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1.
Engineering (Beijing) ; 7(7): 958-965, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1482579

ABSTRACT

The longitudinal immunologic status of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients and its association with the clinical outcome are barely known. Thus, we sought to analyze the temporal profiles of specific antibodies, as well as the associations between the antibodies, proinflammatory cytokines, and survival of patients with coronavirus disease 2019 (COVID-19). A total of 1830 laboratory-confirmed COVID-19 cases were recruited. The temporal profiles of the virus, antibodies, and cytokines of the patients until 12 weeks since illness onset were fitted by the locally weighted scatter plot smoothing method. The mediation effect of cytokines on the associations between antibody responses and survival were explored by mediation analysis. Of the 1830 patients, 1435 were detectable for SARS-CoV-2, while 395 were positive in specific antibodies only. Of the 1435 patients, 2.4% presented seroconversion for neither immunoglobulin G (IgG) nor immunoglobulin M (IgM) during hospitalization. The seropositive rates of IgG and IgM were 29.6% and 48.1%, respectively, in the first week, and plateaued within five weeks. For the patients discharged from the hospital, the IgM decreased slowly, while high levels of IgG were maintained at around 188 AU·mL-1 for the 12 weeks since illness onset. In contrast, in the patients who subsequently died, IgM declined rapidly and IgG dropped to 87 AU·mL-1 at the twelfth week. Elevated interleukin-6, interleukin-8, interleukin-10, interleukin-1ß, interleukin-2R, and tumor necrosis factor-α levels were observed in the deceased patients in comparison with the discharged patients, and 12.5% of the association between IgG level and mortality risk was mediated by these cytokines. Our study deciphers the temporal profiles of SARS-CoV-2-specific antibodies within the 12 weeks since illness onset and indicates the protective effect of antibody response on survival, which may help to guide prognosis estimation.

2.
Neurobiol Sleep Circadian Rhythms ; 10: 100063, 2021 May.
Article in English | MEDLINE | ID: covidwho-1386358

ABSTRACT

Night shift work is a risk factor for viral infection, suggesting that night shift schedules compromise host defense mechanisms. Prior studies have investigated changes in the temporal profiles of circulating cytokines important for priming and restraining the immune response to infectious challenges from night shift work, but not by way of a 24-h constant routine of continuous wakefulness devoid of behavioral or environmental influences. Hence the true endogenous pattern of cytokines, and the combined effect of sleep loss and circadian misalignment on these cytokines remains unknown. Here, 14 healthy young men and women underwent three days of either a simulated night shift or a simulated day shift schedule under dim light in a controlled in-laboratory environment. This was followed by a 24-h constant routine protocol during which venous blood was collected at 3-h intervals. Those who had been in the night shift schedule showed lower mean circulating TNF-α (t13 = -6.03, p < 0.001), without any significant differences in IL-1ß, IL-8 and IL-10, compared with those who had been in the day shift (i.e., control) schedule. Furthermore, circulating IL-6 increased with time awake in both shift work conditions (t13 = 6.03, p < 0.001), such that temporal changes in IL-6 were markedly shifted relative to circadian clock time in the night shift condition. These results indicate that night shift work compromises host defense by creating cytokine conditions that initially impede anti-viral immunity (lower TNF-α) and may eventually promote autoimmunity (mistimed rise in IL-6).

3.
J Cancer Res Ther ; 17(2): 295-302, 2021.
Article in English | MEDLINE | ID: covidwho-1268380

ABSTRACT

The world is fighting the onslaught of COVID 19 for the last 10 months, ever since the first case was reported in December 2019 in Wuhan, China. Now, it has spread to over 200 countries. COVID 19-associated respiratory syndrome is causing a lot of mortality and morbidity. There are reports suggesting that the complications and ARDS associated with COVID 19 is an immune response reaction. The cytokine storm associated with severe cases of COVID 19 acts as a cause of death in many sick patients. It has been shown that COVID 19 is associated with a peculiar immune profile: Decrease in CD3, CD4, CD8, natural killer cell and B-cells; Rise in interleukin (IL)-4, IL-6 and tumor necrosis factor (TNF) alpha; Decrease in IL-10; Decrease in interferon-gamma. Low-dose radiotherapy (LDRT) immunosuppressive features resulting from M2 macrophage phenotype activation, increase in IL-10, transforming growth factor beta, a decrease in IL-6, TNF alpha and an increase in CD3, CD4, and CD8 T cell counts may negate the harmful effects of cytokine release syndrome. Literature review shows that radiation was previously used to treat viral pneumonia with a good success rate. This practice was discontinued in view of the availability of effective antibiotics and antivirals. As there are no scientifically proven treatment for severe COVID 19-associated respiratory distress today, it is prudent that we understand the benefits of LDRT at this critical juncture and take rational decisions to treat the same. This article provides an radioimmunological rationale for the treatment of immune crisis mediated complications in severe cases of COVID 19.


