Abstract

We conducted this systematic review and meta-analysis to evaluate the existing evidence and to quantitatively synthesise evidence on the impact of therapeutic plasma exchange (TPE) on severe COVID-19 patients. This systematic review and meta-analysis protocol was prospectively registered on PROSPERO (CRD42022316331). We systemically searched six electronic databases (PubMed, Scopus, Web of Science, ScienceDirect, clinicaltrial.gov, and Cochrane Central Register of Controlled Trials) from inception until 1 June 2022. We included studies comparing patients who received TPE versus those who received the standard treatment. For risk of bias assessment, we used the Cochrane risk of bias assessment tool, the ROBINS1 tool, and the Newcastle Ottawa scale for RCTs, non-RCTs, and observational studies, respectively. Continuous data were pooled as standardized mean difference (SMD), and dichotomous data were pooled as risk ratio in the random effect model with the corresponding 95% confidence intervals (CI). Thirteen studies (one randomized controlled trials (RCT) and 12 non-RCTs) were included in the meta-analysis, with a total of 829 patients. There is a moderate-quality evidence from one RCT that TPE reduces the lactic dehydrogenase (LDH) levels (SMD -1.09, 95% CI [-1.59 to -0.60]), D-dimer (SMD -0.86, 95% CI [-1.34 to -0.37]), and ferritin (SMD -0.70, 95% CI [-1.18 to -0.23]), and increases the absolute lymphocyte count (SMD 0.54, 95% CI [0.07-1.01]), There is low-quality evidence from mixed-design studies that TPE was associated with lower mortality (relative risk 0.51, 95% CI [0.35-0.74]), lower IL-6 (SMD -0.91, 95% CI [-1.19 to -0.63]), and lower ferritin (SMD -0.51, 95% CI [-0.80 to -0.22]) compared to the standard control. Among severely affected COVID-19 patients, TPE might provide benefits such as decreasing the mortality rate, LDH, D-dimer, IL-6, and ferritin, in addition to increasing the higher absolute lymphocyte count. Further well-designed RCTs are needed.

Abstract

Background and Objectives: Due to the poor prognosis and the very high mortality rate associated with severe SARS-CoV-2 infections, various regimens have been tried to stop the evolution of the inflammatory cascade, such as immunomodulatory therapy and plasma clearance of the acute phase reactants involved. Therefore, the objective of this review was to analyze the effects of using therapeutic plasma exchange (TPE), also known as plasmapheresis, on the inflammatory markers of critically ill COVID-19 patients admitted to the intensive care unit (ICU). Materials and Methods: A thorough scientific database search was performed, and it included a review of articles published on PubMed, Cochrane Database, Scopus, and Web of Science from the beginning of the COVID-19 pandemic in March 2020 until September 2022 that focused on the treatment of SARS-CoV-2 infections using plasma exchange for patients admitted to the ICU. The current study included original articles, reviews, editorials, and short or special communications regarding the topic of interest. Results: A total of 13 articles were selected after satisfying the inclusion criterion of three or more patients enrolled with clinically severe COVID-19 that were eligible for TPE. From the included articles, it was observed that TPE was used as a last-resort salvage therapy that can be regarded as an alternative treatment method when the standard management for these patients fails. TPE significantly decreased the inflammatory status as measured by Interleukin-6 (IL-6), C-reactive protein (CRP), lymphocyte count, and D-dimers, as well as improving the clinical status measured with PaO(2)/FiO(2) and duration of hospitalization. The pooled mortality risk reduction after TPE was 20%. Conclusions: There are sufficient studies and evidence to show that TPE reduces inflammatory mediators and improves coagulation function and the clinical/paraclinical status. Nevertheless, although it was shown that TPE decreases the severe inflammatory status without significant complications, the improvement of survival rate remains unclear.

