Efficacy of Tocilizumab Therapy in Different Subtypes of COVID-19 Cytokine Storm Syndrome.

Background: Cytokine storm in COVID-19 is heterogenous. There are at least three subtypes: cytokine release syndrome (CRS), macrophage activation syndrome (MAS), and sepsis. Methods: A retrospective study comprising 276 patients with SARS-CoV-2 pneumonia. All patients were tested for ferritin, interleukin-6, D-Dimer, fibrinogen, calcitonin, and C-reactive protein. According to the diagnostic criteria, three groups of patients with different subtypes of cytokine storm syndrome were identified: MAS, CRS or sepsis. In the MAS and CRS groups, treatment results were assessed depending on whether or not tocilizumab was used. Results: MAS was diagnosed in 9.1% of the patients examined, CRS in 81.8%, and sepsis in 9.1%. Median serum ferritin in patients with MAS was significantly higher (5894 vs. 984 vs. 957 ng/mL, p < 0.001) than in those with CRS or sepsis. Hypofibrinogenemia and pancytopenia were also observed in MAS patients. In CRS patients, a higher mortality rate was observed among those who received tocilizumab, 21 vs. 10 patients (p = 0.043), RR = 2.1 (95% CI 1.0–4.3). In MAS patients, tocilizumab decreased the mortality, 13 vs. 6 patients (p = 0.013), RR = 0.50 (95% CI 0.25–0.99). Сonclusions: Tocilizumab therapy in patients with COVID-19 and CRS was associated with increased mortality, while in MAS patients, it contributed to reduced mortality.

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Macrophage Activation and Cytokine Release Syndrome in COVID-19: Current Updates and Analysis of Repurposed and Investigational Anti-Cytokine Drugs

Drug Research ◽

10.1055/a-1291-7692 ◽

2021 ◽

Cited By ~ 1

Author(s):

Ashif Iqubal ◽

Farazul Hoda ◽

Abul Kalam Najmi ◽

Syed Ehtaishamul Haque

Keyword(s):

Immune Response ◽

Clinical Trials ◽

Macrophage Activation ◽

Fatality Rate ◽

Cytokine Storm ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Disease Condition ◽

Inflammatory Drugs ◽

Anti Inflammatory

AbstractCoronavirus disease (COVID-19) emerged from Wuhan, has now become pandemic and the mortality rate is growing exponentially. Clinical complication and fatality rate is much higher for patients having co-morbid issues. Compromised immune response and hyper inflammation is hall mark of pathogenesis and major cause of mortality. Cytokine release syndrome (CRS) or cytokine storm is a term used to affiliate the situation of hyper inflammation and therefore use of anti-cytokine and anti-inflammatory drugs is used to take care of this situation. Looking into the clinical benefit of these anti-inflammatory drugs, many of them enter into clinical trials. However, understanding the immunopathology of COVID-19 is important otherwise, indiscriminate use of these drugs could be fetal as there exists a very fine line of difference between viral clearing cytokines and inflammatory cytokines. If any drug suppresses the viral clearing cytokines, it will worsen the situation and hence, the use of these drugs must be based on the clinical condition, viral load, co-existing disease condition and severity of the infection.

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Tocilizumab treatment and outcomes in severe COVID-19 patients: Retrospective study from a tertiary care institute in western India

10.17727/jmsr.2020/8s1-1 ◽

2020 ◽

Vol 8 (S1) ◽

pp. 6-10

Author(s):

Peta RK ◽

Panchal HP ◽

Patel A ◽

Parikh S ◽

Khanikar D ◽

...

Keyword(s):

Diabetes Mellitus ◽

Interleukin 6 ◽

Respiratory Symptoms ◽

Tertiary Care ◽

Western India ◽

Cytokine Storm ◽

Cytokine Release ◽

C Reactive Protein ◽

Reactive Protein ◽

Care Institute

Background: Coronavirus disease 2019 (COVID-19) is a pandemic caused by a novel beta coronavirus severe acute respiratory syndrome coronavirus (SARS-CoV-2). The symptoms range from mild to severe in nature. The severity of respiratory symptoms is due to the cytokine storm. The tocilizumab, interleukin-6 inhibitor, can prevent the cytokine release and decrease the mortality. Patients and methods: This is a retrospective observational study of 20 COVID-19 positive cases who received tocilizumab. Results and conclusion: There were 75% males with a mean age of 47.20±9.68 years in our study. 50% had diabetes mellitus, 35% had hypertension, 5% had Chronic kidney disease, 5% had obesity and 5% had hypothyroidism. Mortality was reduced to 65% with tocilizumab administration. There was statistically significant reduction of C- reactive protein (p<0.00052) and IL-6 (interleukin) (p<0.023) after administration of tocilizumab. Keywords: tocilizumab; interleukin-6; COVID-19; C-reactive protein

