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1.
Allergy ; 77(1): 118-129, 2022 01.
Article in English | MEDLINE | ID: covidwho-1597019

ABSTRACT

BACKGROUND: COVID-19 can present with lymphopenia and extraordinary complex multiorgan pathologies that can trigger long-term sequela. AIMS: Given that inflammasome products, like caspase-1, play a role in the pathophysiology of a number of co-morbid conditions, we investigated caspases across the spectrum of COVID-19 disease. MATERIALS & METHODS: We assessed transcriptional states of multiple caspases and using flow cytometry, the expression of active caspase-1 in blood cells from COVID-19 patients in acute and convalescent stages of disease. Non-COVID-19 subject presenting with various comorbid conditions served as controls. RESULTS: Single-cell RNA-seq data of immune cells from COVID-19 patients showed a distinct caspase expression pattern in T cells, neutrophils, dendritic cells, and eosinophils compared with controls. Caspase-1 was upregulated in CD4+ T-cells from hospitalized COVID-19 patients compared with unexposed controls. Post-COVID-19 patients with lingering symptoms (long-haulers) also showed upregulated caspase-1activity in CD4+ T-cells that ex vivo was attenuated with a select pan-caspase inhibitor. We observed elevated caspase-3/7levels in red blood cells from COVID-19 patients compared with controls that was reduced following caspase inhibition. DISCUSSION: Our preliminary results suggest an exuberant caspase response in COVID-19 that may facilitate immune-related pathological processes leading to severe outcomes. Further clinical correlations of caspase expression in different stages of COVID-19 will be needed. CONCLUSION: Pan-caspase inhibition could emerge as a therapeutic strategy to ameliorate or prevent severe COVID-19.


Subject(s)
COVID-19 , Caspase Inhibitors , CD4-Positive T-Lymphocytes , COVID-19/complications , COVID-19/drug therapy , Caspase 1 , Caspase 3 , Caspase 7 , Caspase Inhibitors/therapeutic use , Caspases/genetics , Humans
2.
J Leukoc Biol ; 110(1): 21-26, 2021 07.
Article in English | MEDLINE | ID: covidwho-1574077

ABSTRACT

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID-19) in humans. Although most patients with COVID-19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi-organ failure, and death. RNA viruses such as SARS-CoV-2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS-CoV-2 infection pathology. Here, we examined genome-wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally-ill, critical COVID-19 patients with confirmed SARS-CoV-2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID-19 HIV coinfected individuals. Cell-type deconvolution analyses confirmed lymphopenia in severe COVID-19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID-19 characterized by hypermethylation of IFN-related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single-cell transcriptional studies of severe COVID-19. Epigenetic clock analyses revealed severe COVID-19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID-19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS-CoV-2.


Subject(s)
COVID-19/genetics , DNA Methylation/genetics , Epigenesis, Genetic , Genome, Human , COVID-19/virology , HIV Infections/genetics , Humans , Influenza, Human/genetics , SARS-CoV-2/physiology
4.
Brain Pathol ; 31(5): e12997, 2021 09.
Article in English | MEDLINE | ID: covidwho-1273078

ABSTRACT

The actual role of SARS-CoV-2 in brain damage remains controversial due to lack of matched controls. We aim to highlight to what extent is neuropathology determined by SARS-CoV-2 or by pre-existing conditions. Findings of 9 Coronavirus disease 2019 (COVID-19) cases and 6 matched non-COVID controls (mean age 79 y/o) were compared. Brains were analyzed through immunohistochemistry to detect SARS-CoV-2, lymphocytes, astrocytes, endothelium, and microglia. A semi-quantitative scoring was applied to grade microglial activation. Thal-Braak stages and the presence of small vessel disease were determined in all cases. COVID-19 cases had a relatively short clinical course (0-32 days; mean: 10 days), and did not undergo mechanical ventilation. Five patients with neurocognitive disorder had delirium. All COVID-19 cases showed non-SARS-CoV-2-specific changes including hypoxic-agonal alterations, and a variable degree of neurodegeneration and/or pre-existent SVD. The neuroinflammatory picture was dominated by ameboid CD68 positive microglia, while only scant lymphocytic presence and very few traces of SARS-CoV-2 were detected. Microglial activation in the brainstem was significantly greater in COVID-19 cases (p = 0.046). Instead, microglial hyperactivation in the frontal cortex and hippocampus was clearly associated to AD pathology (p = 0.001), regardless of the SARS-CoV-2 infection. In COVID-19 cases complicated by delirium (all with neurocognitive disorders), there was a significant enhancement of microglia in the hippocampus (p = 0.048). Although higher in cases with both Alzheimer's pathology and COVID-19, cortical neuroinflammation is not related to COVID-19 per se but mostly to pre-existing neurodegeneration. COVID-19 brains seem to manifest a boosting of innate immunity with microglial reinforcement, and adaptive immunity suppression with low number of brain lymphocytes probably related to systemic lymphopenia. Thus, no neuropathological evidence of SARS-CoV-2-specific encephalitis is detectable. The microglial hyperactivation in the brainstem, and in the hippocampus of COVID-19 patients with delirium, appears as a specific topographical phenomenon, and probably represents the neuropathological basis of the "COVID-19 encephalopathic syndrome" in the elderly.