Subject(s)
COVID-19/radiotherapy , Cytokine Release Syndrome/radiotherapy , SARS-CoV-2/immunology , COVID-19/complications , COVID-19/immunology , COVID-19/virology , Clinical Decision-Making , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Humans , Radiotherapy Dosage , Severity of Illness Index , Treatment Outcome
4.
J Neurol Sci ; 427: 117517, 2021 08 15.
Article in English | MEDLINE | ID: covidwho-1253234

ABSTRACT

OBJECTIVE: To study in cerebrospinal fluid (CSF) of COVID-19 subjects if a "cytokine storm" or neuroinflammation are implicated in pathogenesis of neurological complications. METHODS: Cross-sectional study of CSF neuroinflammatory profiles from 18 COVID-19 subjects with neurological complications categorized by diagnosis (stroke, encephalopathy, headache) and illness severity. COVID-19 CSF was compared with CSF from healthy, infectious and neuroinflammatory disorders and stroke controls (n = 82). Cytokines (IL-6, TNFα, IFNγ, IL-10, IL-12p70, IL-17A), inflammation and coagulation markers (high-sensitivity-C Reactive Protein [hsCRP], ferritin, fibrinogen, D-dimer, Factor VIII) and neurofilament light chain (NF-L), were quantified. SARS-CoV2 RNA and SARS-CoV2 IgG and IgA antibodies in CSF were tested with RT-PCR and ELISA. RESULTS: CSF from COVID-19 subjects showed absence of pleocytosis or specific increases in pro-inflammatory markers (IL-6, ferritin, or D-dimer). Although pro-inflammatory cytokines (IL-6, TNFα, IL-12p70) and IL-10 were increased in CSF of stroke COVID-19 subjects, a similar increase was observed in non-COVID-19 stroke subjects. Anti-SARS-CoV2 antibodies in CSF of COVID-19 subjects (77%) were observed despite no evidence of SARS-CoV2 viral RNA. CSF-NF-L was elevated in subjects with stroke and critical COVID-19 as compared to controls and other COVID-19 severity categories. CSF-hsCRP was present in all subjects with critical stages of COVID-19 (7/18) but only in 1/82 controls. CONCLUSION: The paucity of neuroinflammatory changes in CSF of COVID-19 subjects and lack of SARS-CoV2 RNA do not support the presumed neurovirulence of SARS-CoV2 or neuroinflammation in pathogenesis of neurological complications in COVID-19. The role of CSF SARS-CoV2 IgG antibodies and mechanisms of neuronal damage are still undetermined.


Subject(s)
COVID-19 , Cytokine Release Syndrome , Cross-Sectional Studies , Cytokines , Humans , RNA, Viral , SARS-CoV-2
5.
Front Immunol ; 12: 642860, 2021.
Article in English | MEDLINE | ID: covidwho-1231336

ABSTRACT

Cytokine storm (CS), an excessive release of proinflammatory cytokines upon overactivation of the innate immune system, came recently to the focus of interest because of its role in the life-threatening consequences of certain immune therapies and viral diseases, including CAR-T cell therapy and Covid-19. Because complement activation with subsequent anaphylatoxin release is in the core of innate immune stimulation, studying the relationship between complement activation and cytokine release in an in vitro CS model holds promise to better understand CS and identify new therapies against it. We used peripheral blood mononuclear cells (PBMCs) cultured in the presence of autologous serum to test the impact of complement activation and inhibition on cytokine release, testing the effects of liposomal amphotericin B (AmBisome), zymosan and bacterial lipopolysaccharide (LPS) as immune activators and heat inactivation of serum, EDTA and mini-factor H (mfH) as complement inhibitors. These activators induced significant rises of complement activation markers C3a, C4a, C5a, Ba, Bb, and sC5b-9 at 45 min of incubation, with or without ~5- to ~2,000-fold rises of IL-1α, IL-1ß, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13 and TNFα at 6 and 18 h later. Inhibition of complement activation by the mentioned three methods had differential inhibition, or even stimulation of certain cytokines, among which effects a limited suppressive effect of mfH on IL-6 secretion and significant stimulation of IL-10 implies anti-CS and anti-inflammatory impacts. These findings suggest the utility of the model for in vitro studies on CS, and the potential clinical use of mfH against CS.


