key: cord-0912261-4q6s3jwn
authors: Faqihi, Fahad; Alharthy, Abdulrahman; Abdulaziz, Salman; Balhamar, Abdullah; Alomari, Awad; AlAseri, Zohair; Tamim, Hani; Alqahtani, Saleh A.; Kutsogiannis, Demetrios J; Brindley, Peter G; Karakitsos, Dimitrios; Memish, Ziad A
title: Therapeutic plasma exchange in patients with life-threatening COVID-19: a randomized control clinical trial
date: 2021-04-07
journal: Int J Antimicrob Agents
DOI: 10.1016/j.ijantimicag.2021.106334
sha: 0c7af664dd665c339dada53d1c30e686ba978063
doc_id: 912261
cord_uid: 4q6s3jwn

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.

• Open-label randomized clinical trial of intensive care unit (ICU) patients with life-threatening COVID-19.

• Standard treatment plus therapeutic plasma exchange TPE (n = 43) versus standard treatment (n = 44).

• Days on Mechanical ventilation (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.

Plasma exchange pilot studies showed promise in the treatment of multifaceted life-threatening COVID-19.

The novel SARS-CoV-2 disease (COVID-19) emerged in 2019, in China, and has spread worldwide [1] [2] [3] [4] . Whilst SARS-CoV-2 infection is mostly asymptomatic and/or self-limited, patients can become critically ill, as manifested by acute respiratory distress syndrome (ARDS), thromboemboli, hyperinflammation, and multi-system organ failure (MSOF) [5] [6] [7] [8] [9] [10] [11] [12] . There is no treatment outside of dexamethasone, and the world is still awaiting widespread vaccination [13] [14] [15] [16] [17] [18] . Therefore it is important to explore novel but rational therapies.

Therapeutic plasma exchange (TPE) has been used for severe sepsis, MSOF and SARS-CoV infection [19] [20] [21] . Several groups, including the US Food and Drug Administration (FDA) [22] [23] [24] [25] [26] [27] [28] have also posited that rescue TPE might have a role in severe COVID-19, but, to date, it has been insufficiently studied. The rationale is to suppress cytokine release syndrome (CRS), ameliorate thrombosis, and lessen MSOF [26, 27] . In this randomized clinical trial, we build upon our prior work [24-27] by evaluating TPE (specifically its efficacy and adverse effects) when added to empiric ICU treatment for life-threatening COVID-19 and associated hyperinflammation.

This single center, open label, randomized clinical study enrolled critically ill COVID-19 patients admitted to the level III (300 bed) intensive care unit (ICU) of King Saud Medical City (Riyadh, Saudi Arabia) between July 1 and October 1, 2020. It was conducted according to the principles of the Declaration of Helsinki and approved by our Institutional Review Board [29] .

The study's protocol was registered at ISRCTN (ISRCTN21363594; doi.10.1186/ ISRCTN or legal representatives.

Main inclusion criteria were: 1) Age ≥ 18 years old; 2) Intubation and ICU admission; and 3)

Life-threatening COVID-19 [2-6, 13-15, 27 , 31] defined as: i) ARDS (according to the Berlin criteria) [32, 33] ; ii) Acute Physiology and Chronic Health Evaluation II (APACHE II) score ≥ 20 upon ICU admission [34] ; iii) Presence of severe sepsis/septic shock, and/or multi-system organ failure (MSOF) [35, 36] , and one or more criteria for defining cytokine release syndrome (CRS) [11, 12, [37] [38] [39] [40] , (as previously described [27] and also presented in e- Table 1 , supplement). SARS-CoV-2 infection was confirmed by Real-Time-Polymerase-Chain-Reaction (RT-PCR) assays using QuantiNova Probe RT-PCR kit (Qiagen GmbH, Germany) in a Light-Cycler 480 real-time PCR system (Roche, Basel, Switzerland) [25-27, 41, 42] . Other inclusion criteria were: 1) positive RT-PCR result within 48 hours before randomization, 2) signed informed consent and acceptance of assignment to randomized treatment groups, 3) randomization within the first 48 hours of meeting criteria for life-threatening COVID -19, and 4) no participation in other clinical trials during the study period.

Exclusion criteria were: 1) previous allergic reaction to plasma exchange or its ingredients (i.e., sodium citrate, plasma products), 2) two consecutive negative RT-PCR tests for SARS-CoV-2 taken at least 24 hours apart, 3) participation in other antiviral clinical trials for COVID-19 within 30 days prior to randomization, 4) terminal illness and/or other contraindications (i.e., known immune suppression/deficiency status) as per the discretion of the attending physician.

