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1.
Trials ; 22(1): 674, 2021 Oct 02.
Article in English | MEDLINE | ID: covidwho-1448257

ABSTRACT

BACKGROUND: Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state. This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19. METHODS: In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC. In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC. DISCUSSION: We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578210 . First Posted : October 8, 2020.


Subject(s)
COVID-19 , Lymphopenia , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Humans , Immunologic Memory , Killer Cells, Natural , Lymphopenia/diagnosis , Lymphopenia/therapy , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , SARS-CoV-2 , T-Lymphocytes , Treatment Outcome
3.
J Med Virol ; 93(2): 794-802, 2021 02.
Article in English | MEDLINE | ID: covidwho-1196404

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was found in the intestines and feces, but its clinical significance is not completely clear. We aim to characterize the longitudinal test results of SARS-CoV-2 RNA in anal swabs and to explore the association with disease severity. METHODS: We included laboratory-confirmed coronavirus disease 2019 (COVID-19) patients, who were hospitalized in Guangzhou Eighth People's Hospital and excluded those who had not received anal swabs for SARS-COV-2 RNA testing. Epidemiological, clinical, and laboratory data were obtained. Throat swabs and anal swabs were collected periodically for SARS-COV-2 RNA detection. RESULTS: Two hundred and seventeen eligible patients (median aged 50 years, 50.2% were females) were analyzed. 21.2% (46/217) of the patients were detected with SARS-CoV-2 RNA in anal swabs. The duration of viral RNA was longer, but the viral load was lower in anal swabs than throat swabs in the early stage of the disease. During a median follow-up of 20 days, 30 (13.8%) patients were admitted to the intensive care unit (ICU) for high-flow nasal cannula or higher-level oxygen support measures to correct hypoxemia. Detectable viral RNA in anal swabs (adjusted hazard ratio [aHR], 2.50; 95% confidence interval [CI], 1.20-5.24), increased C-reactive protein (aHR, 3.14; 95% CI, 1.35-7.32) and lymphocytopenia (aHR, 3.12; 95% CI, 1.46-6.67) were independently associated with ICU admission. The cumulative incidence of ICU admission was higher among patients with detectable viral RNA in anal swabs (26.3% vs 10.7%, P = .006). CONCLUSION: Detectable SARS-CoV-2 RNA in the digestive tract was a potential warning indicator of severe disease.


Subject(s)
Anal Canal/virology , COVID-19/diagnosis , Lymphopenia/diagnosis , RNA, Viral/genetics , SARS-CoV-2/genetics , Adult , Antiviral Agents/therapeutic use , C-Reactive Protein/metabolism , COVID-19/pathology , COVID-19/therapy , COVID-19/virology , COVID-19 Testing , Chloroquine/therapeutic use , Female , Hospitalization/statistics & numerical data , Humans , Indoles/therapeutic use , Intensive Care Units/statistics & numerical data , Lymphopenia/pathology , Lymphopenia/therapy , Lymphopenia/virology , Male , Middle Aged , Oseltamivir/therapeutic use , Pharynx/virology , Retrospective Studies , SARS-CoV-2/pathogenicity , Severity of Illness Index , Viral Load/drug effects
4.
Blood ; 136(20): 2290-2295, 2020 11 12.
Article in English | MEDLINE | ID: covidwho-950941

ABSTRACT

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.


Subject(s)
Antibodies, Viral/immunology , B-Lymphocytes/pathology , Betacoronavirus/immunology , Coronavirus Infections/immunology , Immune Sera/administration & dosage , Lymphopenia/therapy , Pneumonia, Viral/immunology , Adult , Aged , B-Lymphocytes/immunology , Blood Component Transfusion , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/therapy , Coronavirus Infections/virology , Female , France , Hematologic Neoplasms/complications , Humans , Immunization, Passive , Lymphopenia/etiology , Lymphopenia/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , SARS-CoV-2
6.
Electromagn Biol Med ; 40(1): 11-25, 2021 Jan 02.
Article in English | MEDLINE | ID: covidwho-872877