Subject(s)
COVID-19/immunology , Complement Activation , Cytokine Release Syndrome/immunology , Interleukin-10/immunology , Interleukin-6/immunology , Leukocytes, Mononuclear/immunology , Models, Immunological , SARS-CoV-2/immunology , COVID-19/pathology , Complement Factor H/immunology , Cytokine Release Syndrome/pathology , Humans , Leukocytes, Mononuclear/pathology , Leukocytes, Mononuclear/virology
6.
Cytokine ; 143: 155523, 2021 07.
Article in English | MEDLINE | ID: covidwho-1163610

ABSTRACT

Cytokines play pleiotropic, antagonistic, and collaborative in viral disease. The high morbidity and mortality of coronavirus disease 2019 (COVID-19) make it a significant threat to global public health. Elucidating its pathogenesis is essential to finding effective therapy. A retrospective study was conducted on 71 patients hospitalized with COVID-19. Data on cytokines, T lymphocytes, and other clinical and laboratory characteristics were collected from patients with variable disease severity. The effects of cytokines on the overall survival (OS) and event-free survival (EFS) of patients were analyzed. The critically severe and severe patients had higher infection indexes and significant multiple organ function abnormalities than the mild patients (P < 0.05). IL-6 and IL-10 were significantly higher in the critically severe patients than in the severe and mild patients (P < 0.05). IL-6 and IL-10 were closely associated with white blood cells, neutrophils, T lymphocyte subsets, D-D dimer, blood urea nitrogen, complement C1q, procalcitonin C-reactive protein. Moreover, the IL-6 and IL-10 levels were closely correlated to dyspnea and dizziness (P < 0.05). The patients with higher IL-10 levels had shorter OS than the group with lower levels (P < 0.05). The older patients with higher levels of single IL-6 or IL-10 tended to have shorter EFS (P < 0.05), while the patients who had more elevated IL-6 and IL-10 had shorter OS (P < 0.05). The Cox proportional hazard model revealed that IL-6 was the independent factor affecting EFS. IL-6 and IL-10 play crucial roles in COVID-19 prognosis.


Subject(s)
COVID-19/blood , COVID-19/pathology , Interleukin-10/blood , Interleukin-6/blood , T-Lymphocyte Subsets/immunology , Adult , Age Factors , Aged , Aging , Blood Coagulation Factors/analysis , COVID-19/mortality , COVID-19/therapy , Cytokine Release Syndrome/pathology , Female , Humans , Lymphocyte Count , Male , Middle Aged , Retrospective Studies , SARS-CoV-2/immunology , Severity of Illness Index , Survival Analysis , T-Lymphocyte Subsets/cytology , Thromboembolism/pathology , Treatment Outcome
7.
Heliyon ; 7(2): e06155, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1068915

ABSTRACT

AIMS: SARS-CoV-2, an infectious agent behind the ongoing COVID-19 pandemic, induces high levels of cytokines such as IL-1, IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ etc in infected individuals that play a role in the underlying patho-physiology. Nonetheless, exact association and contribution of every cytokine towards COVID-19 pathology remains poorly understood. Delineation of the roles of cytokines during COVID-19 holds the key to efficient patient management in clinics. This study performed a comprehensive meta-analysis to establish association between induced cytokines and COVID-19 disease severity to help in prognosis and clinical care. MAIN METHODS: Scientific literature was searched to identify 13 cytokines (IL-1ß, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-17, TNF-α and IFN-γ) from 18 clinical studies. Standardized mean difference (SMD) for selected 6 cytokines IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ between severe and non-severe COVID-19 patient groups were summarized using random effects model. A classifier was built using logistic regression model with cytokines having significant SMD as covariates. KEY FINDINGS: Out of the 13 cytokines, IL-6 and IL-10 showed statistically significant SMD across studies synthesized. Classifier with mean values of both IL-6 and IL-10 as covariates performed well with accuracy of ~92% that was significantly higher than accuracy reported in literature with IL-6 and IL-10 as individual covariates. SIGNIFICANCE: Simple panel proposed by us with only two cytokine markers can be used as predictors for fast diagnosis of patients with higher risk of COVID-19 disease deterioration and thus can be managed well for a favourable prognosis.

