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3.
Biomolecules ; 11(8)2021 08 13.
Article in English | MEDLINE | ID: covidwho-1354915

ABSTRACT

The term 'cytokine storm' (CS) applies to a pathological autoimmune reaction when the interactions that lead to cytokine production are destabilised and may even lead to death. CS may be induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we present our analysis of certain pathological processes that induce a CS in pregnant and postpartum women. We draw our attention to the similarities between the severe course of Coronavirus Disease 2019 (COVID-19) and haemophagocytic lymphohistiocytosis (HLH). It is noteworthy that many of the criteria used to diagnose HLH are described as COVID-19 mortality predictors. Cytokine storms are considered to be an important cause of death in patients with the severe course of SARS-CoV-2 infection. Due to the fact that pregnant women are in an immunosuppressive state, viral pulmonary infections are more perilous for them-possible risks include miscarriage, intrauterine growth restriction or birth before the term; sometimes ventilation support is needed. HLH should be considered in pregnant and puerperal women suffering from moderately severe to severe COVID-19 and presenting with: fever unresponsive to antibiotic therapy, cytopenia, hepatitis and hyperferritinaemia. The HLH disorder is rare and difficult to diagnose; however, its early detection could reduce patient mortality.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Pregnancy Complications, Infectious/pathology , COVID-19/complications , COVID-19/immunology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Female , Humans , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/immunology , Postpartum Period , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/virology
4.
Int J Lab Hematol ; 43(6): 1291-1301, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1258939

ABSTRACT

INTRODUCTION: The clinical and laboratory features of severe COVID-19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes. METHODS: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID-19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME). RESULTS: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H-score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D-dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high-dose pulsed corticosteroid therapy. CONCLUSION: The immune response associated with severe COVID-19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID-19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early.


Subject(s)
Bone Marrow/pathology , COVID-19/complications , Lymphohistiocytosis, Hemophagocytic/etiology , SARS-CoV-2 , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Biomarkers/blood , Blood Proteins/analysis , Bone Marrow Examination , COVID-19/immunology , Creatinine/blood , Diagnosis, Differential , Female , Humans , Leukocyte Count , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Middle Aged , Neutrophils , Severity of Illness Index , Symptom Assessment , Triglycerides/blood
5.
J Med Virol ; 93(9): 5474-5480, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1219314

ABSTRACT

In this study, laboratorial parameters of hospitalized novel coronavirus (COVID-19) patients, who were complicated with severe pneumonia, were compared with the findings of cytokine storm developing in macrophage activation syndrome (MAS)/secondary hemophagocytic lymphohistiocytosis (sHLH). Severe pneumonia occurred as a result of cytokine storm in some patients who needed intensive care unit (ICU), and it is aimed to determine the precursive parameters in this situation. Also in this study, the aim is to identify laboratory criteria that predict worsening disease and ICU intensification, as well as the development of cytokine storm. This article comprises a retrospective cohort study of patients admitted to a single institution with COVID-19 pneumonia. This study includes 150 confirmed COVID-19 patients with severe pneumonia. When they were considered as severe pneumonia patients, the clinic and laboratory parameters of this group are compared with H-score criteria. Patients are divided into two subgroups; patients with worsened symptoms who were transferred into tertiary ICU, and patients with stable symptoms followed in the clinic. For the patients with confirmed COVID-19 infection, after they become complicated with severe pneumonia, lymphocytopenia (55.3%), anemia (12.0%), thrombocytopenia (19.3%), hyperferritinemia (72.5%), hyperfibrinogenemia (63.7%) and elevated lactate dehydrogenase (LDH) (90.8%), aspartate aminotransaminase (AST) (31.3%), alanine aminotransaminase (ALT) (20.7%) are detected. There were no significant changes in other parameters. Blood parameters between the pre-ICU period and the ICU period (in which their situation had been worsened and acute respiratory distress syndrome [ARDS] was developed) were also compared. In the latter group lymphocyte levels were found significantly reduced (p = 0.01), and LDH, highly sensitive troponin (hs-troponin), procalcitonin, and triglyceride levels were significantly increased (p < 0.05). In addition, there was no change in hemoglobin, leukocyte, platelet, ferritin, and liver function test levels, including patients who developed ARDS, similar to the cytokine storm developed in MAS/sHLH. COVID-19 pneumonia has similar findings as hyperinflammatory syndromes but does not seem to have typical features as in cytokine storm developed in MAS/sHLH. In the severe patient group who has started to develop ARDS signs, a decrease in lymphocyte level in addition to the elevated LDH, hs-troponin, procalcitonin, and triglyceride levels can be a predictor in progression to ICU admission and could help in the planning of anti-cytokine therapy.


