Investigation of plasma exchange and hemoperfusion effects and complications for the treatment of patients with severe COVID-19 (SARS-CoV-2) disease: a systematic scoping review
Journal of Medical Virology. 2021
BACKGROUND Some previous studies suggested that the plasma exchange (PE) and hemoperfusion (HP) played a cardinal role in treatment of severe COVID-19 cases through diminishing the cytokine storm. This study aimed to assess the effects of PE and HP on cytokine storm in patients with severe COVID-19 through a systematic scoping review. METHODS Four Electronic databases [Medline (accessed from PubMed), Scopus, Science Direct, and Cochrane library] were searched systematically on February 2, 2021 using MESH terms and related keywords in English language. Considering the titles and abstracts, unrelated studies were excluded. The full texts of the remained studies were evaluated by authors, independently. Then, their findings were assessed and reported. RESULTS Total of 755 articles were obtained within the first step of searching, and 518 ones remained after removing the duplications. Through the title and abstract screening, 438 were removed. Of the rest, 59 papers were excluded. Finally, after reading the full text of the remained articles, 21 ones included in data extraction. Most of the previous reported evidence were case reports and case series. Findings were summarized in two categories; First category encompassed nine studies regarding to HP and continuous renal replacement therapy (CRRT), and second category was included twelve studies about PE. CONCLUSION The results revealed that HP and PE within the cytokine storm phase would be beneficial with high probability in the treatment of severely ill COVID-19 patients. This article is protected by copyright. All rights reserved.
Hyperimmune anti-COVID-19 IVIG (C-IVIG) treatment in severe and critical COVID-19 patients: A phase I/II randomized control trial
BACKGROUND Hyperimmune anti-COVID-19 Intravenous Immunoglobulin (C-IVIG) is an unexplored therapy amidst the rapidly evolving spectrum of medical therapies for COVID-19 and is expected to counter the three most life-threatening consequences of COVID-19 including lung injury by the virus, cytokine storm and sepsis. METHODS A single center, phase I/II, randomized controlled, single-blinded trial was conducted at Dow University of Health Sciences, Karachi, Pakistan. Participants were COVID-19 infected individuals, classified as either severely or critically ill with Acute Respiratory Distress Syndrome (ARDS). Participants were randomized through parallel-group design with sequential assignment in a 4:1 allocation to either intervention group with four C-IVIG dosage arms (0.15, 0.20, 0.25, 0.30 g/kg), or control group receiving standard of care only (n = 10). Primary outcomes were 28-day mortality, patient's clinical status on ordinal scale and Horowitz index (HI), and were analysed in all randomized participants that completed the follow-up period (intention-to-treat population). The trial was registered at clinicaltrials.gov (NCT04521309). FINDINGS Fifty participants were enrolled in the study from June 19, 2020 to February 3, 2021 with a mean age of 56.54±13.2 years of which 22 patients (44%) had severe and 28 patients (56%) had critical COVID-19. Mortality occurred in ten of 40 participants (25%) in intervention group compared to six of ten (60%) in control group, with relative risk reduction in intervention arm I (RR, 0.333; 95% CI, 0.087-1.272), arm II (RR, 0.5; 95% CI, 0.171-1.463), arm III (RR, 0.167; 95% CI, 0.024-1.145), and arm IV (RR, 0.667; 95% CI, 0.268-1.660). In intervention group, median HI significantly improved to 359 mmHg [interquartile range (IQR) 127-400, P = 0.009)] by outcome day, while the clinical status of intervention group also improved as compared to control group, with around 15 patients (37.5%) being discharged by 7th day with complete recovery. Additionally, resolution of chest X-rays and restoration of biomarkers to normal levels were also seen in intervention groups. No drug-related adverse events were reported during the study. INTERPRETATION Administration of C-IVIG in severe and critical COVID-19 patients was safe, increased the chance of survival and reduced the risk of disease progression. FUNDING Higher Education Commission (HEC), Pakistan (Ref no. 20-RRG-134/RGM/R&D/HEC/2020).
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.
