COVID-19-associated secondary hemophagocytic lymphohistiocytosis (cytokine storm syndrome)

In most cases, COVID-19 has a favorable outcome. However, the risk of developing critical forms of the disease, including secondary hemophagocytic lymphohistiocytosis HLH (cytokine storm syndrome), remains high. This dictates the interest in studying pathogenetic mechanisms, features of the clinical picture, laboratory and instrumental criteria for covid-19 disease. The article analyzes the causes of acute respiratory distress syndrome and multiple organ failure as manifestations of HLH. The necessity of monitoring signs of hyperinflammation (ferritin, C-reactive protein, etc., biomarkers of inflammation) and activation of thrombosis is substantiated, in order to make timely decisions about the beginning of pathogenetic therapy. However, there are limitations for routine testing of the level of Pro-inflammatory cytokines. Information about the diagnostic criteria of HLH is summarized, and the expediency of these criteria for establishing secondary HLH, which has complicated the course of COVID-19, is emphasized.

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

Experimental Biology and Medicine ◽

10.1177/1535370220962043 ◽

2020 ◽

pp. 153537022096204 ◽

Cited By ~ 1

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.

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COVID-19: cytokine storm and anticytokine therapy

EMERGENCY MEDICINE ◽

10.22141/2224-0586.17.2.2021.230629 ◽

2021 ◽

Vol 17 (2) ◽

pp. 6-13

Author(s):

M.V. Bondar ◽

M.M. Pylypenko ◽

O.A. Loskutov

Keyword(s):

Distress Syndrome ◽

Intensive Therapy ◽

Evidence Base ◽

Multiple Organ ◽

Cytokine Storm ◽

Multiple Organ Dysfunction ◽

Efficacy And Safety ◽

Nuclear Transcription Factor ◽

Anticytokine Therapy ◽

Pro Inflammatory Cytokines

This review describes in detail one of the key links in the pathogenesis of COVID-19 — the overproduction of pro-inflammatory cytokines that play a key role in the formation of acute respiratory distress syndrome, disseminated intravascular coagulation, multiple organ dysfunction syndromes, and causes high mortality among patients infected with COVID-19. The article deals with the basic directions of intensive therapy for the prevention of development as well as the treatment of cytokine storm and drugs for anti-cytokine therapy. Among drugs with anti-cytokine and anti-inflammatory properties, corticosteroids have the highest evidence base for efficacy and safety. The most promising drugs that require further clinical studies are those that inhibit the activity of the main intracellular regulator of the production of proinflammatory cytokines, the nuclear transcription factor kappa B of immunocompetent cells. These include turmeric-based preparations, which are now at the final stages of the pre-registration studies.

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

Viruses ◽

10.3390/v13061067 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1067

Author(s):

Oleksandr Oliynyk ◽

Wojciech Barg ◽

Anna Slifirczyk ◽

Yanina Oliynyk ◽

Vitaliy Gurianov ◽

...

Keyword(s):

Macrophage Activation Syndrome ◽

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 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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Kinetics of Procalcitonin in Pediatric Patients on Extracorporeal Membrane Oxygenation

Biomarker Insights ◽

10.1177/1177271917751900 ◽

2018 ◽

Vol 13 ◽

pp. 117727191775190 ◽

Cited By ~ 5

Author(s):

Sara Bobillo ◽

Javier Rodríguez-Fanjul ◽

Anna Solé ◽

Julio Moreno ◽

Mònica Balaguer ◽

...

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Prospective Observational Study ◽

Pediatric Patients ◽

Clinical Situation ◽

Multiple Organ ◽

C Reactive Protein ◽

Reactive Protein ◽

Membrane Oxygenation ◽

Neurologic Sequelae ◽

Kinetics Of

Objectives: To assess the kinetics of procalcitonin (PCT) and C-reactive protein (CRP) in pediatric patients who required extracorporeal membrane oxygenation (ECMO) and to analyze its relationship with morbidity and mortality. Patients and methods: Prospective observational study including pediatric patients who required ECMO. Both PCT and CRP were sequentially drawn before ECMO (P0) and until 72 hours after ECMO. Results: A total of 40 patients were recruited. Two cohorts were established based on the value of the P0 PCT (>10 ng/mL). Comparing the kinetics of PCT and CRP in these cohorts, the described curves were the expected for each clinical situation. The cutoff for P0 PCT to predict multiple organ dysfunction syndrome was 2.55 ng/mL (sensibility 83%, specificity 100%). Both PCT and CRP did not predict risk of neurologic sequelae or mortality in any group. Conclusions: Procalcitonin does not seem to be modified by ECMO and could be a good biomarker of evolution.

