Associations between Serum Interleukins (IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10) and Disease Severity of COVID-19: A Systematic Review and Meta-Analysis.

Background: To investigate the association between interleukins (IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10) and the disease severity of coronavirus disease 2019 (COVID-19). Materials and Methods: We systematically searched records investigating the role of interleukins (IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10) in COVID-19 patients in Web of Science, Pubmed, and Embase through December 2020. Data were extracted and pooled, and the weighted mean difference (WMD) and its 95% confidence interval (CI) were calculated. The funnel plot and the nonparametric trim and fill method were used to visualize and adjust the publication bias. Results: In total, 61 studies enrolled 14,136 subjects (14,041 patients and 95 healthy subjects) were enrolled in this meta-analysis. Our results showed that serum IL-2, IL-4, IL-6, and IL-10 levels were elevated in COVID-19 patients compared to healthy controls, and IL-6, IL-8, and IL-10 levels were increased in severe COVID-19 cases compared to nonsevere patients. Additionally, the levels of IL-1ß, IL-6, and IL-8 were elevated in nonsurvivor patients compared to survivors. For patients in the intensive care unit (ICU), IL-6 and IL-8 levels were increased than that in non-ICU patients. Conclusions: Elevated levels of IL-6, IL-8, and IL-10 were associated with the disease severity of COVID-19, and elevated levels of IL-1ß, IL-6, and IL-8 were related to the prognosis of COVID-19 patients, which could be used to evaluate COVID-19 patients' disease severity and prognosis.

Serum IL-28A/IFN-λ2 is linked to disease severity of COVID-19.

Type III interferons (IFNs) play an important role in respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This study aimed to determine whether the expression of serum type III IFNs predicted disease severity among patients with the coronavirus disease (COVID-19). A retrospective cohort study was conducted of patients admitted to a single hospital between March 21, 2020, and March 31, 2021. Patients were divided into mild to moderate I (MM) and moderate II to severe (MS) groups based on the COVID-19 severity classification developed by the Japanese Ministry of Health, Labor and Welfare. A total of 257 patients were included in the analysis. Human interleukin-28A (IL-28A/IFN-λ2) expression was significantly lower, and interleukin (IL)-6 expression was significantly higher in the MS group than in the MM group (both p < 0.001). In addition, IL-28A/IFN-λ2 was statistically significantly inversely correlated with the time from disease onset to negative SARS-CoV-2 PCR results (p = 0.049). Multivariable logistic regression analysis showed that IL-28A/IFN-λ2 was an independent predictor of disease severity (p = 0.021). The low expression of IL-28A/IFN-λ2 may serve as a serum biomarker that predicts the severity of COVID-19, possibly through the mechanism of delayed viral elimination.

Up-regulated serum levels of interleukin (IL)-17A and IL-22 in Egyptian pediatric patients with COVID-19 and MIS-C: Relation to the disease outcome.

Both IL-17A and IL-22 share cellular sources and signaling pathways. They have synergistic action on epithelial cells to stimulate their production of antimicrobial peptides which are protective against infections. However, both interleukins may contribute to ARDS pathology if their production is not controlled. This study aimed to investigate serum levels of IL-17A and IL-22 in relation to the disease outcome in patients with SARS-CoV-2. Serum IL-17A and IL-22 were measured by ELISA in 40 patients with SARS-CoV-2, aged between 2 months and 16 years, (18 had COVID-19 and 22 had multisystem inflammatory syndrome in children "MIS-C") in comparison to 48 age- and sex-matched healthy control children. Patients with COVID-19 and MIS-C had significantly higher serum IL-17A and IL-22 levels than healthy control children (P < 0.001). Increased serum IL-17A and IL-22 levels were found in all patients. Elevated CRP and serum ferritin levels were found in 90% of these patients. Lymphopenia, neutrophilia, neutropenia, thrombocytopenia and elevated ALT, LDH and D-dimer were found in 45%, 42.5 %, 2.5%, 30%, 32.5%, 82.5%, and 65%, respectively of these patients. There were non-significant differences between patients who recovered and those who died or had a residual illness in serum levels of IL-17A, IL-22 and the routine inflammatory markers of COVID-19. In conclusions, serum IL-17A and IL-22 levels were up-regulated in all patients with COVID-19 and MIS-C. Levels of serum IL-17A, IL-22 and the routine inflammatory markers of COVID-19 were not correlated with the disease outcome. Our conclusions are limited by the sample size.

