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2.
Immunol Lett ; 234: 16-32, 2021 06.
Article in English | MEDLINE | ID: covidwho-1173426

ABSTRACT

Inflammasomes are cytosolic multiprotein complexes that crucially contribute to host defense against pathogens but are also involved in the pathogenesis of autoinflammatory diseases. Inflammasome formation leads to activation of effector caspases (caspase-1, 4, 5, or 11), the proteolytic maturation of IL-1ß and IL-18 as well as cleavage of the pore-forming protein Gasdermin D. Dendritic cells are major regulators of immune responses as they bridge innate and adaptive immunity. We here summarize the current knowledge on inflammasome expression and formation in murine bone marrow-, human monocyte-derived as well as murine and human primary dendritic cells. Further, we discuss both, the beneficial and detrimental, involvement of inflammasome activation in dendritic cells in cancer, infections, and autoimmune diseases. As inflammasome activation is typically accompanied by Gasdermin d-mediated pyroptosis, which is an inflammatory form of programmed cell death, inflammasome formation in dendritic cells seems ill-advised. Therefore, we propose that hyperactivation, which is inflammasome activation without the induction of pyroptosis, may be a general model of inflammasome activation in dendritic cells to enhance Th1, Th17 as well as cytotoxic T cell responses.


Subject(s)
Dendritic Cells/immunology , Dendritic Cells/metabolism , Inflammasomes/metabolism , Animals , Biomarkers , Cell Communication/genetics , Cell Communication/immunology , Cytokines/metabolism , Disease Susceptibility/immunology , Humans , Immunomodulation , Inflammation/etiology , Inflammation/metabolism , Inflammation/pathology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism
3.
J Inflamm (Lond) ; 18(1): 21, 2021 May 31.
Article in English | MEDLINE | ID: covidwho-1280587

ABSTRACT

BACKGROUND: Macrophages are indispensable regulators of inflammatory responses. Macrophage polarisation and their secreted inflammatory factors have an association with the outcome of inflammation. Luteolin, a flavonoid abundant in plants, has anti-inflammatory activity, but whether luteolin can manipulate M1/M2 polarisation of bone marrow-derived macrophages (BMDMs) to suppress inflammation is still unclear. This study aimed to observe the effects of luteolin on the polarity of BMDMs derived from C57BL/6 mice and the expression of inflammatory factors, to explore the mechanism by which luteolin regulates the BMDM polarity. METHODS: M1-polarised BMDMs were induced by lipopolysaccharide (LPS) + interferon (IFN)-γ and M2-polarisation were stimulated with interleukin (IL)-4. BMDM morphology and phagocytosis were observed by laser confocal microscopy; levels of BMDM differentiation and cluster of differentiation (CD)11c or CD206 on the membrane surface were assessed by flow cytometry (FCM); mRNA and protein levels of M1/M2-type inflammatory factors were performed by qPCR and ELISA, respectively; and the expression of p-STAT1 and p-STAT6 protein pathways was detected by Western-blotting. RESULTS: The isolated mouse bone marrow cells were successfully differentiated into BMDMs, LPS + IFN-γ induced BMDM M1-phenotype polarisation, and IL-4 induced M2-phenotype polarisation. After M1-polarised BMDMs were treated with luteolin, the phagocytosis of M1-polarized BMDMs was reduced, and the M1-type pro-inflammatory factors including IL-6, tumour necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), and CD86 were downregulated while the M2-type anti-inflammatory factors including IL-10, IL-13, found in inflammatory zone (FIZZ)1, Arginase (Arg)1 and CD206 were upregulated. Additionally, the expression of M1-type surface marker CD11c decreased. Nevertheless, the M2-type marker CD206 increased; and the levels of inflammatory signalling proteins phosphorylated signal transducer and activator of transcription (p-STAT)1 and p-STAT6 were attenuated and enhanced, respectively. CONCLUSIONS: Our study suggests that luteolin may transform BMDM polarity through p-STAT1/6 to regulate the expression of inflammatory mediators, thereby inhibiting inflammation. Naturally occurring luteolin holds promise as an anti-inflammatory and immunomodulatory agent.