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Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia

F1000Research ◽

10.12688/f1000research.51191.3 ◽

2021 ◽

Vol 10 ◽

pp. 228

Author(s):

Agung Putra ◽

Agus Widyatmoko ◽

Sugeng Ibrahim ◽

Fajar Amansyah ◽

Farid Amansyah ◽

...

Keyword(s):

Intensive Care Unit ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Case Series ◽

Cytokine Storm ◽

Blood Gas ◽

C Reactive Protein ◽

Severe Condition ◽

Reactive Protein ◽

D Dimer

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the outbreak of coronavirus disease 2019 (COVID-19), which has been rapidly spreading. Several guideline therapies have been proposed as a possible treatment for SARS-CoV-2, however, these therapies are not sufficient to treat a severe condition of SARS-CoV-2 infection characterised by the increase of D-dimer and C-reactive protein (CRP) levels, and patchy ground-glass opacities (GGOs). Secretome-mesenchymal stem cells (S-MSCs) produced by MSCs under hypoxia could excessively release several anti-inflammatory cytokines and growth factors to control the COVID-19 cytokine storm and accelerate lung injury improvement. This is the first study investigating the clinical outcomes of three severe COVID-19 patients admitted to the intensive care unit of three different hospitals in Indonesia treated with S-MSCs. The decrease of D-dimer and CRP level was reported for all patients treated with S-MSCs. This was in line with improvement of pulmonary radiology, blood gas level, and hematologic assessment. In conclusion, these cases suggest that S-MSCs could effectively control D-dimer, CRP level and GGOs of severe COVID-19 patients associated with recovered pulmonary function.

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Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia

F1000Research ◽

10.12688/f1000research.51191.1 ◽

2021 ◽

Vol 10 ◽

pp. 228

Author(s):

Agung Putra ◽

Agus Widyatmoko ◽

Sugeng Ibrahim ◽

Fajar Amansyah ◽

Farid Amansyah ◽

...

Keyword(s):

Intensive Care Unit ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Case Series ◽

Cytokine Storm ◽

Blood Gas ◽

C Reactive Protein ◽

Severe Condition ◽

Reactive Protein ◽

D Dimer

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the outbreak of coronavirus disease 2019 (COVID-19), which has been rapidly spreading. Several guideline therapies have been proposed as a possible treatment for SARS-CoV-2, however, these therapies are not sufficient to treat a severe condition of SARS-CoV-2 infection characterised by the increase of D-dimer and C-reactive protein (CRP) levels, and patchy ground-glass opacities (GGOs). Secretome-mesenchymal stem cells (S-MSCs) produced by MSCs under hypoxia could excessively release several anti-inflammatory cytokines and growth factors to control the COVID-19 cytokine storm and accelerate lung injury improvement. This is the first study investigating the clinical outcomes of three severe COVID-19 patients admitted to the intensive care unit of three different hospitals in Indonesia treated with S-MSCs. The decrease of D-dimer and CRP level was reported for all patients treated with S-MSCs. This was in line with improvement of pulmonary radiology, blood gas level, and hematologic assessment. In conclusion, these cases suggest that S-MSCs could effectively control D-dimer, CRP level and GGOs of severe COVID-19 patients associated with recovered pulmonary function.

