A Case of a Relapsing Remitting Macrophage Activating Syndrome After Covid-19 Vaccine In a Teenager with UNC13D Heterozygous Variant of Uncertain Significance

Introduction: Macrophage activation syndrome (MAS) is a severe hyper inflammatory condition caused by the over-activation and proliferation of T cells, NK cells and macrophages. It is often associated with complications of rheumatic/immune diseases. We present a case of a 15-year-old female who experiences recurrent episodes of MAS without any known definitive underlying etiology. Case Presentation: A 15-year-old previously healthy female developed fatigue, fevers, myalgia, chest pain, splenomegaly and lymphadenopathy 10 days after receiving her first Pfizer COVID-19 vaccine. Her symptoms recurred 10 days after receiving the second dose. Her myocarditis, MIS-C, and infectious work up was negative except for positive EBV IgG. Laboratory studies revealed anemia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. She initially responded to decadron;however, her symptoms recurred with steroid taper. Bone marrow biopsy revealed hemophagocytosis. Whole exome sequencing (WES) revealed a heterozygous variant of uncertain significance in UNC13D c.962C>A (p.Thr321Asn). She had multiple re-admissions with significantly elevated inflammatory markers, including extremely high IL2-R, IL-18 and CXCL9. Each episode was complicated by an acute viral infection. She responds to high dose steroids, anti-IL-1, and JAK inhibitors. Nonetheless, it has been difficult to wean decadron without triggering a flare. She continues to require increasing doses of baricitinib. Discussion(s): MAS may be seen as a complication of rheumatic diseases, as well as inborn errors of immunity. However, none of these conditions have been diagnosed in this patient despite extensive testing, including WES. The degree of her immune dysregulation has been very severe making her disease process unpredictable and extremely difficult to control. She has frequent flares precipitated by viral infections or attempts at adjusting her immunomodulators. Weaning her medications has been challenging as she continues to require increasing doses of baricitinib and corticosteroids. The UNC13D gene is associated with autosomal recessive familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Our patient is heterozygous for an UNC13D variant of uncertain significance. Additional genetic inquiries with whole genome sequencing to help elucidate the underlying etiology of her severe condition is being conducted. We hypothesize she developed MAS due to a combination of genetic predisposition, prior EBV infection, and immune stress associated with the COVID-19 vaccine. [Formula presented] [Formula presented] [Formula presented]Copyright © 2023 Elsevier Inc.

Hemophagocytosis in the Red Bone Marrow of Patients with Covid-19 with Sars-Cov-2 Infection

Red bone marrow samples investigation in deceased COVID-19 patients enabled to identify the phenomena of secondary hemophagocytosis. Analysis of the data showed that phagocytic reactions during infection of patients with SARS-CoV-2 are manifested both in relation to erythrocytes and leukocytes. The data obtained make it possible to expand the strategy of therapeutic measures, taking into account the new data on the mechanisms of the pathogenesis of COVID-19 in severe viral infection based on morphological findings and additional information on the involvement of young erythrocytes and lymphocytes in the structure of the red bone marrow in the cascade of pathological reactions. The results obtained confirm a wide range of aggressive damaging effects of SARS-CoV-2 in the development of multiple organ failure against the background of COVID-19 and the involvement of the red bone marrow in the pathological process. The authors supplemented information about the mechanisms of hypoxia in COVID-19, which is not only a consequence of damage to the respiratory epithelium, but also the result of damage to erythrocyte differons both at the level of red bone marrow and in peripheral blood. This fact must be taken into account in the development of a treatment strategy and in the creation of new drugs for the treatment of infected patients with various strains of SARS-CoV-2.

Case report: Hemorrhagic fever with renal syndrome presenting as hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis may occur in patients with genetic predisposition and in sporadic cases due to malignancy or infection. We describe a 49-year old man with hemorrhagic fever, type 1 respiratory insufficiency and acute kidney injury. Diagnostic work up showed a hyperinflammatory syndrome, hypertriglyceridemia, hemophagocytosis, very high ferritin and significantly elevated sCD25. The findings were compatible with hemophagocytic lymphohistiocytosis based on the HLH-2004 criteria. Serological testing indentified Puumala virus as the causal pathogen. The patient was successfully treated with pulse corticosteroids, intravenous immunoglobins and supportive therapy.