Subject(s)
COVID-19/pathology , Dementia/virology , Microglia/pathology , Nervous System Diseases/virology , Aged , Aged, 80 and over , Astrocytes/pathology , Brain/pathology , COVID-19/psychology , Case-Control Studies , Dementia/pathology , Dementia/psychology , Female , Humans , Male , Nervous System Diseases/pathology , Nervous System Diseases/psychology , SARS-CoV-2/isolation & purification
5.
Virol J ; 18(1): 126, 2021 06 12.
Article in English | MEDLINE | ID: covidwho-1266497

ABSTRACT

BACKGROUND: Tens of million cases of coronavirus disease-2019 (COVID-19) have occurred globally. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) attacks the respiratory system, causing pneumonia and lymphopenia in infected individuals. The aim of the present study is to investigate the laboratory characteristics of the viral load, lymphocyte subset and cytokines in asymptomatic individuals with SARS-CoV-2 infection in comparison with those in symptomatic patients with COVID-19. METHODS: From January 24, 2020, to April 11, 2020, 48 consecutive subjects were enrolled in this study. Viral loads were detected by RT-PCR from throat-swab, sputum and feces samples. Lymphocyte subset levels of CD3 + , CD4 + , and CD8 + T lymphocytes, B cells and NK cells were determined with biological microscope and flow cytometric analysis. Plasma cytokines (IL2, IL4, IL5, IL6, IL8, IL10, TNF-α, IFN-α and IFN-γ) were detected using flow cytometer. Analysis of variance (ANOVA), Chi-square or Fisher's exact test and Pearson's Correlation assay was used for all data. RESULTS: Asymptomatic (AS), mild symptoms (MS) and severe or critical cases (SCS) with COVID-19 were 11 (11/48, 22.9%), 26 (54.2%, 26/48) and 11 cases (11/48, 22.9%), respectively. The mean age of AS group (47.3 years) was lower than SCS group (63.5 years) (P < 0.05). Diabetes mellitus in AS, MS and SCS patients with COVID-19 were 0, 6 and 5 cases, respectively, and there was a significant difference between AS and SCS (P < 0.05). No statistical differences were found in the viral loads of SARS-CoV-2 between AS, MS and SCS groups on admission to hospital and during hospitalization. The concentration of CD 3 + T cells (P < 0.05), CD3 + CD4 + T cells (P < 0.05), CD3 + CD8 + T cells (P < 0.01), and B cells (P < 0.05) in SCS patients was lower than in AS and MS patients, while the level of IL-5 (P < 0.05), IL-6 (P < 0.05), IL-8 (P < 0.01) and IL-10 (P < 0.01), and TNF-α (P < 0.05) was higher. The age was negatively correlated with CD3 + T cells (P < 0.05), CD3 + CD4 + T cells (P < 0.05), and positively correlated with IL-2 (P < 0.001), IL-5 (P < 0.05), IL-6 (P < 0.05) IL-8 (P < 0.05), and IL-10 (P < 0.05). The viral loads were positively correlated with IL-2 (P < 0.001), IL-5 (P < 0.05), IL-6 (P < 0.05) IL-8 (P < 0.05) and IL-10 (P < 0.05), while negatively correlated with CD 3 + T cells (P < 0.05) and CD3 + CD4 + T cells (P < 0.05). CONCLUSIONS: The viral loads are similar between asymptomatic, mild and severe or critical patients with COVID-19. The severity of COVID-19 may be related to underlying diseases such as diabetes mellitus. Lymphocyte subset and plasma cytokine levels may be as the markers to distinguish severely degrees of disease, and asymptomatic patients may be as an important source of infection for the COVID-19.


Subject(s)
COVID-19/pathology , Cytokines/blood , Lymphocyte Subsets/pathology , SARS-CoV-2 , Viral Load , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Asymptomatic Infections , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Critical Illness , Diabetes Complications/epidemiology , Female , Hospitalization , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/pathogenicity , Young Adult
6.
Cell Discov ; 7(1): 42, 2021 Jun 08.
Article in English | MEDLINE | ID: covidwho-1261993

ABSTRACT

The pathophysiology of coronavirus disease 19 (COVID-19) involves a multitude of host responses, yet how they unfold during the course of disease progression remains unclear. Here, through integrative analysis of clinical laboratory tests, targeted proteomes, and transcriptomes of 963 patients in Shanghai, we delineate the dynamics of multiple circulatory factors within the first 30 days post-illness onset and during convalescence. We show that hypercortisolemia represents one of the probable causes of acute lymphocytopenia at the onset of severe/critical conditions. Comparison of the transcriptomes of the bronchoalveolar microenvironment and peripheral blood indicates alveolar macrophages, alveolar epithelial cells, and monocytes in lungs as the potential main sources of elevated cytokines mediating systemic immune responses and organ damages. In addition, the transcriptomes of patient blood cells are characterized by distinct gene regulatory networks and alternative splicing events. Our study provides a panorama of the host responses in COVID-19, which may serve as the basis for developing further diagnostics and therapy.