4.
OMICS ; 25(6): 342-357, 2021 06.
Article in English | MEDLINE | ID: covidwho-1266096

ABSTRACT

Early cell biology reports demonstrated the presence of cells with stem-like properties in bone marrow, with both hematopoietic and mesenchymal lineages. Over the years, various investigations have purified and characterized mesenchymal stromal/stem cells (MSCs) from different human tissues as cells with multilineage differentiation potential under the appropriate conditions. Due to their appealing characteristics and versatile potentials, MSCs are leveraged in many applications in medicine such as oncology, bioprinting, and as recent as therapeutics discovery and innovation for COVID-19. To date, studies indicate that MSCs have varied differentiation capabilities into different cell types, and demonstrate immunomodulating and anti-inflammatory properties. Different microenvironments or niche for MSCs and their resulting heterogeneity may influence attendant cellular behavior and differentiation capacity. The potential clinical applications of MSCs and exosomes derived from these cells have led to an avalanche of research reports on their properties and hundreds of clinical trials being undertaken. There is ample reason to think, as discussed in this expert review that the future looks bright and promising for MSC research, with many clinical trials under way to ascertain their clinical utility. This review provides a synthesis of the latest advances and trends in MSC research to allow for broad and critically informed use of MSCs. Early observations of the presence of these cells in the bone marrow and their remarkable differentiation capabilities and immunomodulation are also presented.


Subject(s)
Cell Differentiation , Immunomodulation , Mesenchymal Stem Cells/immunology , Humans , Mesenchymal Stem Cells/physiology , Regenerative Medicine , Stem Cell Niche , Tissue Engineering
5.
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
6.
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
7.
Transplant Proc ; 53(8): 2498-2501, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1246217

ABSTRACT

The coronavirus disease 2019 pandemic has made us adjust our standards and cope with unpredictable circumstances affecting the whole world, including the medical field. A 2-year-old boy diagnosed with X-linked lymphoproliferative disease type 2 with concomitant positive polymerase chain reaction test for Epstein-Barr virus-DNA was admitted to our transplant ward. His treatment scheme had to be modified at the last moment because of a donor disqualification due to a positive polymerase chain reaction result for severe acute respiratory syndrome coronavirus 2 just before the apheresis. We decided to perform salvage haploidentical bone marrow transplant from the patient's mother because it was the only possible option. Now, in a 5-month observation period after the hematopoietic stem cell transplantation, our patient is in good general condition. His case convinced us to redirect our approach to transplant procedure preparation. Following the European Group of Blood and Marrow Transplantation recommendations, we use cryopreserved apheresis materials to ensure the availability of stem cell products before the start of a conditioning regimen.


Subject(s)
Bone Marrow Transplantation , COVID-19 , Epstein-Barr Virus Infections , Hematopoietic Stem Cell Transplantation , Lymphohistiocytosis, Hemophagocytic , Salvage Therapy , COVID-19/diagnosis , Child, Preschool , Graft vs Host Disease , Herpesvirus 4, Human , Humans , Lymphohistiocytosis, Hemophagocytic/surgery , Male , Stem Cells , Transplantation Conditioning , Unrelated Donors
8.
Autops Case Rep ; 11: e2021274, 2021 Apr 20.
Article in English | MEDLINE | ID: covidwho-1222268