ABSTRACT

Among haematological parameters of patients seriously ill with the coronavirus infectious disease 2019 (COVID-19), leucocytosis, lymphocytopenia, and the abnormal release of circulating cytokines, termed cytokine storm syndrome (CSS, also known as cytokine release syndrome or CRS), were found associated with disease severity. In particular, according to the serum cytokine profiling, pro-inflammatory interleukin 6 (IL-6) and anti-inflammatory interleukin 10 (IL-10) were observed to be considerably higher in patients experiencing respiratory distress, septic shock and/or multi-organ failure, namely "critical cases" requiring intensive care unit (ICU) admission, very often resulting in death. Interestingly, the production of these cytokines from human lymphocytes was found to be modulated by exposure of 24 h to a 554.2-553.8 mT inhomogeneous static magnetic field (SMF), which elicits IL-10 and suppresses IL-6. Thus, herein, with the aim of restoring lymphocyte count and physiological serum levels of IL-6 and IL-10, the infusion of human leukocyte antigen (HLA)-matched and SMF-exposed allogenic lymphocytes is proposed for the first time as an easy and affordable treatment option for COVID-19 patients. Even if the count of lymphocytes in COVID-19 patients is very low, SMF exposure may be a valuable tool for reprogramming autologous lymphocytes towards physiological conditions. Furthermore, the same procedure could be extended to include the whole autologous or allogenic white blood cells (WBCs). Time-varying/pulsed magnetic fields exerting comparable cell effects could also be employed.


Subject(s)
COVID-19/complications , Cytokine Release Syndrome/therapy , HLA Antigens/immunology , Lymphocytes/cytology , Lymphopenia/therapy , Magnetic Fields , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Humans , Immunotherapy , Interleukin-6/chemistry , Interleukin-6/metabolism , Lymphocytes/immunology , Lymphopenia/complications , Lymphopenia/immunology , Lymphopenia/pathology , Models, Molecular , Protein Conformation , Signal Transduction/immunology
7.
Hum Antibodies ; 29(1): 49-54, 2021.
Article in English | MEDLINE | ID: covidwho-807231

ABSTRACT

Coronavirus disease 2019 (COVID-19) has caused a global pandemic in early 2020. This infectious disorder has a heterogeneous course ranging from asymptomatic disorder to a critical situation needing intensive cares. In the current study, we present a report of affected patients admitted in a single hospital in Iran. Eighty-two hospitalized patients with COVID-19 were assessed. Demographic, clinical, and paraclinical parameters were gathered and statistically analyzed. The median age (IQR) of the patients was 57.32 (45.75, 70) years. At primary evaluation, fever was present in 45.12% of the affected individuals. The most common clinical symptoms were dyspnea (81.71%) and cough (65.85%). Totally, 12 (14.63%) and 14 (17.07%) of patients had low and high WBC counts, respectively. Lymphopenia was detected in 36 (43.9%) of patients, while 6 (7.32%) of patients had lymphocytosis. High levels of Il-6 were detected in 4 (4.88%) of patients. CRP levels were elevated in 69 (84.1%) of patients. The median (IQR) of hospitalization was 7 (5, 9) days. Totally, 26 patients (31%) were hospitalized in ICU. All patients were discharged with good health conditions except for one patient who died. The current study shows the heterogeneous clinical manifestations and paraclinical parameters of COVID-19 patients.


Subject(s)
COVID-19/physiopathology , Cough/physiopathology , Dyspnea/physiopathology , Fever/physiopathology , Lymphocytosis/physiopathology , Lymphopenia/physiopathology , Aged , C-Reactive Protein/metabolism , COVID-19/mortality , COVID-19/therapy , COVID-19/virology , Cough/mortality , Cough/therapy , Cough/virology , Diabetes Mellitus/mortality , Diabetes Mellitus/physiopathology , Diabetes Mellitus/therapy , Diabetes Mellitus/virology , Dyspnea/mortality , Dyspnea/therapy , Dyspnea/virology , Female , Fever/mortality , Fever/therapy , Fever/virology , Hospitals , Humans , Hypertension/mortality , Hypertension/physiopathology , Hypertension/therapy , Hypertension/virology , Iran , Leukocyte Count , Lymphocytosis/mortality , Lymphocytosis/therapy , Lymphocytosis/virology , Lymphopenia/mortality , Lymphopenia/therapy , Lymphopenia/virology , Male , Middle Aged , Obesity/mortality , Obesity/physiopathology , Obesity/therapy , Obesity/virology , Oxygen/therapeutic use , Respiration, Artificial/methods , Retrospective Studies , SARS-CoV-2/pathogenicity , Severity of Illness Index , Survival Analysis
9.
Am J Case Rep ; 21: e925779, 2020 Aug 13.
Article in English | MEDLINE | ID: covidwho-713485

ABSTRACT

BACKGROUND Coronavirus disease 2019 (COVID-19) infection commonly presents as fever, cough, and shortness of breath in adults. Children are thought to have milder respiratory symptoms and to recover more quickly. We describe a new presentation of COVID-19 infection in children consisting of multisystem inflammation with decreased left ventricular function and evidence of lung disease. CASE REPORT Three children presented with fever, conjunctivitis, dry and cracked lips, rash, and/or cervical lymphadenopathy for at least 5 days. Two of these children required mechanical ventilation, and 1 of the 2 needed extracorporeal membrane oxygenation (ECMO) to support cardiorespiratory function. All of these children had moderate to severe hyponatremia and lymphopenia, which is usually seen in COVID-19. They were treated with intravenous immunoglobulin and high-dose aspirin. All of the children recovered. CONCLUSIONS Early recognition of children with multisystem inflammation is important because they are at increased risk for deterioration. Treatment with intravenous immunoglobulin and aspirin was used because this regimen has been shown to be beneficial in vasculitis of Kawasaki disease. The development of shock due to cardiac involvement may require ECMO.


