Tocilizumab May Be a Key in Therapy for Cytokine Release Syndrome in Older Patients With Severe Symptoms of COVID-19

Abstract Background Older adults are more susceptible to the novel coronavirus disease 2019 (hereafter, COVID-19) and more likely to develop severe illness. Cytokine release syndrome (CRS) may be an important factor in the development of severe disease in patients with COVID-19. Interleukin-6 (IL-6) is an important cytokine in CRS, and tocilizumab can block the IL-6 receptor. In this study, we analyzed the therapeutic effects and safety of tocilizumab on CRS in older patients with severe COVID-19. Methods Between February 10 and March 21, 2020, a total of 19 patients with severe or critical COVID-19 aged ≥ 60 years met the study inclusion criteria at Tongji hospital in Wuhan city, Hubei Province, China. Patients were divided into two groups: 1. The tocilizumab group, whose IL-6 levels exceeded the upper limit of normal by > 10-fold; and 2. The no tocilizumab group, with 1L-6 levels < 10-fold the upper normal limit. Results Patients in the tocilizumab group were older (73.20 ± 4.44 vs. 66.21 ± 5.06 years, P = 0.014); had lower lymphocyte counts (0.71 ± 0.18 vs. 1.18 ± 0.59 × 109/L, P = 0.016); and higher high-sensitivity C-reactive protein (hsCRP) levels (94.04 ± 57.24 vs. 51.65 ± 45.37 mg/L, P = 0.035). The increases in ferritin (FER) and hsCRP levels in patients in the tocilizumab group were marked. Except in one patient who died, IL-6, FER, and hsCRP levels, and the neutrophil/lymphocyte ratio, in the remaining four patients decreased following treatment with tocilizumab. Further, patient computerized tomography scan results improved after 3–8 days of tocilizumab treatment. Tocilizumab did not cause any serious adverse reactions. There were no differences in mortality or days until lung computerized tomography improvement between the two groups. The total mortality rate was 10.53%. Conclusions Our results support the therapeutic efficacy and safety of tocilizumab on older patients with severe COVID-19.

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Title: Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

Scientific Reports ◽

10.1038/s41598-020-75260-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Georg Lorenz ◽

Philipp Moog ◽

Quirin Bachmann ◽

Paul La Rosée ◽

Heike Schneider ◽

...

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Severe Disease ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Short Term ◽

Therapeutic Implications ◽

Neutrophil Lymphocyte Ratio ◽

Independent Expert ◽

Clinical Triad ◽

Secondary Hemophagocytic Lymphohistiocytosis

Abstract Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach. Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis. The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio > 3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n = 8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n = 9). Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

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Cytokine release syndrome is not usually caused by secondary hemophagocytic lymphohistiocytosis in a cohort of 19 critically ill COVID-19 patients

10.21203/rs.3.rs-31847/v1 ◽

2020 ◽

Author(s):

Georg Lorenz ◽

Philipp Moog ◽

Quirin Bachmann ◽

Paul La Rosee ◽

Heike Schneider ◽

...

Keyword(s):

Hemophagocytic Lymphohistiocytosis ◽

Severe Disease ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Short Term ◽

Therapeutic Implications ◽

Neutrophil Lymphocyte Ratio ◽

Independent Expert ◽

Clinical Triad ◽

Secondary Hemophagocytic Lymphohistiocytosis

Abstract Background: Severe COVID-19 associated respiratory failure, poses the one challenge of our days. Assessment and treatment of COVID-19 associated hyperinflammation may be key to improve outcomes. It was speculated that in subgroups of patients secondary hemophagocytic lymphohistiocytosis (sHLH) or cytokine release syndrome (CRS) with features of macrophage activation syndrome might drive severe disease trajectories. If confirmed, profound immunosuppressive therapy would be a rationale treatment approach.Methods: Over a median observation period of 11 (IQR: 8; 16) days, 19 consecutive confirmed severe COVID-19-patients admitted to our intensive-care-unit were tested for presence of sHLH by two independent experts. HScores and 2004-HLH diagnostic criteria were assessed. Patients were grouped according to short-term clinical courses: discharge from ICU versus ongoing ARDS or death at time of analysis.Results: The median HScore at admission was 157 (IQR: 98;180), without the key clinical triad of HLH, i.e. progressive cytopenia, persistent fever and organomegaly. Independent expert chart review revealed the absence of sHLH in all cases. No patient reached more than 3/6 of modified HLH 2004 criteria. Nevertheless, patients presented hyperinflammation with peripheral neutrophilic signatures (neutrophil/lymphocyte-ratio>3.5). The latter best paralleled their short-term clinical courses, with declining relative neutrophil numbers prior to extubation (4.4, [IQR: 2.5;6.3]; n=8) versus those with unfavourable courses (7.6, [IQR: 5.2;31], n=9).Conclusion: Our study rules out virus induced sHLH as the leading cause of most severe-COVID-19 trajectories. Instead, an associated innate neutrophilic hyperinflammatory response or virus-associated-CRS appears dominant in patients with an unfavourable clinical course. Therapeutic implications are discussed.

