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5.
Cell Death Dis ; 12(8): 762, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1338531

ABSTRACT

While vaccination is the single most effective intervention to drastically reduce severe disease and death following SARS-CoV-2 infection, as shown in UK and Israel, some serious concerns have been raised for an unusual adverse drug reaction (ADR), including vaccine-induced immune thrombotic thrombocytopenia (VITT) with concurrent low platelets as well as capillary leak syndrome. In fact, the overall safety of the vaccine is highlighted by the low frequency of ADR considering that in UK, by the early June, 40 million first doses and 29 million second doses have been injected; nonetheless, 390 thrombotic events, including 71 fatal events have been reported. Interestingly, the cases reported low platelet counts with the presence of anti-platelet factor-4 (PF4) antibodies, indicating an abnormal clotting reaction. Here, out of three referred cases, we report a post-vaccine clinical case of fatal thrombosis with postmortem examination and whole exome sequencing (WES) analysis, whose pathogenesis appeared associated to a preexisting condition of thrombocytopenia due to myelodysplasia.


Subject(s)
COVID-19 Vaccines/adverse effects , Thrombocytopenia/complications , Thromboembolism/etiology , Bone Marrow/pathology , COVID-19/prevention & control , Fatal Outcome , Female , Humans , Lung/pathology , Middle Aged , Myelodysplastic Syndromes/complications , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/pathology , SARS-CoV-2/immunology , Thrombocytopenia/diagnosis , Thrombocytopenia/pathology
7.
J Hematol Oncol ; 14(1): 87, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259207

ABSTRACT

Cases of thrombotic thrombocytopenia induced by coronavirus disease 2019 (COVID-19) vaccines have been reported recently. Herein, we describe the first case of another critical disorder, hemophagocytic lymphohistiocytosis (HLH), in a healthy individual after COVID-19 vaccination. A 43-year-old Chinese farmer developed malaise, vomiting, and persistent high fever (up to 39.7 °C) shortly after receiving the first dose of the inactivated SARS-CoV-2 vaccine. The initial evaluation showed pancytopenia (neutrophil count, 0.70 × 109/L; hemoglobin, 113 g/L; platelet, 27 × 109/L), elevated triglyceride (2.43 mmol/L), and decreased fibrinogen (1.41 g/L). Further tests showed high serum ferritin levels (8140.4 µg/L), low NK cell cytotoxicity (50.13%-60.83%), and positive tests for Epstein-Barr virus (EBV) DNA. Hemophagocytosis was observed in the bone marrow. Therefore, HLH was confirmed, and dexamethasone acetate (10 mg/day) was immediately prescribed without etoposide. Signs and abnormal laboratory results resolved gradually, and the patient was discharged. HLH is a life-threatening hyperinflammatory syndrome caused by aberrantly activated macrophages and cytotoxic T cells, which may rapidly progress to terminal multiple organ failure. In this case, HLH was induced by the COVID-19 vaccination immuno-stimulation on a chronic EBV infection background. This report indicates that it is crucial to exclude the presence of active EBV infection or other common viruses before COVID-19 vaccination.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/prevention & control , Lymphohistiocytosis, Hemophagocytic/etiology , Adult , Anti-Inflammatory Agents/therapeutic use , Bone Marrow/pathology , Dexamethasone/analogs & derivatives , Dexamethasone/therapeutic use , Humans , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Male , SARS-CoV-2/isolation & purification
8.
Int J Lab Hematol ; 43(6): 1291-1301, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1258939

ABSTRACT

INTRODUCTION: The clinical and laboratory features of severe COVID-19 infection overlap with those of hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder often associated with several viral infections. The clinical syndrome of HLH encompasses fever, organomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, raised transaminases, hypofibrinogenemia, absent natural killer (NK) cell activity, increased soluble CD25 and hemophagocytic lymphohistiocytosis in bone marrow, spleen, and lymph nodes. METHODS: We analyzed clinicopathological and laboratory features of thirteen patients with severe COVID-19 infection suspected to have HLH and found to have hemophagocytic histiocytosis on bone marrow examination (BME). RESULTS: Five of thirteen (38.46%) patients fulfilled five of eight HLH 2004 criteria and/or had a H-score ≥169. Three (23.08%) satisfied four of eight and remainder five (38.46%) satisfied three of eight HLH 2004 criteria. Fever, raised serum ferritin (13/13, 100%), transaminases (9/13, 69.23%), triglycerides (4/13, 30.76%), cytopenias (5/13, 38.46%), hypofibrinogenemia (2/13, 15.38%), and organomegaly (1/13, 7.69%) were observed in our patients. BME showed hemophagocytic histiocytosis without lymphocytosis in all. Contrary to HLH, lymphocytopenia (11/13, 84.61%), leukocytosis (7/13, 53.84%), neutrophilia (7/13, 53.84%), and hyperfibrinogenemia (7/13, 53.84%) were observed. Serum CRP, LDH, and plasma D-dimer were elevated in all, while serum albumin was decreased in 12 of 13 (92.3%) patients. Five patients recovered with high-dose pulsed corticosteroid therapy. CONCLUSION: The immune response associated with severe COVID-19 infection is similar to HLH with few differences. HLH should be suspected in severe COVID-19 infection although all patients may not fulfill required HLH diagnostic criteria. BME should be done in suspected cases so that appropriate therapy may be initiated early.


