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

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.

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

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.

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

2020 ◽  
Author(s):  
Xu Lengnan ◽  
Liu Xin ◽  
Zhou Yangwei ◽  
Liu Aihua ◽  
Xu Xiaomao ◽  
...  
Keyword(s):  
Computerized Tomography ◽  
Older Patients ◽  
Severe Disease ◽  
Total Mortality ◽  
High Sensitivity ◽  
Severe Illness ◽  
Therapeutic Effects ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Neutrophil Lymphocyte Ratio

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.

scholarly journals Secondary hemophagocytic lymphohistiocytosis versus cytokine release syndrome in severe COVID-19 patients

2020 ◽  
pp. 153537022096204 ◽  
Author(s):  
Nausheen N Hakim ◽  
Jeffrey Chi ◽  
Coral Olazagasti ◽  
Johnson M Liu
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Respiratory Distress Syndrome ◽  
Diagnostic Criteria ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Distress Syndrome ◽  
Interleukin 1 ◽  
Cytokine Storm ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Secondary Hemophagocytic Lymphohistiocytosis

COVID-19 or SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome/pneumonia with features of cytokine storm reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH), which can be diagnosed by the calculated HScore. Recent reports have suggested favorable responses to the interleukin-1 receptor antagonist, anakinra in patients with COVID-19 associated secondary HLH. In our single institution study, we compared 14 COVID-19 cytokine storm patients with 10 secondary HLH patients seen immediately prior to the pandemic (non-COVID-19), to determine whether diagnostic features of secondary HLH were typically seen in COVID-19 patients presenting with cytokine storm. Although most of our COVID-19 patients did not fulfill diagnostic criteria for HLH, we hypothesize that identification of HLH may relate to the severity or timing of cytokine release. Based on our observations, we would suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria. Impact statement Severe COVID-19 associated pneumonia and acute respiratory distress syndrome has recently been described with life-threatening features of cytokine storm and loosely referred to as hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS). Although a recent report indicated favorable responses to the interleukin-1 receptor antagonist, anakinra in eight patients with COVID-19 secondary HLH diagnosed using the HScore calculation, others have suggested that the diagnosis of secondary HLH is uncommon and that the use of the HScore has limited value in guiding immunomodulatory therapy for COVID-19. Here, we provide additional perspective on this important controversy based upon comparisons between 14 COVID-19 cytokine storm patients and 10 secondary HLH patients seen immediately prior to the pandemic. We hypothesize that identification of HLH may relate to the severity or timing of cytokine release and suggest distinguishing between cytokine release syndrome and secondary HLH, reserving the latter term for cases fulfilling diagnostic criteria.

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

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.

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

2020 ◽  
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 &ndash; 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 &ndash; 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.

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

2020 ◽  
Vol 78 (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.

scholarly journals Successful Recovery of a Child with COVID-19-Induced Secondary Hemophagocytic Lymphohistiocytosis

2020 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Sayed Nassereddin Mostafavi ◽  
Atefeh Sadeghizadeh ◽  
Sharareh Babaei ◽  
Rana Saleh ◽  
Amin Dehghan ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Close Contact ◽  
Severe Disease ◽  
Laboratory Data ◽  
Complete Recovery ◽  
Positive Real ◽  
Rapid Improvement ◽  
Successful Recovery ◽  
Secondary Hemophagocytic Lymphohistiocytosis

: The coronavirus disease 2019 (COVID-19) pandemic has imposed a significant burden worldwide, manifesting as a severe disease and causing mortality even in children. Severe COVID-19 disease is characterized by cytokine storm with progression to secondary hemophagocytic lymphohistiocytosis (sHLH). We describe an 18-month-old boy in Iran, previously healthy, diagnosed with COVID-19-induced sHLH. Three weeks after close contact with COVID-19 confirmed cases, he was admitted with high fever, lethargy, mild respiratory distress, skin rash, and conjunctivitis with swollen eyelids and lips. Laboratory data revealed elevated levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and liver enzymes, and mild thrombocytopenia. His clinical condition rapidly deteriorated, with septic shock, hepatosplenomegaly, and respiratory failure. Laboratory tests showed cytopenia, coagulopathy, hyperferritinemia, and hypertriglyceridemia, which met the criteria for sHLH diagnosis. Chest computed tomography (CT) revealed bilateral infiltrations that suggested acute respiratory distress syndrome (ARDS) of COVID-19 that was confirmed by a positive real-time polymerase chain reaction (RT-PCR) test. Therefore, the child was treated with intravenous immunoglobulin (IVIG), glucocorticoid, hydroxychloroquine, lopinavir/ritonavir, and interferonβ-1a. This therapeutic strategy enabled complete recovery from fever, regaining consciousness, weaning from respiratory support, and resolving shock. Serial chest radiographs showed diminishing infiltrations. Sequential physical examinations revealed an overall significant reduction in spleen and liver span. Laboratory data showed rapid improvement from cytopenia and coagulopathy, normalization of liver enzyme levels, and reduction in hyperinflammation markers. Although ARDS is the most common cause of death from COVID-19, other complications such as sHLH may be lethal; thus, early diagnosis and appropriate treatment are necessary for saving patients’ lives.

