Haemophagocytic lymphohistiocytosis and liver failure-induced massive hyperferritinaemia in a male COVID-19 patient

Zellweger, Núria; Huber, Jan Patrick; Tsakiris, Dimitrios Α.; Tzankov, Alexandar; Gebhard, Caroline E.; Siegemund, Martin

doi:10.4414/smw.2021.20420

Cited by 5 publications

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References 8 publications

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“…Gene expression profiles in controls were more heterogeneous; cases mapped in proximity to the COVID-19 cluster included one case each of infectious mononucleosis, DAD and draining lymph node of pneumococcus pneumonia. COVID-19 cases in proximity to the control cluster featured cases with longer hospitalization time, notably the one case with HLH ( Figure 1D ) ( 35 ).…”

Section: Resultsmentioning

confidence: 99%

“…Instead, incomplete humoral response may result in antibody-dependent enhancement, characterized by the formation of low-affinity, insufficiently neutralizing antibodies. Upon binding to viral antigens, they facilitate direct entry into macrophages ( 33 ) or enhance macrophage activation, inducing HLH or Kawasaki-like syndrome as observed in a proportion of patients ( 23 , 34 , 35 ). This process has been previously reported in other viral infections and may be a further pathophysiological principle behind a dysregulation of the adaptive immune response in severe COVID-19, potentially leading to an insubstantial durability of immunity ( 36 ).…”

Section: Introductionmentioning

confidence: 99%

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Vascular Damage, Thromboinflammation, Plasmablast Activation, T-Cell Dysregulation and Pathological Histiocytic Response in Pulmonary Draining Lymph Nodes of COVID-19

et al. 2021

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Although initial immunophenotypical studies on peripheral blood and bronchoalveolar lavage samples have provided a glimpse into the immunopathology of COVID-19, analyses of pulmonary draining lymph nodes are currently scarce. 22 lethal COVID-19 cases and 28 controls were enrolled in this study. Pulmonary draining lymph nodes (mediastinal, tracheal, peribronchial) were collected at autopsy. Control lymph nodes were selected from a range of histomorphological sequelae [unremarkable histology, infectious mononucleosis, follicular hyperplasia, non-SARS related HLH, extrafollicular plasmablast activation, non-SARS related diffuse alveolar damage (DAD), pneumonia]. Samples were mounted on a tissue microarray and underwent immunohistochemical staining for a selection of immunological markers and in-situ hybridization for Epstein Barr Virus (EBV) and SARS-CoV-2. Gene expression profiling was performed using the HTG EdgeSeq Immune Response Panel. Characteristic patterns of a dysregulated immune response were detected in COVID-19: 1. An accumulation of extrafollicular plasmablasts with a relative paucity or depletion of germinal centers. 2. Evidence of T-cell dysregulation demonstrated by immunohistochemical paucity of FOXP3+, Tbet+ and LEF1+ positive T-cells and a downregulation of key genes responsible for T-cell crosstalk, maturation and migration as well as a reactivation of herpes viruses in 6 COVID-19 lymph nodes (EBV, HSV). 3. Macrophage activation by a M2-polarized, CD163+ phenotype and increased incidence of hemophagocytic activity. 4. Microvascular dysfunction, evidenced by an upregulation of hemostatic (CD36, PROCR, VWF) and proangiogenic (FLT1, TEK) genes and an increase of fibrin microthrombi and CD105+ microvessels. Taken together, these findings imply widespread dysregulation of both innate and adoptive pathways with concordant microvascular dysfunction in severe COVID-19.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vascular Damage, Thromboinflammation, Plasmablast Activation, T-Cell Dysregulation and Pathological Histiocytic Response in Pulmonary Draining Lymph Nodes of COVID-19

et al. 2021

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“…2d), im Einklang mit den bekannten Phänomenen der Makrophagenaktivierung bei COVID-19 [29,38]. Dennoch bot sich das volle klinische Bild einer HLH nur bei einem der 20 hier untersuchten Patienten [47].…”

