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.

Download Full-text

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

10.20944/preprints202104.0619.v1 ◽

2021 ◽

Author(s):

Oleksandr Oliynyk ◽

Wojciech Barg ◽

Anna Slifirczyk ◽

Yanina Oliynyk ◽

Vitaliy Gurianov ◽

...

Keyword(s):

Group Treatment ◽

Macrophage Activation ◽

Cytokine Storm ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

C Reactive Protein ◽

Treatment Results ◽

Reactive Protein ◽

Median Serum ◽

D Dimer

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 each group, 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 &lt;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.

Download Full-text

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.

Download Full-text

Ferritin and C-reactive protein are predictive biomarkers of mortality and macrophage activation syndrome in adult onset Still’s disease. Analysis of the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort

PLoS ONE ◽

10.1371/journal.pone.0235326 ◽

2020 ◽

Vol 15 (7) ◽

pp. e0235326

Author(s):

Paola Di Benedetto ◽

Paola Cipriani ◽

Daniela Iacono ◽

Ilenia Pantano ◽

Francesco Caso ◽

...

Keyword(s):

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Predictive Biomarkers ◽

Adult Onset Still’S Disease ◽

Still’S Disease ◽

C Reactive Protein ◽

Reactive Protein ◽

Disease Analysis ◽

Adult Onset Still's Disease ◽

Activation Syndrome

Download Full-text

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

Download Full-text

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.

Download Full-text

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

Download Full-text

Abstract 4574: Use of CD19-targeted Chimeric Antigen Receptor-modified T (CART19) cells in ALL and CLL produce transient cytokine release syndrome (CRS), macrophage activation syndrome (MAS) and durable responses.

10.1158/1538-7445.am2013-4574 ◽

2013 ◽

Author(s):

Stephan A. Grupp ◽

Michael Kalos ◽

David M. Barrett ◽

David T. Teachey ◽

Bruce Levine ◽

...

Keyword(s):

Chimeric Antigen Receptor ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Antigen Receptor ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Activation Syndrome

Download Full-text

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.

Download Full-text

Derivation of four computable 24-hour pediatric sepsis phenotypes to facilitate personalized enrollment in early precise anti-inflammatory clinical trials

10.1101/2021.12.02.21267016 ◽

2021 ◽

Author(s):

Yidi Qin ◽

Kate F. Kernan ◽

Zhenjiang Fan ◽

Hyun-Jung Park ◽

Soyeon Kim ◽

...

Keyword(s):

Multiple Organ Failure ◽

Organ Failure ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Multiple Organ ◽

C Reactive Protein ◽

Reactive Protein ◽

Anti Inflammatory ◽

Pediatric Sepsis ◽

Activation Syndrome

ABSTRACTObjectiveThrombotic microangiopathy induced Thrombocytopenia Associated Multiple Organ Failure and hyperinflammatory Macrophage Activation Syndrome are important causes of late pediatric sepsis mortality that are often missed or have delayed diagnosis. Our objective is to derive computable 24-hour sepsis phenotypes to facilitate enrollment in early precise anti-inflammatory trials targeting mortality from these conditions.DesignMachine learning analysis using consensus k-means clustering.SettingNine pediatric intensive care units.Patients404 children with severe sepsis.Interventions24-hour computable phenotypes derived using 25 bedside variables including C-reactive protein and ferritin.Measurements and Main ResultsFour computable phenotypes (PedSep-A, B, C, and D) are derived. Compared to the overall population mean, PedSep-A has the least inflammation (median C-reactive protein 7.3 mg/dL, ferritin 125 ng/mL), younger age, less chronic illness, and more respiratory failure (n = 135; 2% mortality); PedSep-B (median C-reactive protein 13.2 mg/dL, ferritin 225 ng/ mL) has organ failure with intubated respiratory failure, shock, and Glasgow Coma Scale score < 7 (n = 102, 12% mortality); PedSep-C (median C-reactive protein 15.2 mg/dL, ferritin 405 ng/mL) has elevated ferritin, lymphopenia, more shock, more hepatic failure and less respiratory failure (n = 110; mortality 10%); and, PedSep D (median C-reactive protein 13.1 mg/dL ferritin 610 ng/mL), has hyperferritinemic, thrombocytopenic multiple organ failure with more cardiovascular, respiratory, hepatic, renal, hematologic, and neurologic system failures (n = 56, 34% mortality). PedSep-D has highest likelihood of Thrombocytopenia Associated Multiple Organ Failure (Adj OR 47.51 95% CI [18.83-136.83], p < 0.0001) and Macrophage Activation Syndrome (Adj OR 38.63 95% CI [13.26-137.75], p <0.0001), and an observed survivor interaction with combined methylprednisolone and intravenous immunoglobulin therapies (p < 0.05).CONCLUSIONS AND RELEVANCEMachine learning identifies four computable phenotypes (www.pedsepsis.pitt.edu). Membership in PedSep-D appears optimal for enrollment in early anti-inflammatory trials targeting Thrombocytopenia Associated Multiple Organ Failure and Macrophage Activation Syndrome.Author’s CommentQuestionCan machine learning methods derive 24-hour computable pediatric sepsis phenotypes that facilitate early identification of patients for enrollment in precise anti-inflammatory therapy trials?FindingsFour distinct phenotypes (PedSep-A, B, C, and D) were derived by assessing 25 bedside clinical variables in 404 children with sepsis. PedSep-D patients had a thrombotic microangiopathy and hyperinflammatory macrophage activation biomarker response, and improved survival odds associated with combined methylprednisolone plus intravenous immunoglobulin therapy.MeaningFour novel computable 24-hour phenotypes are identifiable (www.pedsepsis.pitt.edu) that could potentially facilitate enrollment in early precise anti-inflammatory trials targeting thrombotic microangiopathy and macrophage activation in pediatric sepsis.

Download Full-text

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.

Download Full-text