8.
Trends Immunol ; 42(1): 3-5, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065236

ABSTRACT

A unique feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of interleukin 10 (IL-10). This was thought to be a negative feedback mechanism to suppress inflammation. However, several lines of clinical evidence suggest that dramatic early proinflammatory IL-10 elevation may play a pathological role in COVID-19 severity.


Subject(s)
COVID-19/immunology , Cytokine Release Syndrome/immunology , Interleukin-10/immunology , SARS-CoV-2/immunology , COVID-19/epidemiology , COVID-19/virology , Cytokine Release Syndrome/metabolism , Epidemics , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , Interleukin-10/metabolism , Lymphocytes/immunology , Lymphocytes/metabolism , Models, Immunological , SARS-CoV-2/physiology , Severity of Illness Index
9.
Int Immunopharmacol ; 90: 107120, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1065209

ABSTRACT

OBJECTIVE: To explore the application value of artificial liver support system in the clinical treatment of coronavirus disease 2019 (COVID-19) patients with cytokine storm. METHODS: Six cases of severe or critically severe COVID-19 patients treated in The First Affiliated Hospital, College of Medicine, Zhejiang University from January 22 to February 4, 2020 were recruited, and all of them received artificial liver support treatment. Statistical analysis was carried out on the change of cytokines (TNF-α, IL-10, IL-6, IFN-γ, IL-2, IL-4), inflammation-related indicators (white blood cell, neutrophil, lymphocyte, C-reactive protein and procalcitonin), immune-related indicators (B lymphocyte percentage, natural killer cell percentage, CD3+CD4+CD8 T cell percentage), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the 6 patients before and after treatment, and the proportions of patients with abnormal indicators were analyzed as well. In addition, computed tomography (CT) was used to observe the absorption of pulmonary lesions before and after the artificial liver support treatment. RESULTS: The levels of cytokines (IL-6 and IL-10) were effectively reduced in the 6 patients after treatment with the artificial liver support system. Meanwhile, the proportions of patients with abnormal TNF-α, IL-10, IL-6 and IFN-γ were all decreased (p < 0.05). The levels of inflammation-related indicators including white blood cell, C-reactive protein and procalcitonin, and the proportions of patients with these abnormal indicators were both significantly reduced (p < 0.05). The level of neutrophil was not effectively reduced before and after the treatment, but the proportion was significantly reduced (p < 0.05). However, the abnormality of lymphocyte in the patients was not improved. There was no significant difference in immune-related indicators, AST and ALT before and after the treatment (p > 0.05). CT imaging showed that the artificial liver support treatment contributed to absorption of pulmonary lesions. CONCLUSIONS: The artificial liver support system had a great clinical effect in the treatment of cytokine storm and inflammation in COVID-19 patients, and it could promote the absorption of infected lesions.


Subject(s)
COVID-19/therapy , Cytokine Release Syndrome/therapy , Life Support Care/methods , Liver, Artificial , Lung/pathology , Lymphocytes/pathology , SARS-CoV-2/physiology , Aged , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Cytokines/blood , Female , Humans , Lung/diagnostic imaging , Male , Middle Aged
10.
Hum Immunol ; 82(4): 247-254, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1039364

ABSTRACT

Immunorelevant genes are among the most probable modulators of coronavirus disease 2019 (COVID-19) progression and prognosis. However, in the few months of the pandemic, data generated on host genetics has been scarce. The present study retrieved data sets of HLA-B alleles, KIR genes and functional single nucleotide polymorphisms (SNPs) in cytokines related to COVID-19 cytokine storm from two publicly available databases: Allele Frequency Net Database and Ensembl, and correlated these frequency data with Case Fatality Rate (CFR) and Daily Death Rates (DDR) across countries. Correlations of eight HLA-B alleles and polymorphisms in three cytokine genes (IL6, IL10, and IL12B) were observed and were mainly associated with DDR. Additionally, HLA-B correlations suggest that differences in allele affinities to SARS-CoV-2 peptides are also associated with DDR. These results may provide rationale for future host genetic marker surveys on COVID-19.