7.
Virus Res ; 301: 198464, 2021 08.
Article in English | MEDLINE | ID: covidwho-1246220

ABSTRACT

The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S., patients will continue to require pharmacologic intervention to reduce morbidity and mortality as vaccine availability remains limited. The rise of new variants makes the development of therapeutic strategies even more crucial to combat the current pandemic and future outbreaks. Evidence from several studies suggests the host immune response to SARS-CoV-2 infection plays a critical role in disease pathogenesis. Consequently, host immune factors are becoming more recognized as potential biomarkers and therapeutic targets for COVID-19. To develop therapeutic strategies to combat current and future coronavirus outbreaks, understanding how the coronavirus hijacks the host immune system during and after the infection is crucial. In this study, we investigated immunological patterns or characteristics of the host immune response to SARS-CoV-2 infection that may contribute to the disease severity of COVID-19 patients. We analyzed large bulk RNASeq and single cell RNAseq data from COVID-19 patient samples to immunoprofile differentially expressed gene sets and analyzed pathways to identify human host protein targets. We observed an immunological profile of severe COVID-19 patients characterized by upregulated cytokines, interferon-induced proteins, and pronounced T cell lymphopenia, supporting findings by previous studies. We identified a number of host immune targets including PERK, PKR, TNF, NF-kB, and other key genes that modulate the significant pathways and genes identified in COVID-19 patients. Finally, we identified genes modulated by COVID-19 infection that are implicated in oncogenesis, including E2F transcription factors and RB1, suggesting a mechanism by which SARS-CoV-2 infection may contribute to oncogenesis. Further clinical investigation of these targets may lead to bonafide therapeutic strategies to treat the current COVID-19 pandemic and protect against future outbreaks and viral escape variants.


Subject(s)
COVID-19/immunology , Immunity , Pandemics , SARS-CoV-2/immunology , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/virology , Carcinogenesis , Cytokines/immunology , High-Throughput Nucleotide Sequencing , Humans , SARS-CoV-2/genetics , Up-Regulation
8.
Front Immunol ; 12: 661052, 2021.
Article in English | MEDLINE | ID: covidwho-1229177

ABSTRACT

While lymphocytopenia is a common characteristic of coronavirus disease 2019 (COVID-19), the mechanisms responsible for this lymphocyte depletion are unclear. Here, we retrospectively reviewed the clinical and immunological data from 18 fatal COVID-19 cases, results showed that these patients had severe lymphocytopenia, together with high serum levels of inflammatory cytokines (IL-6, IL-8 and IL-10), and elevation of many other mediators in routine laboratory tests, including C-reactive protein, lactate dehydrogenase, α-hydroxybutyrate dehydrogenase and natriuretic peptide type B. The spleens and hilar lymph nodes (LNs) from six additional COVID-19 patients with post-mortem examinations were also collected, histopathologic detection showed that both organs manifested severe tissue damage and lymphocyte apoptosis in these six cases. In situ hybridization assays illustrated that SARS-CoV-2 viral RNA accumulates in these tissues, and transmission electronic microscopy confirmed that coronavirus-like particles were visible in the LNs. SARS-CoV-2 Spike and Nucleocapsid protein (NP) accumulated in the spleens and LNs, and the NP antigen restricted in angiotensin-converting enzyme 2 (ACE2) positive macrophages and dendritic cells (DCs). Furthermore, SARS-CoV-2 triggered the transcription of Il6, Il8 and Il1b genes in infected primary macrophages and DCs in vitro, and SARS-CoV-2-NP+ macrophages and DCs also manifested high levels of IL-6 and IL-1ß, which might directly decimate human spleens and LNs and subsequently lead to lymphocytopenia in vivo. Collectively, these results demonstrated that SARS-CoV-2 induced lymphocytopenia by promoting systemic inflammation and direct neutralization in human spleen and LNs.


Subject(s)
COVID-19/immunology , Lymph Nodes/immunology , Lymphopenia/immunology , SARS-CoV-2/immunology , Spleen/immunology , Angiotensin-Converting Enzyme 2/immunology , COVID-19/complications , COVID-19/pathology , Coronavirus Nucleocapsid Proteins/immunology , Cytokines/immunology , Female , Humans , Inflammation/immunology , Inflammation/pathology , Lymph Nodes/ultrastructure , Lymphopenia/etiology , Lymphopenia/pathology , Middle Aged , Phosphoproteins/immunology , RNA, Messenger/immunology , Retrospective Studies , SARS-CoV-2/pathogenicity , SARS-CoV-2/ultrastructure , Spleen/ultrastructure
9.
PLoS One ; 16(4): e0251085, 2021.
Article in English | MEDLINE | ID: covidwho-1209052