Interleukin-21: a potential biomarker for diagnosis and predicting prognosis in COVID-19 patients

Background/aim: COVID-19 patients have a wide spectrum of disease severity. Several biomarkers were evaluated as predictors for progression towards severe disease. IL-21 is a member of common γ-chain cytokine family and creates some specific effects during programming and maintenance of antiviral immunity. We aimed to assess IL-21 as a biomarker for diagnosis and outcome prediction in patients hospitalized with COVID-19. Materials and methods: Patients with a preliminary diagnosis of COVID-19 and pneumonia other than COVID-19 admitted to a tertiary care hospital were included consecutively in this comparative study. Results: The study population consisted of 51 patients with COVID-19 and 11 patients with non-COVID-19 pneumonia. Serum IL-21 concentration was markedly higher, and serum CRP concentration was significantly lower in COVID-19 patients compared to non-COVID-19 pneumonia patients. Within COVID-19 patients, 10 patients showed radiological and clinical progression. Patients with clinical worsening had lower lymphocyte count and haemoglobin. In addition to that, deteriorating patients had higher urea, LDH levels, and elevated concentration of both IL-6 and IL-21. The cut-off value of 106 ng/L for IL-21 has 80.0% sensitivity, %60.9 specificity for discriminating patients with clinical worsening. Multivariable analysis performed to define risk factors for disease progression identified IL-6 and IL-21 as independent predictors. Odds ratio for serum IL-6 concentrations ≥ 3.2 pg/mL was 8.07 (95% CI: 1.37-47.50, p = 0.04) and odds ratio for serum IL-21 concentrations ≥ 106 ng/L was 6.24 (95% CI: 1.04 ­ 37.3, p = 0.02). Conclusion: We identified specific differences in serum IL-21 between COVID-19 and non-COVID-19 pneumonia patients. Serum IL-21 measurement has promising predictive value for disease progression in COVID-19 patients. High serum IL-6 and IL-21 levels obtained upon admission are independent risk factors for clinical worsening.

Upregulation of type 1 conventional dendritic cells implicates antigen cross-presentation in multisystem inflammatory syndrome.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) is an acute, febrile, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated syndrome, often with cardiohemodynamic dysfunction. Insight into mechanism of disease is still incomplete. OBJECTIVE: Our objective was to analyze immunologic features of MIS-C patients compared to febrile controls (FC). METHODS: MIS-C patients were defined by narrow criteria, including having evidence of cardiohemodynamic involvement and no macrophage activation syndrome. Samples were collected from 8 completely treatment-naive patients with MIS-C (SARS-CoV-2 serology positive), 3 patients with unclassified MIS-C-like disease (serology negative), 14 FC, and 5 MIS-C recovery (RCV). Three healthy controls (HCs) were used for comparisons of normal range. Using spectral flow cytometry, we assessed 36 parameters in antigen-presenting cells (APCs) and 29 in T cells. We used biaxial analysis and uniform manifold approximation and projection (UMAP). RESULTS: Significant elevations in cytokines including CXCL9, M-CSF, and IL-27 were found in MIS-C compared to FC. Classic monocytes and type 2 dendritic cells (DCs) were downregulated (decreased CD86, HLA-DR) versus HCs; however, type 1 DCs (CD11c+CD141+CLEC9A+) were highly activated in MIS-C patients versus FC, expressing higher levels of CD86, CD275, and atypical conventional DC markers such as CD64, CD115, and CX3CR1. CD169 and CD38 were upregulated in multiple monocyte subtypes. CD56dim/CD57-/KLRGhi/CD161+/CD38- natural killer (NK) cells were a unique subset in MIS-C versus FC without macrophage activation syndrome. CONCLUSION: Orchestrated by complex cytokine signaling, type 1 DC activation and NK dysregulation are key features in the pathophysiology of MIS-C. NK cell findings may suggest a relationship with macrophage activation syndrome, while type 1 DC upregulation implies a role for antigen cross-presentation.

Role of tumor necrosis factor-α in the mortality of hospitalized patients with severe and critical COVID-19 pneumonia.