scholarly journals The Immunopathology of COVID-19 and the Cannabis Paradigm

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 &gt;99 million people afflicted and &gt;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.

scholarly journals Safety and Short-Term Efficacy of CART Cells in Treatment of Diffuse Large B-Cell Lymphoma with Follicular Transformation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4845-4845
Author(s):  
Kai Hu ◽  
Shaomei Feng
Keyword(s):  
B Cell ◽  
Disease Progression ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Germinal Centers ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Short Term ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background：Tissue transformation to Diffuse large B-cell lymphoma(DLBCL) occurs in some patients with follicular cell lymphoma(FL), and these patients have a poor prognosis, and some patients do not respond well to chemotherapy, relapse or disease progression. In recent years, many clinical trials have found that CART cells are have a relatively good effect on relapsed and refractory DLBCL, but what about the effect on DLBCL transformed by FL? Methods：A total of 13 patients with diffuse large B-cell lymphoma transformed from follicular cell lymphoma who received CART cell therapy in our hospital from January 2020 to January 2021 were observed. All patients had stage III/IV disease (7 patients with stage III and 6 patients with stage IV). Among them, 10 were germinal centers and 3 were non-germinal centers. There were 8 males and 5 females, with a median age of 44 years (33-70 years old), who had undergone more than 2 chemotherapy cycles before admission to our hospital, and the median chemotherapy cycle was 10 cycles (7-19 years old). Among them, 3 had previously undergone other clinical drug trials, 1 had undergone CD20 CART cell immunotherapy, and 1 had undergone radiotherapy. At admission, ECOG was 0-3, and all patients had measurable lesions with a median size of 5cm (1.4cm-12.0cm). After preconditioning, CART cells were reinjected, 12 cases were reinjected with murine anti-CD19-CART, and 1 case was reinjected with humanized anti-CD19-CART. Median volume 3.07×10^6/kg (0.46×10^6/kg -5.43×10^6/kg). The cytokine release syndrome(CRS) and the therapeutic effect of 3 months/6 months after reinfusion were observed, and the endpoint was disease progression or death. Results：The main treatment related adverse reaction was cytokine release syndrome. Among them, there were 12 I CRS, 1 II CRS, and no treatment-related deaths. The short-term efficacy of 3 months after treatment: 4/13CR（30.8%）, 7/13PR（53.8%）, 2/13 SD/PD(15.4%) and ORR was 11/13 (84.6%). The efficacy of 6 months after treatment: 10/13CR（76.9%）, 0/13PR（0%）and ORR was 10/13 (76.9%). One patient with 3-months CR developed disease at 11 months and died at 12 months, and one patient with 3- months PR developed disease at 5 months and died at 8 months. The remaining 6patients with 3- PR have now achieved CR。the median follow-up time was 10 months (6-19months). Of the 2 patients who did not respond to treatment have achieved PR after subsequent treatment. Conclusions: It can be seen from this study that CART cells have obvious efficacy and good safety in the treatment of DLBCL transformed by FL. It should be noted that 7 patients had PR status at 3 months after treatment, 6 patients had CR at 6 months after treatment, and 1 patient had disease progression. Efficacy evaluation of patients with DLBCL with potential transformation from FL after CART cell therapy should be appropriately delayed, except that 6 months may be the best time to evaluate the efficacy. At present, the observation time is short, PFS and OS have not been observed, and long-term observation with a larger sample is under way. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent but clinically inapparent in cancer patients under immune checkpoint therapy

2021 ◽  
Author(s):  
Thomas Walle ◽  
Sunanjay Bajaj ◽  
Joscha A. Kraske ◽  
Thomas Rösner ◽  
Christiane S. Cussigh ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cancer Patients ◽  
Immune Checkpoint ◽  
Elevated Serum ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Serum Cytokine ◽  
Short Term ◽  
Cytokine Levels ◽  
Tumor Types

AbstractCancer patients frequently receive immune checkpoint therapies (ICT) which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a cancer patient who received the BTN162b2 vaccine under ICT. Here, we analyzed adverse events (AEs) in patients of various solid tumor types undergoing (n=64) or not undergoing (n=26) COVID-19 vaccination under ICT as an exploratory endpoint of a prospectively planned cohort study. We did not observe clinically relevant CRS after vaccination (95% CI [0,0.056]). Short term (<4 weeks) serious AEs were rare (12.5%) and overall AEs under ICT were comparable to unvaccinated patients. Despite the absence of CRS symptoms, we observed a pairwise-correlated set of CRS-associated cytokines upregulated in 42% of patients after vaccination and ICT (>1.5fold). Hence, clinically meaningful CRS appears to be rare in cancer patients under ICT and elevated serum cytokine levels are common but not sufficient to establish CRS diagnosis.

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