Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomized control clinical trial
International journal of antimicrobial agents. 2021;:106334
OBJECTIVE To assess the efficacy of therapeutic plasma exchange (TPE) following life-threatening COVID-19. DESIGN, SETTING, AND PARTICIPANTS Open-label, randomized clinical trial of intensive care unit (ICU) patients with life-threatening COVID-19 [positive real-time-polymerase-chain-reaction test, plus acute respiratory distress syndrome (ARDS), sepsis, organ failure, hyperinflammation]. The study was terminated after 87/120 patients were enrolled. INTERVENTION AND RANDOMIZATION Standard treatment plus TPE (n = 43) versus standard treatment (n = 44), and stratified by peripheral arterial oxygen saturation/fraction of inspired oxygen (PaO(2)/FiO(2)) ratio (> 150 versus ≤ 150). MAIN OUTCOMES AND MEASURES Primary outcomes were 35-day mortality and TPE safety. Secondary outcomes were association between TPE and mortality, improvement in Sequential Organ Function Assessment (SOFA) score, change in inflammatory biomarkers, days on mechanical ventilation (MV), and ICU length-of-stay. RESULTS Eighty-seven patients [median years of age 49 (IQR: 34-63); 72 males (82.8%)] were randomized [44 to standard care; 43 to standard care plus TPE]. Days on MV (p=0.007) and ICU length-of-stay (p=0.02) were lower in the TPE group versus controls. Thirty-five-day mortality was lower in the TPE group (20.9% vs. 34.1% in controls), but this did not reach statistical significance [Kaplan-Meir analysis: p=0.582). TPE was associated with increased lymphocytes and ADAMTS-13 activity; plus decreased serum lactate, lactate dehydrogenase, ferritin, D-dimers, and interleukin-6. Multivariable regression analysis provided several predictors of 35-day mortality: PaO(2)/FiO(2) ratio [hazard ratio (HR): 0.98, 95% CI: 0.96-1.00, p=0.02], ADAMTS-13 activity (HR: 0.89, 95% CI: 0.82-0.98, p=0.01), and PE (HR: 3.57, 95% CI: 1.43-8.92, p=0.007). Post-hoc analysis revealed a significant reduction in SOFA score for TPE patients (p<0.05) compared to controls. CONCLUSION In critically ill COVID-19 patients the addition of TPE to standard ICU therapy was associated with faster clinical recovery and no increased 35-day mortality.
Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomised controlled clinical trial
Int J Antimicrob Agents. 2021;:106334-106334
Assessment of efficacy of therapeutic plasma exchange (TPE) following life-threatening COVID-19. This was an open-label, randomised clinical trial of ICU patients with life-threatening COVID-19 (positive RT-qPCR plus ARDS, sepsis, organ failure, hyperinflammation). Study was terminated after 87/120 patients enrolled. Standard treatment plus TPE (n = 43) versus standard treatment (n = 44), and stratified by PaO2/FiO2 ratio (>150 vs. ≤150), were compared. Primary outcomes were 35-day mortality and TPE safety. Secondary outcomes were association between TPE and mortality, improvement in SOFA score, change in inflammatory biomarkers, days on mechanical ventilation (MV), and ICU length of stay (LOS). Eighty-seven patients [median age 49 (IQR 34-63) years; 82.8% male] were randomised (44 standard care; 43 standard care plus TPE). Days on MV (P = 0.007) and ICU LOS (P = 0.02) were lower in the TPE group. 35-Day mortality was non-significantly lower in the TPE group (20.9% vs. 34.1%; Kaplan-Meier, P = 0.582). TPE was associated with increased lymphocytes and ADAMTS-13 activity and decreased serum lactate, lactate dehydrogenase, ferritin, d-dimers and interleukin-6. Multivariable regression analysis provided several predictors of 35-day mortality: PaO2/FiO2 ratio (HR, 0.98, 95% CI 0.96-1.00; P = 0.02]; ADAMTS-13 activity (HR, 0.89, 95% CI 0.82-0.98; P = 0.01); pulmonary embolism (HR, 3.57, 95% CI 1.43-8.92; P = 0.007). Post-hoc analysis revealed a significant reduction in SOFA score for TPE patients (P < 0.05). In critically-ill COVID-19 patients, addition of TPE to standard ICU therapy was associated with faster clinical recovery and no increased 35-day mortality.