ABSTRACT

BACKGROUND: The coronavirus disease (COVID-19) pandemic has severely affected African countries, specifically the countries, such as Libya, that are in constant conflict. Clinical and laboratory information, including mortality and associated risk factors in relation to hospital settings and available resources, about critically ill patients with COVID-19 in Africa is not available. This study aimed to determine the mortality and morbidity of COVID-19 patients in intensive care units (ICU) following 60 days after ICU admission, and explore the factors that influence in-ICU mortality rate. METHODS: This is a multicenter prospective observational study among COVID-19 critical care patients in 11 ICUs in Libya from May 29th to December 30th 2020. Basic demographic data, clinical characteristics, laboratory values, admission Sequential Organ Failure Assessment (SOFA) score, quick SOFA, and clinical management were analyzed. RESULT: We included 465 consecutive COVID-19 critically ill patients. The majority (67.1%) of the patients were older than 60 years, with a median (IQR) age of 69 (56.5-75); 240 (51.6%) were male. At 60 days of follow-up, 184 (39.6%) were discharged alive, while 281 (60.4%) died in the intensive care unit. The median (IQR) ICU length of stay was 7 days (4-10) and non-survivors had significantly shorter stay, 6 (3-10) days. The body mass index was 27.9 (24.1-31.6) kg/m2. At admission to the intensive care unit, quick SOFA median (IQR) score was 1 (1-2), whereas total SOFA score was 6 (4-7). In univariate analysis, the following parameters were significantly associated with increased/decreased hazard of mortality: increased age, BMI, white cell count, neutrophils, procalcitonin, cardiac troponin, C-reactive protein, ferritin, fibrinogen, prothrombin, and d-dimer levels were associated with higher risk of mortality. Decreased lymphocytes, and platelet count were associated with higher risk of mortality. Quick SOFA and total SOFA scores increase, emergency intubation, inotrope use, stress myocardiopathy, acute kidney injury, arrythmia, and seizure were associated with higher mortality. CONCLUSION: Our study reported the highest mortality rate (60.4%) among critically ill patients with COVID-19 60 days post-ICU admission. Several factors were found to be predictive of mortality, which may help to identify patients at risk of mortality during the ongoing COVID-19 pandemic.


Subject(s)
COVID-19/epidemiology , Critical Illness/epidemiology , Aged , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Critical Care , Critical Illness/mortality , Critical Illness/therapy , Female , Hospital Mortality , Humans , Intensive Care Units , Libya/epidemiology , Male , Middle Aged , Prospective Studies , Risk Factors , SARS-CoV-2/isolation & purification , Survival Analysis
10.
Mod Rheumatol Case Rep ; 5(2): 442-447, 2021 07.
Article in English | MEDLINE | ID: covidwho-1203553

ABSTRACT

The new disease concept of multisystem inflammatory syndrome in children (MIS-C), which is a systemic inflammatory syndrome with multiple organ involvement after SARS-CoV2 infection, was established in 2020. MIS-C is common in Hispanic and black children in Europe and North America, with few reports in East Asians. A significant portion of patients with MIS-C develop Kawasaki disease (KD)-like symptoms. Therefore, differential diagnosis is challenging, especially in East Asia, where KD is most prevalent. No Japanese cases have been reported in the literatures so far. We report a case of MIS-C in Japan with KD-like symptoms. A 9-year-old Japanese boy, who was infected with SARS-CoV2 1 month previously along with his family, was admitted to our hospital owing to fever for 6 d and erythema mainly in the groyne and pubic area. He also had conjunctivitis, strawberry tongue and diarrhoea. His laboratory findings were as follows: WBC, 12,840/µL (lymphocytes, 4%); CRP, 22.6 mg/dL, pro-calcitonin, 1.8 ng/mL (normal, <0.50 ng/mL); NT pro-BNP, 7627 pg/mL (<125 pg/mL); and troponin T, 0.14 ng/mL (<0.01 ng/mL). His cardiac function was normal. We initially diagnosed him with KD. His fever rapidly resolved with intravenous immunoglobulin (IVIG) and there were no coronary artery lesions. Desquamation of the fingers was observed later. Finally, a history of SARS-COV2 infection, his age, atypical skin rash, elevation of markers of inflammation and heart failure and lymphopenia suggested the diagnosis of MIS-C rather than KD. Differentiation between KD and MIS-C is necessary even in Japan, especially in patients with atypical features of KD.


