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2.
Int J Immunopathol Pharmacol ; 35: 20587384211048026, 2021.
Article in English | MEDLINE | ID: covidwho-1440891

ABSTRACT

COVID-19 is a highly heterogeneous and complex medical disorder; indeed, severe COVID-19 is probably amongst the most complex of medical conditions known to medical science. While enormous strides have been made in understanding the molecular pathways involved in patients infected with coronaviruses an overarching and comprehensive understanding of the pathogenesis of COVID-19 is lacking. Such an understanding is essential in the formulation of effective prophylactic and treatment strategies. Based on clinical, proteomic, and genomic studies as well as autopsy data severe COVID-19 disease can be considered to be the connection of three basic pathologic processes, namely a pulmonary macrophage activation syndrome with uncontrolled inflammation, a complement-mediated endothelialitis together with a procoagulant state with a thrombotic microangiopathy. In addition, platelet activation with the release of serotonin and the activation and degranulation of mast cells contributes to the hyper-inflammatory state. Auto-antibodies have been demonstrated in a large number of hospitalized patients which adds to the end-organ damage and pro-thrombotic state. This paper provides a clinical overview of the major pathogenetic mechanism leading to severe COVID-19 disease.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , COVID-19/blood , COVID-19/immunology , COVID-19/physiopathology , Complement Activation , Complement System Proteins/metabolism , Cytokines/blood , Disease Progression , Host-Pathogen Interactions , Humans , Inflammation/blood , Inflammation/immunology , Inflammation/physiopathology , Inflammation/virology , Inflammation Mediators/blood , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/immunology , Macrophage Activation Syndrome/physiopathology , Macrophage Activation Syndrome/virology , Platelet Activation , SARS-CoV-2/immunology , Serotonin/blood , Severity of Illness Index , Thrombotic Microangiopathies/blood , Thrombotic Microangiopathies/immunology , Thrombotic Microangiopathies/physiopathology , Thrombotic Microangiopathies/virology
3.
Curr Rheumatol Rep ; 23(8): 58, 2021 07 03.
Article in English | MEDLINE | ID: covidwho-1293440

ABSTRACT

PURPOSE OF REVIEW: In this article, I have reviewed current reports that explore differences and similarities between multisystem inflammatory syndrome in children (MIS-C) and other known multisystem inflammatory diseases seen in children, particularly Kawasaki disease. RECENT FINDINGS: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a human coronavirus causing the COVID-19 disease which emerged in China in December 2019 and spread rapidly to the entire country and quickly to other countries. Currently, there is a pandemic of SARS-CoV-2 infection that results in 20% of patients admitted to hospital with illness, with 3% developing intractable acute respiratory distress syndrome (ARDS) with high mortality. However, pediatric COVID-19 is still reported to be a mild disease, affecting only 8% of children. Pathogenesis in children is comparable to adults. There are suggested impaired activation of IFN-alpha and IFN regulator 3, decreased cell response causing impaired viral defense, yet the clinical course is mild, and almost all children recover from the infection without major complications. Interestingly, there is a subset of patients that develop a late but marked immunogenic response to COVID-19 and develop MIS-C. Clinical features of MIS-C resemble certain pediatric rheumatologic diseases, such as Kawasaki disease (mucocutaneous lymph node syndrome) which affects small-medium vessels. Other features of MIS-C resemble those of macrophage activation syndrome (MAS). However, recent research suggests distinct clinical and laboratory differences between MIS-C, Kawasaki disease, and MAS. Since the start of the SARS-CoV-2 pandemic, MIS-C has become the candidate for the most common cause of acquired heart disease in children.