Subject(s)
COVID-19/pathology , Cytokine Release Syndrome/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Macrophage Activation Syndrome/pathology , SARS-CoV-2/pathogenicity , Aged , Alanine Transaminase/blood , Anemia/blood , Anemia/diagnosis , Anemia/immunology , Anemia/pathology , Aspartate Aminotransferases/blood , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/immunology , Cytokine Release Syndrome/blood , Cytokine Release Syndrome/diagnosis , Cytokine Release Syndrome/immunology , Diagnosis, Differential , Disease Progression , Female , Fibrinogen/metabolism , Humans , Hyperferritinemia/blood , Hyperferritinemia/diagnosis , Hyperferritinemia/immunology , Hyperferritinemia/pathology , Intensive Care Units , L-Lactate Dehydrogenase/blood , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphopenia/blood , Lymphopenia/diagnosis , Lymphopenia/immunology , Lymphopenia/pathology , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/immunology , Male , Middle Aged , Procalcitonin/blood , Retrospective Studies , Thrombocytopenia/blood , Thrombocytopenia/diagnosis , Thrombocytopenia/immunology , Thrombocytopenia/pathology , Triglycerides/blood , Troponin/blood
7.
Blood Rev ; 45: 100707, 2021 01.
Article in English | MEDLINE | ID: covidwho-1064893

ABSTRACT

A subset of patients with severe COVID-19 develop profound inflammation and multi-organ dysfunction consistent with a "Cytokine Storm Syndrome" (CSS). In this review we compare the clinical features, diagnosis, and pathogenesis of COVID-CSS with other hematological CSS, namely secondary hemophagocytic lymphohistiocytosis (sHLH), idiopathic multicentric Castleman disease (iMCD), and CAR-T cell therapy associated Cytokine Release Syndrome (CRS). Novel therapeutics targeting cytokines or inhibiting cell signaling pathways have now become the mainstay of treatment in these CSS. We review the evidence for cytokine blockade and attenuation in these known CSS as well as the emerging literature and clinical trials pertaining to COVID-CSS. Established markers of inflammation as well as cytokine levels are compared and contrasted between these four entities in order to establish a foundation for future diagnostic criteria of COVID-CSS.


Subject(s)
COVID-19/immunology , Castleman Disease/immunology , Cytokine Release Syndrome/immunology , Immunologic Factors/therapeutic use , Lymphohistiocytosis, Hemophagocytic/immunology , SARS-CoV-2/pathogenicity , Adrenal Cortex Hormones/therapeutic use , Antibodies, Monoclonal/therapeutic use , Biomarkers/blood , C-Reactive Protein/immunology , C-Reactive Protein/metabolism , COVID-19/drug therapy , COVID-19/pathology , COVID-19/virology , Castleman Disease/drug therapy , Castleman Disease/pathology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Ferritins/blood , Ferritins/immunology , Gene Expression Regulation , Humans , Immunotherapy, Adoptive/adverse effects , Interleukin-1/antagonists & inhibitors , Interleukin-1/blood , Interleukin-1/immunology , Interleukin-6/antagonists & inhibitors , Interleukin-6/blood , Interleukin-6/immunology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/pathology , Signal Transduction
8.
Am J Clin Pathol ; 155(5): 627-637, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1050118

ABSTRACT

OBJECTIVES: Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with diverse clinical, including hematologic, abnormalities. We describe peripheral blood and bone marrow findings in deceased and living patients with COVID-19. METHODS: We examined bone marrows from 20 autopsies and 2 living patients with COVID-19 using H&E-stained slides and immunohistochemical stains. Clinical history and laboratory values were reviewed. HScore was calculated to estimate risk of hemophagocytic lymphohistocytosis (HLH). RESULTS: The deceased patients included 12 men and 8 women (aged 32 to >89 years; median, 63 years). Hematologic abnormalities included frequent neutrophilic leukocytosis, lymphopenia, anemia, and thrombocytopenia; one patient showed striking erythrocytosis. The bone marrows were all normocellular to hypercellular, most showing maturing trilineage hematopoiesis with myeloid left shift. In all 19 evaluable bone marrows, hemophagocytic histiocytes were identified. The HScore for secondary HLH ranged from 35 to 269 (median, 125; >169 in 5 patients). Coinfections were identified in 6 patients. In 2 living patients, bone marrow showed maturing trilineage hematopoiesis, including one showing few hemophagocytic histiocytes. CONCLUSIONS: Peripheral blood from deceased patients with COVID-19 frequently showed neutrophilic leukocytosis, lymphopenia, and, rarely, secondary polycythemia; hemophagocytosis was common in their bone marrow. Consistent with other studies, we provide histopathologic evidence of secondary HLH development in patients with COVID-19.


