaccination Complications and Common Cause of Hyperimmune/Autoimmune Diseases (preprint)

The host glycosylation mechanism synthesizes the carbohydrates of glycoproteins of viral envelopes. Due to the loss of the Cytidine Monophospho-N-Acetylneuraminic Acid Hydroxylase gene by some mammalian species, including humans (negative-CMAH), Neu5Gc is no longer synthesized. Uptake of Neu5Gc by negative-CMAH species, through the intake of food products derived from positive-CMAH mammals, leads to incorporating Neu5Gc-glycans in the glycocalyx (xenosialylation). Neu5Gc, being a Mammalian-associated Carbohydrate Antigen (MCA), acts as a non-self-antigen, inducing an inflammatory reaction (Xenosialitis), and triggering the production of circulating antiNeu5Gc antibodies to attack/remove all incorporated Neu5Gc. In the state of Xenosialitis, the virus-neutralizing antibodies produced by a heavily xenosialylated patient following exposure to viral infection (including SarsCoV2) or anti SarsCoV2 vaccination cross-react against all incorporated non-self Neu5Gc-MCA glycans due to their resemblance with viral envelope antigens synthesized by the host glycosylation mechanism. In addition, the circulating anti-XeSias antibodies determine the massive removal of the circulating neutralizing FC-xeno-contaminated antibodies by the serum, living only the hyper-inflammatory agalattosylated antiviral IgG antibodies. Therefore, we hypothesize that the combination of antibody cross-reaction against non-self Neu5Gc-MCA glycans and the massive removal of the xeno-contaminated newly formed neutralizing antibodies in favor of hyper reactive antibodies, could be the cause of the massive inflammatory reaction (cytokine storm, coagulopathies, neuropathies) observed in Covid 19 patients or after anti-SarsCoV2 vaccination. This analysis is an invitation to investigate the post-infectious and/or post-vaccination adverse phenomena in the light of xenosialization as a key to understanding the severe post viral and post vaccine complications, including SARS-CoV2 infection or related vaccination.

Understanding Effects of Algorithmic vs. Community Label on Perceived Accuracy of Hyper-partisan Misinformation (preprint)

Hyper-partisan misinformation has become a major public concern. In order to examine what type of misinformation label can mitigate hyper-partisan misinformation sharing on social media, we conducted a 4 (label type: algorithm, community, third-party fact-checker, and no label) X 2 (post ideology: liberal vs. conservative) between-subjects online experiment (N = 1,677) in the context of COVID-19 health information. The results suggest that for liberal users, all labels reduced the perceived accuracy and believability of fake posts regardless of the posts' ideology. In contrast, for conservative users, the efficacy of the labels depended on whether the posts were ideologically consistent: algorithmic labels were more effective in reducing the perceived accuracy and believability of fake conservative posts compared to community labels, whereas all labels were effective in reducing their belief in liberal posts. Our results shed light on the differing effects of various misinformation labels dependent on people's political ideology.

Multisystemic inflammatory syndrome following COVID-19 mRNA vaccine in children: a national post-authorization pharmacovigilance study (preprint)

Importance. Multisystem inflammatory syndrome in children (MIS-C) is the most severe life-threatening clinical entity associated with pediatric SARS-CoV-2 infection. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. Objective. To assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. Design, Setting, and Participants. Post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Each case was assessed for WHO MIS-C criteria. Causality assessment followed 2019 WHO recommendations. Exposure. COVID-19 mRNA vaccine. Main Outcome and Measures. The main outcome was the reporting rate of post-vaccine hyper-inflammatory syndrome per 1,000,000 COVID-19 mRNA vaccine doses in 12-17-year-old children. This reporting rate was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Secondary outcomes included the comparison of clinical features between post-vaccine hyper-inflammatory syndrome and post SARS-CoV-2 MIS-C. Results. From June 2021 to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 9 presented a multisystemic hyper-inflammatory syndrome. All cases fulfilled MIS-C WHO criteria. Main clinical features included male predominance (8/9, 89%), cardiac involvement (8/9, 89%), digestive symptoms (7/9, 78%), coagulopathy (5/9, 54%), cytolytic hepatitis (4/9, 46%), and shock (3/9, 33%). 3/9 (33%) required intensive care unit transfer, and 2/9 (22%) hemodynamic support. All cases recovered. Only three cases had evidence of previous SARS-CoV-2 infection. The reporting rate was 1.1 (95%CI [0.5; 2.1]) per 1,000,000 doses injected. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Clinical features (inflammatory parameters, cytopenia) slightly differed from post-SARS-CoV-2 MIS-C, along with short-term outcomes (less PICU transfer than MIS-C). Conclusion and Relevance. Very few cases of hyper-inflammatory syndromes with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12-17-year-old children. The low reporting rate of this syndrome, compared to the rate of MIS-C among same age children infected by SARS-CoV-2, supports the benefit of SARS-CoV-2 vaccination in children. Further studies are required to explore specific pathways of this entity compared to post-SARS-CoV-2 MIS-C.

