The Impact of Therapeutic Plasma Exchange on Inflammatory Markers and Acute Phase Reactants in Patients with Severe SARS-CoV-2 Infection.

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 PaO2/FiO2 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.

Renal Thrombotic Microangiopathy: A Review.

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.

Peripheral nervous system involvement associated with COVID-19. A systematic review of literature.

There is increasing evidence of both central and peripheral nervous system (PNS) involvement in COVID-19. We conducted this systematic literature review to investigate the characteristics, management and outcomes of patients with PNS, including the types and severity of cranial nerves (CN) involvement. We systematically searched on PubMed for studies reporting adult patients diagnosed with COVID-19 and PNS involvement until July 2021. From 1670 records, 225 articles matched the inclusion criteria, with a total of 1320 neurological events, in 1004 patients. There were 805 (61%) CN, 350 (26.5%) PNS, and 165 (12.5%) PNS plus CN events. The most frequently involved CN were the facial, vestibulo-cochlear and olfactory nerve in 27.3%, 25.4% and 16.1%, respectively. Guillain-Barre syndrome spectrum was identified in 84.2% of PNS events. We analysed 328 patients reported in 225 articles with CN, PNS, and PNS plus CN involvement. The patients with CN involvement were younger (mean age 46.2±17.1, p = .003), and were more frequently treated as outpatients (p < .001), mostly with glucocorticoids (p < .001). Patients that had PNS with or without CN involvement were more likely to be hospitalized (p < .001), and to receive intravenous immunoglobulins (p = .002) or plasma exchange (p = .002). Patients with CN, PNS, and PNS plus CN had severe COVID -19 disease in 24.8%, 37.3%, 34.9% respectively. The most common neurological outcome was mild/moderate sequelae in patients with CN, PNS, and PNS plus CN in 54.7%, 67.5% and 67.8% respectively (p = .1) and no significant difference was found between the three categories regarding death, disease severity, time from disease onset to neurological symptoms, lack of improvement and complete recovery. CN involvement was the most frequent PNS finding. All three categories of PNS involvement were rather associated to non-severe COVID-19 but it may be an important cause of hospitalization and post COVID-19 sequelae.

Therapeutic plasma exchange and continuous renal replacement therapy in pediatric dengue-associated acute liver failure: A case series from Vietnam.

BACKGROUND AND OBJECTIVES: Paediatric dengue-associated acute liver failure (PALF) is a rare and fatal complication. To date, clinical data regarding the combination of therapeutic plasma exchange (TPE) and continuous renal replacement therapy (CRRT) for the treatment of dengue-associated PALF are limited. METHODS: We conducted a single-center, retrospective study of all children with dengue-associated PALF admitted to the paediatric intensive care unit of Children Hospital No.2, Vietnam, who were treated with TPE+CRRT between January 2021 and March 2022. The main study outcomes were in-hospital survival, normalisation of hepatic function, and hepatic encephalopathy improvement. RESULTS: Twelve patients aged from 06 to 12 years underwent TPE+CRRT procedures. Among them, three (25 %) patients died of severe sepsis and septic shock confirmed by Enterobacteriaceae spp. haemocultures (stable on maintenance treatment of COVID-19-associated MIS-C with low dose of oral steroids on hospital admission), acute respiratory distress syndrome (ARDS), and clinically apparent intracranial haemorrhage. Nine patients (75 %) survived. The paediatric mortality risk score improved significantly at discharge compared with PICU admission (P < 0.01). Markedly, all twelve patients were diagnosed with hepatoencephalopathy of grades III and IV on PICU admission. After the combined TPE+CRRT interventions, there were substantial improvements in liver transaminases levels, coagulation profiles, and metabolic biomarkers. Normal neurological functions were observed in nine alive patients at hospital discharge. Only one patient experienced an adverse event of slightly low blood pressure, which rapidly self-resolved. INTERPRETATION AND CONCLUSIONS: Combined TPE+CRRT significantly improved survival outcome, neurological status, and rapid normalisation of liver functions in dengue-associated PALF.

The effect of therapeutic plasma exchange therapy on veno-venous ECMO weaning success in severe COVID-19 ARDS patients.