Subject(s)
COVID-19/immunology , Macrophage Activation Syndrome/immunology , Mucocutaneous Lymph Node Syndrome/immunology , Systemic Inflammatory Response Syndrome/immunology , COVID-19/physiopathology , Humans , Immunity, Cellular/immunology , Interferon Regulatory Factor-3/immunology , Interferon-alpha/immunology , Macrophage Activation Syndrome/physiopathology , Mucocutaneous Lymph Node Syndrome/physiopathology , SARS-CoV-2 , Severity of Illness Index , Systemic Inflammatory Response Syndrome/physiopathology
4.
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
5.
J Trop Pediatr ; 67(1)2021 01 29.
Article in English | MEDLINE | ID: covidwho-1159646

ABSTRACT

LAY SUMMARY: Clinical and laboratory parameters of multisystem inflammatory syndrome in children (MIS-C) mimic Kawasaki disease (KD). KD has been described in association with dengue, scrub typhus and leptospirosis. However, MIS-C with concomitant infection has rarely been reported in literature. A 14-year-old-girl presented with fever and rash with history of redness of eyes, lips and tongue. Investigations showed anemia, lymphopenia, thrombocytosis with elevated erythrocyte sedimentation rate, C-reactive protein, pro-brain natriuretic peptide, Interleukin-6, ferritin and d-dimer. Scrub typhus immunoglobulin M was positive. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) level was also elevated. A diagnosis of MIS-C with concomitant scrub typhus was proffered. Child received azithromycin, intravenous immunoglobulin and methylprednisolone. After an afebrile period of 2.5 days, child developed unremitting fever and rash. Repeat investigations showed anemia, worsening lymphopenia, thrombocytopenia, transaminitis, hypertriglyceridemia, hyperferritinemia and hypofibrinogenemia which were consistent with a diagnosis of macrophage activation syndrome (MAS). KD, MIS-C and MAS represent three distinct phenotypes of hyperinflammation seen in children during coronavirus disease pandemic. Several tropical infections may mimic or coexist with MIS-C which can be a diagnostic challenge for the treating physician. Identification of coexistence or differentiation between the two conditions is important in countries with high incidence of tropical infections to guide appropriate investigations and treatment.


Subject(s)
COVID-19/complications , Macrophage Activation Syndrome/diagnosis , Scrub Typhus/diagnosis , Systemic Inflammatory Response Syndrome , Adolescent , Azithromycin/therapeutic use , Biomarkers/blood , COVID-19/blood , COVID-19/diagnosis , COVID-19/therapy , Child , Female , Fever/etiology , Humans , Immunoglobulin G/blood , Immunoglobulins, Intravenous/therapeutic use , Macrophage Activation Syndrome/complications , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/immunology , Methylprednisolone/administration & dosage , Methylprednisolone/therapeutic use , Pandemics , SARS-CoV-2 , Scrub Typhus/complications , Scrub Typhus/drug therapy , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology
6.
Nat Rev Rheumatol ; 17(3): 145-157, 2021 03.
Article in English | MEDLINE | ID: covidwho-1065891

ABSTRACT

A hyperinflammatory 'cytokine storm' state termed macrophage activation syndrome (MAS), culminating from a complex interplay of genetics, immunodeficiency, infectious triggers and dominant innate immune effector responses, can develop across disparate entities including systemic juvenile idiopathic arthritis (sJIA) and its counterpart adult-onset Still disease (AOSD), connective tissue diseases, sepsis, infection, cancers and cancer immunotherapy. Classifying MAS using the immunological disease continuum model, with strict boundaries that define the limits of innate and adaptive immunity, at one boundary is MAS with loss of immune function, as occurs in the 'perforinopathies' and some cases of sJIA-AOSD. Conversely, at the other boundary, immune hypersensitivity with gain of immune function in MHC class II-associated sJIA-AOSD and with chimeric antigen receptor (CAR) T cell therapy also triggers MAS. This provides a benchmark for evaluating severe inflammation in some patients with COVID-19 pneumonia, which cripples primary type I interferon immunity and usually culminates in a lung-centric 'second wave' cytokine-driven alveolitis with associated immunothrombosis; this phenomenon is generally distinct from MAS but can share features with the proposed 'loss of immune function' MAS variant. This loss and gain of function MAS model offers immune cartography for a novel mechanistic classification of MAS with therapeutic implications.