Subject(s)
Betacoronavirus , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Systemic Inflammatory Response Syndrome/virology , Antipyretics/therapeutic use , Aspirin/therapeutic use , COVID-19 , Child , Child, Preschool , Conjunctivitis/therapy , Conjunctivitis/virology , Coronavirus Infections/therapy , Exanthema/therapy , Exanthema/virology , Extracorporeal Membrane Oxygenation , Female , Fever/therapy , Fever/virology , Heart Failure/therapy , Heart Failure/virology , Humans , Hyponatremia/therapy , Hyponatremia/virology , Immunoglobulins, Intravenous , Lymphadenopathy/therapy , Lymphadenopathy/virology , Lymphopenia/therapy , Lymphopenia/virology , Male , Pandemics , Pneumonia, Viral/therapy , Respiration, Artificial , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/diagnosis , Systemic Inflammatory Response Syndrome/therapy , Vasculitis/therapy , Vasculitis/virology
10.
Acta Haematol ; 144(1): 10-23, 2021.
Article in English | MEDLINE | ID: covidwho-690361

ABSTRACT

Coronavirus disease 2019 (COVID-19) is affecting millions of patients worldwide. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family Coronaviridae, with 80% genomic similarities to SARS-CoV. Lymphopenia was commonly seen in infected patients and has a correlation to disease severity. Thrombocytopenia, coagulation abnormalities, and disseminated intravascular coagulation were observed in COVID-19 patients, especially those with critical illness and non-survivors. This pandemic has caused disruption in communities and hospital services, as well as straining blood product supply, affecting chemotherapy treatment and haematopoietic stem cell transplantation schedule. In this article, we review the haematological manifestations of the disease and its implication on the management of patients with haematological disorders.


Subject(s)
Disseminated Intravascular Coagulation , Hematopoietic Stem Cell Transplantation , Lymphopenia , Pandemics , SARS-CoV-2/metabolism , Thrombocytopenia , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Disseminated Intravascular Coagulation/blood , Disseminated Intravascular Coagulation/mortality , Disseminated Intravascular Coagulation/therapy , Disseminated Intravascular Coagulation/virology , Humans , Lymphopenia/blood , Lymphopenia/mortality , Lymphopenia/therapy , Lymphopenia/virology , Thrombocytopenia/blood , Thrombocytopenia/mortality , Thrombocytopenia/therapy , Thrombocytopenia/virology
11.
Clin Immunol ; 217: 108486, 2020 08.
Article in English | MEDLINE | ID: covidwho-436697

ABSTRACT

The lymphopenia exhibited in patients with COVID-19 has been associated with a worse prognosis in the development of the disease. To understand the factors associated with a worse evolution of COVID-19, we analyzed comorbidities, indicators of inflammation such as CRP and the ratio of neutrophils/lymphocytes, as well as the count of blood cells with T-lymphocyte subtypes in 172 hospitalized patients with COVID-19 pneumonia. Patients were grouped according to their needs for mechanical ventilation (ICU care) or not. Within the comorbidities studied, obesity was the only associated with greater severity and ICU admission. Both the percentage and the absolute number of neutrophils were higher in patients needing ICU care than non-ICU patients, whereas absolute lymphocyte count, and especially the percentage of lymphocytes, presented a deep decline in critical patients. There was no difference between the two groups of patients for CD4 T-lymphocytes, neither in percentage of lymphocyte nor in absolute number, however for CD8 T-cells the differences were significant for both parameters which were in decline in ICU patients. There was a firm correlation between the highest values of inflammation indicators with the decrease in percentage of CD8 T-lymphocytes. This effect was not seen with CD4 cells. Obesity together with lymphopenia, especially whether preferentially affects to CD8 T- lymphocytes, are factors that can predict a poor prognosis in patients with COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , CD8-Positive T-Lymphocytes/pathology , Coronavirus Infections/immunology , Lymphopenia/immunology , Neutrophils/pathology , Obesity/immunology , Pneumonia, Viral/immunology , Aged , Aged, 80 and over , Betacoronavirus/immunology , Biomarkers/blood , C-Reactive Protein/metabolism , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/pathology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19 , Case-Control Studies , Coronavirus Infections/complications , Coronavirus Infections/mortality , Coronavirus Infections/therapy , Female , Humans , Intensive Care Units , Lymphocyte Count , Lymphopenia/complications , Lymphopenia/mortality , Lymphopenia/therapy , Male , Middle Aged , Neutrophils/immunology , Neutrophils/virology , Obesity/complications , Obesity/mortality , Obesity/therapy , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/mortality , Pneumonia, Viral/therapy , Prognosis , Respiration, Artificial , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Survival Analysis
12.
Cell Biol Int ; 44(9): 1792-1797, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-382103