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An Insight of comparison between COVID-19 (2019-nCoV disease) and SARS in pathology and pathogenesis

10.31219/osf.io/hw34x ◽

2020 ◽

Cited By ~ 9

Author(s):

Xiaolong Cai

Keyword(s):

Cd8 T Cells ◽

Older Patients ◽

Case Fatality Rate ◽

Clinical Characteristics ◽

Case Fatality ◽

Spike Protein ◽

Potential Candidate ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

System Disorder

COVID-19, a novel pathogenic coronavirus (2019-nCoV, now named SARS-CoV2) induced disease, emerged in China and spread globally rapidly. 2019-nCoV(SARS-CoV2) shares above 85% identity in genome with SARS-CoV. Patients infected by 2019-nCoV and SARS-CoV also reveal similar clinical characteristics. Here we compare the clinical and pathological features between patients of COVID-19 and SARS respectively. Conclusions:1. Older patients refer to a higher case fatality rate (CFR) than young. 2. Males show a higher CFR than females, and this difference may converge as age increase.3.COVID-19 may cause a kidney and testis damage. Combined with higher CFR in males, genitourinary system disorder caused by the COVID-19 needs to be cautioned.4. It is critical to control the cytokine release syndrome(CRS) in COVID-19. IL-6, IL-10 and their receptors may be the drugable target.5. Consistently to decrease of CD4+T and CD8+T cells, spleen damage, and lymphocyte depletion may exist inCOVID-19 patients. Approaches for T cell rescued may be considered. 6. Compared with SARS-CoV’s Spike protein, 2019-nCoV(SARS-CoV2) Spike protein present a higher binding affinity to ACE2, which suggests that soluble ACE2 might be a potential candidate for COVID-19 treatment. Other receptors, such as L-SIGN and DC-SIGN, need to be investigated in the future.

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Staphylococcus aureus costochondritis and chest wall abscess in a COVID-19 patient treated with tocilizumab

Turkish Journal of Physical Medicine and Rehabilitation ◽

10.5606/tftrd.2021.8208 ◽

2021 ◽

Vol 67 (3) ◽

pp. 382-385

Author(s):

İlkay Ergenç ◽

Canan Şanal Toprak ◽

Zekaver Odabaşı

Keyword(s):

Intensive Care Unit ◽

Staphylococcus Aureus ◽

Chest Wall ◽

Distress Syndrome ◽

Severe Disease ◽

Severe Pneumonia ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Chest Wall Abscess ◽

Promising Treatment

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic, causing a global health threat. Up to 15% of the confirmed cases develop severe disease, requiring hospitalization or intensive care unit (ICU) admission. Tocilizumab, an IL-6 receptor antagonist, is a promising treatment of severe pneumonia with acute respiratory distress syndrome (ARDS) or cytokine release syndrome (CRS) in the course of COVID-19. We report a suppurative costochondritis and chest wall abscess in a severe COVID-19 patient treated with tocilizumab.

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Cytokine Release Syndrome-Associated Encephalopathy in Patients with COVID-19

10.20944/preprints202006.0103.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Peggy Perrin ◽

Nicolas Collongues ◽

Seyyid Baloglu ◽

Dimitri Bedo ◽

Xavier Bassand ◽

...

Keyword(s):

Clinical Decision Making ◽

Clinical Laboratory ◽

Severe Disease ◽

Brain Mri ◽

Case Series ◽

Neurological Manifestations ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Mri Findings ◽

Depth Analysis

Severe disease and uremia are risk factors for neurological complications of coronavirus disease-2019 (COVID-19). An in-depth analysis of a case series was conducted to describe the neurological manifestations of patients with COVID-19 and gain pathophysiological insights that may guide clinical decision-making – especially with respect to the cytokine release syndrome (CRS). Extensive clinical, laboratory, and imaging phenotyping was performed in five patients. Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. SARS-CoV-2 was undetectable in the cerebrospinal fluid. Hyperalbuminorachy and increased levels of the astroglial protein S100B were suggestive of blood-brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. Patients with COVID-19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor-T cell-related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune-mediated mechanisms.