Subject(s)
COVID-19/complications , Cytokines , Systemic Inflammatory Response Syndrome , COVID-19/diagnosis , Child , Cytokines/blood , Diagnosis, Differential , Humans , Japan , Male , Mucocutaneous Lymph Node Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis
11.
J Trop Pediatr ; 67(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-1159646

ABSTRACT

LAY SUMMARY: Clinical and laboratory parameters of multisystem inflammatory syndrome in children (MIS-C) mimic Kawasaki disease (KD). KD has been described in association with dengue, scrub typhus and leptospirosis. However, MIS-C with concomitant infection has rarely been reported in literature. A 14-year-old-girl presented with fever and rash with history of redness of eyes, lips and tongue. Investigations showed anemia, lymphopenia, thrombocytosis with elevated erythrocyte sedimentation rate, C-reactive protein, pro-brain natriuretic peptide, Interleukin-6, ferritin and d-dimer. Scrub typhus immunoglobulin M was positive. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) level was also elevated. A diagnosis of MIS-C with concomitant scrub typhus was proffered. Child received azithromycin, intravenous immunoglobulin and methylprednisolone. After an afebrile period of 2.5 days, child developed unremitting fever and rash. Repeat investigations showed anemia, worsening lymphopenia, thrombocytopenia, transaminitis, hypertriglyceridemia, hyperferritinemia and hypofibrinogenemia which were consistent with a diagnosis of macrophage activation syndrome (MAS). KD, MIS-C and MAS represent three distinct phenotypes of hyperinflammation seen in children during coronavirus disease pandemic. Several tropical infections may mimic or coexist with MIS-C which can be a diagnostic challenge for the treating physician. Identification of coexistence or differentiation between the two conditions is important in countries with high incidence of tropical infections to guide appropriate investigations and treatment.


Subject(s)
COVID-19/complications , Macrophage Activation Syndrome/diagnosis , Scrub Typhus/diagnosis , Systemic Inflammatory Response Syndrome , Adolescent , Azithromycin/therapeutic use , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/therapy , Child , Female , Fever/etiology , Humans , Immunoglobulin G/blood , Immunoglobulins, Intravenous/therapeutic use , Macrophage Activation Syndrome/complications , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/immunology , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic use , Pandemics , SARS-CoV-2 , Scrub Typhus/complications , Scrub Typhus/drug therapy , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology
12.
Life Sci ; 276: 119376, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1157590

ABSTRACT

The severe forms and worsened outcomes of COVID-19 (coronavirus disease 19) are closely associated with hypertension and cardiovascular disease. Endothelial cells express Angiotensin-Converting Enzyme 2 (ACE2), which is the entrance door for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The hallmarks of severe illness caused by SARS-CoV-2 infection are increased levels of IL-6, C-reactive protein, D-dimer, ferritin, neutrophilia and lymphopenia, pulmonary intravascular coagulopathy and microthrombi of alveolar capillaries. The endothelial glycocalyx, a proteoglycan- and glycoprotein-rich layer covering the luminal side of endothelial cells, contributes to vascular homeostasis. It regulates vascular tonus and permeability, prevents thrombosis, and modulates leukocyte adhesion and inflammatory response. We hypothesized that cytokine production and reactive oxygen species (ROS) generation associated with COVID-19 leads to glycocalyx degradation. A cohort of 20 hospitalized patients with a confirmed COVID-19 diagnosis and healthy subjects were enrolled in this study. Mechanisms associated with glycocalyx degradation in COVID-19 were investigated. Increased plasma concentrations of IL-6 and IL1-ß, as well as increased lipid peroxidation and glycocalyx components were detected in plasma from COVID-19 patients compared to plasma from healthy subjects. Plasma from COVID-19 patients induced glycocalyx shedding in cultured human umbilical vein endothelial cells (HUVECs) and disrupted redox balance. Treatment of HUVECs with low molecular weight heparin inhibited the glycocalyx perturbation. In conclusion, plasma from COVID-19 patients promotes glycocalyx shedding and redox imbalance in endothelial cells, and heparin treatment potentially inhibits glycocalyx disruption.


Subject(s)
COVID-19/blood , COVID-19/pathology , Glycocalyx/pathology , Heparin/pharmacology , Aged , Blood Coagulation Disorders/blood , Blood Coagulation Disorders/virology , COVID-19/metabolism , COVID-19 Testing , Case-Control Studies , Cell Adhesion/physiology , Endothelium, Vascular/metabolism , Female , Glycocalyx/metabolism , Glycocalyx/virology , Human Umbilical Vein Endothelial Cells , Humans , Interleukin-1beta/blood , Interleukin-6/blood , Male , Middle Aged , Oxidation-Reduction , SARS-CoV-2 , Thrombosis/metabolism
13.
Clin Infect Dis ; 71(16): 2150-2157, 2020 11 19.
Article in English | MEDLINE | ID: covidwho-1153175