Subject(s)
Biomarkers/blood , Bone Marrow/pathology , COVID-19/blood , COVID-19/pathology , Hematologic Diseases/virology , Lymphohistiocytosis, Hemophagocytic/virology , Adult , Aged , Aged, 80 and over , Bone Marrow/immunology , COVID-19/complications , COVID-19/immunology , Female , Hematologic Diseases/blood , Hematologic Diseases/diagnosis , Hematologic Diseases/pathology , Humans , Immunohistochemistry , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Middle Aged , Retrospective Studies
9.
Am J Clin Pathol ; 154(4): 466-474, 2020 09 08.
Article in English | MEDLINE | ID: covidwho-1015195

ABSTRACT

OBJECTIVES: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH. METHODS: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores. RESULTS: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96. CONCLUSIONS: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphohistiocytosis, Hemophagocytic/virology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Aged , Aged, 80 and over , Autopsy , Bone Marrow/pathology , COVID-19 , Coronavirus Infections/complications , Fatal Outcome , Female , Humans , Liver/pathology , Lung/pathology , Lymph Nodes/pathology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , SARS-CoV-2 , Spleen/pathology
10.
Histopathology ; 78(5): 727-737, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-991400

ABSTRACT

AIMS: Haemophagocytosis in the bone marrow of patients who have succumbed to coronavirus disease 19 (COVID-19) has not been widely studied. The aims of the present study were to perform morphological analyses and morphometry of haemophagocytosis in the bone marrow of patients with severe COVID-19, and to correlate the findings with the clinical course of the disease. METHODS AND RESULTS: In this single-centre study performed at the University Hospital Jena, bone marrow specimens of 15 deceased patients who had experienced a severe course of COVID-19 were sampled from the vertebral column during autopsy. Slides of the bone marrow were stained with routine stains or immunohistochemically, and further examined for haemophagocytosis by the use of light microscopy. To substantiate the morphological findings, additional slides were stained for CD163 and morphometry was performed. In all bone marrow samples, an increase in cellularity was found. Haemophagocytes with erythrophagocytosis were detected in 67% of the deceased patients. In tissues with low numbers of haemophagocytes or ill-defined haemophagocytes, an increase in iron deposits was frequently seen. Morphological findings were then correlated with several important clinical data, and the HScore (probability of having a reactive hemophagocytic syndrome) was calculated to posthumously confirm the diagnosis of secondary haemophagocytic lymphohistiocytosis. The median duration of disease and the hospitalisation time were lower in patients with haemophagocytosis (n = 10) than in patients without haemophagocytosis (n = 5). In addition, patients with haemophagocytes showed increased inflammatory parameters 2-5 days prior to death, in contrast to patients without haemophagocytes. CONCLUSIONS: Haemophagocytosis is a common finding in the bone marrow of deceased individuals with severe COVID-19, and may indicate fatal severe acute respiratory syndrome coronavirus 2 infections.


Subject(s)
COVID-19/virology , Lymphohistiocytosis, Hemophagocytic/virology , SARS-CoV-2/physiology , Aged , Aged, 80 and over , Autopsy , Bone Marrow/pathology , Bone Marrow/virology , COVID-19/complications , COVID-19/pathology , Female , Hospitalization , Humans , Immunohistochemistry , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Middle Aged
11.
Sci Rep ; 10(1): 18277, 2020 10 26.
Article in English | MEDLINE | ID: covidwho-892043

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.


Subject(s)
Coronavirus Infections/pathology , Cytokine Release Syndrome/etiology , Lymphohistiocytosis, Hemophagocytic/pathology , Pneumonia, Viral/pathology , Aged , Betacoronavirus/isolation & purification , COVID-19 , Cohort Studies , Coronavirus Infections/complications , Coronavirus Infections/virology , Critical Illness , Cytokine Release Syndrome/diagnosis , Female , Ferritins/analysis , Humans , Intensive Care Units , Interleukin-6/metabolism , Lymphocytes/cytology , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , Middle Aged , Neutrophils/cytology , Pandemics , Pilot Projects , Pneumonia, Viral/complications , Pneumonia, Viral/virology , SARS-CoV-2
12.
Front Immunol ; 11: 2055, 2020.
Article in English | MEDLINE | ID: covidwho-807548