Subject(s)
COVID-19/epidemiology , Cytokines/metabolism , Macrophage Activation Syndrome/immunology , Macrophages/immunology , Pandemics , SARS-CoV-2 , COVID-19/immunology , Cytokines/immunology , Humans , Macrophage Activation Syndrome/etiology
7.
Front Immunol ; 11: 1665, 2020.
Article in English | MEDLINE | ID: covidwho-945649

ABSTRACT

We report a case of an 8-year-old girl who underwent a SARS-CoV-2 infection manifesting with atypical symptoms spearheaded by abdominal discomfort and systemic inflammation and partially mimicking hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS), which however did not fulfill the HLH/MAS diagnostic criteria. In this case of what has since been described as Pediatric Inflammatory Multisystem Syndrome Temporally associated with SARS-COV-2 (PIMS-TS) we documented excellent clinical response to immunosuppression with systemic corticosteroids and intravenous immunoglobulins. We show a detailed longitudinal development of neutrophil immunophenotype which suggests activation and engagement of neutrophils during PIMS-TS with compensatory contraction of the response and contra-regulation of neutrophil phenotype during recovery.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Betacoronavirus , Coronavirus Infections , Immunoglobulins, Intravenous/administration & dosage , Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome , Pandemics , Pneumonia, Viral , Betacoronavirus/immunology , Betacoronavirus/metabolism , COVID-19 , Child , Coronavirus Infections/blood , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Female , Humans , Inflammation/diagnosis , Inflammation/drug therapy , Inflammation/immunology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/immunology , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/immunology , Neutrophils , Pneumonia, Viral/blood , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , SARS-CoV-2
8.
J Clin Invest ; 130(11): 5942-5950, 2020 11 02.
Article in English | MEDLINE | ID: covidwho-670865

ABSTRACT

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , Betacoronavirus/metabolism , Immunoglobulins, Intravenous/administration & dosage , Immunomodulation , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Systemic Inflammatory Response Syndrome , Adolescent , Biomarkers/blood , COVID-19 , Child , Child, Preschool , Female , Fibrin Fibrinogen Degradation Products/metabolism , Humans , Infant , Interleukin-10/blood , Interleukin-6/blood , Macrophage Activation Syndrome/blood , Macrophage Activation Syndrome/diagnosis , Macrophage Activation Syndrome/drug therapy , Macrophage Activation Syndrome/immunology , Male , Mucocutaneous Lymph Node Syndrome/blood , Mucocutaneous Lymph Node Syndrome/diagnosis , Mucocutaneous Lymph Node Syndrome/drug therapy , Mucocutaneous Lymph Node Syndrome/immunology , Natriuretic Peptide, Brain/blood , Retrospective Studies , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/blood , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/drug therapy , Systemic Inflammatory Response Syndrome/immunology
10.
Clin Rheumatol ; 39(7): 2085-2094, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-436778

ABSTRACT

COVID-19 infection has a heterogenous disease course; it may be asymptomatic or causes only mild symptoms in the majority of the cases, while immunologic complications such as macrophage activation syndrome also known as secondary hemophagocytic lymphohistiocytosis, resulting in cytokine storm syndrome and acute respiratory distress syndrome, may also occur in some patients. According to current literature, impairment of SARS-CoV-2 clearance due to genetic and viral features, lower levels of interferons, increased neutrophil extracellular traps, and increased pyroptosis and probable other unknown mechanisms create a background for severe disease course complicated by macrophage activation syndrome and cytokine storm. Various genetic mutations may also constitute a risk factor for severe disease course and occurrence of cytokine storm in COVID-19. Once, immunologic complications like cytokine storm occur, anti-viral treatment alone is not enough and should be combined with appropriate anti-inflammatory treatment. Anti-rheumatic drugs, which are tried for managing immunologic complications of COVID-19 infection, will also be discussed including chloroquine, hydroxychloroquine, JAK inhibitors, IL-6 inhibitors, IL-1 inhibitors, anti-TNF-α agents, corticosteroids, intravenous immunoglobulin (IVIG), and colchicine. Early recognition and appropriate treatment of immunologic complications will decrease the morbidity and mortality in COVID-19 infection, which requires the collaboration of infectious disease, lung, and intensive care unit specialists with other experts such as immunologists, rheumatologists, and hematologists.


