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.

Keywords: COVID‐19; SARS‐CoV‐2; blood differential count; hemato‐morphology; peripheral blood smear.

FIGURE 1

Morphologic aberrations in blood smears in COVID‐19. A and B, Aberrant lymphocytes with multi‐lobulated nuclei and large cytoplasmatic granula (B); C and D, aberrant lymphoplasmocytoid cells; E, Mott cell; F, enlarged lymphocyte with basophilic cytoplasm, undergoing apoptosis with signs of karyolysis; G and H, lympho‐monocytoid cells with aberrant lobulated nuclei; I and J, monocytes with aberrant nuclei (clumped chromatin) and basophilic cytoplasms; K and L, left shift with myelocytes/metamyelocytes (*) and hypergranulation; M, granulocytes with hypergranulation (*); L and M, (◄) apoptotic cells; N, neutrophil granulocyte with hypolobulated nucleus, pseudo‐Pelger‐Huët anomaly; O, giant platelet with cytoplasmic vacuoles; P, giant platelets and aggregated platelets; Q and R, aberrant erythropoiesis: anisocytosis of RBCs, basophilic stippling (Q◄), stomatocytes (R◄), target‐cell and nucleated RBC (←); S, Prussian blue staining showing large iron‐containing deposits (◄); T, patient with CLL: two atypical lymphocytes (←) (CLL) and one large aberrant lymphocyte with basophilic cytoplasm, likely plasmablast with clumped chromatin(◄), neutrophil granulocyte with hypergranulation and aberrant segmentation of the nucleus

FIGURE 2

Representative ultrastructural changes of aberrant cells. A, Lymphocyte with invagination of the cytoplasm (arrowhead) containing a mitochondrion (arrow). B, Lymphocyte with highly lobulated nucleus. C, Markedly elongated lymphocyte. D and E, Ultrastructural change of platelets and granulocytes: D, a mixture of normally sized platelets (arrows) and giant platelets (E) was obvious. F, Granulocyte, showing apoptosis with nuclear pycnosis with shrinking (arrowhead) and chromatin condensation (*)