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IMMUNOPATHOLOGY AND IMMUNOPHARMACOTHERAPY OF CORONAVIRUS DISEASE 2019 (COVID-19): FOCUS ON INTERLEUKIN 6

Rheumatology Science and Practice ◽

10.14412/1995-4484-2020-245-261 ◽

2020 ◽

Vol 58 (3) ◽

pp. 245-261 ◽

Cited By ~ 3

Author(s):

E. L. Nasonov

Keyword(s):

Interleukin 6 ◽

Prognostic Value ◽

Macrophage Activation ◽

Critical Conditions ◽

Malignant Neoplasms ◽

Inflammatory Rheumatic Diseases ◽

Cytokine Storm ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Immune Mediated

The Coronavirus Disease 2019 (COVID-19) pandemic has drawn closer attention than ever before to the problems of the immunopathology of human diseases, many of which have been reflected when studying immune-mediated inflammatory rheumatic diseases (IIRDs). The hyperimmune response called a cytokine storm, the pathogenetic subtypes of which include hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and cytokine release syndrome, is among the most serious complications of IIRDs or treatment for malignant neoplasms and may be a stage of COVID-19 progression. A premium is placed to interleukin-6 (IL-6) in the spectrum of cytokines involved in the pathogenesis of the cytokine storm syndrome. The clinical introduction of monoclonal antibodies (mAbs) that inhibit the activity of this cytokine (tocilizumab, sarilumab, etc.) is one of the major advances in the treatment of IIRDs and critical conditions within the cytokine storm syndrome in COVID-19. The review discusses data on the clinical and prognostic value of IL-6 and the effectiveness of anti-IL-6 receptor and anti-IL-6 mAbs, as well as prospects for personalized therapy of the cytokine storm syndrome in COVID-19.

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Biomarkers of cytokine storm as red flags for severe and fatal COVID-19 cases: A living systematic review and meta-analysis

PLoS ONE ◽

10.1371/journal.pone.0253894 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0253894

Author(s):

Ana Karla G. Melo ◽

Keilla M. Milby ◽

Ana Luiza M. A. Caparroz ◽

Ana Carolina P. N. Pinto ◽

Rodolfo R. P. Santos ◽

...

Keyword(s):

Lactate Dehydrogenase ◽

Interleukin 6 ◽

Aspartate Aminotransferase ◽

Laboratory Data ◽

Cytokine Storm ◽

Red Flags ◽

C Reactive Protein ◽

Laboratory Parameters ◽

Reactive Protein ◽

D Dimer

Objective To describe the laboratory parameters and biomarkers of the cytokine storm syndrome associated with severe and fatal COVID-19 cases. Methods A search with standardized descriptors and synonyms was performed on November 28th, 2020 of the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, LILACS, and IBECS to identify studies of interest. Grey literature searches and snowballing techniques were additionally utilized to identify yet-unpublished works and related citations. Two review authors independently screened the retrieved titles and abstracts, selected eligible studies for inclusion, extracted data from the included studies, and then assessed the risk of bias using the Newcastle-Ottawa Scale. Eligible studies were those including laboratory parameters—including serum interleukin-6 levels—from mild, moderate, or severe COVID-19 cases. Laboratory parameters, such as interleukin-6, ferritin, hematology, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer, were extracted from the studies. Meta-analyses were conducted using the laboratory data to estimate mean differences with associated 95% confidence intervals. Data synthesis The database search yielded 9,620 records; 40 studies (containing a total of 9,542 patients) were included in the final analysis. Twenty-one studies (n = 4,313) assessed laboratory data related to severe COVID-19 cases, eighteen studies (n = 4,681) assessed predictors for fatal COVID-19 cases and one study (n = 548) assessed laboratory biomarkers related to severe and fatal COVID-19 cases. Lymphopenia, thrombocytopenia, and elevated levels of interleukin-6, ferritin, D-dimer, aspartate aminotransferase, C-Reactive-Protein, procalcitonin, creatinine, neutrophils and leucocytes were associated with severe and fatal COVID-19 cases. Conclusions This review points to interleukin-6, ferritin, leukocytes, neutrophils, lymphocytes, platelets, C-Reactive Protein, procalcitonin, lactate dehydrogenase, aspartate aminotransferase, creatinine, and D-dimer as important biomarkers of cytokine storm syndrome. Elevated levels of interleukin-6 and hyperferritinemia should be considered as red flags of systemic inflammation and poor prognosis in COVID-19.

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C-reactive protein: not always a reliable marker of ongoing cytokine release syndrome in CAR-T therapy following IL-6 blockade

Leukemia & Lymphoma ◽

10.1080/10428194.2020.1757667 ◽

2020 ◽

Vol 61 (9) ◽

pp. 2280-2282

Author(s):

Jonathan Siglin ◽

Ali Bukhari ◽

Forat Lutfi ◽

Noa G. Holtzman ◽

Carl Shanholtz ◽

...