The coronavirus disease 2019 (COVID-19) is presently the most pressing public health concern worldwide. Cytokine storm is an important factor leading to death of patients with COVID-19. This study aims to characterize serum cytokines of patients with severe or critical COVID-19. Clinical records were obtained from 149 patients who were tested at the Sino-French New City Branch of Tongji Hospital from 30 January to 30 March 2020. Data regarding the clinical features of the patients was collected and analyzed. Among the 149, 45 (30.2%) of them had severe conditions and 104 (69.8%) of that presented critical symptoms. In the meantime, 80 (53.7%) of that 149 died during hospitalization. Of all, male patients accounted for 94 (69.1%). Compared with patients in severe COVID-19, those who in critical COVID-19 had significantly higher levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-8, and IL-10. Moreover, the passed-away patients had considerably higher levels of TNF-α, IL-6, IL-8, and IL-10 than those survived from it. Regression analysis revealed that serum TNF-α level was an independent risk factor for the death of patient with severe conditions. Among the proinflammatory cytokines (IL-1ß, TNF-α, IL-8, and IL-6) analyzed herein, TNF-α was seen as a risk factor for the death of patients with severe or critical COVID-19. This study suggests that anti-TNF-α treatment allows patients with severe or critical COVID-19 pneumonia to recover.

Analysis of serum cytokine and protective vitamin D levels in severe cases of COVID-19.

In this study, we investigated the role and relationship between the cytokine profile and protective vitamin D by measuring their serum levels in COVID-19 intensive care unit patients with severe illnesses. A total of 74 patients were included in our study. Patients were divided into two groups. Patients in the COVID-19 group (n = 31) and individuals without a history of serious illness or infection were used as the control group (n = 43). The serum concentrations of interleukin-1 (IL-1), IL-6, IL-10, IL-21, and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assays. Levels of serum vitamin D were detected with Liquid chromatography-mass spectrometry methodologies. TNF-α, IL-1, IL-6, IL-10, IL-21, and vitamin D levels were measured in all patients. The serum cytokine levels in the COVID-19 patient group were significantly higher (151.59 ± 56.50, 140.37 ± 64.32, 249.02 ± 62.84, 129.04 ± 31.64, and 123.58 ± 24.49, respectively) than control groups. Serum vitamin D was also significantly low (6.82 ± 3.29) in patients in the COVID-19 group than the controls (21.96 ± 5.39). Regarding the correlation of vitamin D with cytokine levels, it was significantly variable. Our study shows that COVID-19 patients are associated with lower serum vitamin D and higher pro-inflammatory cytokines associated with increased virus presence. Our data provide more evidence of the anti-inflammatory effect of vitamin D on COVID-19 patients and the protective effects of vitamin D on risk were demonstrated.

Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS.

The interplay between inflammation and oxidative stress is a vicious circle, potentially resulting in organ damage. Essential micronutrients such as selenium (Se) and zinc (Zn) support anti-oxidative defense systems and are commonly depleted in severe disease. This single-center retrospective study investigated micronutrient levels under Se and Zn supplementation in critically ill patients with COVID-19 induced acute respiratory distress syndrome (ARDS) and explored potential relationships with immunological and clinical parameters. According to intensive care unit (ICU) standard operating procedures, patients received 1.0 mg of intravenous Se daily on top of artificial nutrition, which contained various amounts of Se and Zn. Micronutrients, inflammatory cytokines, lymphocyte subsets and clinical data were extracted from the patient data management system on admission and after 10 to 14 days of treatment. Forty-six patients were screened for eligibility and 22 patients were included in the study. Twenty-one patients (95%) suffered from severe ARDS and 14 patients (64%) survived to ICU discharge. On admission, the majority of patients had low Se status biomarkers and Zn levels, along with elevated inflammatory parameters. Se supplementation significantly elevated Se (p = 0.027) and selenoprotein P levels (SELENOP; p = 0.016) to normal range. Accordingly, glutathione peroxidase 3 (GPx3) activity increased over time (p = 0.021). Se biomarkers, most notably SELENOP, were inversely correlated with CRP (rs = -0.495), PCT (rs = -0.413), IL-6 (rs = -0.429), IL-1ß (rs = -0.440) and IL-10 (rs = -0.461). Positive associations were found for CD8+ T cells (rs = 0.636), NK cells (rs = 0.772), total IgG (rs = 0.493) and PaO2/FiO2 ratios (rs = 0.504). In addition, survivors tended to have higher Se levels after 10 to 14 days compared to non-survivors (p = 0.075). Sufficient Se and Zn levels may potentially be of clinical significance for an adequate immune response in critically ill patients with severe COVID-19 ARDS.