Subject(s)
Bone Marrow/pathology , COVID-19/complications , Lymphohistiocytosis, Hemophagocytic/etiology , SARS-CoV-2 , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Biomarkers/blood , Blood Proteins/analysis , Bone Marrow Examination , COVID-19/immunology , Creatinine/blood , Diagnosis, Differential , Female , Humans , Leukocyte Count , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Middle Aged , Neutrophils , Severity of Illness Index , Symptom Assessment , Triglycerides/blood
9.
Lancet ; 397(10286): 1749, 2021 05 08.
Article in English | MEDLINE | ID: covidwho-1219082
12.
Am J Clin Pathol ; 155(5): 627-637, 2021 04 26.
Article in English | MEDLINE | ID: covidwho-1050118

ABSTRACT

OBJECTIVES: Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with diverse clinical, including hematologic, abnormalities. We describe peripheral blood and bone marrow findings in deceased and living patients with COVID-19. METHODS: We examined bone marrows from 20 autopsies and 2 living patients with COVID-19 using H&E-stained slides and immunohistochemical stains. Clinical history and laboratory values were reviewed. HScore was calculated to estimate risk of hemophagocytic lymphohistocytosis (HLH). RESULTS: The deceased patients included 12 men and 8 women (aged 32 to >89 years; median, 63 years). Hematologic abnormalities included frequent neutrophilic leukocytosis, lymphopenia, anemia, and thrombocytopenia; one patient showed striking erythrocytosis. The bone marrows were all normocellular to hypercellular, most showing maturing trilineage hematopoiesis with myeloid left shift. In all 19 evaluable bone marrows, hemophagocytic histiocytes were identified. The HScore for secondary HLH ranged from 35 to 269 (median, 125; >169 in 5 patients). Coinfections were identified in 6 patients. In 2 living patients, bone marrow showed maturing trilineage hematopoiesis, including one showing few hemophagocytic histiocytes. CONCLUSIONS: Peripheral blood from deceased patients with COVID-19 frequently showed neutrophilic leukocytosis, lymphopenia, and, rarely, secondary polycythemia; hemophagocytosis was common in their bone marrow. Consistent with other studies, we provide histopathologic evidence of secondary HLH development in patients with COVID-19.


Subject(s)
Biomarkers/blood , Bone Marrow/pathology , COVID-19/blood , COVID-19/pathology , Hematologic Diseases/virology , Lymphohistiocytosis, Hemophagocytic/virology , Adult , Aged , Aged, 80 and over , Bone Marrow/immunology , COVID-19/complications , COVID-19/immunology , Female , Hematologic Diseases/blood , Hematologic Diseases/diagnosis , Hematologic Diseases/pathology , Humans , Immunohistochemistry , Lymphohistiocytosis, Hemophagocytic/blood , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Middle Aged , Retrospective Studies
14.
Am J Clin Pathol ; 154(4): 466-474, 2020 09 08.
Article in English | MEDLINE | ID: covidwho-1015195