ABSTRACT

BACKGROUND: Myelodysplastic syndromes (MDS) mainly occur in the elderly but can rarely affect younger individuals too. The correct diagnosis relies on careful morphologic evaluation, cytogenetic/molecular results, and excluding reactive conditions mimicking MDS. We present the clinical, pathologic, cytogenetic, and molecular features of a case of MDS with excess blasts-2 (MDS-EB-2) in a 30-year-old male who was found to have pancytopenia during his hospitalization for coronavirus disease 2019 (COVID-19) and discuss the diagnostic challenges of MDS in patients with COVID-19. CASE PRESENTATION: A 30-year-old man presented to an outside hospital with fever, chills, weakness, coughing spells, dizziness and shortness of breath and was diagnosed with bilateral pneumonia due to COVID-19. At the outside hospital, he was found to be pancytopenic, and a subsequent bone marrow aspiration and biopsy raised concern for a COVID-19 induced hemophagocytic lymphohistiocytosis. In addition, MDS could not be ruled out. The patient was thus referred to our institute for further management. The patient's peripheral blood showed pancytopenia with occasional dysplastic neutrophils and a few teardrop cells. Given the diagnostic uncertainty, a bone marrow aspiration and a biopsy were repeated revealing a hypercellular bone marrow with erythroid hyperplasia, megakaryocytic hyperplasia, trilineage dysplasia, increased blasts (13%), many ring sideroblasts, and mild to moderate myelofibrosis, consistent with MDS-EB-2. Chromosomal analysis revealed isochromosome 14. Next generation sequencing demonstrated SF3B1 K700E mutation. DISCUSSION AND CONCLUSION: The diagnosis of MDS can be challenging, particularly in young patients. Cytopenia and myelodysplastic features have been reported in COVID-19 patients, making the diagnosis of MDS more elusive. A careful pathologic examination of the bone marrow with ancillary studies including flow cytometry, immunohistochemistry, and cytogenetic and molecular studies in combination with a thorough clinical evaluation, leads to the accurate diagnosis.

9.
Int J Biol Sci ; 17(5): 1277-1288, 2021.
Article in English | MEDLINE | ID: covidwho-1191953

ABSTRACT

The angiotensin-converting enzyme 2 (ACE2) receptor has been identified as the cell entry point for SARS-CoV-2. Although ACE2 receptors are present in the bone marrow, the effects of SARS-CoV-2 on the biological activity of bone tissue have not yet been elucidated. In the present study we sought to investigate the impact of SARS-CoV-2 on osteoblastic activity in the context of fracture healing. MicroRNA-4485 (miR-4485), which we found to be upregulated in COVID-19 patients, negatively regulates osteogenic differentiation. We demonstrate this effect both in vitro and in vivo. Moreover, we identified the toll-like receptor 4 (TLR-4) as the potential target gene of miR-4485, and showed that reduction of TLR-4 induced by miR-4485 suppresses osteoblastic differentiation in vitro. Taken together, our findings highlight that up-regulation of miR-4485 is responsible for the suppression of osteogenic differentiation in COVID-19 patients, and TLR-4 is the potential target through which miR-4485 acts, providing a promising target for pro-fracture-healing and anti-osteoporosis therapy in COVID-19 patients.


Subject(s)
COVID-19/pathology , Cell Differentiation , Fracture Healing , MicroRNAs/metabolism , Osteogenesis , SARS-CoV-2/physiology , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/virology , Female , Humans , Male , Middle Aged , SARS-CoV-2/isolation & purification , Toll-Like Receptor 4/metabolism
10.
Case Rep Infect Dis ; 2021: 6629966, 2021.
Article in English | MEDLINE | ID: covidwho-1175214

ABSTRACT

BACKGROUND: Similarities in the febrile course and other manifestations of some diseases may lead to clinical misdiagnosis of COVID-19 infection. Here, we report a case in a young child with a potentially confusing clinical course. Case Presentation. A 29-month-old boy presented with a 2-month history of fever. His PCR test for COVID-19 was positive, and there was pleural effusion plus positive findings in the lower left lobe of the lung on computed tomography scan. Mid-sized splenomegaly was found on abdominal ultrasound, and laboratory tests disclosed pancytopenia. In light of the atypical lymphocyte counts in laboratory tests, he underwent bone marrow aspiration. The suggested diagnosis was hemophagocytic lymphohistiocytosis, and prednisolone was initiated. Subsequently, Leishman-Donovan bodies were seen in the bone marrow aspirate, and treatment was started with amphotericin, which led to clinical improvement. CONCLUSION: In cases with vague clinical symptoms in tropical countries where other infectious diseases occur, possible simultaneous infection should be considered even during a pandemic. Familiarity with the possible differential diagnoses and appropriate, step-by-step consideration to rule out other possible causes are needed in all situations, and the coexistence of infectious disease should be considered in evaluating the clinical conditions of patients in tropical countries.