Clinical features and prognostic factors in Covid-19: A prospective cohort study.

BACKGROUND: Mortality rates are high among hospitalized patients with COVID-19, especially in those intubated on the ICU. Insight in pathways associated with unfavourable outcome may lead to new treatment strategies. METHODS: We performed a prospective cohort study of patients with COVID-19 admitted to general ward or ICU who underwent serial blood sampling. To provide insight in the pathways involved in disease progression, associations were estimated between outcome risk and serial measurements of 64 biomarkers in potential important pathways of COVID-19 infection (inflammation, tissue damage, complement system, coagulation and fibrinolysis) using joint models combining Cox regression and linear mixed-effects models. For patients admitted to the general ward, the primary outcome was admission to the ICU or mortality (unfavourable outcome). For patients admitted to the ICU, the primary outcome was 12-week mortality. FINDINGS: A total of 219 patients were included: 136 (62%) on the ward and 119 patients (54%) on the ICU; 36 patients (26%) were included in both cohorts because they were transferred from general ward to ICU. On the general ward, 54 of 136 patients (40%) had an unfavourable outcome and 31 (23%) patients died. On the ICU, 54 out of 119 patients (45%) died. Unfavourable outcome on the general ward was associated with changes in concentrations of IL-6, IL-8, IL-10, soluble Receptor for Advanced Glycation End Products (sRAGE), vascular cell adhesion molecule 1 (VCAM-1) and Pentraxin-3. Death on the ICU was associated with changes in IL-6, IL-8, IL-10, sRAGE, VCAM-1, Pentraxin-3, urokinase-type plasminogen activator receptor, IL-1-receptor antagonist, CD14, procalcitonin, tumor necrosis factor alfa, tissue factor, complement component 5a, Growth arrest-specific 6, angiopoietin 2, and lactoferrin. Pathway analysis showed that unfavourable outcome on the ward was mainly driven by chemotaxis and interleukin production, whereas death on ICU was associated with a variety of pathways including chemotaxis, cell-cell adhesion, innate host response mechanisms, including the complement system, viral life cycle regulation, angiogenesis, wound healing and response to corticosteroids. INTERPRETATION: Clinical deterioration in patients with severe COVID-19 involves multiple pathways, including chemotaxis and interleukin production, but also endothelial dysfunction, the complement system, and immunothrombosis. Prognostic markers showed considerable overlap between general ward and ICU patients, but we identified distinct differences between groups that should be considered in the development and timing of interventional therapies in COVID-19. FUNDING: Amsterdam UMC, Amsterdam UMC Corona Fund, and Dr. C.J. Vaillant Fonds.

Linkage of Lambda Interferons in Protection Against Severe COVID-19.

The most recently discovered interferon (IFN) family, type III IFNs or lambda IFNs (IFN-λs) are caused by viral infection and act in mucosal barriers, such as the respiratory tract. In this study, we assessed the serum levels of IFN-λs in new coronavirus disease-2019 (COVID-19) patients. Sixty-four COVID-19 patients were enrolled in this study. All cases were divided into the intensive care unit (ICU) and non-ICU groups according to their symptoms. Fourteen samples of healthy controls were also included. The serum levels of IFN-λ1 and IFN-λ2 were analyzed by specific enzyme-linked immunosorbent assay (ELISA) kits. The concentrations of IFN-λ1 and IFN-λ2 induced in the serum of non-ICU patients (836.7 ± 284.6 and 798.8 ± 301.5 pg/mL, respectively) were higher than found in ICU patients (81.57 ± 34.25 and 48.32 ± 28.13 pg/mL, respectively) (P = 0.004 and P = 0.006, respectively) and healthy controls (85.57 ± 33.63 and 65.82 ± 21.26 pg/mL, respectively) (P = 0.03 and P = 0.04, respectively). Meanwhile, no significant differences were found in the concentration of both cytokines between the ICU patients and healthy controls. We conclude that higher levels of IFN-λs are associated with decreased clinical manifestations in COVID-19 patients. These cytokines could be a promising therapeutic agent to avoid the overwhelming consequences of COVID-19.

Downregulation of type III interferons in patients with severe COVID-19.