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The association between frailty and severe disease among COVID-19 patients aged over 60 years in China: a prospective cohort study

BMC Medicine ◽

10.1186/s12916-020-01761-0 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 5

Author(s):

Yao Ma ◽

Lisha Hou ◽

Xiufang Yang ◽

Zhixin Huang ◽

Xue Yang ◽

...

Keyword(s):

Cohort Study ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Older Patients ◽

Poor Prognosis ◽

Severe Disease ◽

White Blood Count ◽

Severe Illness ◽

Geriatric Syndrome ◽

Frail Patients

Abstract Background The coronavirus disease 2019 (COVID-19) has been a pandemic worldwide. Old age and underlying illnesses are associated with poor prognosis among COVID-19 patients. However, whether frailty, a common geriatric syndrome of reduced reserve to stressors, is associated with poor prognosis among older COVID-19 patients is unknown. The aim of our study is to investigate the association between frailty and severe disease among COVID-19 patients aged ≥ 60 years. Methods A prospective cohort study of 114 hospitalized older patients (≥ 60 years) with confirmed COVID-19 pneumonia was conducted between 7 February 2020 and 6 April 2020. Epidemiological, demographic, clinical, laboratory, and outcome data on admission were extracted from electronic medical records. All patients were assessed for frailty on admission using the FRAIL scale, in which five components are included: fatigue, resistance, ambulation, illnesses, and loss of weight. The outcome was the development of the severe disease within 60 days. We used the Cox proportional hazards models to identify the unadjusted and adjusted associations between frailty and severe illness. The significant variables in univariable analysis were included in the adjusted model. Results Of 114 patients, (median age, 67 years; interquartile range = 64–75 years; 57 [50%] men), 39 (34.2%), 39 (34.2%), and 36 (31.6%) were non-frail, pre-frail, and frail, respectively. During the 60 days of follow-up, 43 severe diseases occurred including eight deaths. Four of 39 (10.3%) non-frail patients, 15 of 39 (38.5%) pre-frail patients, and 24 of 36 (66.7%) frail patients progressed to severe disease. After adjustment of age, sex, body mass index, haemoglobin, white blood count, lymphocyte count, albumin, CD8+ count, D-dimer, and C-reactive protein, frailty (HR = 7.47, 95% CI 1.73–32.34, P = 0.007) and pre-frailty (HR = 5.01, 95% CI 1.16–21.61, P = 0.03) were associated with a higher hazard of severe disease than the non-frail. Conclusions Frailty, assessed by the FRAIL scale, was associated with a higher risk of developing severe disease among older COVID-19 patients. Our findings suggested that the use of a clinician friendly assessment of frailty could help in early warning of older patients at high-risk with severe COVID-19 pneumonia.

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SARS, MERS and COVID-19: clinical manifestations and organ-system complications: a mini review

Pathogens and Disease ◽

10.1093/femspd/ftaa033 ◽

2020 ◽

Vol 78 (4) ◽

Cited By ~ 4

Author(s):

Jad Gerges Harb ◽

Hussein A Noureldine ◽

Georges Chedid ◽

Mariam Nour Eldine ◽

Dany Abou Abdallah ◽

...

Keyword(s):

Middle East ◽

Severe Acute Respiratory Syndrome ◽

Severe Disease ◽

Clinical Manifestations ◽

Disease Process ◽

Organ System ◽

Middle East Respiratory Syndrome ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Clinical Presentations

ABSTRACT Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) are caused by three distinct coronaviruses belonging to the same genus. COVID-19 and its two predecessors share many important features in their clinical presentations, and in their propensity for progression to severe disease which is marked by high rates of morbidity and mortality. However, comparison of the three viral illnesses also reveals a number of specific differences in clinical manifestations and complications, which suggest variability in the disease process. This narrative review delineates the pulmonary, cardiac, renal, gastrointestinal, hepatic, neurological and hematologic complications associated with these three respiratory coronaviruses. It further describes the mechanisms of immune hyperactivation—particularly cytokine release syndrome—implicated in the multi-organ system injury seen in severe cases of MERS, SARS and COVID-19.

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The Immunopathology of COVID-19 and the Cannabis Paradigm

Frontiers in Immunology ◽

10.3389/fimmu.2021.631233 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nicole Paland ◽

Antonina Pechkovsky ◽

Miran Aswad ◽

Haya Hamza ◽

Tania Popov ◽

...

