[The neurology of COVID-19]. / La neurología de COVID-19.

The clinical manifestations of COVID-19 are reminiscent of those of acute respiratory distress syndrome induced by cytokine release syndrome and secondary hemophagocytic lymphohistiocytosis that is observed in patients with other coronaviruses such as SARS-CoV and MERS-CoV. Neurologists face the challenge of assessing patients with pre-existing neurological diseases who have contracted SARS-CoV-2, patients with COVID-19 who present neurological emergencies, and patients who are carriers of the virus and have developed secondary neurological complications, either during the course of the disease or after it. Some authors and recent literature reports suggest that the presence of neurological manifestations in patients who are carriers of SARS-CoV-2 may be associated with a greater severity of the disease.

Las manifestaciones clínicas de COVID-19 recuerdan las del síndrome de insuficiencia respiratoria aguda inducido por el síndrome de liberación de citocinas y la linfohistiocitosis hemofagocitica observada en pacientes con otros coronavirus como SARS-CoV y MERS-CoV. Los neurólogos tienen el reto de evaluar pacientes con enfermedades neurológicas preexistentes que contraen SARS-CoV-2, pacientes con COVID-19 que presentan emergencias neurológicas y pacientes portadores del virus que desarrollan complicaciones neurológicas secundarias, durante el curso de la enfermedad o posterior a la misma. Algunos autores y reportes en la literatura recientes sugieren que las manifestaciones neurológicas en pacientes portadores de SARS-CoV-2 pueden asociarse con mayor gravedad de la enfermedad.

Tissue injury and leukocyte changes in post-acute sequelae of SARS-CoV-2: review of 2833 post-acute patient outcomes per immune dysregulation and microbial translocation in long COVID.

A significant number of persons with coronavirus disease 2019 (COVID-19) experience persistent, recurrent, or new symptoms several months after the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This phenomenon, termed post-acute sequelae of SARS-CoV-2 (PASC) or long COVID, is associated with high viral titers during acute infection, a persistently hyperactivated immune system, tissue injury by NETosis-induced micro-thrombofibrosis (NETinjury), microbial translocation, complement deposition, fibrotic macrophages, the presence of autoantibodies, and lymphopenic immune environments. Here, we review the current literature on the immunological imbalances that occur during PASC. Specifically, we focus on data supporting common immunopathogenesis and tissue injury mechanisms shared across this highly heterogenous disorder, including NETosis, coagulopathy, and fibrosis. Mechanisms include changes in leukocyte subsets/functions, fibroblast activation, cytokine imbalances, lower cortisol, autoantibodies, co-pathogen reactivation, and residual immune activation driven by persistent viral antigens and/or microbial translocation. Taken together, we develop the premise that SARS-CoV-2 infection results in PASC as a consequence of acute and/or persistent single or multiple organ injury mediated by PASC determinants to include the degree of host responses (inflammation, NETinjury), residual viral antigen (persistent antigen), and exogenous factors (microbial translocation). Determinants of PASC may be amplified by comorbidities, age, and sex.

Investigation of Serum Interleukin 6, High-Sensitivity C-Reactive Protein and White Blood Cell Levels during the Diagnosis and Treatment of Paediatric Appendicitis Patients Before and during the COVID-19 Pandemic.

Introduction: In this study, we prospectively investigated changes in serum interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and full white blood cell (WBC) counts during the diagnosis and treatment of paediatric patients with appendicitis. We also investigated the effects of the COVID-19 pandemic on the diagnosis and treatment processes of paediatric appendicitis patients. Materials and Methods: A non-perforated appendicitis group (n = 110), a perforated appendicitis group (n = 35) and an appendicitis + COVID-19 group (n = 8) were formed. Blood samples were taken upon admission and every day until the three studied parameters returned to normal values. To investigate the effects of the COVID-19 pandemic on paediatric appendicitis patients, the perforated appendicitis rates and the times from the onset of the first symptoms to the operation before and during the pandemic were compared. Results: WBC, IL-6, and hsCRP dropped below the upper limits on the second postoperative day in the non-perforated appendicitis group, four to six days postoperatively in the perforated appendicitis group, and three to six days postoperatively in the appendicitis + COVID-19 group. These parameters were not within normal range in patients who developed complications during follow-up. The time from the onset of abdominal pain to the surgery was significantly longer during than before the pandemic in both the non-perforated appendicitis group and the perforated appendicitis group. Conclusions: Our results show that WBC, IL-6, and hsCRP are useful laboratory parameters that can complete clinical examinations in the diagnosis of appendicitis in paediatric patients and the identification of complications that may develop postoperatively.