Coronavirus disease 2019 (COVID-19) is globally rampant, and to curb the growing burden of this disease, in-depth knowledge about its pathophysiology is needed. This was an observational study conducted at a single center to investigate serum cytokine and chemokine levels of COVID-19 patients, based on disease severity. We included 72 consecutive COVID-19 patients admitted to our hospital from March 21 to August 31, 2020. Patients were divided into Mild-Moderate I (mild) and Moderate II-Severe (severe) groups based on the COVID-19 severity classification developed by the Ministry of Health, Labor and Welfare (MHLW) of Japan. We compared the patient characteristics as well as the serum cytokine and chemokine levels on the day of admission between the two groups. Our findings indicated that the severe group had significantly higher levels of serum fibrinogen, d-dimer, lactate dehydrogenase, C-reactive protein, ferritin, Krebs von den Lungen-6, surfactant protein (SP)-D, and SP-A than the mild group. Strikingly, the levels of interleukin (IL)-28A/interferon (IFN)-λ2 were significantly lower in the severe group than in the mild group. We believe that reduced levels of type III interferons (IFN-λs) and alterations in the levels of other cytokines and chemokines may impact the severity of the disease.

Thymulin and peroxiredoxin 6 have protective effects against streptozotocin-induced type 1 diabetes in mice.

Protective effects of peroxiredoxin 6 (PRDX6) in RIN-m5F ß-cells and of thymulin in mice with alloxan-induced diabetes were recently reported. The present work was aimed at studying the efficiency of thymulin and PRDX6 in a type 1 diabetes mellitus model induced by streptozotocin in mice. Effects of prolonged treatment with PRDX6 or thymic peptide thymulin on diabetes development were evaluated. We assessed the effects of the drugs on the physiological status of diabetic mice by measuring blood glucose, body weight, and cell counts in several organs, as well as effects of thymulin and PRDX6 on the immune status of diabetic mice measuring concentrations of pro-inflammatory cytokines in blood plasma (TNF-α, interleukin-5 and 17, and interferon-γ), activity of NF-κB and JNK pathways, and Hsp90α expression in immune cells. Both thymulin and PRDX6 reduced the physiological impairments in diabetic mice at various levels. Thymulin and PRDX6 provide beneficial effects in the model of diabetes via very different mechanisms. Taken together, the results of our study indicated that the thymic peptide and the antioxidant enzyme have anti-inflammatory functions. As increasing evidences show diabetes mellitus as a distinct comorbidity leading to acute respiratory distress syndrome and increased mortality in patients with COVID-19 having cytokine storm, thymulin, and PRDX6 might serve as a supporting anti-inflammatory treatment in the therapy of COVID 19 in diabetic patients.

Interleukin-38 ameliorates poly(I:C) induced lung inflammation: therapeutic implications in respiratory viral infections.

Interleukin-38 has recently been shown to have anti-inflammatory properties in lung inflammatory diseases. However, the effects of IL-38 in viral pneumonia remains unknown. In the present study, we demonstrate that circulating IL-38 concentrations together with IL-36α increased significantly in influenza and COVID-19 patients, and the level of IL-38 and IL-36α correlated negatively and positively with disease severity and inflammation, respectively. In the co-cultured human respiratory epithelial cells with macrophages to mimic lung microenvironment in vitro, IL-38 was able to alleviate inflammatory responses by inhibiting poly(I:C)-induced overproduction of pro-inflammatory cytokines and chemokines through intracellular STAT1, STAT3, p38 MAPK, ERK1/2, MEK, and NF-κB signaling pathways. Intriguingly, transcriptomic profiling revealed that IL-38 targeted genes were associated with the host innate immune response to virus. We also found that IL-38 counteracts the biological processes induced by IL-36α in the co-culture. Furthermore, the administration of recombinant IL-38 could mitigate poly I:C-induced lung injury, with reduced early accumulation of neutrophils and macrophages in bronchoalveolar lavage fluid, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines and permeability of the alveolar-epithelial barrier. Taken together, our study indicates that IL-38 plays a crucial role in protection from exaggerated pulmonary inflammation during poly(I:C)-induced pneumonia, thereby providing the basis of a novel therapeutic target for respiratory viral infections.

Elevated interleukin levels are associated with higher severity and mortality in COVID 19 - A systematic review, meta-analysis, and meta-regression.