INTRODUCTION: Primarily, this study aimed to investigate the effect of TPE (therapeutic plasma exchange) treatment on successful ECMO weaning in severe COVID-19 ARDS patients treated with V-V ECMO. METHODS: The study was applied retrospectively on patients over the age of 18 who were hospitalized in the ICU between January 1, 2020 and March 1, 2022. RESULTS: The study was performed on 33 patients, 36.3% (n: 12) of whom received TPE treatment. The rate of successful ECMO weaning was statistically higher in the TPE treatment group (without TPE: 14.3% [n: 3], with TPE: 50% [n: 6], p = 0.044). The 1-month mortality was also statistically lower in the TPE treatment group (p = 0.044). In the logistic analysis, It was found that the risk of unsuccessful ECMO weaning increased 6 times in those who did not receive TPE treatment (OR; 6.0, 95% CI; 1.134-31.735, p = 0.035). CONCLUSION: TPE treatment may increase the success rate of V-V ECMO weaning in severe COVID-19 ARDS patients treated with V-V ECMO.

Efficacy of therapeutic plasma exchange in patients with severe COVID-19: A systematic review and meta-analysis.

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.

Impact of plasmapheresis on severe COVID-19.

The clinical course of COVID-19 may show severe presentation, potentially involving dynamic cytokine storms and T cell lymphopenia, which are leading causes of death in patients with SARS-CoV-2 infection. Plasma exchange therapy (PLEX) effectively removes pro-inflammatory factors, modulating and restoring innate and adaptive immune responses. This clinical trial aimed to evaluate the impact of PLEX on the survival of patients with severe SARS-CoV-2 and the effect on the cytokine release syndrome. Hospitalized patients diagnosed with SARS-CoV-2 infection and cytokine storm syndrome were selected to receive 2 sessions of PLEX or standard therapy. Primary outcome was all-cause 60-days mortality; secondary outcome was requirement of mechanical ventilation, SOFA, NEWs-2 scores modification, reduction of pro-inflammatory biomarkers and hospitalization time. Twenty patients received PLEX were compared against 40 patients receiving standard therapy. PLEX reduced 60-days mortality (50% vs 20%; OR 0.25, 95%CI 0.071-0.880; p = 0.029), and this effect was independent from demographic variables and drug therapies used. PLEX significantly decreased SOFA, NEWs-2, pro-inflammatory mediators and increased lymphocyte count, accompanied with a trend to reduce affected lung volume, without effect on SatO2/FiO2 indicator or mechanical ventilation requirement. PLEX therapy provided significant benefits of pro-inflammatory clearance and reduction of 60-days mortality in selected patients with COVID-19, without significant adverse events.

Efficacy of Therapeutic Plasma Exchange in Severe Acute Respiratory Distress Syndrome in COVID-19 Patients from the Western Part of Romania.

Background and Objectives: The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has surprised the medical world with its devastating effects such as severe acute respiratory distress syndrome (ARDS) and cytokine storm, but also with the scant therapeutic solutions which have proven to be effective against the disease. Therapeutic plasma exchange (TPE) has been proposed from the very beginning as a possible adjuvant treatment in severe cases. Our objective was to analyze the evolution of specific biological markers of the COVID-19 disease before and one day after a therapeutic plasma exchange session, how a change in these parameters influences the patient's respiratory status, as well as the impact of TPE on the survival rate. Materials and Methods: In this retrospective study, we include 65 patients with COVID-19 admitted to the intensive care unit department of our hospital between March 2020 and December 2021, and who received a total of 120 sessions of TPE. Results: TPE significantly reduced the following inflammation markers (p < 0.001): interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), fibrinogen, ferritin, and erythrocyte sedimentation rate. This procedure significantly increased the number of lymphocytes and decreased D-dimers levels (p = 0.0024). TPE significantly improved the PaO2/FiO2 ratio (p < 0.001) in patients with severe acute respiratory distress syndrome (PaO2/FiO2 < 100). Survival was improved in intubated patients who received TPE. Conclusions: TPE involved the reduction in inflammatory markers in critical patients with COVID-19 disease and the improvement of the PaO2/FiO2 ratio in patients with severe ARDS and had a potential benefit on the survival of patients with extremely severe COVID-19 disease.

Successful treatment of acute encephalitis and hepatitis in a child with COVID-19 infection.