11.
BMJ Case Rep ; 14(3)2021 Mar 31.
Article in English | MEDLINE | ID: covidwho-1166386

ABSTRACT

Haemophagocytic lymphohistiocytosis (HLH) is a rare diagnosis that carries a high degree of mortality. We present this case of a previously healthy 22-year-old woman, who was admitted acutely ill to the hospital. One week prior, she had been seen by her primary care physician for fatigue and malaise. At that time, she was noted to have anterior and posterior cervical lymphadenopathy. She was referred to the emergency room and was diagnosed with acute Epstein-Barr virus (EBV) mononucleosis based on her clinical symptoms and positive heterophile antibody test. She was discharged after an uneventful 48-hour stay on the wards. She represented 7 days after discharge with cough, fatigue, nausea, vomiting, epigastric abdominal pain, diarrhoea, weight loss and subjective fevers. She had also reported haematemesis, epistaxis and melaena. Vital signs included temperature 36.9°C, blood pressure 90/50 mm Hg, heart rate 130 beats per minute and respiratory rate 32 breaths per minute. Physical examination was notable for an acutely ill appearing woman with scleral icterus, hepatosplenomegaly and palpable cervical and axillary lymphadenopathy. Complete blood count showed pancytopaenia with haemoglobin 59 g/L (normal 120-160 g/L), white blood cell count 2.7×109/L (normal 4-10.5×109/L) and platelet count 50×109/L (normal 150-450×109/L). The white blood cell count differential included 58% neutrophils (normal 38%-77%) with immature neutrophils in band form elevated at 45% (normal <14%), 16% lymphocytes (normal 20%-48%), 7% monocytes (normal <12%) and no eosinophils (normal <6%). Blood smear revealed anisocytosis, poikilocytosis and hypochromia. Coagulation panel showed elevated levels of d-dimer level at 1.39 µg/mL (normal <0.45 µg/mL), prolonged prothrombin time at 34.4 s (normal 11-15 s), prolonged activated partial thromboplastin time of 55.6 s (normal 25-34 s), prolonged international normalised ratio at 3.31 (normal <1.1) and low fibrinogen 60 mg/dL (normal >200 mg/dL). Lipid panel showed cholesterol at 114 mg/dL (normal 125-200 mg/dL), triglycerides 207 mg/dL (normal 30-150 mg/dL), high-density lipoprotein cholesterol 10 mg/dL (normal 40-60 mg/dL) and low-density lipoprotein cholesterol 63 mg/dL (normal <100 mg/dL). Other lab abnormalities included elevated ferritin of 6513 ng/mL (normal 10-150 ng/mL) and elevated lactate dehydrogenase of 1071 unit/L (normal 95-240 unit/L). Soluble interleukin-2 receptor alpha level was elevated at 60 727 units/mL (normal 223-710 units/mL). Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed abnormal tracer localisation within the paratracheal, hilar, pelvic, abdominal and subcarinal lymph nodes, along with FDG-PET positive hepatosplenomegaly. A bone marrow biopsy showed hypercellular marrow (95% cellularity) with trilineage haematopoiesis, haemophagocytic cells, polytypic plasmacytosis and T-cell lymphocytosis, along with positive latent membrane protein-1 immunohistochemical staining for EBV. EBV quantitative DNA PCR showed >1 million copies. These findings were consistent with a diagnosis of HLH secondary to EBV infection. Despite intense therapy with the HLH-94 protocol, the patient expired from her illness after a prolonged hospital course.