Brain Leukocytes as the Potential Therapeutic Target for Post-COVID-19 Brain Fog.

After recovering from the acute phase of coronavirus disease 2019 (COVID-19), many patients struggle with additional symptoms of long COVID during the chronic phase. Among them, the neuropsychiatric manifestations characterized by a short-term memory loss and inability to concentrate are called "brain fog". Recent studies have revealed the involvement of "chronic neuro-inflammation" in the pathogenesis of brain fog following COVID-19 infection. In the COVID-related brain fog, similarly to neurodegenerative disorders caused by neuro-inflammation, brain leukocytes, such as microglia and lymphocytes, are hyperactivated, suggesting the overexpression of delayed rectifier K+-channels (Kv1.3) within the cells. In our previous patch-clamp studies, drugs, such as antihistamines, statins, nonsteroidal anti-inflammatory drugs, antibiotics and anti-hypertensive drugs, suppressed the Kv1.3-channel activity and reduced the production of pro-inflammatory cytokines. Additionally, newer generation antihistamines, antibiotics and corticosteroids strongly stabilize mast cells that directly activate microglia in the brain. Taking such pharmacological properties of these commonly used drugs into account, they may be useful in the treatment of COVID-related brain fog, in which the enhanced innate and adaptive immune responses are responsible for the pathogenesis.

Differential Leukocyte Expression of IFITM1 and IFITM3 in Patients with Severe Pandemic Influenza A(H1N1) and COVID-19.

Interferon-induced transmembrane (IFITM) proteins mediate protection against enveloped viruses by blocking membrane fusion at endosomes. IFITM1 and IFITM3 are crucial for protection against influenza, and various single nucleotide polymorphisms altering their function have been linked to disease susceptibility. However, bulk IFITM1 and IFITM3 mRNA expression dynamics and their correlation with clinical outcomes have not been extensively addressed in patients with respiratory infections. In this study, we evaluated the expression of IFITM1 and IFITM3 in peripheral leukocytes from healthy controls and individuals with severe pandemic influenza A(H1N1) or coronavirus disease 2019 (COVID-19). Comparisons between participants grouped according to their clinical characteristics, underlying disease, and outcomes showed that the downregulation of IFITM1 was a distinctive characteristic of severe pandemic influenza A(H1N1) that correlated with outcomes, including mortality. Conversely, increased IFITM3 expression was a common feature of severe pandemic influenza A(H1N1) and COVID-19. Using a high-dose murine model of infection, we confirmed not only the downregulation of IFITM1 but also of IFITM3 in the lungs of mice with severe influenza, as opposed to humans. Analyses in the comparative cohort also indicate the possible participation of IFITM3 in COVID-19. Our results add to the evidence supporting a protective function of IFITM proteins against viral respiratory infections in humans.

Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic markings.

COVID-19 induces chromatin remodeling in host immune cells, and it had previously been shown that vitamin B12 downregulates some inflammatory genes via methyl-dependent epigenetic mechanisms. In this work, whole blood cultures from moderate or severe COVID-19 patients were used to assess the potential of B12 as adjuvant drug. The vitamin normalized the expression of a panel of inflammatory genes still dysregulated in the leukocytes despite glucocorticoid therapy during hospitalization. B12 also increased the flux of the sulfur amino acid pathway, that regulates the bioavailability of methyl. Accordingly, B12-induced downregulation of CCL3 strongly and negatively correlated with the hypermethylation of CpGs in its regulatory regions. Transcriptome analysis revealed that B12 attenuates the effects of COVID-19 on most inflammation-related pathways affected by the disease. As far as we are aware, this is the first study to demonstrate that pharmacological modulation of epigenetic markings in leukocytes favorably regulates central components of COVID-19 physiopathology.

Immune cell landscape in symptomatic and asymptomatic SARS-CoV-2 infected adults and children in urban Dhaka, Bangladesh.