Hemophagocytic Lymphohistiocytosis syndrome (HLH) associated with acute pancreatitis: A case report.

Hemophagocytic Lymphohistiocytosis syndrome is fatal hyper-inflammatory condition due to over-activation of the immune system, being of primary and secondary types. This case report emphasizes the difficulty and challenge in and of the HLH diagnosis, and therapy should be employed promptly given the high mortality associated with HLH.

Hemophagocytosis in a Severe COVID-19 Patient

The novel coronavirus (SARS-CoV-2) infection has become a heavy burden on global health. Although the coronavirus disease 2019 (COVID-19) may adversely affect multiple organs and systems of infected patients, to the best of our knowledge, there is little investigation of the SARS-CoV-2's impact on bone marrow. Our clinical and cytological findings in this case of severe COVID-19 infection provide novel insights into the pathogenesis of SARS-CoV-2 infection in the hematopoietic system. We recommend that physicians consider SARS-CoV-2 infection's effect on bone marrow in patients who are slow to recover and suggest that a better understanding of the bone marrow morphology in COVID-19-infected patients is needed. © 2022 Journal of Bone and Joint Surgery Inc.. All rights reserved.

RED BONE MARROW DAMAGE IN COVID-19 PATHOGENESIS CAUSED BY SARS-COV-2

With the emerging of new strains of the SARS-CoV-2 coronavirus (such as B.1.1.529 for example), despite numerous studies to create effective vaccines, it becomes obvious that the relevance of studying the pathomorphology of tissue structures with damaged cellular targets has increased manifold. Most knowledge on genes of pathogenicity loses its importance for the development of antiviral agents since the reservoir for the virus is the cells, in which SARS-CoV-2 then persists. These data are more important for the development of vaccines, and the treatment strategy should be based on damaged cellular targets. The mechanisms of hypoxia in patients infected by SARS-CoV-2 with COVID-19 do not have an exhaustive explanation based only on the acute alveolar damage. Our investigation deals with the data on pathologic red bone marrow in patients with a fatal COVID-19 outcome against the background of various indicators of erythrocytes in clinical blood tests. We found in the structure of the red bone marrow that there is damage to the stroma and parenchyma as well as pathomorphological signs of damage to erythropoiesis in the patients of both groups. The data obtained on the cellular targets of SARS-CoV-2 can serve as a fundamental platform for the development of targeted conservative therapy in the treatment of patients infected with SARS-CoV-2, and should also be taken into account in severe COVID-19 cases with the risk of unfavorable prognosis.

Hemophagocytic lymphohistiocytosis in adults: A key issue in the COVID-19 era.

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by persistent activation of the mononuclear phagocytic system, systemic inflammation, and hypercytokinaemia, which can lead to liver failure, "sepsis-like syndrome" and ultimately, to multiple organ failure and death. These disorders can be divided into primary and secondary (or reactive), the first, also known as familial HLH, is a genetic condition of childhood, which affects the function of TCD8 and NK cells, and usually presents in the first year of life. The secondary HLH affects mainly adults and adolescents and, it's more related to dysregulation of the immune system. In face of the COVID-19 pandemic and several reports of HLH by SARS-CoV-2, it is necessary to discuss the pathophysiology of HLH in adults more clearly. Thus, we present, for the first time, a didactic approach using illustrations and tables, compiling the most recent and relevant information to better understand this entity.

Hemophagocytic histiocytosis in severe SARS-CoV-2 infection: A bone marrow study.

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.

Bone Marrow and Peripheral Blood Findings in Patients Infected by SARS-CoV-2.

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.

SARS-CoV-2 Infection-Associated Hemophagocytic Lymphohistiocytosis.

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.