Subject(s)
Epstein-Barr Virus Infections , Infectious Mononucleosis , Lymphohistiocytosis, Hemophagocytic , Pancytopenia , Adult , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/diagnosis , Female , Herpesvirus 4, Human , Humans , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Young Adult
12.
Med Sci Monit ; 27: e928837, 2021 Feb 13.
Article in English | MEDLINE | ID: covidwho-1161104

ABSTRACT

BACKGROUND Coronavirus 2 (SARS-CoV-2) was declared a pandemic by the World Health Organization (WHO) in March 2020. To further reveal the pathologic associations between coronavirus and hypoxemia, we report the findings of 4 complete systematic autopsies of severe acute respiratory syndrome coronavirus 2-positive individuals who died of multiple organ failure caused by severe hypoxemia. MATERIAL AND METHODS We examined the donated corpses of 4 deceased patients who had been diagnosed with severe acute respiratory syndrome coronavirus 2. A complete post-mortem examination was carried out on each corpse, and multiple organs were macroscopically examined. RESULTS The 4 corpses were 2 males and 2 females, with an average age of 69 years. Bilateral lungs showed various degrees of atrophy and consolidation, with diffusely tough and solid texture in the sections. A thromboembolism was found in the main pulmonary artery extending into the atrium in 1 corpse, and significant atherosclerotic plaques tagged in the inner wall of the aortic arch were found in 2 corpses. Two corpses were found to have slightly atrophied bilateral renal parenchyma. Atrophic changes in the spleen were found in 2 corpses. Notably, there were significantly expanded alveolar septa and prominent fibroblastic proliferation. CONCLUSIONS The laboratory data of these corpses showed a progressive decrease in blood oxygen saturation, followed by refractory and irreversible hypoxemia. Clinical and laboratory information and autopsy and histologic presentations of multiple organs showed insufficient air exchange due to abnormalities in the respiratory system, and reduced erythropoiesis in bone marrow may play a role.


Subject(s)
Autopsy , COVID-19/pathology , COVID-19/virology , Hypoxia/complications , Hypoxia/pathology , Pneumonia/pathology , Pneumonia/virology , SARS-CoV-2/physiology , Aged , Aged, 80 and over , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/pathology , COVID-19/complications , Cell Aggregation , Female , Humans , Lung/pathology , Macrophages/pathology , Male , Middle Aged , Mucus/metabolism , Myocardium/pathology , Necrosis , Pneumonia/complications , Thoracic Cavity/pathology
13.
Stem Cell Res Ther ; 12(1): 192, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-1140512

ABSTRACT

Over recent years, mesenchymal stem/stromal cells (MSCs) and their potential biomedical applications have received much attention from the global scientific community in an increasing manner. Firstly, MSCs were successfully isolated from human bone marrow (BM), but in the next steps, they were also extracted from other sources, mostly from the umbilical cord (UC) and adipose tissue (AT). The International Society for Cellular Therapy (ISCT) has suggested minimum criteria to identify and characterize MSCs as follows: plastic adherence, surface expression of CD73, D90, CD105 in the lack of expression of CD14, CD34, CD45, and human leucocyte antigen-DR (HLA-DR), and also the capability to differentiate to multiple cell types including adipocyte, chondrocyte, or osteoblast in vitro depends on culture conditions. However, these distinct properties, including self-renewability, multipotency, and easy accessibility are just one side of the coin; another side is their huge secretome which is comprised of hundreds of mediators, cytokines, and signaling molecules and can effectively modulate the inflammatory responses and control the infiltration process that finally leads to a regulated tissue repair/healing or regeneration process. MSC-mediated immunomodulation is a direct result of a harmonic synergy of MSC-released signaling molecules (i.e., mediators, cytokines, and chemokines), the reaction of immune cells and other target cells to those molecules, and also feedback in the MSC-molecule-target cell axis. These features make MSCs a respectable and eligible therapeutic candidate to be evaluated in immune-mediated disorders, such as graft versus host diseases (GVHD), multiple sclerosis (MS), Crohn's disease (CD), and osteoarthritis (OA), and even in immune-dysregulating infectious diseases such as the novel coronavirus disease 2019 (COVID-19). This paper discussed the therapeutic applications of MSC secretome and its biomedical aspects related to immune-mediated conditions. Sources for MSC extraction, their migration and homing properties, therapeutic molecules released by MSCs, and the pathways and molecular mechanisms possibly involved in the exceptional immunoregulatory competence of MSCs were discussed. Besides, the novel discoveries and recent findings on immunomodulatory plasticity of MSCs, clinical applications, and the methods required for their use as an effective therapeutic option in patients with immune-mediated/immune-dysregulating diseases were highlighted.