Section: Histopathologieunclassified

Reaktionsmuster der lokoregionären Lymphknoten im Abflussgebiet von COVID-19-Lungen

et al. 2021

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Zusammenfassung Hintergrund Eine dysregulierte Immunantwort, z. B. in der Form eines Zytokinsturmes, einer Störung des Immunglobulinklassenwechsels, eines sog. antikörpervermitteltem Enhancements oder einer aberranten Antigenpräsentation wurde bereits in schweren Krankheitsverläufen von COVID-19 beschrieben. Ziel der Arbeit Zur Charakterisierung der COVID-19-Immunantwort wurde die Histomorphologie der Lymphknoten des pulmonalen Abflussgebietes untersucht. Material und Methoden Regionale Lymphknoten des pulmonalen Abflussgebiets wurden bei COVID-19-Autopsien asserviert (n = 20). Deren Histomorphologie, SARS-CoV-2-qRT-PCR sowie Genexpressionsanalysen von gängigen Genen der Immunantwort wurden berücksichtigt. Ergebnisse Histologisch zeigten sich ein mäßig- bis schwergradiges Ödem mit Kapillarostase, eine erhöhte Anzahl von extrafollikulären Plasmablasten, milde bis mäßige Plasmazytose, vermehrte CD8+-T-Zellen und CD11c/CD68+-Histiozyten mit Hämophagozytoseaktivität. Von 20 Fällen wiesen 18 hypoplastische oder fehlende Keimzentren sowie eine Verminderung der follikulären dendritischen Zellen und follikulären T‑Helferzellen auf. In 14 von 20 Fällen war der qRT-PCR-Nachweis von SARS-CoV‑2 positiv, jedoch zeigte sich nur bei einem einzigen Fall eine immunhistochemische Positivität für SARS-CoV-2-N-Antigene in Sinushistiozyten. In Genexpressionsanalysen war eine erhöhte Expression von STAT1, CD163, Granzym B, CD8A, MZB1 und PAK1, neben CXCL9 zu beobachten. Diskussion Die Befunde in den Lymphknoten deuten auf eine dysregulierte Immunantwort bei schweren COVID-19-Krankheitsverläufen hin. Insbesondere impliziert das Ausbleiben der Keimzentrumsreaktion und die vermehrte Präsenz von Plasmablasten eine nur transiente B‑Zellreaktion, welche die Entwicklung einer Langzeitimmunität infrage stellt.

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Histomorphological patterns of regional lymph nodes in COVID-19 lungs

et al. 2021

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Background A dysregulated immune response is considered one of the major factors leading to severe COVID-19. Previously described mechanisms include the development of a cytokine storm, missing immunoglobulin class switch, antibody-mediated enhancement, and aberrant antigen presentation. Objectives To understand the heterogeneity of immune response in COVID-19, a thorough investigation of histomorphological patterns in regional lymph nodes was performed. Materials and methods Lymph nodes from the cervical, mediastinal, and hilar regions were extracted from autopsies of patients with lethal COVID-19 (n = 20). Histomorphological characteristics, SARS-CoV‑2 qRT-PCR, and gene expression profiling on common genes involved in immunologic response were analyzed. Results Lymph nodes displayed moderate to severe capillary stasis and edema, an increased presence of extrafollicular plasmablasts, mild to moderate plasmacytosis, a dominant population of CD8+ T‑cells, and CD11c/CD68+ histiocytosis with hemophagocytic activity. Out of 20 cases, 18 presented with hypoplastic or missing germinal centers with a decrease of follicular dendritic cells and follicular T‑helper cells. A positive viral load was detected by qRT-PCR in 14 of 20 cases, yet immunohistochemistry for SARS-CoV-2 N-antigen revealed positivity in sinus histiocytes of only one case. Gene expression analysis revealed an increased expression of STAT1, CD163, granzyme B, CD8A, MZB1, and PAK1, as well as CXCL9. Conclusions Taken together, our findings imply a dysregulated immune response in lethal COVID-19. The absence/hypoplasia of germinal centers and increased presence of plasmablasts implies a transient B‑cell response, implying an impaired development of long-term immunity against SARS-CoV‑2 in such occasions.

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Haemophagocytic lymphohistiocytosis and liver failure-induced massive hyperferritinaemia in a male COVID-19 patient

Cited by 5 publications

References 8 publications

Vascular Damage, Thromboinflammation, Plasmablast Activation, T-Cell Dysregulation and Pathological Histiocytic Response in Pulmonary Draining Lymph Nodes of COVID-19

Vascular Damage, Thromboinflammation, Plasmablast Activation, T-Cell Dysregulation and Pathological Histiocytic Response in Pulmonary Draining Lymph Nodes of COVID-19

Reaktionsmuster der lokoregionären Lymphknoten im Abflussgebiet von COVID-19-Lungen

Histomorphological patterns of regional lymph nodes in COVID-19 lungs

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