Keyword(s):

Cytokine Release ◽

Cytokine Release Syndrome ◽

C Reactive Protein ◽

Reactive Protein ◽

Car T ◽

Reliable Marker

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Prediction of Cytokine Storm and Mortality in Patients with COVID-19 Admitted to ICU: Do Markers Tell the Story?

Dubai Medical Journal ◽

10.1159/000514406 ◽

2021 ◽

pp. 1-9

Author(s):

Rashid Nadeem ◽

Ashraf Mahmoud Elhoufi ◽

Naheed Elahi Iqbal ◽

Zainab Abdulameer Obaida ◽

Doaa Mohamed Elgohary ◽

...

Keyword(s):

Logistic Regression ◽

Regression Analysis ◽

Length Of Stay ◽

Multiple Logistic Regression Analysis ◽

Intensive Treatment ◽

Cytokine Storm ◽

Multiple Logistic Regression ◽

C Reactive Protein ◽

Reactive Protein ◽

D Dimer

Introduction: COVID-19 has caused approximately one million deaths worldwide as of November 24, 2020. Markers of disease activity like ferritin, C-reactive protein (CRP), and D-dimers are frequently monitored to detect the best opportunity for intensive treatment. Methods: All patients of >18 years of age were included. The primary variables of interest, ferritin, CRP, and D-dimers, for each patient throughout hospitalization were recorded. Primary clinical outcomes of length of stay in ICU and survival were recorded. Demographics: age, gender, BMI, and nationality. Ferritin, CRP, and D-dimers were recorded daily if available for the whole ICU stay, and all other variables were recorded on admission day to ICU. Results: The sample includes 235 records. More than 95% of patients have all markers on the day of admission to ICU were ferritin (median 1,278; IQR 1,424), D-dimer 1.21 (3.4), and CRP 129.5 (121). Daily average levels of markers were different from their admission day level: ferritin 1,395 (1,331), D-dimer 3.11 (5.52), and CRP 107 (75.8). Multiple logistic regression analysis determined that average CRP during the stay was the only predictor of survival. Discussion: Data on markers utilization to detect the acute phase of inflammation help clinicians focus on the opportunity window for intensive treatment. Conclusion: Average CRP during the stay in ICU is higher than CRP on admission. Average CRP is the only factor that predicts survival.

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Case series of the first three severe COVID-19 patients treated with the secretome of hypoxia-mesenchymal stem cells in Indonesia

F1000Research ◽

10.12688/f1000research.51191.2 ◽

2021 ◽

Vol 10 ◽

pp. 228

Author(s):

Agung Putra ◽

Agus Widyatmoko ◽

Sugeng Ibrahim ◽

Fajar Amansyah ◽

Farid Amansyah ◽

...

Keyword(s):

Intensive Care Unit ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Case Series ◽

Cytokine Storm ◽

Blood Gas ◽

C Reactive Protein ◽

Severe Condition ◽

Reactive Protein ◽

D Dimer

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the outbreak of coronavirus disease 2019 (COVID-19), which has been rapidly spreading. Several guideline therapies have been proposed as a possible treatment for SARS-CoV-2, however, these therapies are not sufficient to treat a severe condition of SARS-CoV-2 infection characterised by the increase of D-dimer and C-reactive protein (CRP) levels, and patchy ground-glass opacities (GGOs). Secretome-mesenchymal stem cells (S-MSCs) produced by MSCs under hypoxia could excessively release several anti-inflammatory cytokines and growth factors to control the COVID-19 cytokine storm and accelerate lung injury improvement. This is the first study investigating the clinical outcomes of three severe COVID-19 patients admitted to the intensive care unit of three different hospitals in Indonesia treated with S-MSCs. The decrease of D-dimer and CRP level was reported for all patients treated with S-MSCs. This was in line with improvement of pulmonary radiology, blood gas level, and hematologic assessment. In conclusion, these cases suggest that S-MSCs could effectively control D-dimer, CRP level and GGOs of severe COVID-19 patients associated with recovered pulmonary function.

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