Subject(s)
COVID-19/pathology , Cytokines/genetics , HLA-B Antigens/genetics , Receptors, KIR/genetics , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/mortality , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Gene Frequency/genetics , Genetic Markers/genetics , Humans , Interleukin-10/genetics , Interleukin-12 Subunit p40/genetics , Interleukin-6/genetics , Polymorphism, Single Nucleotide/genetics
11.
BMC Infect Dis ; 20(1): 901, 2020 Nov 30.
Article in English | MEDLINE | ID: covidwho-1005880

ABSTRACT

BACKGROUND: Staphylococcus aureus bacteremia (SAB) presents heterogeneously, owing to the differences in underlying host conditions and immune responses. Although Toll-like receptor 2 (TLR2) is important in recognizing S. aureus, its function during S. aureus infection remains controversial. We aimed to examine the association of TLR2 expression and associated cytokine responses with clinical SAB outcomes. METHODS: Patients from a prospective SAB cohort at two tertiary-care medical centers were enrolled. Blood was sampled at several timepoints (≤5 d, 6-9 d, 10-13 d, 14-19 d, and ≥ 20 d) after SAB onset. TLR2 mRNA levels were determined via real-time PCR and serum tumor necrosis factor [TNF]-α, interleukin [IL]-6, and IL-10 levels were analyzed with multiplex-high-sensitivity electrochemiluminescent ELISA. RESULTS: TLR2 levels varied among 59 SAB patients. On days 2-5, TLR2 levels were significantly higher in SAB survivors than in healthy controls (p = 0.040) and slightly but not significantly higher than non-survivors (p = 0.120), and SAB patients dying within 7 d had lower TLR2 levels than survivors (P = 0.077) although statistically insignificant. IL-6 and IL-10 levels were significantly higher in non-survivors than in survivors on days 2-5 post-bacteremia (P = 0.010 and P = 0.021, respectively), and those dying within 7 d of SAB (n = 3) displayed significantly higher IL-10/TNF-α ratios than the survivors did (P = 0.007). CONCLUSION: TLR2 downregulation and IL-6 and IL-10 concentrations suggestive of immune dysregulation during early bacteremia may be associated with mortality from SAB. TLR2 expression levels and associated cytokine reactions during early-phase SAB may be potential prognostic factors in SAB, although larger studies are warranted.


Subject(s)
Bacteremia/metabolism , Bacteremia/mortality , Cytokines/metabolism , Down-Regulation/genetics , Staphylococcal Infections/metabolism , Staphylococcal Infections/mortality , Staphylococcus aureus/isolation & purification , Toll-Like Receptor 2/genetics , Adult , Aged , Aged, 80 and over , Cytokines/analysis , Female , Humans , Male , Middle Aged , Prognosis , Prospective Studies , RNA, Messenger/genetics , Real-Time Polymerase Chain Reaction , Staphylococcal Infections/microbiology , Staphylococcus aureus/metabolism , Survivors , Tertiary Care Centers
12.
Curr Pharm Biotechnol ; 22(12): 1584-1590, 2021.
Article in English | MEDLINE | ID: covidwho-999940

ABSTRACT

N-Acetylcysteine (NAC) has been proposed to be used to treat Coronavirus Disease 2019 (COVID-19). By reviewing the existing pathological studies of COVID-19, it was found that abundant mucus secretion, formation of a hyaline membrane (supportive of acute respiratory distress syndrome), and interstitial fibrous exudation may be important characteristics of COVID-19 and pathological targets of drug therapy. In addition, multiple extrapulmonary organ injuries in COVID- 19 may be associated with cytokine storm. NAC is an important antioxidant and anti-inflammatory drug. NAC has been demonstrated to have mucolytic effects in bronchitis, relieve respiratory failure in acute respiratory distress syndrome, and inhibit fibrous exudation in interstitial lung disease in clinical studies. These findings suggest that NAC may have a therapeutic effect on the pathological targets of COVID-19. Furthermore, NAC decreases TNF-α, IL-1ß, IL-6, IL-8, IL-10, and IL-17 serum levels in patients with sepsis, severe burns, acute liver failure, or peritoneal dialysis and may also reduce cytokine storm in COVID-19. The antiviral effect of NAC on other respiratory viruses may also benefit COVID-19 patients. Summarizing the potential mechanisms of NAC in treating COVID-19 suggests that the role of NAC in COVID-19 treatment is worthy of further research.