OBJECTIVES: The study of cellular immunity to SARS-CoV-2 is crucial for evaluating the course of the COVID-19 disease and for improving vaccine development. We aimed to assess the phenotypic landscape of circulating lymphocytes and mononuclear cells in adults and children who were seropositive to SARS-CoV-2 in the past 6 months. METHODS: Blood samples (n = 350) were collected in a cross-sectional study in Dhaka, Bangladesh (Oct 2020-Feb 2021). Plasma antibody responses to SARS-CoV-2 were determined by an electrochemiluminescence immunoassay while lymphocyte and monocyte responses were assessed using flow cytometry including dimensionality reduction and clustering algorithms. RESULTS: SARS-CoV-2 seropositivity was observed in 52% of adults (18-65 years) and 56% of children (10-17 years). Seropositivity was associated with reduced CD3+T cells in both adults (beta(ß) = -2.86; 95% Confidence Interval (CI) = -5.98, 0.27) and children (ß = -8.78; 95% CI = -13.8, -3.78). The frequencies of T helper effector (CD4+TEFF) and effector memory cells (CD4+TEM) were increased in seropositive compared to seronegative children. In adults, seropositivity was associated with an elevated proportion of cytotoxic T central memory cells (CD8+TCM). Overall, diverse manifestations of immune cell dysregulations were more prominent in seropositive children compared to adults, who previously had COVID-like symptoms. These changes involved reduced frequencies of CD4+TEFF cells and CD163+CD64+ classical monocytes, but increased levels of intermediate or non-classical monocytes, as well as CD8+TEM cells in symptomatic children. CONCLUSION: Seropositive individuals in convalescence showed increased central and effector memory T cell phenotypes and pro-resolving/healing monocyte phenotypes compared to seronegative subjects. However, seropositive children with a previous history of COVID-like symptoms, displayed an ongoing innate inflammatory trait.

JAK-STAT inhibition reduces endothelial prothrombotic activation and leukocyte-endothelial proadhesive interactions.

BACKGROUND: Vascular activation is characterized by increased proinflammatory, pro thrombotic, and proadhesive signaling. Several chronic and acute conditions, including Bcr-abl-negative myeloproliferative neoplasms (MPNs), graft-vs-host disease, and COVID-19 have been noted to have increased activation of the janus kinase (JAK)-signal transducer and downstream activator of transcription (STAT) pathways. Two notable inhibitors of the JAK-STAT pathway are ruxolitinib (JAK1/2 inhibitor) and fedratinib (JAK2 inhibitor), which are currently used to treat MPN patients. However, in some conditions, it has been noted that JAK inhibitors can increase the risk of thromboembolic complications. OBJECTIVES: We sought to define the anti-inflammatory and antithrombotic effects of JAK-STAT inhibitors in vascular endothelial cells. METHODS: We assessed endothelial activation in the presence or absence of ruxolitinib or fedratinib by using immunoblots, immunofluorescence, qRT-PCR, and function coagulation assays. Finally, we used endothelialized microfluidics perfused with blood from normal and JAK2V617F+ individuals to evaluate whether ruxolitinib and fedratinib changed cell adhesion. RESULTS: We found that both ruxolitinib and fedratinib reduced endothelial cell phospho-STAT1 and STAT3 signaling and attenuated nuclear phospho-NK-κB and phospho-c-Jun localization. JAK-STAT inhibition also limited secretion of proadhesive and procoagulant P-selectin and von Willebrand factor and proinflammatory IL-6. Likewise, we found that JAK-STAT inhibition reduced endothelial tissue factor and urokinase plasminogen activator expression and activity. CONCLUSIONS: By using endothelialized microfluidics perfused with whole blood samples, we demonstrated that endothelial treatment with JAK-STAT inhibitors prevented rolling of both healthy control and JAK2V617F MPN leukocytes. Together, these findings demonstrate that JAK-STAT inhibitors reduce the upregulation of critical prothrombotic pathways and prevent increased leukocyte-endothelial adhesion.

Platelets' morphology, metabolic profile, exocytosis, and heterotypic aggregation with leukocytes in relation to severity and mortality of COVID-19-patients.