Subject(s)
COVID-19 , Immunomodulation , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/immunology , SARS-CoV-2/immunology , COVID-19/immunology , COVID-19/therapy , Humans
14.
J Clin Pathol ; 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1136101

ABSTRACT

BACKGROUND: Secondary haemophagocytic lymphohistiocytosis (sHLH) is characterised by a hyper activation of immune system that leads to multiorgan failure. It is suggested that excessive immune response in patients with COVID-19 could mimic this syndrome. Some COVID-19 autopsy studies have revealed the presence of haemophagocytosis images in bone marrow, raising the possibility, along with HScore parameters, of sHLH. AIM: Our objective is to ascertain the existence of sHLH in some patients with severe COVID-19. METHODS: We report the autopsy histological findings of 16 patients with COVID-19, focusing on the presence of haemophagocytosis in bone marrow, obtained from rib squeeze and integrating these findings with HScore parameters. CD68 immunohistochemical stains were used to highlight histiocytes and haemophagocytic cells. Clinical evolution and laboratory parameters of patients were collected from electronic clinical records. RESULTS: Eleven patients (68.7%) displayed moderate histiocytic hyperplasia with haemophagocytosis (HHH) in bone marrow, three patients (18.7%) displayed severe HHH and the remainder were mild. All HScore parameters were collected in 10 patients (62.5%). Among the patients in which all parameters were evaluable, eight patients (80%) had an HScore >169. sHLH was not clinically suspected in any case. CONCLUSIONS: Our results support the recommendation of some authors to use the HScore in patients with severe COVID-19 in order to identify those who could benefit from immunosuppressive therapies. The presence of haemophagocytosis in bone marrow tissue, despite not being a specific finding, has proved to be a very useful tool in our study to identify these patients.

15.
Hum Vaccin Immunother ; 17(8): 2808-2813, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1114800

ABSTRACT

Conventional vaccines to combat COVID-19 through different approaches are at various stages of development. The complexity of COVID-19 such as the potential mutations of the virus leading to antigenic drift and the uncertainty on the duration of the immunity induced by the vaccine have hampered the efforts to control the COVID-19 pandemic. Thus, we suggest an alternative interim treatment strategy based on biological response modifier glucans such as the Aureobasidium pullulans AFO-202-derived ß-glucan, which has been reported to induce trained immunity, akin to that induced by the Bacille Calmette-Guérin vaccine, by epigenetic modifications at the central level in the bone marrow. These ß-glucans act as pathogen-associated molecular patterns, activating mucosal immunity by binding with specific pathogen recognition receptors such as dectin-1 and inducing both the adaptive and innate immunity by reaching distant lymphoid organs. ß-Glucans have also been used as immune adjuvants for vaccines such as the influenza vaccine. Therefore, until a conventional vaccine is widely available, an orally consumable vaccine adjuvant that acts like biosimilars, termed as the wide-spectrum immune-balancing food-supplement-based enteric (ß-WIFE) vaccine adjuvant approach, with well-reported safety is worth in-depth investigation and can be considered for a clinical trial.