Subject(s)
COVID-19 , Coronavirus Infections , Acetylcysteine/therapeutic use , COVID-19/drug therapy , Humans , SARS-CoV-2
13.
Eur Rev Med Pharmacol Sci ; 24(23): 12536-12544, 2020 12.
Article in English | MEDLINE | ID: covidwho-995014

ABSTRACT

OBJECTIVE: We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS: The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS: The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS: The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.


Subject(s)
COVID-19/immunology , Cytokines/immunology , T-Lymphocyte Subsets/immunology , Aged , Aged, 80 and over , CD4 Lymphocyte Count , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Female , Humans , Interferon-alpha/immunology , Interleukin-10/immunology , Interleukin-12/immunology , Interleukin-17/immunology , Interleukin-1beta/immunology , Interleukin-2/immunology , Interleukin-4/immunology , Interleukin-5/immunology , Interleukin-6/immunology , Interleukin-8/immunology , Leukocyte Common Antigens/immunology , Longitudinal Studies , Lymphocyte Count , Male , Middle Aged , Prognosis , SARS-CoV-2 , Severity of Illness Index , Tumor Necrosis Factor-alpha/immunology
14.
J Transl Med ; 18(1): 457, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-958039

ABSTRACT

BACKGROUND: Although immune modulation is a promising therapeutic avenue in coronavirus disease 2019 (COVID-19), the most relevant targets remain to be found. COVID-19 has peculiar characteristics and outcomes, suggesting a unique immunopathogenesis. METHODS: Thirty-six immunocompetent non-COVID-19 and 27 COVID-19 patients with severe pneumonia were prospectively enrolled in a single center, most requiring intensive care. Clinical and biological characteristics (including T cell phenotype and function and plasma concentrations of 30 cytokines) and outcomes were compared. RESULTS: At similar baseline respiratory severity, COVID-19 patients required mechanical ventilation for significantly longer than non-COVID-19 patients (15 [7-22] vs. 4 (0-15) days; p = 0.0049). COVID-19 patients had lower levels of most classical inflammatory cytokines (G-CSF, CCL20, IL-1ß, IL-2, IL-6, IL-8, IL-15, TNF-α, TGF-ß), but higher plasma concentrations of CXCL10, GM-CSF and CCL5, compared to non-COVID-19 patients. COVID-19 patients displayed similar T-cell exhaustion to non-COVID-19 patients, but with a more unbalanced inflammatory/anti-inflammatory cytokine response (IL-6/IL-10 and TNF-α/IL-10 ratios). Principal component analysis identified two main patterns, with a clear distinction between non-COVID-19 and COVID-19 patients. Multivariate regression analysis confirmed that GM-CSF, CXCL10 and IL-10 levels were independently associated with the duration of mechanical ventilation. CONCLUSION: We identified a unique cytokine response, with higher plasma GM-CSF and CXCL10 in COVID-19 patients that were independently associated with the longer duration of mechanical ventilation. These cytokines could represent the dysregulated immune response in severe COVID-19, as well as promising therapeutic targets. ClinicalTrials.gov: NCT03505281.


Subject(s)
COVID-19/diagnosis , COVID-19/immunology , Immunity, Innate/physiology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Aged , Aged, 80 and over , COVID-19/mortality , COVID-19/therapy , Critical Care , Female , France/epidemiology , Humans , Immunophenotyping , Lymphocyte Activation/physiology , Male , Middle Aged , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Prognosis , Respiration, Artificial , SARS-CoV-2/physiology , Severity of Illness Index
15.
Sci Rep ; 10(1): 19839, 2020 11 16.
Article in English | MEDLINE | ID: covidwho-927249

