Haemophagocytic syndrome and COVID-19

Retamozo, Soledad; Brito-Zerón, Pilar; Sisó‐Almirall, Antoni; Flores-Chávez, Alejandra; Cárdenas, M.J. Soto; Ramos‐Casals, Manuel

doi:10.1007/s10067-020-05569-4

Cited by 63 publications

(72 citation statements)

References 92 publications

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“…Thus, high ferritin, hypertriglyceridemia and low platelets are predictive of sHLH and should be measured in patients with severe COVID-19, to identify and facilitate specific treatment of sHLH. In addition, the prediction value of "peak TG, ferritin, and low PLT" in COVID-19 patients were supported by a series of previous studies [22][23][24].…”

Section: Discussionsupporting

confidence: 63%

Risk factors for secondary hemophagocytic lymphohistiocytosis in severe coronavirus disease 2019 adult patients

et al. 2021

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Background Secondary hemophagocytic lymphohistiocytosis (sHLH) is a life-threatening hyperinflammatory event and a fatal complication of viral infections. Whether sHLH may also be observed in patients with a cytokine storm induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still uncertain. We aimed to determine the incidence of sHLH in severe COVID-19 patients and evaluate the underlying risk factors. Method Four hundred fifteen severe COVID-19 adult patients were retrospectively assessed for hemophagocytosis score (HScore). A subset of 7 patients were unable to be conclusively scored due to insufficient patient data. Results In 408 patients, 41 (10.04%) had an HScore ≥169 and were characterized as “suspected sHLH positive”. Compared with patients below a HScore threshold of 98, the suspected sHLH positive group had higher D-dimer, total bilirubin, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, triglycerides, ferritin, interleukin-6, C-reactive protein, procalcitonin, lactate dehydrogenase, creatine kinase isoenzyme, troponin, Sequential Organ Failure Assessment (SOFA) score, while leukocyte, hemoglobin, platelets, lymphocyte, fibrinogen, pre-albumin, albumin levels were significantly lower (all P < 0.05). Multivariable logistic regression revealed that high ferritin (>1922.58 ng/mL), low platelets (<101 × 109/L) and high triglycerides (>2.28 mmol/L) were independent risk factors for suspected sHLH in COVID-19 patients. Importantly, COVID-19 patients that were suspected sHLH positive had significantly more multi-organ failure. Additionally, a high HScore (>98) was an independent predictor for mortality in COVID-19. Conclusions HScore should be measured as a prognostic biomarker in COVID-19 patients. In particular, it is important that HScore is assessed in patients with high ferritin, triglycerides and low platelets to improve the detection of suspected sHLH.

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Section: Discussionsupporting

confidence: 63%

Risk factors for secondary hemophagocytic lymphohistiocytosis in severe coronavirus disease 2019 adult patients

et al. 2021

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“…2 Unfortunately, the mortality rate of COVID-19-induced HLH is reported to be as high as 54%. 13 The patient described in this case report meets the criteria for a postacute COVID-19 syndrome as he had a documented infection 6 weeks prior and his repeat COVID-19 PCR tests during this admission (six in total) were all negative. What is striking, however, is that this patient suffered from a pauci-symptomatic COVID-19 illness as he did not require treatment nor hospitalisation and his symptoms self-resolved within 1 week, yet he developed HLH, a life-threatening immune reaction.…”

Section: Discussionmentioning

confidence: 76%

Haemophagocytic lymphohistiocytosis in an adult with postacute COVID-19 syndrome

et al. 2021

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Haemophagocytic lymphohistiocytosis (HLH) causing multiorgan failure has been reported as an acute clinical presentation of COVID-19. However, the literature surrounding HLH in the context of a postacute COVID-19 syndrome is limited. This report presents a case of a life-threatening HLH occurring 6 weeks after a pauci-symptomatic COVID-19 infection in a previously healthy adult. A bone marrow aspirate confirmed the HLH and the patient was successfully treated with dexamethasone and etoposide. To our knowledge, this is the first case of HLH occurring as a postacute COVID-19 syndrome following a pauci-symptomatic initial infection.

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“…Severe forms of COVID-19 share many clinical and laboratory features with MAS. The life-threatening inflammation in severe COVID-19 is likewise sustained by a cytokine storm and strongly increased systemic levels of ferritin, LDH and HMGB1 represent additional common denominators (Colafrancesco et al 2020 ; Retamozo et al 2021 ). Extracellular LDH and HMGB1 are consequences of lytic cell death occurring particularly in respiratory epithelial cells in severe SARS-CoV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome

Palmblad

Schierbeck

Sundberg

et al. 2021

Mol Med

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Background Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein released extracellularly during proinflammatory lytic cell death or secreted by activated macrophages, NK cells, and additional cell types during infection or sterile injury. Extracellular HMGB1 orchestrates central events in inflammation as a prototype alarmin. TLR4 and the receptor for advanced glycation end products operate as key HMGB1 receptors to mediate inflammation. Methods Standard ELISA and cytometric bead array-based methods were used to examine the kinetic pattern for systemic release of HMGB1, ferritin, IL-18, IFN-γ, and MCP-1 before and during treatment of four children with critical MAS. Three of the patients with severe underlying systemic rheumatic diseases were treated with biologics including tocilizumab or anakinra when MAS developed. All patients required intensive care therapy due to life-threatening illness. Add-on etoposide therapy was administered due to insufficient clinical response with standard treatment. Etoposide promotes apoptotic rather than proinflammatory lytic cell death, conceivably ameliorating subsequent systemic inflammation. Results This therapeutic intervention brought disease control coinciding with a decline of the increased systemic HMGB1, IFN-γ, IL-18, and ferritin levels whereas MCP-1 levels evolved independently. Conclusion Systemic HMGB1 levels in MAS have not been reported before. Our results suggest that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of HMGB1 antagonists. They also advocate therapeutic etoposide administration in severe MAS and provide a possible biological explanation for its mode of action.

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Haemophagocytic syndrome and COVID-19

Cited by 63 publications

References 92 publications

Risk factors for secondary hemophagocytic lymphohistiocytosis in severe coronavirus disease 2019 adult patients

Risk factors for secondary hemophagocytic lymphohistiocytosis in severe coronavirus disease 2019 adult patients

Haemophagocytic lymphohistiocytosis in an adult with postacute COVID-19 syndrome

Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome

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