Roles of platelets during infections surpass the classical thrombus function and are now known to modulate innate immune cells. Leukocyte-platelet aggregations and activation-induced secretome are among factors recently gaining interest but little is known about their interplay with severity and mortality during the course of SARS-Cov-2 infection. The aim of the present work is to follow platelets' bioenergetics, redox balance, and calcium homeostasis as regulators of leukocyte-platelet interactions in a cohort of COVID-19 patients with variable clinical severity and mortality outcomes. We investigated COVID-19 infection-related changes in platelet counts, activation, morphology (by flow cytometry and electron microscopy), bioenergetics (by Seahorse analyzer), mitochondria function (by high resolution respirometry), intracellular calcium (by flow cytometry), reactive oxygen species (ROS, by flow cytometry), and leukocyte-platelet aggregates (by flow cytometry) in non-intensive care unit (ICU) hospitalized COVID-19 patients (Non-ICU, n=15), ICU-survivors of severe COVID-19 (ICU-S, n=35), non-survivors of severe COVID-19 (ICU-NS, n=60) relative to control subjects (n=31). Additionally, molecular studies were carried out to follow gene and protein expressions of mitochondrial electron transport chain complexes (ETC) in representative samples of isolated platelets from the studied groups. Our results revealed that COVID-19 infection leads to global metabolic depression especially in severe patients despite the lack of significant impacts on levels of mitochondrial ETC genes and proteins. We also report that severe patients' platelets exhibit hyperpolarized mitochondria and significantly lowered intracellular calcium, concomitantly with increased aggregations with neutrophil. These changes were associated with increased populations of giant platelets and morphological transformations usually correlated with platelets activation and inflammatory signatures, but with impaired exocytosis. Our data suggest that hyperactive platelets with impaired exocytosis may be integral parts in the pathophysiology dictating severity and mortality in COVID-19 patients.

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients.

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes and associated with COVID-19 susceptibility genetic variants. More broadly, we demonstrate how capturing acute, disease-mediated changes in transcription initiation can provide insight into the underlying molecular mechanisms and stratify patient disease severity.

Blood leukocyte transcriptional modules and differentially expressed genes associated with disease severity and age in COVID-19 patients.

Since the molecular mechanisms determining COVID-19 severity are not yet well understood, there is a demand for biomarkers derived from comparative transcriptome analyses of mild and severe cases, combined with patients' clinico-demographic and laboratory data. Here the transcriptomic response of human leukocytes to SARS-CoV-2 infection was investigated by focusing on the differences between mild and severe cases and between age subgroups (younger and older adults). Three transcriptional modules correlated with these traits were functionally characterized, as well as 23 differentially expressed genes (DEGs) associated to disease severity. One module, correlated with severe cases and older patients, had an overrepresentation of genes involved in innate immune response and in neutrophil activation, whereas two other modules, correlated with disease severity and younger patients, harbored genes involved in the innate immune response to viral infections, and in the regulation of this response. This transcriptomic mechanism could be related to the better outcome observed in younger COVID-19 patients. The DEGs, all hyper-expressed in the group of severe cases, were mostly involved in neutrophil activation and in the p53 pathway, therefore related to inflammation and lymphopenia. These biomarkers may be useful for getting a better stratification of risk factors in COVID-19.

An untargeted metabolomic approach to investigate antiviral defence mechanisms in memory leukocytes secreting anti-SARS-CoV-2 IgG in vitro.

Evidence shows that individuals infected by SARS-CoV-2 experience an altered metabolic state in multiple organs. Metabolic activities are directly involved in modulating immune responses against infectious diseases, yet our understanding of how host metabolism relates to inflammatory responses remains limited. To better elucidate the underlying biochemistry of the leukocyte response, we focused our analysis on possible relationships between SARS-CoV-2 post-infection stages and distinct metabolic pathways. Indeed, we observed a significant altered metabolism of tryptophan and urea cycle pathways in cultures of peripheral blood mononuclear cells obtained 60-90 days after infection and showing in vitro IgG antibody memory for spike-S1 antigen (n = 17). This work, for the first time, identifies metabolic routes in cell metabolism possibly related to later stages of immune defence against SARS-CoV-2 infection, namely, when circulating antibodies may be absent but an antibody memory is present. The results suggest reprogramming of leukocyte metabolism after viral pathogenesis through activation of specific amino acid pathways possibly related to protective immunity against SARS-CoV-2.

Soluble Signal Inhibitory Receptor on Leukocytes-1 Is Released from Activated Neutrophils by Proteinase 3 Cleavage.