Keyword(s):

Lower Respiratory Tract ◽

Therapeutic Potential ◽

Severe Disease ◽

Endocannabinoid System ◽

The Novel ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Biological Functions ◽

Critical Stage ◽

Anti Inflammatory

Coronavirus disease-19 caused by the novel RNA betacoronavirus SARS-CoV2 has first emerged in Wuhan, China in December 2019, and since then developed into a worldwide pandemic with >99 million people afflicted and >2.1 million fatal outcomes as of 24th January 2021. SARS-CoV2 targets the lower respiratory tract system leading to pneumonia with fever, cough, and dyspnea. Most patients develop only mild symptoms. However, a certain percentage develop severe symptoms with dyspnea, hypoxia, and lung involvement which can further progress to a critical stage where respiratory support due to respiratory failure is required. Most of the COVID-19 symptoms are related to hyperinflammation as seen in cytokine release syndrome and it is believed that fatalities are due to a COVID-19 related cytokine storm. Treatments with anti-inflammatory or anti-viral drugs are still in clinical trials or could not reduce mortality. This makes it necessary to develop novel anti-inflammatory therapies. Recently, the therapeutic potential of phytocannabinoids, the unique active compounds of the cannabis plant, has been discovered in the area of immunology. Phytocannabinoids are a group of terpenophenolic compounds which biological functions are conveyed by their interactions with the endocannabinoid system in humans. Here, we explore the anti-inflammatory function of cannabinoids in relation to inflammatory events that happen during severe COVID-19 disease, and how cannabinoids might help to prevent the progression from mild to severe disease.

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Important updates from the AACR virtual meeting: COVID-19 and cancer

Future Science OA ◽

10.2144/fsoa-2020-0132 ◽

2020 ◽

pp. FSO630

Author(s):

Jacob Ripp ◽

Anup Kasi

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Older Patients ◽

Cancer Therapeutics ◽

Hematologic Malignancies ◽

Phase Iii ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Phase Iii Trial ◽

Virtual Meeting

In this article, we present the pivotal abstracts presented at the ‘AACR Virtual Meeting: COVID-19 and Cancer’ held in July 2020. Much is unknown regarding the effect of COVID-19 on cancer patients, and this conference presented important updates in therapeutics and epidemiology. Specifically, cancer therapeutics have been hypothesized to treat cytokine release syndrome in patients with COVID-19, and the JAK1/2 inhibitor, ruxolitinib, is currently being used in a Phase III trial to assess its efficacy. Additionally, similar to other studies, morbidity and mortality in patients with COVID-19 and cancer appear to be worse in older patients and in males. We also present various COVID-19 data related to breast cancer, lung cancer, hematologic malignancies, melanoma and prostate cancer.

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Targeting CDK7 suppresses super enhancer-linked inflammatory genes and alleviates CAR T cell-induced cytokine release syndrome

Molecular Cancer ◽

10.1186/s12943-020-01301-7 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Ye Wei ◽

Chong Li ◽

Huifang Bian ◽

Wei Qian ◽

Kairui Jin ◽

...

Keyword(s):

T Cell ◽

Inflammatory Response ◽

Therapeutic Effects ◽

Cytokine Release ◽

Cytokine Release Syndrome ◽

Antitumor Effects ◽

Inflammatory Genes ◽

Chip Sequencing ◽

Car T Cell ◽

Car T

Abstract Background Cytokine release syndrome (CRS) is a systemic inflammatory response characterized by the overexpression of inflammatory genes. Controlling CRS is essential for improving the therapeutic effects of chimeric antigen receptor (CAR) engineered T cells. However, current treatment options are limited given the complexity of cytokine interactions so it is important to seek a mild strategy with broad-spectrum inhibition to overcome this challenge. Methods Using THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), we demonstrated the transcriptional suppression of inflammatory genes in activated macrophages. RNA sequencing and ChIP sequencing were conducted to identify the key target genes of the inflammatory response. Pathogen- and CAR T cell-induced CRS models were also established to assess the efficacy and safety of targeting CDK7. Results CDK7 blockade attenuated cytokine release, mitigated hyperinflammatory states and rescued mice from lethal CRS. Targeting CDK7 preferentially suppressed a set of inflammatory genes, of which STAT1 and IL1 were the key targets associated with super enhancers. Furthermore, we confirmed the potent efficacy of THZ1 in alleviating the CRS induced by CAR T cell infusion without causing tissue injury or impairing antitumor effects. Conclusions Our work indicates the CDK7-dependent transcription addiction of inflammatory genes. Targeting CDK7 is a promising strategy for treating CRS by inhibiting multiple cytokines.

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