ABSTRACT

BACKGROUND: Thymosin alpha 1 (Tα1) had been used in the treatment of viral infections as an immune response modifier for many years. However, clinical benefits and the mechanism of Tα1 treatment for COVID-19 patients are still unclear. METHODS: We retrospectively reviewed the clinical outcomes of 76 severe COVID-19 cases admitted to 2 hospitals in Wuhan, China, from December 2019 to March 2020. The thymus output in peripheral blood mononuclear cells from COVID-19 patients was measured by T-cell receptor excision circles (TRECs). The levels of T-cell exhaustion markers programmed death-1 (PD-1) and T-cell immunoglobulin and mucin domain protein 3 (Tim-3) on CD8+ T cells were detected by flow cytometry. RESULTS: Compared with the untreated group, Tα1 treatment significantly reduced the mortality of severe COVID-19 patients (11.11% vs 30.00%, P = .044). Tα1 enhanced blood T-cell numbers in COVID-19 patients with severe lymphocytopenia. Under such conditions, Tα1 also successfully restored CD8+ and CD4+ T-cell numbers in elderly patients. Meanwhile, Tα1 reduced PD-1 and Tim-3 expression on CD8+ T cells from severe COVID-19 patients compared with untreated cases. It is of note that restoration of lymphocytopenia and acute exhaustion of T cells were roughly parallel to the rise of TRECs. CONCLUSIONS: Tα1 treatment significantly reduced mortality of severe COVID-19 patients. COVID-19 patients with counts of CD8+ T cells or CD4+ T cells in circulation less than 400/µL or 650/µL, respectively, gained more benefits from Tα1. Tα1 reversed T-cell exhaustion and recovered immune reconstitution through promoting thymus output during severe acute respiratory syndrome-coronavirus 2 infection.


Subject(s)
COVID-19/mortality , Lymphopenia/metabolism , SARS-CoV-2/pathogenicity , Thymalfasin/metabolism , Adult , Aged , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , COVID-19/virology , Female , Humans , Male , Middle Aged , Retrospective Studies , Thymalfasin/genetics , Thymus Gland/metabolism
14.
Int Immunopharmacol ; 95: 107586, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1149235

ABSTRACT

The incidence of the novel coronavirus disease (COVID-19) outbreak caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought daunting complications for people as well as physicians around the world. An ever-increasing number of studies investigating the characteristics of the disease, day by day, is shedding light on a new feature of the virus with the hope that eventually these efforts lead to the proper treatment. SARS-CoV-2 activates antiviral immune responses, but in addition may overproduce pro-inflammatory cytokines, causing uncontrolled inflammatory responses in patients with severe COVID-19. This condition may lead to lymphopenia and lymphocyte dysfunction, which in turn, predispose patients to further infections, septic shock, and severe multiple organ dysfunction. Therefore, accurate knowledge in this issue is important to guide clinical management of the disease and the development of new therapeutic strategies in patients with COVID-19. In this review, we provide a piece of valuable information about the alteration of each subtype of lymphocytes and important prognostic factors associated with these cells. Moreover, through discussing the lymphopenia pathophysiology and debating some of the most recent lymphocyte- or lymphopenia-related treatment strategies in COVID-19 patients, we tried to brightening the foreseeable future for COVID-19 patients, especially those with severe disease.


Subject(s)
COVID-19/drug therapy , COVID-19/immunology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/virology , Lymphopenia/immunology , Lymphopenia/physiopathology , SARS-CoV-2/immunology , COVID-19/complications , Humans , Lymphopenia/etiology , Lymphopenia/virology , Prognosis
15.
Aging (Albany NY) ; 13(6): 7713-7722, 2021 03 10.
Article in English | MEDLINE | ID: covidwho-1134586

ABSTRACT

If age boundaries are arbitrarily or roughly defined, age-related analyses can result in questionable findings. Here, we aimed to delineate the uniquely age-dependent immune features of coronavirus disease 2019 (COVID-19) in a retrospective study of 447 patients, stratified according to age distributions of COVID-19 morbidity statistics into well-defined age-cohorts (2-25y, 26-38y, 39-57y, 58-68y, and 69-79y). Age-dependent susceptibilities and severities of the disease were observed in COVID-19 patients. A comparison of the lymphocyte counts among the five age-groups indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection led to age-dependent lymphopenia. Among the lymphocyte subsets, the CD8+ T cell count alone was significantly and age-dependently decreased (520, 385, 320, 172, and 139 n/µl in the five age-groups, respectively). In contrast, the CD4+ T cell, B cell, and natural killer cell counts did not differ among age-cohorts. Age and CD8+ T cell counts (r=‒0.435, p<0.0001) were negatively correlated in COVID-19 patients. Moreover, SARS-CoV-2 infection age-dependently increased the plasma C-reactive protein concentrations (2.0, 5.0, 9.0, 11.6, and 36.1 mg/L in the five age-groups, respectively). These findings can be used to elucidate the role of CD8+ T cells in age-related pathogenesis and to help develop therapeutic strategies for COVID-19.