Evaluation of the efficacy and safety of recombinant erythropoietin on the improvement of hospitalised COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial
OBJECTIVES To evaluate the effect of recombinant erythropoietin on hospitalised COVID-19 patients. TRIAL DESIGN Concealed, randomized, single-blinded, phase 2 controlled clinical trial with two arm parallel-group design of 20 patients allocated with 1:1 ratio and using the placebo in the control group. PARTICIPANTS This study will be performed at Shahid Mohammadi Hospital in Bandar Abbas, Hormozgan in Iran. All positive (PCR confirmed) COVID-19 patients ≤65 years old who have Hb≤9 and at least one of the severe COVID-19 symptoms (tachypnea (breathing rate> 30 beats per minute), hypoxemia (O2 ≤93 saturation, the partial pressure ratio of arterial oxygen <300), Lung infiltration (> 50% of lung field within 24 to 48 hours), progressive lymphopenia, LDH>245 U/I, CRP>100) and are willing to cooperate in this project will be included in the study. Patients with a history of coronary heart disease, thrombosis, deep vein thrombosis, chronic lung disease, diabetes mellitus, weakened immune system, end-stage renal disease, liver disease, and patients with a history of taking oral contraceptive pills, systolic blood pressure more than 160 mm Hg, diastolic blood pressure more than 90 mm Hg and age over 65 and erythropoietin above 500 are excluded. INTERVENTION AND COMPARATOR Patients will receive the standard of care (SOC) based on the treatment protocols of the Iranian National Committee of COVID-19 and recombinant erythropoietin (EPREX Manufactured by Johnson and Johnson Pharmaceutical Company) 300 units / Kg or 4000IU as subcutaneous (SQ) injection three times a day for 5 days and simultaneously Enoxaparin 1 mg/kg SQ daily is also taken to prevent thrombosis in the intervention group. Patients' blood pressure, along with other vital signs, are checked regularly and at regular intervals. In the control group, patients received SOC and the placebo (distilled water) is given as a subcutaneous injection three times a day for 5 days. We use sterile water for injection (EXIRpharmaceutical company) as the placebo. To the same appearance of the placebo and the recombinant erythropoietin, they are taken in a separate room in the same size syringes and cover with labels before injection. MAIN OUTCOMES The main outcome for this study is a composite endpoint for Patient clinical symptoms (Respiratory rate, Oxygen saturation state and arterial oxygen partial pressure ratio, Lung infiltration status, blood pressure), Laboratory tests (LDH, CRP, Lymphocyte count, Endogenous erythropoietin, and Haemoglobin level). All of these will be assessed at the beginning of the study (before the intervention) and day 5 after the intervention. The study will also evaluate side effects and how to manage them. RANDOMISATION Eligible participants (20) will be randomized in two arms in the ratio of 1: 1 (10 per arm) by permuted block randomization method using online web-based tools. BLINDING (MASKING): Patients participating in the study will not be aware of the assignment to the intervention or control group. The principal investigator, health care personnel, data collectors, and those evaluating the outcome are aware of patient grouping. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 20 patients will participate in this study, who are randomly allocated to the 2 arms with a 1:1 ratio; 10 patients in the intervention group will receive SOC and recombinant erythropoietin, and 10 patients in the control group will receive SOC and placebo. TRIAL STATUS The protocol version is 3.0, approved by the Deputy of Research and Technology and the ethics committee of Hormozgan University of Medical Sciences on 6(th) June 2020, with the local grant number of 990108. The expected recruitment end date was on 21(th) December 2020 but since we had a wide and careful exclusion criteria because of the adverse reactions of the medication, the recruitment (for both cases and controls) was not so easy and did not finish on the expected date and we are still recruiting now. Recruitment began on 17(th) August 2020 and the updated expected recruitment end date is 1(st) August 2021. TRIAL REGISTRATION The protocol was registered before starting subject recruitment under the title: Evaluation of the effect of recombinant erythropoietin on the improvement of COVID-19 patients, IRCT20200509047364N1, at Iranian Registry of clinical trials ( https://en.irct.ir/trial/49282 ) on 2020/08/09. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).
A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in Coronavirus Disease 2019 Patients With Regular Intravenous Immunoglobulin Therapy
J Infect Dis. 2021;223(9):1538-1543
BACKGROUND Currently, there is no specific drug for the treatment of coronavirus disease 2019 (COVID-19). Therapeutic benefits of intravenous immunoglobulin (IVIG) have been demonstrated in wide range of diseases. The present study is conducted to evaluate the safety and efficacy of IVIG in the treatment of COVID-19 patients with moderate pneumonia. METHODS An open-label, multicenter, comparative, randomized study was conducted on COVID-19 patients with moderate pneumonia. One hundred eligible patients were randomized in 1:1 ratio either to receive IVIG + standard of care (SOC) or SOC. RESULTS Duration of hospital stay was significantly shorter in the IVIG group compared with that of SOC alone (7.7 vs 17.5 days). Duration for normalization of body temperature, oxygen saturation, and mechanical ventilation were significantly shorter in IVIG compared with SOC. Percentages of patients on mechanical ventilation in 2 groups were not significantly different (24% vs 38%). Median time to reverse-transcription polymerase chain reaction negativity was significantly shorter with IVIG than SOC (7 vs 18 days). There were only mild to moderate adverse events in both groups except for 1 patient (2%), who died in SOC. CONCLUSIONS Intravenous immunoglobulin was safe and efficacious as an adjuvant with other antiviral drugs in the treatment of COVID-19.