We present the case of a 6-year-old Taiwanese boy with a fulminant course of COVID-19 manifesting as high fever, acute consciousness changes, and status epilepticus. Brain MRI showed restricted diffusion in the bilateral hemisphere. Electroencephalogram showed diffuse slow waves with few spikes. CSF study was clear without evidence of common pathogens. He received treatment with antiviral agents, corticosteroids, intravenous immunoglobulins, and anti-IL-6 monoclonal antibodies. However, progressive fulminant hepatitis, hyperammonaemia, and disseminated intravascular coagulopathy developed. Rescue therapy with hybrid continuous renal replacement therapy and plasma exchange were performed in the first 11 days. The patient improved and was extubated on the 11th day. After physical therapy, his neurological function improved significantly. The patient was discharged under rehabilitation after 1 month of hospitalization. Viral sequencing confirmed infection with the Omicron BA.2.3 variant, one of the dominant strains in Taiwan and Hong Kong. Whole-exome sequencing revealed heterozygous uncertain significance variants in TICAM-1, RNF 31, and mitochondrial MT-RNR1, which provide additional support for the fulminant course. To the best of our knowledge, this is the first reported case of COVID-19 in a child with a fulminant course of acute encephalitis and hepatitis who successfully recovered by hybrid continuous renal replacement therapy and plasma exchange.

Anti-factor H antibody and its role in atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) an important form of a thrombotic microangiopathy (TMA) that can frequently lead to acute kidney injury (AKI). An important subset of aHUS is the anti-factor H associated aHUS. This variant of aHUS can occur due to deletion of the complement factor H genes, CFHR1 and CFHR3, along with the presence of anti-factor H antibodies. However, it is a point of interest to note that not all patients with anti-factor H associated aHUS have a CFHR1/R3 deletion. Factor-H has a vital role in the regulation of the complement system, specifically the alternate pathway. Therefore, dysregulation of the complement system can lead to inflammatory or autoimmune diseases. Patients with this disease respond well to treatment with plasma exchange therapy along with Eculizumab and immunosuppressant therapy. Anti-factor H antibody associated aHUS has a certain genetic predilection therefore there is focus on further advancements in the diagnosis and management of this disease. In this article we discuss the baseline characteristics of patients with anti-factor H associated aHUS, their triggers, various treatment modalities and future perspectives.

Therapeutic plasma exchange: A potential therapeutic modality for critically ill adults with severe acute respiratory syndrome coronavirus 2 infection.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection can be severe and fatal due to cytokine storm. Therapeutic plasma exchange (TPE) potentially mitigates the harmful effects of such cytokines. We investigated the use of TPE, as rescue therapy, in patients with severe Coronavirus disease 2019 (COVID-19) infection. STUDY DESIGN AND METHODS: A retrospective analysis on COVID-19 patients admitted to the intensive care unit and treated with TPE from April 17, 2020 to July 2, 2020. This group was compared with COVID-19 patients who received standard therapy without TPE. The following outcomes were analyzed: changes in laboratory parameters, length of hospital stay (LOS), days on mechanical ventilation, mortality at days 14 and overall mortality. RESULTS: A total of 95 patients were included, among whom 47% (n = 45) received TPE. Patients who received TPE had reductions in C-reactive protein (P = .002), ferritin (P < .001) and interleukin-6 (P = .013). After employing entropy-balancing matching method, those on TPE were also more likely to discontinue inotropes (72% vs 21%; P < .001). However, they were more likely to be associated with longer LOS (23 vs 14 days; P = .002) and longer days on ventilatory support (14 vs 8 days; P < .001). Despite marginal mortality benefit at 14-days (7.9% vs 24%; P = .071), there was no significant differences in overall mortality (21% vs 31%; P = .315) between the groups. CONCLUSIONS: TPE was effective in reducing inflammatory markers in patients with severe COVID-19 infection, however, further research is warranted.

COVID-19 Associated Guillain-Barré Syndrome: A Report of Nine New Cases and a Review of the Literature.