Subject(s)
Age Distribution , CD3 Complex/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/complications , Lymphopenia/complications , Patient Admission , Adolescent , Adult , Aged , COVID-19/virology , Child , Child, Preschool , Cohort Studies , Female , Humans , Lymphocyte Count , Lymphopenia/immunology , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/isolation & purification , Young Adult
16.
JHEP Rep ; 3(3): 100258, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1096062

ABSTRACT

BACKGROUND & AIMS: Abnormal liver tests are common in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but a possible direct role of the virus in liver injury and its association with short-term outcomes are controversial. Therefore, we aimed to compare the pattern of abnormal liver tests in patients with SARS-CoV-2 with those of patients infected with influenza, a non-hepatotropic respiratory virus, and their association with worse outcomes during hospitalisation. METHODS: We performed a retrospective cohort study of 1,737 hospitalised patients (865 with influenza and 872 with SARS-CoV-2) in a tertiary medical centre. We defined abnormal liver tests as alanine transaminase or aspartate transaminase ≥40 IU/ml at any time-point during hospitalisation. RESULTS: Abnormal liver tests were mild to moderate in most patients regardless of infection type, but the majority of patients with influenza had a transaminase peak earlier during hospitalisation compared with patients with SARS-CoV-2. Abnormal liver tests correlated with markers of severe disease in either influenza or SARS-CoV-2 infections, and were associated with death, occurring mainly in patients with severe liver test abnormalities (>200 IU/L) (38.7% and 60% of patients with influenza or SARS-CoV-2, respectively). In multivariate analysis, controlling for age, sex, lymphopaenia, and C-reactive protein, liver test abnormalities remained significantly associated with death for influenza (odds ratio 4.344; 95% CI 2.218-8.508) and SARS-CoV-2 (odds ratio 3.898; 95% CI 2.203-6.896). These results were confirmed upon propensity score matching. CONCLUSIONS: Abnormal liver tests during hospitalisation with SARS-CoV-2 or influenza infections are common, may differ in their time course, and reflect disease severity. They are associated with worse outcomes, mainly in patients with severe liver test abnormalities, regardless of infection type. LAY SUMMARY: Coronavirus disease 2019 (COVID-19) is a serious global health pandemic, the causative agent of which is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Abnormal liver tests are common among SARS-CoV-2 infected patients and are often associated with worse outcomes. Herein, we compare the pattern of abnormal liver tests and their association with disease severity between 2 major non-hepatotropic respiratory viruses: SARS-CoV-2 and influenza. We show that abnormal liver tests are common in both infections, may slightly differ in their kinetics, and are associated with worse outcomes, especially in patients with severe liver test abnormalities. These results strongly suggest that abnormal liver tests in SARS-CoV-2 patients reflect disease severity, rather than a virus-mediated direct liver injury, and should be closely followed in admitted patients.

17.
Biomed Res Int ; 2021: 9101082, 2021.
Article in English | MEDLINE | ID: covidwho-1066963

ABSTRACT

OBJECTIVE: To compare the difference of inflammatory cytokines and lymphocyte subsets between deceased patients and survivors with COVID-19. METHODS: This retrospective study included 254 confirmed patients from 10 January to 11 March, 2020, at Tongji Hospital of Wuhan, China. Laboratory and immunologic features were collected and analyzed, and the main outcomes focused on inflammatory cytokines and lymphocyte subsets. RESULTS: A trend of markedly higher levels of inflammatory cytokines as well as lower lymphocyte subset levels in deceased patients was observed compared with survivors. ROC curve analyses indicated that inflammatory cytokines and the decrease levels of T cell, Th (helper T cells) cell, Ts (suppressor T cells) cell, B cell, and NK cell along with Th/Ts ratio increase could be used to predict the death of COVID-19. Multivariate analyses showed that higher levels of IL-6, IL-8, and IL-10 remained significantly correlated with shorter survival time and that the amount of Ts cells was negatively associated with the possibility of death in COVID-19 patients. In conclusion, SARS-CoV-2 would cause lymphopenia and result in decreased lymphocyte subset cells, particularly in Ts cell counts, which further induces hyperinflammatory response and cytokine storm. IL-6, IL-8, IL-10, and Ts cell might be independent predictors for the poor outcome of COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/immunology , Lymphocyte Subsets/immunology , Aged , B-Lymphocytes/immunology , Biomarkers/blood , COVID-19/blood , COVID-19/epidemiology , COVID-19/virology , China/epidemiology , Female , Humans , Kaplan-Meier Estimate , Killer Cells, Natural/immunology , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/isolation & purification
18.
Expert Opin Biol Ther ; 21(9): 1173-1179, 2021 09.
Article in English | MEDLINE | ID: covidwho-1066146

ABSTRACT

INTRODUCTION: Immune checkpoint inhibition (ICI) is a novel cancer immunotherapy, which is administered in patients with metastatic, refractory, or relapsed solid cancer types. Since the initiation of the Coronavirus Disease 2019 (COVID-19) pandemic, many studies have reported a higher severity and mortality rate of COVID-19 among patients with cancer in general. AREAS COVERED: The immunomodulatory effects of ICI can modify the patients' immune system function in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There is controversy over whether the severity of COVID-19 in cancer patients who previously received ICI compared to other patients with cancer has increased. There is evidence that the upregulation of immune checkpoint molecules in T cells, lymphopenia, and inflammatory cytokine secretion are associated with the severity of COVID-19 symptoms. EXPERT OPINION: ICI can interrupt the T cell exhaustion and depletion by interrupting the inhibitory signaling of checkpoint molecules in T cells, and augments the immune system response in COVID-19 patients with lymphopenia. However, ICI may also increase the risk of cytokine release syndrome. ICI can be considered not only as a cancer immunotherapy but also as immunotherapy in COVID-19. More studies are needed to assess the safety of ICI in COVID-19 patients with or without cancer.


