Coronavirus disease 2019 induces multi‐lineage, morphologic changes in peripheral blood cells

Abstract

The clinical course of coronavirus disease 2019 (COVID‐19) varies from mild symptoms to acute respiratory distress syndrome, hyperinflammation, and coagulation disorder. The hematopoietic system plays a critical role in the observed hyperinflammation, particularly in severely ill patients. We conducted a prospective diagnostic study performing a blood differential analyzing morphologic changes in peripheral blood of COVID‐19 patients. COVID‐19 associated morphologic changes were defined in a training cohort and subsequently validated in a second cohort (n = 45). Morphologic aberrations were further analyzed by electron microscopy (EM) and flow cytometry of lymphocytes was performed. We included 45 COVID‐19 patients in our study (median age 58 years; 82% on intensive care unit). The blood differential showed a specific pattern of pronounced multi‐lineage aberrations in lymphocytes (80%) and monocytes (91%) of patients. Overall, 84%, 98%, and 98% exhibited aberrations in granulopoiesis, erythropoiesis, and thrombopoiesis, respectively. Electron microscopy revealed the ultrastructural equivalents of the observed changes and confirmed the multi‐lineage aberrations already seen by light microscopy. The morphologic pattern caused by COVID‐19 is characteristic and underlines the serious perturbation of the hematopoietic system. We defined a hematologic COVID‐19 pattern to facilitate further independent diagnostic analysis and to investigate the impact on the hematologic system during the clinical course of COVID‐19 patients.

Patient-Reported Health Outcomes After Treatment of COVID-19 with Nebulized and/or Intravenous Neutral Electrolyzed Saline Combined with Usual Medical Care Versus Usual Medical care alone: A Randomized, Open-Label, Controlled Trial.

“…Monocytes and pulmonary monocytes play a key early role in the progression to severe COVID-19, by promoting a cytokine storm, ARDS, and disseminated peripheral tissue damage [ 13 ]. The aberrant monocytes that decreased after the experimental treatment were larger than normal monocytes, with clumped chromatin and basophilic cytoplasm [ 46 ]. Morphologically altered monocytes, especially larger ones, are associated with a hyperinflammatory gene expression profile and with admission to intensive care units in type 2 diabetes patients with COVID-19 [ 54 ].…”

“…Patients with any kind of steroidal or hormonal treatment were excluded. Systemic inflammation markers (erythrocyte sedimentation rate and C-reactive protein) were also evaluated and rapid staining of blood smears with staining kits (Hycel, Mexico, Mexico) were performed to quantify: 1) reactive lymphocytes, also called virocytes, 2) large granular lymphocytes, a representation of natural killer cells or cytotoxic T lymphocytes, 3) activated monocytes, and 4) monocytes with aberrant nuclei (clumped chromatin) and basophilic cytoplasm [ 45 ][ 46 ][ 13 ].…”

Additional analyses exploring the hypothesized transdifferentiation of plasmablasts to developing neutrophils in severe COVID-19

“…First, we would like to reiterate that such an explanation would be expected to result in an increase in complexity (# genes detected per # UMI sequenced per cell) of developing neutrophils, which we did not observe (Extended Data Figure 9 of our original manuscript 2 ). While it is possible that internalization of one cell into another, either by emperipolesis or hemophagocytosis, could confound our interpretation, these mechanisms of intact cell ingestions are exceptionally rare behaviors of both neutrophils and B lymphocytes at any differentiation stage, and none of the published series of peripheral smears in COVID-19 have revealed this phenomenon 10 – 12 . In addition, none of the patients in our cohort had clinical characteristics of HLH and none received granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy on the original authors’ review.…”

Secondary hemophagocytic lymphohistiocytosis and severe liver injury induced by hepatic SARS-CoV-2 infection unmasking Wilson’s disease: Balancing immunosuppression

“…Peripheral blood smear showed thrombocytopenia and activated lymphocytes likely associated with COVID-19. ( Lüke et al, 2020 ) Ferritin was massively elevated while ceruloplasmin was severely depressed hinting possible Wilson’s disease, thus 24 h urine collection and copper analysis was initiated. Liver function tests were elevated combined with a severe impairment of liver synthesis parameters (supplementary Table 1).…”