Low risk of SARS-CoV-2 in blood transfusion
PloS one. 2021;16(4):e0249069
BACKGROUND The novel coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), continues to remain a global challenge. There is emerging evidence of SARS-CoV-2 virus found in the blood of patients from China and some developed countries. However, there is inadequate data reported in Ghana and other parts of Africa, where blood transfusion service heavily relies on voluntary and replacement blood donors. This study aimed to investigate whether plasma of infected individuals could pose significant transfusion transmitted risk of COVID-19 in Ghanaian populations. METHODS This cross-sectional retrospective study was conducted at the Kumasi Centre for Collaborative Research into Tropical Medicine (KCCR), KNUST, Ghana. Study subjects comprised contacts of COVID-19 individuals, those with classical symptoms of COVID-19 and individuals who had recovered based on the new Ghana discharge criteria. Whole blood, sputum or deep coughed saliva samples were collected and transported to KCCR for SARS-CoV-2 testing. Viral nucleic acid was extracted from sputum/nasopharyngeal samples using Da An Gene column based kit and from plasma using LBP nucleic acid extraction kit. Real-Time PCR was performed specifically targeting the ORF1ab and Nucleocapsid (N) genomic regions of the virus. RESULTS A total of 97 individuals were recruited into the study, with more than half being males (58; 59.7%). The mean age of all subjects was 33 years (SD = 7.7) with minimum being 22 years and maximum 56 years. Majority (76; 78.4%) of all the subjects were asymptomatic, and among the few symptomatic subjects, cough (10; 10.3%) was the most predominant symptom. Of the 97 sputum samples tested, 79 (81.4%) were positive for SARS-CoV-2. We identified SARS-CoV-2 viral RNA in the plasma of 1 (1.03%) subject who had clinically recovered. CONCLUSION This study reports the identification of SARS-CoV-2 viral RNA in a convalescent individual in Ghana. Due to the low prevalence observed and the marginal cycling thresholds associated, the risk of transfusion transmission of SARS-CoV-2 is negligible. Well-powered studies and advanced diagnostics to determine infectious viremia is recommended to further evaluate the potential risk of hematogenous transmission among recovered patients.
Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children
IMPORTANCE Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. OBJECTIVE To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. EXPOSURES IVIG and methylprednisolone vs IVIG alone. MAIN OUTCOMES AND MEASURES The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. RESULTS Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). CONCLUSIONS AND RELEVANCE Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.
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 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.
The Impact of COVID-19 on Blood Transfusion Services: A Systematic Review and Meta-Analysis
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur Transfusionsmedizin und Immunhamatologie. 2021;30:1-12
INTRODUCTION While SARS-CoV-2's main transmission route is through respiratory droplets, research has found that viral RNA could be detected in blood samples, causing concerns over the safety of blood donations and blood products. This paper therefore aims to systematically search for studies that have addressed their country's lack of donations and analyse the risk of blood transfusion-transmission. As such, it will answer the question "should blood services focus more on donation vigilance or worry more about the risks of transmission through blood products?" METHODS 38 articles were identified through a systematic review adopting the PRISMA and STROBE guidelines. Meta-analysis was conducted using OpenMeta software. RESULTS The average decrease in blood donations was found to be 38%, with some regions showing up to 67% decrease. To assess the risk of actual blood transfusion-transmission, three datasets were analysed. Firstly, the viral load in COVID-19 patients was studied and found to have less than 1% detection rate (ARD = -0.831, 95% -0.963, -0.699). Secondly, the prevalence of finding viral RNA in a pool of donations was nearly -1.503 (ARD = -1.538, -1.468). Lastly, recipients who were given blood products of positive donors were found to be -0.911 (ARD 95% = -1.247, -0.575). DISCUSSION/CONCLUSION Blood centres should focus more on launching initiatives and policies that would increase their countries' blood supply as the virus has no direct threat to blood safety.
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.
Antiviral agents, glucocorticoids, antibiotics, and intravenous immunoglobulin usage in 1142 patients with coronavirus disease 2019: a systematic review and meta-analysis
Pol Arch Intern Med. 2020
INTRODUCTION Treatment effects of antiviral agents, glucocorticoids, antibiotics, and intravenous immunoglobulin are controversial in patients with Coronavirus disease 2019 (COVID-19). OBJECTIVES To evaluate the impact of drug therapy on the risk of death in patients with COVID-19. PATIENTS AND METHODS The PubMed, EMBASE, Web of Science, Cochrane Library, and major preprint platforms were searched to retrieve articles till 7 April 2020. The effects of specific drug interventions on mortality were assessed in COVID-19 patients. Odds ratios (ORs) and Risk Ratios (RRs) with corresponding 95% confidence intervals (CIs) were pooled using random-effects models. RESULTS Of 3421 references, six studies were included. Pooled results from retrospective studies revealed that antiviral agents may contribute to survival benefit (OR, 0.42, 95% CI, 0.17-0.99, p=0.048, I2=82.8%), while the RCT found no effects of antiviral agent on mortality (RR 0.77, 95% CI, 0.45-1.30, p=0.33). Glucocorticoids usage leads to an increased risk of death (OR 2.43, 95% CI, 1.44-4.10, p=0.001, I2=61.9%). Antibiotics intervention did not significantly affect mortality (OR 1.13, 95% CI, 0.67-1.89, p=0.64, I2=0%). Likewise, intravenous immunoglobulin had non-significant effects on mortality (OR 2.66, 95% CI, 0.72-9.89, p=0.14, I2=93.1%). CONCLUSIONS With the varied heterogeneities across interventions, the current evidence indicated a probable survival benefit of antiviral agent usage and a harmful effect of glucocorticoids in patients with COVID-19. None of antibiotics or intravenous immunoglobulin usage was associated with survival benefit in patients with COVID-19.