Subject(s)
Biosimilar Pharmaceuticals , COVID-19 , beta-Glucans , Adjuvants, Immunologic , BCG Vaccine , Humans , Immunity, Innate , Pandemics , SARS-CoV-2 , Spouses
16.
Am J Health Syst Pharm ; 78(9): 794-799, 2021 04 22.
Article in English | MEDLINE | ID: covidwho-1093468

ABSTRACT

PURPOSE: To report a case of ribavirin-associated severe hyperuricemia in an immunocompromised patient treated for respiratory syncytial virus (RSV) infection. SUMMARY: A 21-year-old male with a past medical history of B-cell acute lymphoblastic leukemia was in full remission after allogenic bone marrow transplantation complicated with chronic graft-versus-host disease. He was hospitalized due to fever, malaise, and respiratory symptoms. A diagnosis of RSV upper respiratory tract infection complicated by secondary pneumonia was made, and oral ribavirin (600 mg in 3 divided doses daily) and intravenous levofloxacin (750 mg once daily) were initiated. On day 2 of the hospital admission, the patient's uric acid levels had increased from a baseline of 4 to 6 mg/dL to 19.3 and 22.2 mg/dL after the fourth and fifth doses of ribavirin, respectively, and his serum creatinine steadily had increased from a baseline of 0.7 to 0.8 mg/dL to 1.6 mg/dL. Ribavirin was discontinued after the sixth dose, and a single dose of intravenous rasburicase (7.5 mg) was administered. On day 3, the patient's serum uric and creatinine concentrations had decreased to 4.7 mg/dL and 1.1 mg/dL, respectively. He continued to recover on antibiotics and was discharged with normal uric acid and serum creatinine levels. CONCLUSION: We report a case of severe hyperuricemia and acute kidney injury that developed early after initiation of ribavirin for RSV infection and suspected bacterial pneumonia in an immunocompromised patient without hepatitis C, requiring ribavirin discontinuation and rasburicase administration. To our knowledge, this is the first reported case of severe hyperuricemia in a patient treated with ribavirin for RSV infection rather than chronic hepatitis C. Clinicians should be aware of the possibility of acute and severe hyperuricemia following ribavirin administration.


Subject(s)
Acute Kidney Injury , Hyperuricemia , Adult , Creatinine , Humans , Hyperuricemia/chemically induced , Hyperuricemia/diagnosis , Hyperuricemia/drug therapy , Male , Ribavirin/adverse effects , Uric Acid , Young Adult
18.
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
19.
J Ophthalmic Inflamm Infect ; 10(1): 39, 2021 Jan 08.
Article in English | MEDLINE | ID: covidwho-1015833

ABSTRACT

PURPOSE: Acute macular neuroretinopathy (AMN) is a visual-deteriorating rare clinical entity with an uncertain etiology. We aimed to report a case of AMN and underlying disease of acute myeloid leukemia (AML). CASE PRESENTATION: A thirty-five-year-old female patient with bone marrow biopsy confirmed AML, and bicytopenia, under chemotherapy, complained of sudden paracentral visual field defect in her right eye was referred. Visual acuity was 20/20 in both eyes. Posterior segment evaluation revealed multiple Roth's spots. Optical coherence tomography (OCT) demonstrated hyper-reflectivity band, in the outer nuclear layer and outer plexiform layer, nasal to the fovea of the right eye, and hyperreflective patch in outer retina segmentation en-face OCT, suggestive of the diagnosis of AMN. Nine days after AMN diagnosis, dyspnea, malaise, and cough was initiated. Ground glass opacities in lung CT scan, beside reverse transcription polymerase chain reaction of severe acute respiratory syndrome coronavirus-2, was conclusive of coronavirus disease 2019 (COVID-19). The patient deceased after 6 days. CONCLUSION: We report a rare case of AMN following AML. Our findings support the role of ischemia in the outer retina, of which AML may contributed to the pathophysiological process. The patient has deceased less than 2 weeks from AMN initiation.

20.
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
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