Signal inhibitory receptor on leukocytes-1 (SIRL-1) is an immune inhibitory receptor expressed on human granulocytes and monocytes that dampens antimicrobial functions. We previously showed that sputum neutrophils from infants with severe respiratory syncytial virus (RSV) bronchiolitis have decreased SIRL-1 surface expression compared with blood neutrophils and that SIRL-1 surface expression is rapidly lost from in vitro activated neutrophils. This led us to hypothesize that activated neutrophils lose SIRL-1 by ectodomain shedding. Here, we developed an ELISA and measured the concentration of soluble SIRL-1 (sSIRL-1) in patients with RSV bronchiolitis and hospitalized patients with COVID-19, which are both characterized by neutrophilic inflammation. In line with our hypothesis, sSIRL-1 concentration was increased in sputum compared with plasma of patients with RSV bronchiolitis and in serum of hospitalized patients with COVID-19 compared with control serum. In addition, we show that in vitro activated neutrophils release sSIRL-1 by proteolytic cleavage and that this diminishes the ability to inhibit neutrophilic reactive oxygen species production via SIRL-1. Finally, we found that SIRL-1 shedding is prevented by proteinase 3 inhibition and by extracellular adherence protein from Staphylococcus aureus. Notably, we recently showed that SIRL-1 is activated by PSMα3 from S. aureus, suggesting that S. aureus may counteract SIRL-1 shedding to benefit from preserved inhibitory function of SIRL-1. In conclusion, we report that SIRL-1 is released from activated neutrophils by proteinase 3 cleavage and that endogenous sSIRL-1 protein is present in vivo.

COVID-19 can lead to rapid progression of cervical intraepithelial neoplasia by dysregulating the immune system: A hypothesis.

COVID-19 is a multisystem disease and cause of a global pandemic. Lately, cases of disease progression of HPV-infected CIN under SARS-CoV-2 infection were reported giving rise to the hypothesis of direct virus-infection induced pro-carcinogenic effect of SARS-CoV-2. We herein present a case of rapid progression from HPV-induced CIN 2 to microinvasive carcinoma within three months under COVID-19 without direct virus infection. Histopathologic evaluation, Fluorescence-in-situ hybridization and qRT-PCR against SARS-CoV-2 RNA as well as gene expression analysis were performed from the available FFPE-tissue and accompanied by an analysis of white blood cell differential. No signs of direct SARS-CoV-2 infection or COVID-19 typical alterations of cervical tissue were found. As expected, p53 decreased in expression with progression of dysplasia, while APOBEC3A and VISTA showed a decrease in expression contrary to observations in dysplasia progression. PD-L1 was expressed consistently or increased slightly but did not show the expected strong induction of expression. DNMT1 showed an increase in expression in CIN III and a slight decrease in carcinoma, while DNMT3a is consistently expressed in CIN II and decreased in carcinoma. Blood tests after COVID-19 showed substantial reduction of lymphocytes, eosinophils, T-cells, and NK-cells. Our results hint at an indirect effect of COVID-19 on the cervical neoplasm. We conclude that the immune system might be preoccupied and exhausted by the concurring COVID-19 disease, leading to less immunological pressure on the HPV-infected cervical dysplasia enabling rapid disease progression. Further, indirect proangiogenic and proinflammatory micromilieu due to the multisystemic effects of COVID-19 might play an additional role.

Quantitative Assay of SARS-CoV-2 RNA and Level of Proinflammatory Protein Gene Transcripts in Peripheral Blood Leukocytes after a Novel Coronavirus Infection.

The possibility of finding persistent SARS-CoV-2 viral particles in human peripheral blood leukocytes after a novel coronavirus infection was shown. The results of droplet digital PCR showed that 19 of 24 examined subjects had from 4 to 555 copies of the Nsp4 SARS-CoV-2 gene in 5-6 months after infection. The presence of this transcript in peripheral blood leukocytes was associated with reduced expression of FOXP3 gene and increased level of RORγ gene mRNA. The copy number of the Nsp4 gene negatively correlated with the level of FOXP3 gene mRNA (r=-0.45; p=0.028), but showed a positive correlation with the DANCR long non-coding RNA (r=0.94; p<0.001). In SARS-CoV-2-positive healthy individuals, the level of TLR2, NLRP3, and IL1B gene transcripts was higher than in SARS-CoV-2-negative donors. The presence of SARS-CoV-2 in a persistent form is probably associated with impaired immunosuppression and the development of chronic inflammation in apparently healthy volunteers after a new coronavirus infection.

A telepathology based screening tool for COVID-19 by leveraging morphological changes related to leukocytes in peripheral blood smears.