Short-term Outcomes in Children Recovered from Multisystem Inflammatory Syndrome associated with SARS-CoV-2 infection (preprint)

Background: Multi System Inflammatory Syndrome in children (MIS-C) associated with COVID-19 is a recently recognised potentially life-threatening entity. There is limited data on post MIS-C sequelae. Methods: 21 children fulfilling the WHO criteria for MIS-C were included in our study. Data was collected at baseline and at 12-16 weeks post discharge to look for any persistent sequelae mainly relating to the lungs or heart including coronary arteries. Results: Fever was the most common presentation found in 18 (85.7%) patients. All had marked hyper-inflammatory state. Low ejection fraction (EF) was found in 10 (47.6%) but none had any coronary artery abnormality. All received corticosteroids while 7 (33.3%) children required additional treatment with intravenous Immunoglobulins. 20 children improved while 1 left against medical advice. At discharge 3 children had impaired left ventricular function. At median 15 weeks follow-up no persistent complications were found. EF had returned to normal and no coronary artery abnormalities were found during repeat echocardiography. Chest radiographs showed no fibrosis and all biochemical parameters had normalized. Conclusion: The children with MIS-C are extremely sick during the acute stage. Timely and adequate management led to full recovery without any sequelae at a median follow-up of 15 weeks.

Monocyte Distribution Width (MDW) as Novel Inflammatory Marker with Prognostic Significance in COVID-19 Patients (preprint)

Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p<0.001), fibrinogen (p<0.001) and ferritin (p<0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC=0.76, 95% CI: 0.66-0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR=4.91, 95% CI: 1.73-13.96; OR=7.14, 95% CI: 2.06-24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (i) easy to obtain, (ii) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (iii) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (iv) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.

Analytical and clinical evaluation of four anti-SARS-CoV-2 serologic (IgM, IgG, and total) immunoassays (preprint)

Introduction: Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is diagnosed by molecular-based detection of SARS-CoV-2 RNA. Serologic testing detects antibodies specific to SARS-CoV-2 and IgM specifically may serve as an adjunct test to PCR early in disease. We evaluated the Abbott anti-SARS-CoV-2 IgM and IgG assays along with DiaSorin anti-SARS-CoV-2 IgG and Roche anti-SARS-CoV-2 Total. Methods: Specimens from 175 PCR-positive patients and 107 control specimens were analyzed using Abbott IgM and IgG, DiaSorin IgG, and Roche Total (IgA, IgG, IgM) assays. Sensitivity, specificity, cross-reactivity, concordance between assays, trends over time, positive predictive value (PPV), and negative predictive value (NPV) were determined. Results: Abbott IgM sensitivity was 63.6% at 0 days post-PCR positivity, 76.5% at 1-5d, 76.3% at 6-14d, 85.2% at 15-30d, and 63.6% at >30d. All assays exhibited highest sensitivity 15-30d post-PCR positivity (83.3-85.2%). Combining Abbott IgM and IgG improved sensitivity by 22.7% compared to IgG alone when tested 0d post-PCR positivity. All assays had a specificity of 100% and only Abbott IgG exhibited cross-reactivity (anti-dsDNA). Cohen's kappa varied between 0.86-0.93. Time to seroconversion from PCR positivity was lowest for Abbott IgM and highest for Abbott IgG. NPV was highest for Abbott IgM <14 days post-PCR positivity and Abbott IgG [≥]14 days. Conclusion: The Abbott IgM assay exhibited the earliest response and greatest signal in most patients evaluated for serial sampling and had the highest NPV <14 days post-PCR positivity, suggesting its potential utility as an adjunct test to PCR early in disease course.