ABSTRACT

OBJECTIVES: A subset of coronavirus disease 2019 (COVID-19) patients exhibit clinical features of cytokine storm. However, clinicopathologic features diagnostic of hemophagocytic lymphohistiocytosis (HLH) have not been reported. We studied the reticuloendothelial organs of 4 consecutive patients who died of COVID-19 and correlated with clinical and laboratory parameters to detect HLH. METHODS: Autopsies were performed on 4 patients who died of COVID-19. Routine H&E staining and immunohistochemical staining for CD163 were performed to detect hemophagocytosis. Clinical and laboratory results from premortem blood samples were used to calculate H-scores. RESULTS: All 4 cases demonstrated diffuse alveolar damage within the lungs. Three of the 4 cases had histologic evidence of hemophagocytosis within pulmonary lymph nodes. One case showed hemophagocytosis in the spleen but none showed hemophagocytosis in liver or bone marrow. Lymphophagocytosis was the predominant form of hemophagocytosis observed. One patient showed diagnostic features of HLH with an H-score of 217, while a second patient likely had HLH with a partial H-score of 145 due to a missing triglyceride level. The remaining 2 patients had H-scores of 131 and 96. CONCLUSIONS: This is the first report of severe acute respiratory syndrome coronavirus 2-associated HLH. Identification of HLH in a subset of patients with severe COVID-19 will inform clinical trials of therapeutic strategies.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnosis , Coronavirus Infections/pathology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphohistiocytosis, Hemophagocytic/virology , Pneumonia, Viral/diagnosis , Pneumonia, Viral/pathology , Aged , Aged, 80 and over , Autopsy , Bone Marrow/pathology , COVID-19 , Coronavirus Infections/complications , Fatal Outcome , Female , Humans , Liver/pathology , Lung/pathology , Lymph Nodes/pathology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Male , Middle Aged , Pandemics , Pneumonia, Viral/complications , SARS-CoV-2 , Spleen/pathology
15.
Histopathology ; 78(5): 727-737, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-991400

ABSTRACT

AIMS: Haemophagocytosis in the bone marrow of patients who have succumbed to coronavirus disease 19 (COVID-19) has not been widely studied. The aims of the present study were to perform morphological analyses and morphometry of haemophagocytosis in the bone marrow of patients with severe COVID-19, and to correlate the findings with the clinical course of the disease. METHODS AND RESULTS: In this single-centre study performed at the University Hospital Jena, bone marrow specimens of 15 deceased patients who had experienced a severe course of COVID-19 were sampled from the vertebral column during autopsy. Slides of the bone marrow were stained with routine stains or immunohistochemically, and further examined for haemophagocytosis by the use of light microscopy. To substantiate the morphological findings, additional slides were stained for CD163 and morphometry was performed. In all bone marrow samples, an increase in cellularity was found. Haemophagocytes with erythrophagocytosis were detected in 67% of the deceased patients. In tissues with low numbers of haemophagocytes or ill-defined haemophagocytes, an increase in iron deposits was frequently seen. Morphological findings were then correlated with several important clinical data, and the HScore (probability of having a reactive hemophagocytic syndrome) was calculated to posthumously confirm the diagnosis of secondary haemophagocytic lymphohistiocytosis. The median duration of disease and the hospitalisation time were lower in patients with haemophagocytosis (n = 10) than in patients without haemophagocytosis (n = 5). In addition, patients with haemophagocytes showed increased inflammatory parameters 2-5 days prior to death, in contrast to patients without haemophagocytes. CONCLUSIONS: Haemophagocytosis is a common finding in the bone marrow of deceased individuals with severe COVID-19, and may indicate fatal severe acute respiratory syndrome coronavirus 2 infections.


Subject(s)
COVID-19/virology , Lymphohistiocytosis, Hemophagocytic/virology , SARS-CoV-2/physiology , Aged , Aged, 80 and over , Autopsy , Bone Marrow/pathology , Bone Marrow/virology , COVID-19/complications , COVID-19/pathology , Female , Hospitalization , Humans , Immunohistochemistry , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/pathology , Male , Middle Aged
17.
J Infect Dis ; 222(11): 1807-1815, 2020 11 09.
Article in English | MEDLINE | ID: covidwho-919293

ABSTRACT

BACKGROUND: Descriptions of the pathological features of coronavirus disease-2019 (COVID-19) caused by the novel zoonotic pathogen severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emanate from tissue biopsies, case reports, and small postmortem studies restricted to the lung and specific organs. Whole-body autopsy studies of COVID-19 patients have been sparse. METHODS: To further define the pathology caused by SARS-CoV-2 across all body organs, we performed autopsies on 22 patients with COVID-19 (18 with comorbidities and 4 without comorbidities) who died at the National Institute for Infectious Diseases Lazzaro Spallanzani-IRCCS Hospital, Rome, Italy. Tissues from the lung, heart, liver, kidney, spleen, and bone marrow (but not the brain) were examined. Only lung tissues were subject to transmission electron microscopy. RESULTS: COVID-19 caused multisystem pathology. Pulmonary and cardiovascular involvement were dominant pathological features. Extrapulmonary manifestations included hepatic, kidney, splenic, and bone marrow involvement, and microvascular injury and thrombosis were also detected. These findings were similar in patients with or without preexisting medical comorbidities. CONCLUSIONS: SARS-CoV-2 infection causes multisystem disease and significant pathology in most organs in patients with and without comorbidities.