BACKGROUND AND AIMS: COVID 19 pneumonia commonly leads to ARDS. The occurrence of ARDS in COVID 19 patients is thought to occur secondary to an exaggerated immunologic response. In this meta-analysis, we aim to comprehensively study the various levels of immunological parameters in patients with COVID 19. MATERIALS AND METHODS: We performed a systematic literature search from PubMed, EuropePMC, SCOPUS, Cochrane Central Database, and medRxiv with the search terms, "COVID-19" and "Interleukin". The outcome of interest was prognosis in COVID 19 patients. RESULTS: We performed meta analysis of 16 studies. Higher counts of CD4 and CD8 with Lower Levels of TNF-a, IL2R, IL6, IL8 were observed on patients with good prognosis compared to patients with poor prognosis; -0.57 (pg/mL) (-1.10, -0.04, p = 0.04), (I2 91%, p < 0.001); -579.84 (U/mL) (-930.11, -229.57, p < 0.001), (I2 96%, p < 0.001); -1.49 (pg/mL) (-1.97, -1.01, p < 0.001), (I2 94%, p < 0.001); -0.80 (pg/mL) (-1.21, -0.40, p < 0.001), (I2 79%, p < 0.001); -2.51 (pg/mL) (-3.64, -1.38, p < 0.00001), (I2 98%, p < 0.001) respectively. Meta-regression showed age and hypertension (coefficient: 1.99, and -1.57, p = 0.005, and 0.006) significantly influenced association between IL-6 and poor outcome. CONCLUSION: Elevated immune response to coronavirus occurs in COVID 19 patients. Higher counts of CD4 and CD8 were seen in patients with good prognosis compared to patients with poor prognosis, with Lower levels of TNF-a, IL2R, IL6, IL8, were observed in patients with good prognosis compared to patients with poor prognosis.

Characteristics of inflammatory factors and lymphocyte subsets in patients with severe COVID-19.

To investigate the inflammatory factors and lymphocyte subsets which play an important role in the course of severe coronavirus disease 2019 (COVID-19). A total of 27 patients with severe COVID-19 who were admitted to Tongji Hospital in Wuhan from 1 to 21 February 2020 were recruited to the study. The characteristics of interleukin-1ß (IL-1ß), IL-2 receptor (IL-2R), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF)-α, C-reactive protein (CRP), serum ferritin and procalcitonin (PCT), and lymphocyte subsets of these patients were retrospectively compared before and after treatment. Before treatment, there was no significant difference in most inflammatory factors (IL-1ß, IL-2R, IL-6, IL-8, IL-10, CRP, and serum ferritin) between male and female patients. Levels of IL-2R, IL-6, TNF-α, and CRP decreased significantly after treatment, followed by IL-8, IL-10, and PCT. Serum ferritin was increased in all patients before treatment but did not decrease significantly after treatment. IL-1ß was normal in most patients before treatment. Lymphopenia was common among these patients with severe COVID-19. Analysis of lymphocyte subsets showed that CD4+ and particularly CD8+ T lymphocytes increased significantly after treatment. However, B lymphocytes and natural killer cells showed no significant changes after treatment. A pro-inflammatory response and decreased level of T lymphocytes were associated with severe COVID-19.

Impaired natural killer cell counts and cytolytic activity in patients with severe COVID-19.

The global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-driven coronavirus disease 2019 (COVID-19) has caused unprecedented human death and has seriously threatened the global economy. Early data suggest a surge in proinflammatory cytokines in patients with severe COVID-19, which has been associated with poor outcomes. We recently postulated that the inflammatory response in patients with severe COVID-19 disease is not inhibited by natural killer (NK) cells, resulting in a "cytokine storm." Here, we assessed the NK-cell functional activity and the associated cytokines and soluble mediators in hospitalized COVID-19 patients. Significantly impaired NK-cell counts and cytolytic activity were observed in COVID-19 patients when compared with healthy controls. Also, cytokines like interleukin 12 (IL12), IL15, and IL21 that are important for NK-cell activity were not detected systematically. Serum concentrations of soluble CD25 (sCD25)/soluble IL2 receptor α (sIL2-Rα) were significantly elevated and were inversely correlated with the percentage of NK cells. Impaired NK-cell cytolytic activity together with other laboratory trends including elevated sCD25 were consistent with a hyperinflammatory state in keeping with macrophage-activation syndrome. Our findings suggest that impaired counts and cytolytic activity of NK cells are important characteristics of severe COVID-19 and can potentially facilitate strategies for immunomodulatory therapies.

A score combining early detection of cytokines accurately predicts COVID-19 severity and intensive care unit transfer.