Abstract

BACKGROUND The post-COVID-19 condition (PCC) consists of a wide array of symptoms including fatigue and impaired daily living. People seek a wide variety of approaches to help them recover. A new belief, arising from a few laboratory studies, is that 'microclots' cause the symptoms of PCC. This belief has been extended outside these studies, suggesting that to recover people need plasmapheresis (an expensive process where blood is filtered outside the body). We appraised the laboratory studies, and it was clear that the term 'microclots' is incorrect to describe the phenomenon being described. The particles are amyloid and include fibrin(ogen); amyloid is not a part of a thrombus which is a mix of fibrin mesh and platelets. Initial acute COVID-19 infection is associated with clotting abnormalities; this review concerns amyloid fibrin(ogen) particles in PCC only. We have reported here our appraisal of laboratory studies investigating the presence of amyloid fibrin(ogen) particles in PCC, and of evidence that plasmapheresis may be an effective therapy to remove amyloid fibrin(ogen) particles for treating PCC. OBJECTIVES Laboratory studies review To summarize and appraise the research reports on amyloid fibrin(ogen) particles related to PCC. Randomized controlled trials review To assess the evidence of the safety and efficacy of plasmapheresis to remove amyloid fibrin(ogen) particles in individuals with PCC from randomized controlled trials. SEARCH METHODS Laboratory studies review We searched for all relevant laboratory studies up to 27 October 2022 using a comprehensive search strategy which included the search terms 'COVID', 'amyloid', 'fibrin', 'fibrinogen'. Randomized controlled trials review We searched the following databases on 21 October 2022: Cochrane COVID-19 Study Register; MEDLINE (Ovid); Embase (Ovid); and BIOSIS Previews (Web of Science). We also searched the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov for trials in progress. SELECTION CRITERIA Laboratory studies review Laboratory studies that investigate the presence of amyloid fibrin(ogen) particles in plasma samples from patients with PCC were eligible. This included studies with or without controls. Randomized controlled trials review Studies were eligible if they were of randomized controlled design and investigated the effectiveness or safety of plasmapheresis for removing amyloid fibrin(ogen) particles for treating PCC. DATA COLLECTION AND ANALYSIS Two review authors applied study inclusion criteria to identify eligible studies and extracted data. Laboratory studies review We assessed the risk of bias of included studies using pre-developed methods for laboratory studies. We planned to perform synthesis without meta-analysis (SWiM) as described in our protocol. Randomized controlled trials review We planned that if we identified any eligible studies, we would assess risk of bias and report results with 95% confidence intervals. The primary outcome was recovery, measured using the Post-COVID-19 Functional Status Scale (absence of symptoms related to the illness, ability to do usual daily activities, and a return to a previous state of health and mind). MAIN RESULTS Laboratory studies review We identified five laboratory studies. Amyloid fibrin(ogen) particles were identified in participants across all studies, including those with PCC, healthy individuals, and those with diabetes. The results of three studies were based on visual images of amyloid fibrin(ogen) particles, which did not quantify the amount or size of the particles identified. Formal risk of bias assessment showed concerns in how the studies were conducted and reported. This means the results were insufficient to support the belief that amyloid fibrin(ogen) particles are associated with PCC, or to determine whether there is a difference in the amount or size of amyloid fibrin(ogen) particles in the plasma of people with PCC compared to healthy controls. Randomized controlled trials review We identified no trials meeting our inclusion criteria. AUTHORS' CONCLUSIONS In the absence of reliable research showing that amyloid fibrin(ogen) particles contribute to the pathophysiology of PCC, there is no rationale for plasmapheresis to remove amyloid fibrin(ogen) particles in PCC. Plasmapheresis for this indication should not be used outside the context of a well-conducted randomized controlled trial.

Abstract

BACKGROUND With the emergence of the coronavirus disease 2019 (COVID-19) and inability of healthcare systems to control the disease, various therapeutic theories with controversial responses have been proposed. Plasmapheresis was administered as a medication. However, the knowledge of its efficacy and indications is inadequate. This study evaluated the use of plasmapheresis in critically ill patients with cancer. METHODS This randomized clinical trial was conducted on 86 patients with malignancies, including a control group (N=41) and an intervention group (N=45) with severe COVID-19 during 2020-21. Both groups were treated with routine medications for COVID-19 management according to national guidelines, and plasmapheresis was applied to the intervention group. C-reactive protein (CRP), D-dimer, ferritin, lactate dehydrogenase, hemoglobin, and white blood cell, polymorphonuclear, lymphocyte, and platelet levels were measured at admission and at the end of plasmapheresis. Other variables included neutrophil recovery, intensive care unit admission, intubation requirements, length of hospital stay, and hospitalization outcomes. RESULTS CRP (p<0.001), D-dimer (p<0.001), ferritin (p=0.039), and hemoglobin (p=0.006) levels were significantly different between the groups after the intervention. Neutrophil recovery was remarkably higher in the case than in the control group (p<0.001). However, plasmapheresis did not affect the length of hospital stay (p=0.076), which could have significantly increased survival rates (p<0.001). CONCLUSION Based on the study findings, plasmapheresis led to a significant improvement in laboratory markers and survival rate in patients with severe COVID-19. These findings reinforce the value of plasmapheresis in cancer patients as a critical population suffering from neutropenia and insufficient immune responses.

Abstract

BACKGROUND AND OBJECTIVES Therapeutic plasma exchange (TPE) has been used in severe COVID-19 disease to eliminate the cytokine storm. This meta-analysis aims to assess the effectiveness of TPE in reducing mortality in severe COVID-19 disease compared to standard treatment. MATERIALS AND METHODS A comprehensive literature search was performed in PubMed, the Cochrane database and the International Clinical Trial Registry Platform (ICTRP). The random-effect model was used to calculate the risk ratio and standardized mean difference (SMD) as pooled effect size for the difference in mortality and length of the intensive care unit (ICU) stay. The risk of bias and publication bias were assessed in R version 4.1.0. The certainty of the evidence was calculated using the GradePro tool. RESULTS The database identified 382 participants from six studies, including one randomized control trial. Egger's test did not detect any publication bias (p = 0.178). The random model analysis for mortality evaluated a risk ratio of 0.38 (95% CI: 0.28-0.52) with a significant reduction in the TPE group. The certainty of the evidence was moderate, with a risk ratio of 0.34 (95% CI: 0.24-0.49). Length of ICU stays between TPE versus standard care showed an SMD of 0.08 (95% CI: -0.38, 0.55) and was not significant. CONCLUSION The length of ICU stay in the TPE group was not different from standard care. However, this meta-analysis revealed a significant benefit of TPE in reducing mortality in severe COVID-19 disease compared to standard treatment.