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MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN: DIAGNOSTIC MARKERS AND FEATURES OF PHARMACOTHERAPY

Medical Science of Ukraine (MSU) ◽

10.32345/2664-4738.1.2021.03 ◽

2021 ◽

Vol 17 (1) ◽

pp. 24-28

Author(s):

M.V. Кhaitovych ◽

L.M. Voroniuk ◽

G.Yu. Borisova ◽

N.V. Diudenko ◽

N.M. Miagka

Keyword(s):

Distress Syndrome ◽

The United States ◽

C Reactive Protein ◽

Reactive Protein ◽

Markers Of Inflammation ◽

Laboratory Markers ◽

Mucous Membranes ◽

Coronavirus Infection ◽

Polymerase Chain ◽

Inflammatory Syndrome

Relevance. In 2020, children were hospitalized with fever and multisystem inflammation throughout the world during the COVID-19 pandemic. In the United States, this condition is called MIS-C (Multisystem Inflammatory Syndrome in Children). This syndrome is thought to be similar to the severe course of COVID-19 in adults (cytokine storm). The objective of the work is to evaluate the features of the course and pharmacotherapy of multisystem inflammatory syndrome in children. Materials and methods. The study included 17 children (10 boys and 7 girls) aged 3-16 years (on average – 9.5±3.4 years). Diagnosis of coronavirus infection was performed by polymerase chain reaction with real-time detection, determined the level of immunoglobulins M and G before coronavirus infection. Results. The duration of fever in patients was 5-21 days (average 8.1±4.0 days), the duration of inpatient treatment – 7-35 days (average 15.7±7.0 days). Blood albumin levels were reduced in 53.8% of children; the level of fibrinogen was increased in 88.2% of children, the level of C-reactive protein, ferritin, and D-dimer – in all patients. 15 (88.2%) children had pathology of the digestive system, 13 (76.5%) – cardiovascular system (7 children were diagnosed with carditis, 2 – dilation of coronary arteries, 7 – cardiac arrhythmia). Acute respiratory distress -syndrome was found in a 13-year-old girl, shock - in an 11-year-old boy, 11 children (64.7%) were diagnosed with the pathology of the respiratory system (pleurisy, pneumonia), skin and mucous membranes, and 4 children (23.5%) there were manifestations of central nervous system disorders (meningism, decreased reflexes, ataxia), in 2 (11.8%) – renal failure. On average, each patient had lesions of 3.9 ±1.2 systems. Conclusions. MIS-C was manifested by prolonged fever, high levels of laboratory markers of inflammation, hypoalbuminemia, hypercoagulation, often – pathological manifestations of the cardiovascular, digestive, respiratory systems, skin, and mucous membranes. The treatment included intravenous immunoglobulin, steroids, anticoagulant, and antibacterial therapy and was effective.

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Experience of using tocilizumab in the research unit of infectious hospital for patients with coronavirus infection (CoVID-19)

Immunopathology Allergology Infectology ◽

10.14427/jipai.2020.4.27 ◽

2020 ◽

pp. 27-33

Author(s):

M Petrushin ◽

V Leontyeva ◽

A Malygin ◽

M Demidova

Keyword(s):

Pulse Therapy ◽

Research Unit ◽

Lung Lesion ◽

Lesion Volume ◽

Lung Involvement ◽

Cytokine Storm ◽

C Reactive Protein ◽

Case Histories ◽

Reactive Protein ◽

Coronavirus Infection

The objective of the study was the evaluation of the effectiveness of tocilizumab in patients with coronavirus infection COVID-19 who were treated in the intensive care unit of an infectious diseases hospital. Material and methods. There was carried out a retrospective analysis of the case histories of 40 patients with confirmed severe and extremely severe coronavirus infection COVID-19. The average age of the patients was 58.3 ± 1.8 years, the total lung lesion volume was 83.2 ± 2.0%. Results: The survival rate of patients who received immunosuppressive therapy with tocilizumab in combination with pulse therapy of glucocorticosteroids was 55%, and 44% of patients with 100% lung involvement. The use of tocilizumab (4-8 mg / kg) led to a statistically significant decrease in the level of C-reactive protein in the blood, which was an indicator of adequate pharmacotherapy of the "cytokine storm" in the ICU.