Subject(s)
Antirheumatic Agents , Coronavirus Infections , Cytokine Release Syndrome , Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome , Pandemics , Pneumonia, Viral , Antirheumatic Agents/classification , Antirheumatic Agents/immunology , Antirheumatic Agents/pharmacology , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Humans , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/therapy , Macrophage Activation Syndrome/etiology , Macrophage Activation Syndrome/immunology , Macrophage Activation Syndrome/therapy , Patient Selection , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , SARS-CoV-2 , Time-to-Treatment
11.
RMD Open ; 6(1)2020 05.
Article in English | MEDLINE | ID: covidwho-334790

ABSTRACT

Some of the articles being published during the severe acute respiratory syndrome-coronavirus (SARS-CoV)-2 pandemic highlight a link between severe forms of coronavirus disease 2019 (COVID-19) and the so-called cytokine storm, also with increased ferritin levels. However, this scenario is more complex than initially thought due to the heterogeneity of hyperinflammation. Some patients with coronavirus 2019 disease (COVID-19) develop a fully blown secondary haemophagocytic lymphohistiocytosis (sHLH), whereas others, despite a consistent release of pro-inflammatory cytokines, do not fulfil sHLH criteria but still show some features resembling the phenotype of the hyperferritinemic syndrome. Despite the final event (the cytokine storm) is shared by various conditions leading to sHLH, the aetiology, either infectious, autoimmune or neoplastic, accounts for the differences in the various phases of this process. Moreover, the evidence of a hyperinflammatory microenvironment provided the rationale to employ immunomodulating agents for therapeutic purposes in severe COVID-19. This viewpoint aims at discussing the pitfalls and issues to be considered with regard to the use of immunomodulating agents in COVID-19, such as timing of treatment based on the viral load and the extent of cytokine/ferritin overexpression. Furthermore, it encompasses recent findings in the paediatric field about a novel multisystem inflammatory disease resembling toxic shock syndrome and atypical Kawasaki disease observed in children with proven SARS-CoV2 infection. Finally, it includes arguments in favour of adding COVID-19 to the spectrum of the recently defined 'hyperferritinemic syndrome', which already includes adult-onset Still's disease, macrophage activation syndrome, septic shock and catastrophic anti-phospholipid syndrome.


Subject(s)
Coronavirus Infections/immunology , Coronavirus/immunology , Cytokines/immunology , Macrophage Activation Syndrome/immunology , Pneumonia, Viral/immunology , Adult , Antiphospholipid Syndrome , Betacoronavirus , COVID-19 , Child , Coronavirus/pathogenicity , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/pathology , Humans , Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome/complications , Macrophage Activation Syndrome/pathology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Pneumonia, Viral/pathology , SARS-CoV-2 , Still's Disease, Adult-Onset , Viral Load
13.
Autoimmun Rev ; 19(6): 102537, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-52387

ABSTRACT

Severe COVID-19 associated pneumonia patients may exhibit features of systemic hyper-inflammation designated under the umbrella term of macrophage activation syndrome (MAS) or cytokine storm, also known as secondary haemophagocytic lymphohistocytosis (sHLH). This is distinct from HLH associated with immunodeficiency states termed primary HLH -with radically different therapy strategies in both situations. COVID-19 infection with MAS typically occurs in subjects with adult respiratory distress syndrome (ARDS) and historically, non-survival in ARDS was linked to sustained IL-6 and IL-1 elevation. We provide a model for the classification of MAS to stratify the MAS-like presentation in COVID-19 pneumonia and explore the complexities of discerning ARDS from MAS. We discuss the potential impact of timing of anti-cytokine therapy on viral clearance and the impact of such therapy on intra-pulmonary macrophage activation and emergent pulmonary vascular disease.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/immunology , Interleukin-6/immunology , Macrophage Activation Syndrome/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Respiratory Distress Syndrome/immunology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/pathology , Humans , Interleukin-1/immunology , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/immunology , Macrophage Activation Syndrome/complications , Macrophage Activation Syndrome/pathology , Pandemics , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/pathology , SARS-CoV-2
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