ABSTRACT

Severe pneumonia and multiorgan dysfunction in COVID-19 and dengue haemorrhagic fever (DHF) are two diseases that can associate with an altered immune response to the infecting virus. To determine the similarities and differences in the cytokine and chemokine responses in these two infections, we compared responses in patients with varying severity of COVID-19 and acute dengue at different time points of illness. During early disease, patients who proceeded to develop COVID-19 severe pneumonia (SP) and DHF had significantly higher levels of IL-6, IL-10 and MIP3α than those who developed mild illness. The lowest levels of IFNγ in early illness were seen in those who succumbed to their illness due to COVID-19. Levels of serum IL-10 (p = 0.0001), IL-6 (p = 0.002), MIP-3α (p = 0.02) and CD40-L levels (p = 0.002) significantly increased from 5 to 9 day of illness to 10-21 day of illness in patients with moderate-to-severe COVID-19, but not in those with mild illness. In contrast, these cytokine/chemokine levels remained unchanged in those with DHF or dengue fever (DF) during febrile and critical phases. Although IL-10 levels were significantly higher in COVID-19 patients with SP, patients with DHF had 25-fold higher levels, whereas IL-6 levels were 11-fold higher in those with COVID-19 SP. IL-10 and other cytokines were evaluated in a larger cohort of patients during early illness (≤ 4 days) who proceeded to develop DF (n = 71) or DHF (n = 64). Of the cytokines evaluated, IL-10 was significantly higher (p < 0.0001) in those who went on to develop DHF compared to DF. Low IFNγ response to the SARS-CoV2 and high levels of immunosuppressive IL-10 in both COVID-19 and dengue during early illness are indicators of an altered antiviral response potentially contributing to disease severity.


Subject(s)
COVID-19/blood , Cytokine Release Syndrome/blood , Dengue/blood , COVID-19/immunology , COVID-19/pathology , Chemokine CCL20/blood , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Dengue/immunology , Dengue/pathology , Humans , Interferon-gamma/blood , Interleukin-10/blood , Interleukin-6/blood
16.
J Clin Immunol ; 41(1): 11-22, 2021 01.
Article in English | MEDLINE | ID: covidwho-893311

ABSTRACT

PURPOSE: Cytokine storm, an uncontrolled overproduction of inflammatory cytokines contributing to an aberrant systemic inflammatory response, is a major pathological feature of acute respiratory distress syndromes being severe manifestations of COVID-19, thus highlighting its potential as a biomarker and therapeutic target for COVID-19. We aimed to determine associations of circulating levels of inflammatory cytokines with severity and mortality of COVID-19 by systematic review and meta-analysis. METHODS: A comprehensive literature search in electronic databases consisting of PubMed, Scopus, and Cochrane Library and in a hand searching of reference lists from inception to July 31, 2020, was performed using the following search terms: COVID-19, interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha (TNF-α). Mean difference (MD) from individual studies was pooled using a random-effects model. Quality assessment, publication bias, meta-regression, subgroup, and sensitivity analyses were performed. RESULTS: A total of 6212 COVID-19 patients from 24 eligible studies were included. Compared with non-severe COVID-19 patients, systemic levels of IL-6 and IL-10, but not TNF-α, were significantly elevated in severe COVID-19 patients (MD = 18.63, 95% CI: 10.91, 26.35, P < 0.00001; MD = 2.61, 95% CI: 2.00, 2.32, P < 0.00001; respectively). For COVID-19 mortality, circulating levels of IL-6, IL-10, and TNF-α were found to be significantly increased in non-survivors when compared with survivors (MD = 57.82, 95% CI: 10.04, 105.59, P = 0.02; MD = 4.94, 95% CI: 3.89, 6.00, P < 0.00001; MD = 5.60, 95% CI: 4.03, 7.17, P < 0.00001; respectively). CONCLUSION: Circulating levels of IL-6 and IL-10 might have great potential as biomarkers for the disease severity and mortality in COVID-19 patients.


Subject(s)
COVID-19/diagnosis , Cytokine Release Syndrome/diagnosis , Interleukin-10/blood , Interleukin-6/blood , Biomarkers/blood , COVID-19/blood , COVID-19/mortality , COVID-19/virology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Humans , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Severity of Illness Index , Tumor Necrosis Factor-alpha
17.
Clin Immunol ; 218: 108524, 2020 09.
Article in English | MEDLINE | ID: covidwho-639598

ABSTRACT

The outbreak of SARS-CoV-2-associated pneumonia, a disease called COVID-19, has caused a pandemic worldwide. To investigate the immune responses after infection of SARS-CoV-2 in non-critical patients may help to better understand the disease progression. We collected 334 confirmed COVID-19 cases including 212 still in hospital with nucleic acid test positive on halfway for SARS-CoV-2 and 122 discharged from hospital, compared specific antibodies, immune cells, and cytokine changes between the hospitalized and discharged patients. The hospitalized patients had a longer illness time compared with discharged patients. Analysis of viral loads explained long-term or persistent infection of SARS-CoV-2, which existed with the median time of 18.5 days of the positive nucleic acid test. Serum analysis showed that the specific anti-N IgG antibody was positive in all detected patients after infection of two weeks. Neutrophils, Monocytes, NK cells, and CD4+ T cells significantly increased, while total lymphocytes and CD8+ T cells decreased from non-critical hospitalized patients after longer-term infection. Further analysis of the cytokines showed that IL-6, TNF-α, IFN-γ, IL-2, IL-4, and IL-10 from the hospitalized patients were significantly higher, indicating a potential of the increased CD4+ T cell differentiation.