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Experimental Evaluation of the Impact of Gadolinium Orthovanadate GdVO4:Eu3+ Nanoparticles on the Carrageenan-Induced Intestinal Inflammation

Acta Medica (Hradec Kralove Czech Republic) ◽

10.14712/18059694.2020.11 ◽

2020 ◽

Vol 63 (1) ◽

pp. 18-24

Author(s):

Anton S. Tkachenko ◽

Galina I. Gubina-Vakulyck ◽

Vladimir K. Klochkov ◽

Nataliya S. Kavok ◽

Anatolii I. Onishchenko ◽

...

Keyword(s):

Blood Serum ◽

Intestinal Inflammation ◽

Intestinal Morphology ◽

Oral Exposure ◽

C Reactive Protein ◽

Reactive Protein ◽

Tnf Α ◽

Small Intestinal ◽

The Impact ◽

Pro Inflammatory Cytokines

Aim: To evaluate the effects of orally administered gadolinium orthovanadate GdVO4:Eu3+ nanoparticles (VNPs) on the course of chronic carrageenan-induced intestinal inflammation. Methods: Samples of small intestinal tissue were collected from four groups of rats (intact, after administration of VNPs, with carrageenaninduced intestinal inflammation, with carrageenan-induced intestinal inflammation orally exposed to VNPs) to assess the intestinal morphology and HSP90α expression. Levels of seromucoid, C-reactive protein, TNF-α, IL-1β and IL-10 were determined in blood serum. Results: Oral exposure to VNPs was associated with neither elevation of inflammation markers in blood serum nor HSP90α overexpression in the small intestine, i.e. no toxic effects of VNPs were observed. Carrageenan-induced intestinal inflammation was accompanied by higher levels of TNF-α and IL-1β, as well as HSP90α upregulation in the intestinal mucosa, compared with controls. Administration of VNPs to rats with enteritis did not lead to statistically significant changes in concentrations of circulating pro-inflammatory cytokines with the trend towards their increase. Conclusion: No adverse effects were observed in rats orally exposed to VNPs at a dose of 20 μg/kg during two weeks. Using the experimental model of carrageenan-induced enteritis, it was demonstrated that VNPs at the dose used in our study did not affect the course of intestinal inflammation.

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Changes in the Clinical Characteristics of 62 Patients Who Died from Coronavirus Disease 2019

BioMed Research International ◽

10.1155/2020/3280908 ◽

2020 ◽

Vol 2020 ◽

pp. 1-5

Author(s):

Jingli Chen ◽

Jishi Ye ◽

Hui Li ◽

Zhongyuan Xia ◽

Hong Yan

Keyword(s):

Disease Progression ◽

Median Time ◽

Symptom Onset ◽

Clinical Characteristics ◽

Multiple Organ ◽

Rapid Progression ◽

Cytokine Storm ◽

Reactive Protein ◽

Clinical Changes

Background. Since the first reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in December 2019 in Wuhan, China, the virus has spread to other parts of China and across the world. Although a few studies have assessed the clinical course of coronavirus disease 2019 (COVID-19), the changes in clinical characteristics during disease progression remain unclear. Methods. We retrospectively analyzed the clinical characteristics of 62 patients who died from COVID-19 at the Central Hospital of Wuhan between January 26 and February 17, 2020. We compared the clinical features on admission and at the last follow-up before death. Results. Of the 62 patients with COVID-19, 41 (66%) patients were male, and 21 (34%) were female. The median age was 72 years (interquartile range (IQR), 54-88), and 45 (72.5%) patients had preexisting conditions. The median time from symptom onset to the first visit at the clinic was three days, while the median time from symptom onset to death was 18.5 days. During disease progression, the amounts of arterial gases worsened, and liver, renal, and heart dysfunction was observed. Due to the cytokine storm, infection-related biomarkers, including lactic acid, C-reactive protein, and interleukine-6, gradually worsened during hospitalization. Conclusion. Our findings suggest that during hospitalization, many COVID-19 patients experienced multiple organ dysfunction and cytokine storm. The time from symptom onset to death was only 18.5 days, highlighting the disease’s rapid progression. The better understanding of the clinical changes during disease progression might provide further insight into the COVID-19 pathophysiology.

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