Refractory Multi-inflammatory Syndrome in a two weeks old neonate with COVID-19 Treated Successfully with Intravenous Immunoglobulin, Steroids and Anakinra (preprint)

Background: World Health Organization (WHO) and other Health officials alert clinicians about a rare but severe inflammatory condition seen in children and linked to Corona Virus Disease 2019(COVID-19). The WHO is describing the condition as a multisystem inflammatory syndrome in children (MIS-C) and is recommending clinicians to report those cases to get a better understanding of the disease and clinicians can learn more.Case presentation: We are reporting the clinical course of the youngest case of COVID-19 related MIS-c; a two-week-old term neonate with COVID-19 infection and features suggestive of MIS-C , managed with intravenous immunoglobulin (IVIG), pulse steroid, and interleukin-1 inhibitor (Anakinra).By reviewing the literature, our baby is the first neonatal case who has been diagnosed with MIS-C.Conclusion: COVID-19 infection in pediatrics are likely to present with a mild course; however, some may develop a hyper-inflammatory syndrome. Pediatricians should be aware of such presentation, the clinical course, the management modalities, and inform parents and caregivers about common signs and symptoms. Anakinra may consider as effective second agent in (IVIG and steroid-refractory pediatric cases).

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity (preprint)

Epidemiological and clinical reports have indicated that the host immune response to SARS-CoV-2, more so than viral factors, determines COVID-19 disease severity. To elucidate the immunopathology underlying COVID-19 severity, cytokine and multiplex immune profiling was performed in mild-moderate and critically-ill COVID-19 patients. Hypercytokinemia in COVID-19 differed from the IFN-γ-driven cytokine storm in macrophage activation syndrome, and was more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels followed by deep-immune profiling showed that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Expression of antigen presenting machinery was reduced in critical disease, while also neutrophils contributed to disease severity and local tissue damage by amplifying hypercytokinemia and neutrophil extracellular trap formation. We suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Evaluation of two commercial and two non-commercial immunoassays for the detection of prior infection to SARS-CoV-2 (preprint)

Background Seroepidemiology is an important tool to characterize the epidemiology and immunobiology of SARS-CoV-2 but many immunoassays have not been externally validated raising questions about reliability of study findings. To ensure meaningful data, particularly in a low seroprevalence population, assays need to be rigorously characterized with high specificity. Methods We evaluated two commercial (Roche Diagnostics and Epitope Diagnostics IgM/IgG) and two non-commercial (Simoa and Ragon/MGH IgG) immunoassays against 68 confirmed positive and 232 pre-pandemic negative controls. Sensitivity was stratified by time from symptom onset. The Simoa multiplex assay applied three pre-defined algorithm models to determine sample result. Results The Roche and Ragon/MGH IgG assays each registered 1/232 false positive, the primary Simoa model registered 2/232 false positives, and the Epitope registered 2/230 and 3/230 false positives for the IgG and IgM assays respectively. Sensitivity >21 days post symptom-onset was 100% for all assays except Epitope IgM, but lower and/or with greater variability between assays for samples collected 9-14 days (67-100%) and 15-21 days (69-100%) post-symptom onset. The Simoa and Epitope IgG assays demonstrated excellent sensitivity earlier in the disease course. The Roche and Ragon/MGH IgG assays were less sensitive during early disease, particularly among immunosuppressed individuals. Conclusions The Epitope IgG demonstrated good sensitivity and specificity. The Roche and Ragon/MGH IgG assays registered rare false positives with lower early sensitivity. The Simoa assay primary model had excellent sensitivity and few false positives.