A Phase II Safety and Efficacy Study on Prognosis of Moderate Pneumonia in COVID-19 patients with Regular Intravenous Immunoglobulin Therapy
The Journal of infectious diseases. 2021
BACKGROUND Currently, there is no specific drug for the treatment of COVID-19. Therapeutic benefits of intravenous immunoglobin (IVIG) have been demonstrated in wide range of diseases. The present study is conducted to evaluate the safety and efficacy of IVIG in the treatment of COVID-19 patients with moderate pneumonia. METHODS An open-label, multicenter, comparative, randomized study was conducted on COVID-19 patients with moderate pneumonia. 100 eligible patients were randomized in 1:1 ratio either to receive IVIG + standard of care (SOC) or SOC. RESULTS Duration of hospital stay was significantly shorter in IVIG group to that of SOC alone (7.7 Vs. 17.5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation in two groups were not significantly different (24% Vs. 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 Vs.18 days). There were only mild to moderate adverse events in both groups except for one patient (2%), who died in SOC. CONCLUSIONS IVIG was safe and efficacious as an adjuvant with other antiviral drugs in the treatment of COVID-19. The trial was registered under Clinical Trial Registry, India (CTRI/2020/06/026222).
COVID-19 patients with moderate pneumonia (n= 100).
Intravenous immunoglobin (IVIG, n= 50).
Standard of care (SOC, n= 50).
Duration of hospital stay was significantly shorter in IVIG group to that of SOC alone (7.7 vs. 17.5 days). Duration for normalization of body temperature, oxygen saturation and mechanical ventilation were significantly shorter in IVIG compared to SOC. Percentages of patients on mechanical ventilation in two groups were not significantly different (24% vs. 38%). Median time to RT-PCR negativity was significantly shorter with IVIG than SOC (7 vs.18 days). There were only mild to moderate adverse events in both groups except for one patient (2%), who died in SOC.
Effect of Methylene Blue Pathogen Inactivation on the Integrity of Immunoglobulin M and G
Transfusion Medicine and Hemotherapy. 2021
Introduction: In the light of the ongoing SARS-CoV-2 pandemic, convalescent plasma is a treatment option for CO-VID-19 In contrast to usual therapeutic plasma, the therapeutic agents of convalescent plasma do not represent clotting factor activities, but immunoglobulins Quarantine storage of convalescent plasma as a measure to reduce the risk of pathogen transmission is not feasible Therefore, pathogen inactivation (e g , Theraflex®-MB, Macopharma, Mouvaux, France) is an attractive option Data on the impact of pathogen inactivation by methylene blue (MB) treatment on antibody integrity are sparse Methods: Antigen-specific binding capacity was tested before and after MB treatment of plasma (n = 10) IgG and IgM isoagglutinin titers were tested by agglutination in increasing dilutions Furthermore, the binding of anti-EBV and anti-tetanus toxin IgG to their specific antigens was assessed by ELISA, and IgG binding to Fc receptors was assessed by flow cytometry using THP-1 cells expressing FcRI and FcRII Results: There was no significant difference in the isoagglutinin titers, the antigen binding capacity of anti-EBV and anti-tetanus toxin IgG, as well as the Fc receptor binding capacity before and after MB treatment of plasma Conclusion: MB treatment of plasma does not inhibit the binding capacity of IgM and IgG to their epitopes, or the Fc receptor interaction of IgG Based on these results, MB treatment of convalescent plasma is appropriate to reduce the risk of pathogen transmission if quarantine storage is omitted
No evidence of SARS-CoV-2 transmission through transfusion of human blood products: A systematic review
The presence of viral nucleic material in the circulation poses a theoretical risk of transmission through transfusion. However, little is known about the possibility of the actual transmission through transfusion or transplantation of blood products. A PROSPERO registered systematic review pooled evidence from PubMed/MEDLINE, Google Scholar and CINAHL. The search included studies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission through human blood products. In total 537 studies were extracted, and only eight articles (1.5%) were eligible for the final analysis. A total of 14 patients received blood products from coronavirus disease-2019 (COVID-19) virus-positive donors, and six (42.9%) tested negative for COVID-19 RT-PCR for up to 14 days post-transfusion/transplantation. There were no documented clinical details on the COVID-19 test for eight (57.1%) blood products recipients. Of the eight patients, none of them developed any COVID-19-related symptoms. In conclusion, there is limited evidence of transfusion transmission of SARS-CoV-2 via human blood products. Consolidation of further evidence, as it emerges, is warranted.