Abstract

BACKGROUND This study sought to evaluate and compare the effectiveness of plasmapheresis, Tocilizumab, and Tocilizumab with plasmapheresis treatment on the removal of inflammatory cytokines and improvement clinically of patients with severe COVID-19 in Intensive Care Units (ICU) due to the association between increased cytokine release and the severity of COVID-19. METHODS This clinical trial study was conducted in three treatment arms in Iran. All patients received standard care and randomization into one of three treatment groups; Tocilizumab (TCZ) alone, plasmapheresis alone, or a combination of Tocilizumab and plasmapheresis. Demographics, clinical evaluation, oxygenation status, laboratory tests and imaging data were evaluated in the three groups and re-checked 48 h after the end of treatment trials. Primary outcomes were oxygenation status, the need for mechanical ventilation and the rate of death. RESULTS Ninety-four patients were included in the trial after meeting the eligibility requirements. Twenty-eight patients received Tocilizumab alone, 33 had plasmapheresis alone, and 33 received both Tocilizumab and plasmapheresis. Baseline characteristics did not differ between three groups that included demographic, clinical and laboratory parameters. Following therapy, there was no difference between the three groups for CRP, ferritin, d-dimer, IL-6, pro-calcitonin and neutrophil to lymphocyte ratio (NLR) (P > 0.05). While a significant reduction was found in CRP levels within each group (32.04 ± 42.43 to 17.40 ± 38.11, 51.28 ± 40.96 to 26.36 ± 33.07 and 41.20 ± 34.27 to 21.56 ± 24.96 in the tocilizumab, plasmapheresis, and combined group, respectively) (p < 0.05), procalcitonin levels were elevated significantly in the Tocilizumab group (0.28 ± 0.09 to 0.37 ± 0.11) (p < 0.05). Clinically there was no difference between the three groups following treatment for O(2) saturation levels with supplementary oxygen at discharge, endotracheal intubation rate, use of NIVPP, mortality, mean hospital and ICU length of stay (p > 0.05). CONCLUSION Study results showed that the reduction of serum inflammatory markers, the rate of intubation and therapeutic complications including death were no different between the three groups; however, CRP levels were significantly reduced in all three groups, indicating that the interventions reduced inflammation likely through a reduction in the cytokine storm, though clinical outcomes were unaffected.

Abstract

OBJECTIVE The COVID-19 pandemic continues, and the death toll continues to surge. This systematic review and meta-analysis aimed to determine the efficacy of therapeutic plasma exchange (TPE) on mortality in patients with COVID-19. METHODS A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Controlled clinical trials on treatment of COVID-19 with TPE, compared with standard of care, were reviewed. Studies were pooled according to risk ratios (RRs) and weighted mean differences, with 95% confidence intervals (CIs). RESULTS A total of six trials (enrolling 343 participants) met the inclusion criteria. Therapeutic plasma exchange showed significant effect on mortality (RR 0.41, 95% CI 0.24 to 0.69; P = 0.0008). CONCLUSION TPE significantly reduced mortality in hospitalized patients with moderate-to-critical COVID-19. Plasma exchange therapy should be considered for patients with COVID-19.

Abstract

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.

Abstract

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.

Abstract

INTRODUCTION Since the COVID-19 pandemic outbreak, multiple promising treatment modalities have been tested, however, only several of them were proven to be effective. Therapeutic plasma exchange (TPE) has been recently discussed as a possible supportive treatment for severe cases. METHODS To investigate a possible role of TPE in severe COVID-19 we used a structured systematic search strategy to retrieve all relevant publications in the field. We screened in PubMed, EMBASE, Web of Science, Cochrane Library and clinicaltrials.gov for data published until the 4 June 2021. RESULTS We identified 18 papers, enrolling 384 patients, 220 of whom received TPE. The number of TPE sessions ranged from 1 to 9 and the type of replacement fluid varied markedly between studies (fresh frozen plasma or 5% albumin solution, or convalescent plasma). Biochemical improvement was observed in majority of studies as far as C-reactive protein (CRP), interleukin-6 (IL-6), ferritin, lactate dehydrogenase (LDH), D-dimer concentrations and lymphocyte count are concerned. The improvement at a laboratory level was associated with enhancement of respiratory function. Adverse effects were limited to five episodes of transient hypotension and one femoral artery puncture and thrombophlebitis. CONCLUSIONS Although the effect of therapeutic plasma exchange on mortality remains unclarified, the procedure seems to improve various secondary end-points such as PaO(2)/FiO(2) ratio or biomarkers of inflammation. Therapeutic plasma exchange appears to be a safe treatment modality in COVID-19 patients in terms of side effects.