ABSTRACT

The clinical and laboratory features of COVID-19 are reviewed with attention to the immunologic manifestations of the disease. Recent COVID-19 publications describe a variety of clinical presentations including an asymptomatic state, pneumonia, a hemophagocytic lymphohistiocytosis like syndrome, Multisystem Inflammatory Syndrome in Children (MIS-C) but, also called Pediatric Inflammatory Multisystem Syndrome-Toxic Shock (PIMS-TS), Kawasaki Disease, and myocarditis. A common theme amongst multiple reports suggests an overexuberant autoimmune component of the disease but a common pathophysiology to explain the variations in clinical presentation has been elusive. Review of the basic science of other viral induced autoimmune disorders may give clues as to why immunosuppressive and immunomodulating regimens now appear to have some efficacy in COVID-19. Review of the immunopathology also reveals other therapies that have yet to be explored. There is potential use of T cell depleting therapies and possibly anti-CD20 therapy for COVID-19 and clinical research using these medications is warranted.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections , Immunosuppressive Agents/therapeutic use , Lymphocyte Depletion , Pandemics , Pneumonia, Viral , Systemic Inflammatory Response Syndrome , T-Lymphocytes , COVID-19 , Child , Child, Preschool , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Humans , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphohistiocytosis, Hemophagocytic/therapy , Lymphohistiocytosis, Hemophagocytic/virology , Mucocutaneous Lymph Node Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/pathology , Mucocutaneous Lymph Node Syndrome/therapy , Mucocutaneous Lymph Node Syndrome/virology , Myocarditis/immunology , Myocarditis/therapy , Myocarditis/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/immunology , Systemic Inflammatory Response Syndrome/pathology , Systemic Inflammatory Response Syndrome/therapy , Systemic Inflammatory Response Syndrome/virology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
13.
Mod Pathol ; 33(11): 2139-2146, 2020 11.
Article in English | MEDLINE | ID: covidwho-634770

ABSTRACT

The spectrum of COVID-19 infection includes acute respiratory distress syndrome (ARDS) and macrophage activation syndrome (MAS), although the histological basis for these disorders has not been thoroughly explored. Post-mortem pulmonary and bone marrow biopsies were performed in 33 patients. Samples were studied with a combination of morphological and immunohistochemical techniques. Bone marrow studies were also performed in three living patients. Bone marrow post-mortem studies showed striking lesions of histiocytic hyperplasia with hemophagocytosis (HHH) in most (16/17) cases. This was also observed in three alive patients, where it mimicked the changes observed in hemophagocytic histiocytosis. Pulmonary changes included a combination of diffuse alveolar damage with fibrinous microthrombi predominantly involving small vessels, in particular the alveolar capillary. These findings were associated with the analytical and clinical symptoms, which helps us understand the respiratory insufficiency and reveal the histological substrate for the macrophage activation syndrome-like exhibited by these patients. Our results confirm that COVID-19 infection triggers a systemic immune-inflammatory disease and allow specific therapies to be proposed.


Subject(s)
Coronavirus Infections/pathology , Histiocytes/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphohistiocytosis, Hemophagocytic/virology , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/virology , Aged , Aged, 80 and over , Betacoronavirus , Bone Marrow/pathology , COVID-19 , Female , Humans , Hyperplasia/pathology , Hyperplasia/virology , Lung/pathology , Male , Middle Aged , Pandemics , SARS-CoV-2
15.
Exp Biol Med (Maywood) ; 245(11): 970-976, 2020 06.
Article in English | MEDLINE | ID: covidwho-401600

ABSTRACT

The recent outbreak of coronavirus disease (COVID 19), spreading from China all around the world in early 2020, has led scientists to investigate the immuno-mediated mechanisms underlying the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Depending on the amount of cytokines released as the result of the immunological activation induced by SARS-CoV2, three major clinical phenotypes can be identified: "mild",symbolized as a "drizzle" of cytokines, severe as a "storm", and critical as a "hurricane". In patients with mild symptoms, the release of pro-inflammatory cytokines is balanced to obtain a defense response against the virus which is often self-limiting and overcomes without tissue damage. In severe phenotype, resembling a "cytokine-release syndrome", SARS-CoV2 causes the lysis of the immune-mediators leading to a cytokine storm able to induce lung epithelium damage and acute respiratory distress syndrome. In critical patients, the immune response may become uncontrolled, thus the cytokine burst resembles a form of secondary hemophagocytic lymphohistiocytosis which may result in a multi organ failure. In addition to the standard of care, an immune-modulatory therapy tailored to each one of the different phenotypes should be used in order to prevent or reduce the release of cytokines responsible for organ damage and disease progression.


Subject(s)
Acute Lung Injury/pathology , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Cytokines/blood , Pneumonia, Viral/pathology , Acute Lung Injury/immunology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Humans , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphopenia/pathology , Pandemics , Pneumonia, Viral/immunology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2
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