Primary outcomes were: mortality 35-days post ICU-admission and the safety of TPE in lifethreatening COVID-19. Secondary outcomes were: improvement in Sequential Organ Function Assessment (SOFA) score [43] , the effect of TPE on mortality, change in inflammatory biomarkers within 24 hours of the final TPE session, days on mechanical ventilation (MV), and ICU length-of-stay [27, 30] . Upon ICU admission, further screening was performed by computed tomography pulmonary angiograms (CT-PA) in subjects with a peripheral arterial oxygen saturation/fraction of inspired oxygen (PaO 2 /FiO 2 ) < 80 for > 24 hours. Hence, pulmonary embolism (PE) was categorized, if discovered, as arising from main/lobar, segmental and subsegmental lung regions according to standard criteria [44] .

Patients were randomly assigned via computer-generated random numbering (1:1) to receive standard treatment plus TPE (intervention group) or standard treatment alone (control group).

Eligible consented patients were further stratified into two groups, based upon a peripheral arterial oxygen saturation/fraction of inspired oxygen (PaO 2 /FiO 2 ) ratio of > 150 versus ≤ 150.

Randomization occurred in variable block sizes of 4 to 8 patients. We utilized a web-based randomization service (randomize.net) to allocate patients to their respective stratification prior to intervention or control therapy.

Given the difficulty in blinding TPE, the intervention was unblinded (open label); hence, no enrollment concealment was expedited [30] .We defined the time point of appropriateness for ICU transfer as a surrogate for the time of discharge from ICU. This was chosen irrespective of treatment allocation; while recognizing patients randomized to TPE could have improved to the point of being appropriate for a medical ward but would need to stay to ICU to deliver remaining TPE doses. To minimize further assessment bias, clinical outcomes were evaluated by an investigator who was blind to the study group allocation.

Patients in the control group received standard empiric therapy for COVID-19, which was based on the evolving Saudi Ministry of Health treatment protocol [45] . Empiric therapies included antivirals (ribavirin 400 mg every 12 hours for 14 days), antibacterial medications, dexamethasone (6 mg/day for 7 days), anticoagulation, and ICU supportive care [14, 15, 27, 30, 45 ].

Patients in the intervention group received the standard empiric therapeutic regime plus TPE without protective antibodies. TPE was initiated using the Spectra Optia TM Apheresis System (Terumo BCT Inc., USA), which incorporates acid-citrate dextrose anticoagulant as per Kidney Disease Improving Global Outcomes 2019 guidelines [28, 48] . TPE can remove significant proportions of interferon-gamma, interleukins -3, -10, -1B, -6, -8, and tumor necrosis factoralpha [12, [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] . A dose of 1.5 plasma volumes was used for the first daily treatment, then one plasma volume daily (sessions lasted for 4 hours) to a maximum of 5 doses as per clinical case scenario. Intravenous calcium replacement and chlorpheniramine 10 mg were administered during TPE to reduce side effects [26] . Plasma was replaced with either fresh frozen plasma or artificial Octaplas LG ® (Octapharma AG, USA): a fresh frozen pooled plasma product that has undergone viral/prion inactivation [49] . To evaluate TPE's ability to remove the inflammatory mediators associated with COVID-19 patients [12, [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] we measured serum C-reactive protein (CRP), D-dimer, lactate dehydrogenase (LDH), ferritin, and interleukin-6 (IL-6) prior to initiation, and within 24 hours after the last TPE session. CRP was defined as elevated if it was > 5.0 mg/L and IL-6 if > 7.0 pg/mL [50] . To determine thromboinflammation risk, we also normal vital signs, no need for supplemental oxygen, and two consecutive RT-PCR test results from nasopharyngeal swabs at least 48 hours apart (after which no more testing was performed)

[30].

This was an open-label, randomized clinical study. The original sample size was determined to be 60 for each group, which would provide 80% power, with a two-sided significance level of p = 0.05, to detect a 20% reduction in 35-day mortality in the TPE arm from an estimated 40% mortality in the control arm based on previous studies of critically ill COVID-19 patients [3-5, 13, 15] . Analysis was performed according to the full data set, which is defined as the sum of all randomized patients who received at least one treatment. The primary efficacy analysis was conducted on the intention-to-treat population, defined as all patients who underwent randomization and received TPE plus standard therapy or standard therapy alone before death or at 35 days after randomization. Continuous data were summarized as median values with interquartile range (IQR) and compared among groups with Wilcoxon's rank sum test. Discrete data were summarized as number (%) and compared by chi square or Fisher's exact test.

Standard comparisons of the changes in clinical and laboratory parameters were also performed by Tukey boxplots in intervention and control groups. Pearson's correlation coefficient (r) measured the strength of association between studied markers of thromboinflammation such as D-dimers, Il-6, and ADAMTS-13 activity. Thirty five days survival distributions between intervention (TPE) and control groups were described using proportions and Kaplan Meier analysis. Crude differences were tested using a chi square test and a log-rank test, respectively.