Subject(s)
Betacoronavirus/pathogenicity , Cardiovascular Diseases/immunology , Coronavirus Infections/immunology , Diabetes Mellitus/immunology , Immunity, Innate , Lung Diseases/immunology , Neoplasms/immunology , Pneumonia, Viral/immunology , Aged , Antibodies, Viral/blood , Betacoronavirus/immunology , COVID-19 , Cardiovascular Diseases/epidemiology , Cardiovascular Diseases/pathology , Cardiovascular Diseases/virology , China/epidemiology , Comorbidity , Convalescence , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/blood , Diabetes Mellitus/epidemiology , Diabetes Mellitus/pathology , Diabetes Mellitus/virology , Female , Hospitalization , Humans , Killer Cells, Natural/immunology , Killer Cells, Natural/pathology , Killer Cells, Natural/virology , Lung Diseases/epidemiology , Lung Diseases/pathology , Lung Diseases/virology , Lymphocyte Subsets/immunology , Lymphocyte Subsets/pathology , Lymphocyte Subsets/virology , Male , Middle Aged , Monocytes/immunology , Monocytes/pathology , Monocytes/virology , Neoplasms/epidemiology , Neoplasms/pathology , Neoplasms/virology , Neutrophils/immunology , Neutrophils/pathology , Neutrophils/virology , Pandemics , Patient Discharge , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2 , Time Factors , Viral Load/immunology
18.
JCI Insight ; 5(13)2020 07 09.
Article in English | MEDLINE | ID: covidwho-541270

ABSTRACT

BACKGROUND: Identifying immune correlates of COVID-19 disease severity is an urgent need for clinical management, vaccine evaluation, and drug development. Here, we present a temporal analysis of key immune mediators, cytokines, and chemokines in blood of hospitalized COVID-19 patients from serial sampling and follow-up over 4 weeks. METHODS: A total of 71 patients with laboratory-confirmed COVID-19 admitted to Beijing You'an Hospital in China with either mild (53 patients) or severe (18 patients) disease were enrolled with 18 healthy volunteers. We measured 34 immune mediators, cytokines, and chemokines in peripheral blood every 4-7 days over 1 month per patient using a bioplex multiplex immunoassay. RESULTS: We found that the chemokine RANTES (CCL5) was significantly elevated, from an early stage of the infection, in patients with mild but not severe disease. We also found that early production of inhibitory mediators including IL-10 and IL-1RA were significantly associated with disease severity, and a combination of CCL5, IL-1 receptor antagonist (IL-1RA), and IL-10 at week 1 may predict patient outcomes. The majority of cytokines that are known to be associated with the cytokine storm in virus infections such as IL-6 and IFN-γ were only significantly elevated in the late stage of severe COVID-19 illness. TNF-α and GM-CSF showed no significant differences between severe and mild cases. CONCLUSION: Together, our data suggest that early intervention to increase expression of CCL5 may prevent patients from developing severe illness. Our data also suggest that measurement of levels of CCL5, as well as IL-1RA and IL-10 in blood individually and in combination, might be useful prognostic biomarkers to guide treatment strategies.


Subject(s)
Chemokine CCL5/immunology , Coronavirus Infections/immunology , Interleukin 1 Receptor Antagonist Protein/immunology , Interleukin-10/immunology , Pneumonia, Viral/immunology , Adult , Aged , Betacoronavirus , COVID-19 , Case-Control Studies , Coronavirus Infections/physiopathology , Cytokine Release Syndrome/immunology , Female , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Hospitalization , Humans , Immunoassay , Interferon-gamma/immunology , Interleukin-6/immunology , Longitudinal Studies , Male , Middle Aged , Pandemics , Pneumonia, Viral/physiopathology , SARS-CoV-2 , Severity of Illness Index , Tumor Necrosis Factor-alpha/immunology
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