Subject(s)
COVID-19/pathology , Adult , Aged , Aged, 80 and over , Autopsy/methods , Bone Marrow/pathology , COVID-19/epidemiology , COVID-19/virology , Comorbidity , Female , Humans , Italy/epidemiology , Kidney/pathology , Liver/pathology , Lung/pathology , Male , Middle Aged , Spleen/pathology , Thrombosis/pathology , Vascular Diseases/pathology , Vascular Diseases/virology
19.
Pediatr Transplant ; 25(5): e13875, 2021 08.
Article in English | MEDLINE | ID: covidwho-781009

ABSTRACT

Respiratory viral infections are known causes of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we report a unique case of a child with viral pneumonia caused by coinfection with human metapneumovirus (MPV), respiratory syncytial virus (RSV), and SARS-CoV-2 after HSCT. A 9-year-old girl with acute lymphoblastic leukemia underwent allogeneic HSCT from a matched, unrelated donor. During the post-transplant period, in profound leukopenia (below 10 leukocytes/µL), she was diagnosed with SARS-CoV-2, MPV, and RSV pneumonia and was treated with ribavirin and chloroquine. Before leukocyte recovery, the girl became asymptomatic, and SARS-CoV-2 and RSV clearance was achieved. The shedding of SARS-CoV-2 stopped before immune system recovery, and one may hypothesize that the lack of an inflammatory response might have been a contributing factor to the mild clinical course. Post-transplant care in HSCT recipients with COVID-19 infection is feasible in regular transplant units, provided the patient does not present with respiratory failure. Early and repeated testing for SARS-CoV-2 in post-transplant patients with concomitant infection mitigation strategies should be considered in children after HSCT who develop fever, respiratory symptoms, and perhaps gastrointestinal symptoms to control the spread of COVID-19 both in patients and in healthcare workers in hospital environments. Training of staff and the availability of personal protective equipment are crucial for containing SARS-CoV-2 infection.


Subject(s)
COVID-19/immunology , COVID-19/virology , Hematopoietic Stem Cell Transplantation/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , SARS-CoV-2 , Anemia, Aplastic/pathology , Bone Marrow/pathology , COVID-19/complications , COVID-19/drug therapy , Child , Female , Humans , Metapneumovirus , Pneumonia, Viral/complications , Pneumonia, Viral/virology , Postoperative Period , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/virology , Respiratory Syncytial Virus Infections/complications , Respiratory Syncytial Virus Infections/therapy , Respiratory Syncytial Viruses , Ribavirin/therapeutic use , Transplantation, Homologous
20.
Platelets ; 31(8): 1085-1089, 2020 Nov 16.
Article in English | MEDLINE | ID: covidwho-733448

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a global public health emergency with many clinical facets, and new knowledge about its pathogenetic mechanisms is deemed necessary; among these, there are certainly coagulation disorders. In the history of medicine, autopsies and tissue sampling have played a fundamental role in order to understand the pathogenesis of emerging diseases, including infectious ones; compared to the past, histopathology can be now expanded by innovative techniques and modern technologies. For the first time in worldwide literature, we provide a detailed postmortem and biopsy report on the marked increase, up to 1 order of magnitude, of naked megakaryocyte nuclei in the bone marrow and lungs from serious COVID-19 patients. Most likely related to high interleukin-6 serum levels stimulating megakaryocytopoiesis, this phenomenon concurs to explain well the pulmonary abnormal immunothrombosis in these critically ill patients, all without molecular or electron microscopy signs of megakaryocyte infection.


Subject(s)
Betacoronavirus/pathogenicity , Bone Marrow/pathology , Coronavirus Infections/pathology , Cytokine Release Syndrome/pathology , Disseminated Intravascular Coagulation/pathology , Lung/pathology , Pneumonia, Viral/pathology , Thrombosis/pathology , Adult , Aged , Autopsy , Betacoronavirus/immunology , Bone Marrow/immunology , Bone Marrow/virology , COVID-19 , Cell Nucleus/immunology , Cell Nucleus/pathology , Cell Nucleus/virology , Coronavirus Infections/complications , Coronavirus Infections/immunology , Coronavirus Infections/virology , Critical Illness , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/complications , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/virology , Fatal Outcome , Host-Pathogen Interactions/immunology , Humans , Interleukin-6/biosynthesis , Interleukin-6/immunology , Lung/immunology , Lung/virology , Male , Megakaryocytes/immunology , Megakaryocytes/pathology , Megakaryocytes/virology , Middle Aged , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2 , Severity of Illness Index , Thrombopoiesis/immunology , Thrombosis/complications , Thrombosis/immunology , Thrombosis/virology
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