A multivariable analysis of the primary 35-days survival outcome was conducted using a Cox proportional hazard model with 95% confidence intervals (CI), where the main effect of TPE (intervention versus control) and relevant variables including age, admission PaO 2 /FiO 2 ratio, laboratory parameters, admission APACHE II/SOFA scores, and high risk (> 3 criteria, e- Table   1 . supplement) for developing CRS were entered as covariates. Variables that achieved a p-value < 0.10 on univariate analysis were fit into a multivariable regression model predicting 35-day mortality. The final logistic model included variables which achieve a p-value of ≤ 0.05 on forward stepwise selection and after examination for collinearity. Moreover, a post hoc analysis (with a Bonferroni correction of the p-values for repeated measures) was added to compare the progression of SOFA scores at days 0, 7, 14, and 35 post-ICU admission. All statistical tests were two tailed, and considered significant if p value < 0.05. Statistical software SPSS 24.0 was used.

Due to the mitigation of the SARS-CoV-2 outbreak in Saudi Arabia the numbers of COVID-19 cases decreased significantly by mid-September 2020. Our last patient was enrolled on October 1, 2020. Thereafter we did not have any potential recruitment targets or expectation of a second COVID-19 wave. After preliminary data analysis, and discussions that were held with our expert infectious disease panel, institutional review board, and the primary investigator on October 30, 2020, the study was provisionally terminated with 87 patients enrolled.

During the study period, a total of 280 critically ill patients was admitted to the ICU. Of these, 80 Baseline characteristics and outcome measures for the 87 COVID-19 patients are in Table 1 .

Median age was 49 (IQR: 34-63) years, 72 patients were males (82.8%), and median body mass index (BMI) was 26 (IQR: 21-31). Overall and within the PaO 2 /FiO 2 ratio stratification groups, there were no significant differences in age, sex, BMI, prevalence of comorbidities, duration of symptom onset to ICU admission, and APACHE II/SOFA scores between patients that underwent TPE versus controls. However, TPE patients did have a higher prevalence of PE and risk for developing CRS compared to controls (Table 1) Following ICU admission, the median time to randomization was 2 days (IQR: 0.5-2.5), (Table   1 ). Baseline recorded clinical and laboratory parameters of the COVID-19 study population are presented in Table 2 . Upon ICU admission, 30 patients of the control group (68.1%) and 33 patients of the intervention group (76.7%) were receiving vasopressors. At baseline, there were no significant differences between the TPE and control groups for median arterial blood pressure, noradrenaline infusion dose, white blood cell and platelet counts, serum lactate and creatinine levels, and the overall coagulation profile. However, patients in the TPE group had significantly lower baseline lymphocyte counts and ADAMTS-13 activity, and increased baseline levels of LDH, ferritin, D-dimers, and IL-6 compared to controls (p < 0.05, Table 2 ).

There were no adverse events recorded in either group. Specifically, TPE patients did not experience any allergic reactions, fever, coagulopathy, cardiac and/or renal failure. The incidence of hospital acquired infections was comparable between groups ( Table 1 ). The baseline incidence of PE was higher in the TPE group (13 patients, 30.2%) versus the control group (6 patients, 13.6%). Of 13 PEs in the intervention group, 1 was massive, 10 were segmental, and 2 were sub-segmental. Of 6 PEs in the control group, 4 were segmental and 2 sub-segmental.

Survivors from both groups had improved clinical and laboratory parameters after the completion of therapy (Table 3) . Notably, TPE patients showed a marked and sustainable posttherapeutic increase in lymphocyte counts and ADAMTS-13 activity, and a significant decrease of serum lactate, C-RP, LDH, ferritin, D-dimers, and Il-6, compared to baseline ( Table 3 ). The temporal changes in the aforementioned parameters before and after therapy in COVID-19 patients are displayed in the supplementary appendix (supplement; e- fig.1 to e-fig.9 ). With respect to baseline thromboinflammatory markers in all 87 COVID-19 patients, ADAMTS-13 activity had an inverse linear association with IL-6 (r = -0.159, p = 0.14) and D-dimer levels (r = -0.317, p = 0.003), (e- fig.10 and e-fig.11, supplement) . Also, D-dimers had a positive linear association with IL-6 levels (r = 0.491, p = 0.001), (e- fig.12, supplement) .

There was not a significant difference in the mean survival distributions between patients in the TPE group versus the control group by Kaplan Meier analysis (p = 0.582, log-rank test), (Fig. 2) .

