Histiocytic hyperplasia with hemophagocytosis and acute alveolar damage in COVID-19 infection

Abstract

The spectrum of COVID-19 infection includes acute respiratory distress syndrome (ARDS) and macrophage activation syndrome (MAS), although the histological basis for these disorders has not been thoroughly explored. Post-mortem pulmonary and bone marrow biopsies were performed in 33 patients. Samples were studied with a combination of morphological and immunohistochemical techniques. Bone marrow studies were also performed in three living patients. Bone marrow post-mortem studies showed striking lesions of histiocytic hyperplasia with hemophagocytosis (HHH) in most (16/17) cases. This was also observed in three alive patients, where it mimicked the changes observed in hemophagocytic histiocytosis. Pulmonary changes included a combination of diffuse alveolar damage with fibrinous microthrombi predominantly involving small vessels, in particular the alveolar capillary. These findings were associated with the analytical and clinical symptoms, which helps us understand the respiratory insufficiency and reveal the histological substrate for the macrophage activation syndrome-like exhibited by these patients. Our results confirm that COVID-19 infection triggers a systemic immune-inflammatory disease and allow specific therapies to be proposed.

Macrophage responses associated with COVID-19: A pharmacological perspective

“…HH is the histological counterpart of the macrophage activation syndrome. A clinical study performed on post-mortem bone marrow samples taken from patients who died from COVID- 19 showed findings highly consistent with the diagnosis of HH ( Prieto-Pérez et al, 2020 ). Elevated blood ferritin has also been shown to be associated with poor outcome in a retrospective study of 150 COVID-19 patients ( Mehta et al, ).…”

“…Nor is it clear what relationship there is between the cytokine storm and thrombocytopenia, which is common in patients with COVID-19 and may ultimately contribute to adverse outcome, although both enhanced platelet activation/consumption and destruction are likely outcomes of the cytokine storm. Multi-organ (micro-) thrombosis seems to characterize severe COVID-19 cases ( McFadyen et al, 2020 ; Prieto-Pérez et al, 2020 ), and likely reflects in part the production of pro-inflammatory cytokines, such as IL-1β and TNF-α, by macrophages ( Conti et al, 2020a ).…”

Red Blood Cell Distribution Width (RDW) Predicts COVID-19 Severity: A Prospective, Observational Study from the Cincinnati SARS-CoV-2 Emergency Department Cohort

“…Abnormalities of lipid metabolism could also be identified, encompassing especially acyl-carnitines, sphingolipids, along with short- and medium-chain saturated fatty acids. A direct bone marrow injury secondary to SARS-CoV-2 infection has also been described in several reports, mostly manifesting as hemophagocytosis, with clear evidence of erythrophagocytic phenomena characterized by macrophages engulfed with both erythroblasts and mature erythrocytes [ 20 ].…”

Haemophagocytic syndrome and COVID-19

“…Although early studies stated that patients with severe COVID-19 may not be in a good enough condition to undertake a bone marrow examination searching for HLH, the severe clinical scenario is not different from that in HLH patients, and should be carried out when HLH is suspected. Haemophagocytosis can be linked to one of the key immunological abnormalities reported in severe COVID-19 (abnormal macrophage activation) and has been started to be described in patients with COVID-19, both in post-mortem and clinical studies [ 33 , 36 , 61 – 63 ].…”