As we approach the aftermath of a global pandemic caused by Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2), the importance of quickly developing rapid screening tests has become very clear from the point of view of containment and also saving lives. Here, we present an explorative study to develop a telepathology-based screening tool using peripheral blood smears (PBS) to identify Coronavirus Disease (COVID-19)-positive cases from a group of 138 patients with flu-like symptoms, consisting of 82 positive and 56 negative samples. Stained blood smear slides were imaged using an automated slide scanner (AI 100) and the images uploaded to the cloud were analyzed by a pathologist to generate semi-quantitative leukocyte morphology-related data. These telepathology data were compared with the data generated from manual microscopy of the same set of smear slides and also the same pathologist. Besides good correlation between the data from telepathology and manual microscopy, we were able to achieve a sensitivity and specificity of 0.83 and 0.71, respectively, for identifying positive and negative COVID-19 cases using a six-parameter combination associated with leukocyte morphology. The morphological features included plasmacytoid cells, neutrophil dysplastic promyelocyte, neutrophil blast-like cells, apoptotic cells, smudged neutrophil, and neutrophil-to-immature granulocyte ratio. Although Polymerase Chain Reaction (PCR) and antibody tests have a superior performance, the PBS-based telepathology tool presented here has the potential to be an interim screening tool in resource-limited settings in underdeveloped and developing countries.

Loss of mitochondrial membrane potential (ΔΨm ) in leucocytes as post-COVID-19 sequelae.

The mitochondrial membrane potential (ΔΨm ) is a parameter often used to determine mitochondrial function; therefore, it can be used to determine the integrity and functionality of cells. A decrement of ΔΨm is implicated in several inflammatory-related pathologies, such phenomena can be related to COVID-19 infection. The present work aimed to compare the ΔΨm in leucocytes (human PBMCs; HPBMC) isolated from healthy control (HC) subjects, patients with COVID-19 (C-19), recovered subjects at 40 ± 13 (R1) and 335 ± 20 (R2) days after infection (dai). Obtained data showed that ΔΨm decreased in HPBMC of subjects with C-19, R1, and R2 compared with HC. When analyzing the ΔΨm data by sex, in females, a significant decrease was observed in R1 and R2 groups versus HC. Regarding men, a significant decrease of ΔΨm was observed in R1, with respect to HC, contrary to R2 group, who reestablished this parameter. Obtained results suggest that the loss of ΔΨm could be related to the long-COVID.

Leukocyte glucose index as a novel biomarker for COVID-19 severity.

The severity of coronavirus disease 2019 (COVID-19) quickly progresses with unfavorable outcomes due to the host immune response and metabolism alteration. Hence, we hypothesized that leukocyte glucose index (LGI) is a biomarker for severe COVID-19. This study involved 109 patients and the usefulness of LGI was evaluated and compared with other risk factors to predict COVID 19 severity. LGI was identified as an independent risk factor (odds ratio [OR] = 1.727, 95% confidence interval [CI]: 1.026-3.048, P = 0.041), with an area under the curve (AUC) of 0.749 (95% CI: 0.642-0.857, P < 0.0001). Interestingly, LGI was a potential risk factor (OR = 2.694, 95% CI: 1.575-5.283, P_corrected < 0.05) for severe COVID-19 in female but not in male patients. In addition, LGI proved to be a strong predictor of the severity in patients with diabetes (AUC = 0.915 (95% CI: 0.830-1), sensitivity = 0.833, and specificity = 0.931). The AUC of LGI, together with the respiratory rate (LGI + RR), showed a considerable improvement (AUC = 0.894, 95% CI: 0.835-0.954) compared to the other biochemical and respiratory parameters analyzed. Together, these findings indicate that LGI could potentially be used as a biomarker of severity in COVID-19 patients.

Human acute inflammatory recovery is defined by co-regulatory dynamics of white blood cell and platelet populations.

Inflammation is the physiologic reaction to cellular and tissue damage caused by trauma, ischemia, infection, and other pathologic conditions. Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not well established. Here we studied inflammatory recovery from trauma, ischemia, and infection by tracking longitudinal dynamics of clinical laboratory measurements in hospitalized patients. We identified a universal recovery trajectory defined by exponential WBC decay and delayed linear growth of platelet count (PLT). Co-regulation of WBC-PLT dynamics is a fundamental mechanism of acute inflammatory recovery and provides a generic approach for identifying high-risk patients: 32x relative risk (RR) of adverse outcomes for cardiac surgery, 9x RR of death from COVID-19, 9x RR of death from sepsis, and 5x RR of death from myocardial infarction.