Assessment of the Hemophagocytic Lymphohistiocytosis HScore in Patients With Coronavirus Disease 2019

Clark, Kristina E N; Nevin, William D; Mahungu, Tabitha; Lachmann, Helen; Singh, Animesh

doi:10.1093/cid/ciaa1463

Cited by 17 publications

(23 citation statements)

References 12 publications

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“…In children with MIS-C there was a significant reduction of lymphocytes and platelets as compared to the COVID-19 group. Notably lymphopenia and thrombocytopenia are also typical of the hyperinflammatory form of COVID-19 in adults (7,12). The analysis of the plasmatic levels of inflammatory chemokines and cytokines in patients with COVID-19 and MIS-C showed higher levels of IL-6, CXCL8, CCL2/MCP-1, CXCL9/MIG, and CXCL10/IP-10 in MIS-C, whereas CCL5 levels were significantly higher in the COVID-19 group.…”

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

“…Cardinal features of sHLH include unremitting fever, cytopenias, hepatosplenomegaly with liver dysfunction, skin rash, coagulopathy, and hyperferritinaemia, and variable neurologic symptoms; pulmonary involvement (including ARDS) occurs in approximately 50% of patients (6). Thus, ferritin, D-dimer, lactate dehydrogenase (LDH), liver enzymes, and frequent monitoring of the blood cell count have been included in routine laboratory tests, confirming some features of sHLH in critical ill COVID-19 adult patients, although the classic HLH criteria are usually not satisfied (7,10,12). Zhou F and colleagues found that the factors associated with admission to the Intensive Care Unit (ICU) and death in a cohort of COVID-19 patients were older age, comorbidity conditions, and elevated body mass index, together with lymphopenia, elevated blood levels of liver enzymes, LDH, D-dimer, and ferritin (13).…”

Section: Introductionmentioning

confidence: 99%

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Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

et al. 2021

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BackgroundSARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).ObjectiveWith this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.MethodsWe investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.ResultsPatients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-γ. By contrast, we detected IFN-α in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-α, showed profound depletion of this subset in MIS-C, but not in COVID-19.ConclusionsOur results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

et al. 2021

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“…Of the 19 patients studied by Lorenz et al, only one patient reached a threshold >169 in the absence of the bone marrow aspirate criterion and six patients reached a threshold >169 if the bone marrow aspirate criterion was assumed positive [ 172 ]. Clark et al retrospectively reviewed 152 patients with polymerase chain reaction confirmed COVID-19 patients and demonstrated a median HScore of 52, with the majority of patients not reaching sufficient thresholds for an HLH diagnosis, although notably, many variables were missing including 46 patients who did not have ferritin levels and no patients having bone marrow biopsies collected [ 174 ]. These studies raise the question of the utility of the HScore in COVID-19 patients and highlight a need for more specific, accessible means of identifying HLH.…”

Section: Covid-19: Secondary Hlh Sepsis or Hlh-sepsis Overlap?mentioning

confidence: 99%

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis

Chu

Eeden

Suresh

et al. 2021

IJMS

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The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality across the world, with no current effective treatments available. Recent studies suggest the possibility of a cytokine storm associated with severe COVID-19, similar to the biochemical profile seen in hemophagocytic lymphohistiocytosis (HLH), raising the question of possible benefits that could be derived from targeted immunosuppression in severe COVID-19 patients. We reviewed the literature regarding the diagnosis and features of HLH, particularly secondary HLH, and aimed to identify gaps in the literature to truly clarify the existence of a COVID-19 associated HLH. Diagnostic criteria such as HScore or HLH-2004 may have suboptimal performance in identifying COVID-19 HLH-like presentations, and criteria such as soluble CD163, NK cell activity, or other novel biomarkers may be more useful in identifying this entity.

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“…Persistent infection-induced inflammation is a shared feature of COVID-19 and XLP-2. Though caused by different viruses (EBV versus SARS-CoV-2) and the clinical syndromes of COVID-19 being distinct from the HLH of XLP-2 [151,152], inflammatory cell death likely represents a turning point from infection to irreversible inflammation in both COVID-19 and XLP-2.…”

Section: Therapeutic Implications For Covid-19mentioning

confidence: 99%

Infection‐induced inflammation from specific inborn errors of immunity to COVID‐19

Chen

Lai

2021

The FEBS Journal

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Inborn errors of immunity (IEIs) are a group of genetically defined disorders leading to defective immunity. Some IEIs have been linked to mutations of immune receptors or signaling molecules, resulting in defective signaling of respective cascades essential for combating specific pathogens. However, it remains incompletely understood why in selected IEIs, such as X‐linked lymphoproliferative syndrome type 2 (XLP‐2), hypo‐immune response to specific pathogens results in persistent inflammation. Moreover, mechanisms underlying the generation of anticytokine autoantibodies are mostly unknown. Recently, IEIs have been associated with coronavirus disease 2019 (COVID‐19), with a small proportion of patients that contract severe COVID‐19 displaying loss‐of‐function mutations in genes associated with type I interferons (IFNs). Moreover, approximately 10% of patients with severe COVID‐19 possess anti‐type I IFN‐neutralizing autoantibodies. Apart from IEIs that impair immune responses to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), SARS‐CoV‐2 encodes several proteins that suppress early type I IFN production. One primary consequence of the lack of type I IFNs during early SARS‐CoV‐2 infection is the increased inflammation associated with COVID‐19. In XLP‐2, resolution of inflammation rescued experimental subjects from infection‐induced mortality. Recent studies also indicate that targeting inflammation could alleviate COVID‐19. In this review, we discuss infection‐induced inflammation in IEIs, using XLP‐2 and COVID‐19 as examples. We suggest that resolving inflammation may represent an effective therapeutic approach to these diseases.

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Assessment of the Hemophagocytic Lymphohistiocytosis HScore in Patients With Coronavirus Disease 2019

Cited by 17 publications

References 12 publications

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

Do COVID-19 Infections Result in a Different Form of Secondary Hemophagocytic Lymphohistiocytosis

Infection‐induced inflammation from specific inborn errors of immunity to COVID‐19

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