Subject(s)
COVID-19 , Immune Checkpoint Inhibitors , COVID-19/drug therapy , Humans , Immune Checkpoint Inhibitors/therapeutic use , Pandemics , Risk Assessment , SARS-CoV-2
19.
Cureus ; 13(1): e12622, 2021 Jan 11.
Article in English | MEDLINE | ID: covidwho-1059541

ABSTRACT

Background and objective Neutrophils are primarily responsible for activating the immune system, and systemic inflammation destroys CD4+ T lymphocytes and increases suppressor CD8+ T lymphocytes, thereby leading to an increased neutrophil-to-lymphocyte ratio (NLR). An increase in the apoptosis of lymphocytes leads to lymphopenia and elevated thrombopoietin (THPO) promotes megakaryocyte production. The reflections of these inflammatory changes can be vital in gauging the progression of the disease. This study aimed at examining the prognostic value of normal and derived neutrophil-to-lymphocyte, lymphocyte-to-monocyte, platelet-to-lymphocyte, and mean platelet volume (MPV)-to-platelet count ratios in patients with coronavirus disease 2019 (COVID-19). Methodology This was a retrospective cross-sectional study conducted in the wards of Chigateri General Hospital, Davangere for a period of two months. Complete blood count was ordered for all patients at the time of admission along with confirmation of the disease by reverse transcription-polymerase chain reaction (RT-PCR). Results The final study population consisted of 100 patients. The mean age of patients who survived (43 years) was significantly lower than the mean age of non-survivors (59.1 years), with a p-value of <0.001. NLR was raised in 60% of the population and was significantly higher in patients who survived the disease, with a p-value of 0.004. The platelet-to-lymphocyte ratio (PLR) also followed a similar trend with a p-value of 0.017. Even though the lymphocyte-to-monocyte ratio (LMR) also mimicked the trend, the statistical association was not significant (p-value: 0.09). The derived NLR and MPV-to-platelets ratios were not found to be significantly associated with mortality in this study. Discussion Younger patients had better clinical outcomes in our study population compared to the geriatric age group. A significant correlation between LMR and mortality was observed when a cut-off of 2.5 was considered as a differentiating benchmark. Conflicting trends were observed in NLR and PLR in our study; however, LMR was in accordance with most other studies. The phase that a patient is in with regard to the natural history of the disease also influences the blood cell ratios. Nonetheless, all three ratios can be used as crucial screening and prognostic tools as they are readily available with the help of a complete hemogram. This is an investigation modality that is widely accessible even in remote areas and resource-limited settings. Conclusion These hematological ratios can facilitate in categorizing the disease severity and progression in patients, thereby enabling us to make appropriate and informed clinical decisions. Since the second wave of the novel coronavirus is on the verge of arrival, it is imperative to channel resources for the patients early in their disease course to ultimately prevent complications and reduce mortality.

20.
Ann Hematol ; 100(2): 309-320, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1014126

ABSTRACT

Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2. Primarily an infection of the lower respiratory tract, it is now well known to cause multisystem abnormalities. Hematologic manifestations constitute a significant area of concern. Severe acute respiratory syndrome coronavirus 2 infects monocytes and endothelial cells leading to a complex downstream cascade, cytokine storm, and eventual intravascular thrombosis. Coronavirus disease 2019 causes lymphopenia, neutrophilia, and thrombocytopenia. Prophylactic anticoagulation is vital in patients with coronavirus disease 2019, as its effect on the coagulation system is associated with significant morbidity and mortality. The disease can cause both arterial and venous thromboses, especially pulmonary embolism and pulmonary microthrombi. A high index of suspicion is indispensable in recognizing these complications, and timely institution of therapeutic anticoagulation is vital in treating them. Virus-induced disseminated intravascular coagulation is uncommon but shares some similarities to sepsis-induced disseminated intravascular coagulation. Marked elevations in hematologic biomarkers such as lactate dehydrogenase, D-dimer, ferritin, and C-reactive protein are associated with worse outcomes. Understanding the pathophysiology and recognizing factors associated with poor prognosis are crucial in improving patient outcomes with coronavirus disease 2019.


Subject(s)
Anticoagulants/therapeutic use , COVID-19/complications , SARS-CoV-2/isolation & purification , Biomarkers/blood , COVID-19/prevention & control , COVID-19/virology , Ferritins/blood , Fibrin Fibrinogen Degradation Products/analysis , Hematologic Diseases/blood , Hematologic Diseases/complications , Hematologic Diseases/drug therapy , Humans , Lymphopenia/blood , Lymphopenia/complications , Lymphopenia/drug therapy , SARS-CoV-2/physiology , Thrombocytopenia/blood , Thrombocytopenia/complications , Thrombocytopenia/drug therapy
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