Successful Treatment of Pediatric Inflammatory Multisystem Syndrome Temporally Associated with COVID-19 (PIMS-TS) with Split Doses of Immunoglobulin G and Estimation of PIMS-TS Incidence in a County District in Southern Germany
Pediatric inflammatory multisystem syndrome temporally associated with SARS Cov2 (PIMS-TS) is a newly encountered disease in children sharing clinical features with Kawasaki disease, toxic shock syndrome, or macrophage-activating syndrome Pathogenically, it is associated with immune-mediated post-infectious hyperinflammation leading to short-term myocardial injury with yet unknown long-term outcome We herein present three cases of PIMS-TS treated in our institution with divided doses of immunoglobulins and high dose acetyl salicylic acid, according to existing Kawasaki disease guidelines Due to greater weight in adolescents affected and concerns of rheological sequelae following possible hyperviscosity, doses of immunoglobulins were divided and given 24 h apart with good tolerability All patients recovered rapidly with normalization of previously encountered cardiac manifestations As diagnosis of PIMS-TS should be made promptly, timing of therapy is of paramount importance for a favorable outcome To date, no randomized controlled trial data exist concerning treatment recommendations 1 8% (95% CI: 1 7% to 2 0%) of all children and adolescents in the county district of Ostallgäu were tested positive for SARS CoV-2, incidence of PIMS-TS was 1 7% (95% CI: 0 9% to 3 1%) among SARS CoV-2 positive tested earlier As the pandemic is still ongoing, rising numbers of PIMS-TS in children might be expected
Transfusion requirements in patients with COVID-19
European Journal of Haematology. 2021;106(1):132-134
Since the emergence of COVID‐19 in late 2019, our knowledge of the clinical implications of infection with SARS‐CoV‐2 has steadily grown. The clinical spectrum of COVID‐19 is broad, ranging from asymptomatic infection to multi‐organ failure. COVID‐19 induces a proinflammatory state, activating systemic coagulation and resulting in markedly elevated D‐Dimers, fibrinogen and a prolongation of the prothrombin time (PT) (Tang et al, 2020). Initial studies reported the development of Disseminated Intravascular Coagulation (DIC), associated with poorer outcomes (Tang et al, 2020). DIC results from perturbations in the normal haemostatic balance and may produce a clinical phenotype of thrombosis, bleeding or a combination thereof. Subsequently, the International Society on Thrombosis and Haemostasis (ISTH) issued guidance on the management of DIC in this setting (Thachil et al, 2020). This guidance was controversial, recommending admission based on coagulation parameters and more liberal transfusion thresholds (maintaining platelets >25 in non‐bleeding patients). At this time, COVID‐19 represented a particular challenge to transfusion services as concerns existed that transfusion requirements may be increased at a time of limited donor availability. Despite increasing data on thrombotic sequalae of COVID‐19, there remains a paucity of information on transfusion requirements in this clinical setting. This is of importance, not only for physicians, but for clinical transfusion services in order to plan stock management during the pandemic. To address this deficit, we retrospectively analysed the transfusion records and outcomes of a large cohort of patients with COVID‐19.
Efficacy of IVIG (Intravenous Immunoglobulin) for Corona Virus Disease 2019 (COVID-19): a meta-analysis
International Immunopharmacology. 2021;:107732-107732
Background The benefit of IVIG (Intravenous Immunoglobulin) therapy for COVID-19 remains controversial We performed a meta-analysis to investigate the efficacy of IVIG treatment in patients with COVID-19 Methods We searched articles from Web of Science, PubMed, Embase, the Cochrane Library, MedRxiv between 1 January 2020 and February 17, 2021 We selected randomized clinical trials and observational studies with a control group to assess the efficiency of IVIG in treating patients with COVID-19 Subjects were divided into ‘non-severe’, ‘severe’ and ‘critical’ three subgroups based on the information of the study and the World Health Organization (WHO) definition of severity We pooled the data of mortality and other outcomes using either a fixed-effect model or a random-effects model Results Our meta-analysis retrieved 4 clinical trials and 3 cohort studies including 825 hospitalized patients The severity of COVID-19 is associated with the efficiency of IVIG In critical subgroup, IVIG could reduce the mortality compared with the control group [RR=0 63 (0 45-0 88,I2=25%) But there was no significant difference in the severe or non-severe subgroups Conclusion IVIG has demonstrated clinical efficacy on critical ill patients with COVID-19 There may be a relationship between the efficacy of IVIG and the COVID-19 disease severity Well-designed clinical trials to identify the clinical and biochemical characteristics in COVID-19 patients’ population that could benefit from IVIG are warranted in the future