BACKGROUND: Guillain-Barré syndrome (GBS)-a rare condition characterized by acute-onset immune-mediated polyneuropathy-has been registered as a neurological manifestation of COVID-19, suggesting a possible link between these two conditions. METHODS: We report a case series of patients with COVID-19-related GBS hospitalized in the Neurology Department of Colentina Clinical Hospital, Bucharest, Romania, between March 2020 and March 2021. Several variables were analyzed, such as the mean interval between the onset of COVID-19 symptoms and neurological ones, clinical features, treatment course, and outcome. Further on, we conducted a thorough literature review based on the PubMed and ScienceDirect scientific databases. RESULTS: A total of 9 COVID-19 patients developed symptoms of GBS, out of which in 7, it manifested as an acute inflammatory demyelinating polyneuropathy (AIDP). Five patients presented respiratory failure, 2 requiring mechanical ventilation. All patients received a course of intravenous immunoglobulins, 2 additionally requiring plasma exchange. Upon discharge, all but 1 patient (who had not regained the ability to walk) had a positive outcome, and 1 died during admission. In the literature review, we analyzed the published sources at the time of writing. CONCLUSIONS: A link between COVID-19 and GBS might be possible; therefore, increased vigilance is required in the early identification of these cases for prompt diagnosis and treatment. Some notable differences such as an earlier onset of GBS symptoms, higher respiratory dysfunction, and higher mortality rates in COVID-19 patients have been observed between the presentation of GBS in the context of COVID-19 and GBS of other causes.

Role of therapeutic plasma exchange in the management of COVID-19-induced cytokine storm syndrome.

The risk of mortality in patients with coronavirus disease 2019 (COVID-19) is largely related to an excessive immune response, resulting in a hyperinflammatory and hypercoagulable condition collectively referred to as cytokine storm syndrome (CSS). Management of critically ill patients with COVID-19 has included attempts to abate this process, prevent disease progression, and reduce mortality. In this context, therapeutic plasma exchange (TPE) offers an approach to eliminate inflammatory factors and cytokines, offset the pathologic coagulopathy, and reduce the CSS effects. The aim of this review is to analyze available data on the use of TPE for the treatment of CSS in patients with COVID-19. Systematic searches of PubMed, Scopus and COVID-19 Research were conducted to identify articles published between March 1, 2020 and May 26, 2021 reporting the use of TPE for the treatment of COVID-19-induced CSS. A total of 34 peer-reviewed articles (1 randomized controlled trial, 4 matched case-control series, 15 single-group case series, and 14 case reports), including 267 patients, were selected. Despite the low evidence level of the available data, TPE appeared to be a safe intervention for critically ill patients with COVID-19-induced CSS. Although inconsistencies exist between studies, they showed a general trend for decreased interleukin-6, C-reactive protein, ferritin, D-dimer, and fibrinogen levels and increased lymphocyte counts following TPE, supporting the immunomodulatory effect of this treatment. Moreover, TPE was associated with improvements in clinical outcomes in critically ill patients with COVID-19. While TPE may offer a valuable option to treat patients with COVID-19-induced CSS, high-quality randomized controlled clinical trials are needed to confirm its potential clinical benefits, feasibility, and safety. Moreover, clear criteria should be established to identify patients with CSS who might benefit from TPE.

Integrated therapeutic plasma exchange and traditional Chinese medicine treatment in a patient with severe COVID-19: A case report.

This report presents the case of a 59-year-old man with severe COVID-19 that gradually progressed to cytokine release syndrome and then acute respiratory distress syndrome; he was successfully treated via integration of therapeutic plasma exchange and traditional Chinese medicine. The patient initially presented with a sore throat, severe muscle aches, productive cough and fever. On the worsening of symptoms, remdesivir was administered. However, as the symptoms continued to worsen and a cytokine release syndrome was suspected, oxygen was provided through a high-flow nasal cannula (50 L/min) and therapeutic plasma exchange was performed to prevent worsening of the acute respiratory distress syndrome. On the same day, a course of traditional Chinese medicine was introduced in consultation with the infectious house staff. The patient's symptoms gradually improved; the levels of C-reactive protein and D-dimers reduced, and the patient was weaned to a simple oxygen mask and eventually to room air. This is the first reported case of the integration of these treatments. Together, they prevented the patient from requiring intubation, played a role in cytokine management, and also improved the clinical symptoms, including productive purulent sputum, cough, frequent stool passage and intermittent fever, with no adverse effects. As a result, the patient was discharged within two weeks of the integration of these treatments. Therefore, the integration of therapeutic plasma exchange and traditional Chinese medicine is an effective therapy for patients with severe COVID-19.