OBJECTIVES: We aimed to explore cytokine profile in patients as it relates to Coronavirus Disease 2019 (COVID-19) severity, and to establish a predictive cytokine score to discriminate severe from non-severe cases and provide a prognosis parameter for patients that will require intensive care unit (ICU) transfer. METHODS: Serum samples of 63 patients diagnosed with SARS-CoV-2 infection were collected early after hospital admission (day 0-3). Patients were categorized in five groups based on the clinical presentation, the PaO2/FiO2 ratio and the requirement of mechanical ventilation. RESULTS: Three cytokines, IL-6, IL-8 and IL-10, were markedly higher in severe forms (n = 44) than in non-severe forms (n = 19) (p < 0.005). A score combining levels of these three cytokines (IL-6*IL-8*IL-10) had the highest performance to predict severity: sensitivity of 86.4% (95% CI, 72.4-94.8) and specificity of 94.7% (95% CI, 74.0-99.9) for a cutoff value of 2068 pg/mL. Elevated levels of IL-6, IL-8 and IL-10 were also found in critically ill patients. The combination of IL-6*IL-10 serum levels allowed the highest predictability for ICU transfer: AUC of 0.898 (p < 0.0001). CONCLUSION: The combinatorial IL-6*IL-8*IL-10 score at presentation was highly predictive of the progression to a severe form of the disease, and could contribute to improve patient triage and to adapt therapeutic strategy within clinical trials more accurately and efficiently.

Fungal co-infection in COVID-19 patients: Should we be concerned?

Critically ill COVID-19 patients have higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4, IL-10) cytokine levels, less CD4 interferon-gamma expression, and fewer CD4 and CD8 cells. This severe clinical situation increases the risk of serious fungal infections, such as invasive pulmonary aspergillosis, invasive candidiasis or Pneumocystis jirovecii pneumonia. However, few studies have investigated fungal coinfections in this population. We describe an update on published reports on fungal coinfections and our personal experience in three Spanish hospitals. We can conclude that despite the serious disease caused by SARS-CoV-2 in many patients, the scarcity of invasive mycoses is probably due to the few bronchoscopies and necropsies performed in these patients because of the high risk in aerosol generation. However, the presence of fungal markers in clinically relevant specimens, with the exception of bronchopulmonary colonization by Candida, should make it advisable to early implement antifungal therapy.

The absorbing filter Oxiris in severe coronavirus disease 2019 patients: A case series.

Hypercytokines cause acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) patients, which is the main reason for intensive care unit treatment and the leading cause of death in COVID-19 patients. Cytokine storm is a critical factor in the development of ARDS. This study evaluated the efficacy and safety of Oxiris filter in the treatment of COVID-19 patients. Five patients with COVID-19 who received continuous renal replacement therapy (CRRT) in Henan provincial people's hospital between January 23, 2019 and March 28, 2020, were enrolled in this study. Heart rate (HR), mean arterial pressure (MAP), oxygenation index (PaO2 /FiO2 ), renal function, C-reactive protein (CRP), cytokines, procalcitonin (PCT), acute physiology and chronic health evaluation II (APACHE II), sequential organ failure score (SOFA), and prognosis were compared after CRRT. Five COVID-19 patients, three males and two females, aged 70.2 ± 19.6 years, were enrolled. After treatment, HR (101.4 ± 14.08 vs. 83.8 ± 6.22 bpm/min), CRP (183 ± 25.21 vs. 93.78 ± 70.81 mg/L), IL-6 (3234.49 (713.51, 16038.36) vs. 181.29 (82.24, 521.39) pg/mL), IL-8 (154.86 (63.97, 1476.1) vs. 67.19 (27.84, 85.57) pg/mL), and IL-10 (17.43 (9.14, 41.22) vs. 4.97 (2.39, 8.70) pg/mL), APACHE II (29 ± 4.92 vs. 18.4 ± 2.07), and SOFA (17.2 ± 1.92 vs. 11.2 ± 3.4) significantly decreased (P < .05), while MAP (75.8 ± 4.92 vs. 85.8 ± 6.18 mm Hg), and PaO2 /FiO2 (101.2 ± 7.49 vs. 132.6 ± 26.15 mm Hg) significantly increased (P < .05). Among the five patients, negative conversion of nucleic acid test was found in three cases, while two cases died. No adverse events occurred during the treatment. Our study observed a reduced level of overexpressed cytokines, stabilization of hemodynamic status, and staged improvement of organ function during the treatment with Oxiris filter.