A scoping review of the pathophysiology of COVID-19.

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.

Current Understanding of Multisystem Inflammatory Syndrome (MIS-C) Following COVID-19 and Its Distinction from Kawasaki Disease.

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.

Hemophagocytic lymphohistiocytosis: a review inspired by the COVID-19 pandemic.

Hemophagocytic syndrome (HPS) or hemophagocytic lymphohistiocytosis (HLH) is an acute and rapidly progressive systemic inflammatory disorder characterized by cytopenia, excessive cytokine production, and hyperferritinemia. Common clinical manifestations of HLH are acute unremitting fever, lymphadenopathy, hepatosplenomegaly, and multiorgan failure. Due to a massive cytokine release, this clinical condition is considered as a cytokine storm syndrome. HPS has primary and acquired (secondary, reactive) forms. Its primary form is mostly seen in childhood and caused by various mutations with genetic inheritance and, therefore, is called familial HLH. Secondary HLH may be caused in the presence of an underlying disorder, that is, secondary to a malignant, infectious, or autoimmune/autoinflammatory stimulus. This paper aims to review the pathogenesis and the clinical picture of HLH, and its severe complication, the cytokine storm, with a special emphasis on the developed classification criteria sets for rheumatologists, since COVID-19 infection has clinical symptoms resembling those of the common rheumatologic conditions and possibly triggers HLH. MED-LINE/Pubmed was searched from inception to April 2020, and the following terms were used for data searching: "hemophagocytic syndrome" OR "macrophage activation syndrome" OR "hemophagocytic lymphohistiocytosis", OR "cytokine storm". Finally, AND "COVID-19" was included in this algorithm. The selection is restricted to the past 5 years and limited numbers of earlier key references were manually selected. Only full-text manuscripts, published in an English language peer-reviewed journal were included. Manuscript selection procedure and numbers are given in Fig. 2. Briefly, the database search with the following terms of "Hemophagocytic syndrome" OR "Macrophage activation syndrome" OR "Hemophagocytic lymphohistiocytosis" OR "Cytokine storm" yielded 6744 results from inception to April 2020. The selection is restricted to the past 5 years and only limited numbers of earlier key references were selected, and this algorithm resulted in 3080 manuscripts. The addition of (AND "COVID-19") resulted in 115 publications of which 47 studies, together with four sections of an online book were used in the final review. No statistical method was used. HLH is triggered by genetic conditions, infections, malignancies, autoimmune-autoinflammatory diseases, and some drugs. In COVID-19 patients, secondary HLH and cytokine storm may be responsible for unexplained progressive fever, cytopenia, ARDS, neurological and renal impairment. Differentiation between the primary and secondary forms of HLH is utterly important, since primary form of HLH requires complicated treatments such as hematopoietic stem cell transplantation. Further studies addressing the performance of HScore and other recommendations in the classification of these patients is necessary.

Haemophagocytic syndrome and COVID-19.

Primary and secondary haemophagocytic lymphohistiocytosis (HLH) are hyperferritinaemic hyperinflammatory syndromes with a common terminal pathway triggered by different etiopathogenetic factors. HLH is characterised by a decreased capacity of interferon gamma production with an activated NK phenotype profile similar to other hyperinflammatory syndromes. Viruses are closely linked to the development of HLH as infectious triggers, and the break of tolerance to self-antigens is considered a critical mechanism involved in the development of immune-mediated conditions triggered by viral infections. Emerging studies in patients with COVID-19 are suggesting a key role of monocytes/macrophages in the pathogenesis of this viral infection, and there is a significant overlap between several features reported in severe COVID-19 and the features included in the HLH-2004 diagnostic criteria. Therefore, SARS-Cov-2, as other respiratory viruses, may also be considered a potential etiological trigger of HLH. The frequency of HLH in adult patients with severe COVID-19 is lower than 5%, although this figure could be underestimated considering that most reported cases lacked information about some specific criteria (mainly the histopathological criteria and the measurement of NK cell function and sCD25 levels). Because HLH is a multi-organ syndrome, the diagnostic approach in a patient with severe COVID-19 in whom HLH is suspected must be carried out in a syndromic and holistic way, and not in the light of isolated clinical or laboratory features. In COVID-19 patients presenting with persistent high fever, progressive pancytopenia, and hepatosplenic involvement, together with the characteristic triad of laboratory abnormalities (hyperferritinaemia, hypertriglyceridaemia, and hypofibrinogenaemia), the suspicion of HLH is high, and the diagnostic workup must be completed with specific immunological and histopathological studies.

Macrophage responses associated with COVID-19: A pharmacological perspective.

COVID-19 has caused worldwide death and economic destruction. The pandemic is the result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has demonstrated high rates of infectivity leading to great morbidity and mortality in vulnerable populations. At present, scientists are exploring various approaches to curb this pandemic and alleviate its health consequences, while racing to develop a vaccine. A particularly insidious aspect of COVID-19 is the delayed overactivation of the body's immune system that is manifested as the cytokine storm. This unbridled production of pro-inflammatory cytokines and chemokines can directly or indirectly cause massive organ damage and failure. Systemic vascular endothelial inflammation and thrombocytopenia are potential consequences as well. In the case of COVID-19, the cytokine storm often fits the pattern of the macrophage activation syndrome with lymphocytopenia. The basis for the imbalance between the innate and adaptive immune systems is not clearly defined, but highlights the effect of SARS-CoV-2 on macrophages. Here we discuss the potential underlying basis for the impact of SARS-CoV-2 on macrophages, both direct and indirect, and potential therapeutic targets. These include granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 6 (IL-6), interferons, and CXCL10 (IP-10). Various biopharmaceuticals are being repurposed to target the cytokine storm in COVID-19 patients. In addition, we discuss the rationale for activating the macrophage alpha 7 nicotinic receptors as a therapeutic target. A better understanding of the molecular consequences of SARS-CoV-2 infection of macrophages could lead to novel and more effective treatments for COVID-19.