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is uncontrollably spread all over the world. The host immune responses strongly try to confront it with all the potential cells and cytokines. With chronically condition of SARS-CoV-2, natural killer cells and T cells become exhausted and decreasing their count leads to lymphopenia. Inability to eradicate the infected organ makes hyperinitiation of the immune system, which releases the excessive inflammatory cytokines to compensate the exhausted one as well as the low lymphocytes counts; it consequently leads to the cytokine storm syndrome. These mechanisms and the potential therapeutic targeting are discussed in this paper.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Coronavirus Infections/therapy , Lymphopenia/immunology , Lymphopenia/therapy , Pneumonia, Viral/immunology , Pneumonia, Viral/therapy , COVID-19 , Coronavirus Infections/epidemiology , Cytokines/antagonists & inhibitors , Cytokines/immunology , Humans , Immunosuppressive Agents/administration & dosage , Immunotherapy/methods , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Lymphopenia/epidemiology , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
13.
J Exp Med ; 217(6)2020 06 01.
Article in English | MEDLINE | ID: covidwho-156716

ABSTRACT

The novel 2019 strain of coronavirus is a source of profound morbidity and mortality worldwide. Compared with recent viral outbreaks, COVID-19 infection has a relatively high mortality rate, the reasons for which are not entirely clear. Furthermore, treatment options for COVID-19 infection are currently limited. In this Perspective, we explore the contributions of the innate and adaptive immune systems to both viral control as well as toxicity during COVID-19 infections and offer suggestions to both understand and therapeutically modulate anti-COVID immunity.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Adaptive Immunity/drug effects , Adaptive Immunity/immunology , Betacoronavirus/drug effects , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/therapy , Humans , Hypoxia/pathology , Hypoxia/therapy , Immunity, Innate/drug effects , Immunity, Innate/immunology , Inflammation/immunology , Inflammation/pathology , Inflammation/therapy , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Lymphopenia/immunology , Lymphopenia/pathology , Lymphopenia/therapy , Macrophages/immunology , Macrophages/pathology , Middle East Respiratory Syndrome Coronavirus/immunology , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Respiration, Artificial , Respiratory Distress Syndrome/pathology , Respiratory Distress Syndrome/therapy , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2
14.
Acta Haematol ; 143(5): 410-416, 2020.
Article in English | MEDLINE | ID: covidwho-94334

ABSTRACT

We provide our recommendations (not evidence based) for managing multiple myeloma patients during the pandemic of COVID-19. We do not recommend therapy for smoldering myeloma patients (standard or high risk). Screening for COVID-19 should be done in all patients before therapy. For standard-risk patients, we recommend the following: ixazomib, lenalidomide, and dexamethasone (IRd) (preferred), cyclophosphamide lenalidomide and dexamethasone (CRd), daratumumab lenalidomide and dexamethasone (DRd), lenalidomide, bortezomib, and dexamethasone (RVd), or cyclophosphamide, bortezomib, and dexamethasone (CyBorD). For high-risk patients we recommend carfilzomib, lenalidomide, and dexamethasone (KRd) (preferred) or RVd. Decreasing the dose of dexamethasone to 20 mg and giving bortezomib subcutaneously once a week is recommended. We recommend delaying autologous stem cell transplant (ASCT), unless the patient has high-risk disease that is not responding well, or if the patient has plasma cell leukemia (PCL). Testing for COVID-19 should be done before ASCT. If a patient achieves a very good partial response or better, doses and frequency of drug administration can be modified. After 10-12 cycles, lenalidomide maintenance is recommended for standard-risk patients and bortezomib or ixazomib are recommended for high-risk patients. Daratumumab-based regimens are recommended for relapsed patients. Routine ASCT is not recommended for relapse during the epidemic unless the patient has an aggressive relapse or secondary PCL. Patients on current maintenance should continue their therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphopenia/therapy , Multiple Myeloma/therapy , Pandemics , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Clinical Decision-Making , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dexamethasone/therapeutic use , Disease Management , Hematopoietic Stem Cell Transplantation/methods , Humans , Lymphopenia/epidemiology , Lymphopenia/immunology , Lymphopenia/virology , Multiple Myeloma/epidemiology , Multiple Myeloma/immunology , Multiple Myeloma/virology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Risk Assessment , SARS-CoV-2 , Time Factors , Transplantation, Autologous
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