Multivariable Cox proportional hazards model showed no significant effect of TPE on 35-day survival after adjustment for relevant confounders (Table 4 ). In the univariate model, the (Table 4 ). Although the effect of TPE on survival did not reach statistical significance, TPE resulted in a significant decrease of SOFA scores in the intervention group compared to controls (e- fig.13 , supplement).

patients over time is displayed in Fig.3 and Table 5 . There was a significant reduction of SOFA score values, suggesting improved organ function, in the TPE group compared to the control group on days 7 and 14 after the initiation of therapy.

This randomized control clinical trial suggests that TPE could be a safe adjunct rescue therapy in critically ill COVID-19 patients with ARDS, sepsis, and CRS [27] . Whilst the addition of TPE to standard ICU treatment was associated with lower crude 35-day mortality (20.9% vs 34.1%) the difference did not reach statistical significance nor was a mortality benefit seen after adjustment for important confounders [3-5, 13, 15, 22-27] . This mirrors a randomized clinical trial on convalescent plasma transfusion (CPT) [13] . Both TPE (which does not include protective antibodies) and CPT (which does) are plausible immunomodulatory therapies for severe COVID-19 [13, 27] . Both need to be rigorously studied, especially because there are pertinent differences. CPT relies on antibodies to neutralize the virus, but carries the putative risk of amplifying an antibody-mediated response. Also, CPT does not decrease thromboinflammation: a hallmark of severe COVID-19 [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [22] [23] [24] [25] [26] [27] . TPE removes cytokines such as interferongamma, interleukins -3, -10, -1B, -6, -8, and tumor necrosis factor-alpha [19-27, 54, 55] . Our study has shown that TPE can reduce inflammatory biomarkers, improve oxygenation, and ameliorate the clinical course of life-threatening COVID-19.

TPE could conceivably cause immunosuppression [19] [20] [21] [22] [23] [24] [25] [26] [27] [56] [57] [58] . It is therefore relevant that we found no obvious side effects: no coagulopathy, no worsening renal or cardiac function, and no allergies. The incidence of hospital acquired infections was also similar between the intervention and control groups. TPE has a cutoff of 1.000.000 Daltons (Da), and thus inflammatory mediators such as C-RP (120.000 Da), ferritin (474.000 Da), LDH (144.000 Da), D-dimers (180.000 Da), and IL-6 (21.000 Da) should be removed. TPE may also remove immunoglobulins and complement components 3 and 4. Conceivably, this could mean immunoparalysis, which could exacerbate viral and bacterial infections [56-58]. Adding natural and artificial plasma products in the TPE regime could mitigate immunoparalysis by replenishing immunoglobulins; hence mitigating acquired infections and coagulopathy [19] [20] [21] [22] [23] [24] [25] [26] [27] . For this reason, we used fresh frozen plasma and an artificial plasma product, both of which appeared to be safe and effective.

Following TPE, we showed significant decreases in all inflammatory biomarkers, and a marked sustained increase in lymphocyte count [22] [23] [24] [25] [26] [27] . We did not record any severe COVID-19 related coagulopathy, or overlapping features of hemophagocytic syndrome and antiphospholipid antibodies [26, 59] . We found suppressed levels of ADAMTS-13 activity, which were negatively correlated with increased levels of IL-6 and D-dimers. Also, IL-6 was positively correlated with D-dimers. These findings, recorded prior to therapy, may help explain the thromboinflammatory microangiopathy in severe COVID-19 [7-12, 22-27, 60, 61] . We also showed that decreased ADAMTS-13 appears to portend a worse prognosis, which in turn could indicate more rapid progression towards MSOF [62] . Consistent with this speculation, after TPE, we found that markers of COVID-19 associated thromboinflammation such as ADAMTS-13 activity, IL-6 and D-dimers were significantly corrected. Moreover, alongside these laboratory improvements we demonstrated better organ function in the intervention group compared to controls as per our post hoc SOFA scores on day -7 and -14 following ICU admission. This clinical observation mirrors previous studies in septic patients who underwent TPE [21, 63] . Overall, while TPE has not been shown to definitively save lives in the intervention group, prompt initiation following complex 

All patients received empiric and supportive ICU therapy including anticoagulation and dexamethasone [14, 15] . Also, there were no differences in demographic, clinical, and laboratory parameters between groups of patients and within the PaO 2 /FiO 2 ratio strata. The absence of protocol violations and the rapidity of TPE invitation should strengthen our conclusions [20, 21, 63] ; however there are limitations. For example, upon ICU admission, TPE patients had significantly higher incidence of PE and more criteria for developing CRS compared to controls.

The pivotal role of IL-6 in the development of CRS was outlined in previous studies using tocilizumab, a monoclonal antibody against IL-6 [16, [74] [75] [76] [77] [78] [79] [80] [81] . Although we showed a decrease in IL-6 following TPE [19] [20] [21] [22] [23] [24] [25] [26] [27] , inflammatory biomarkers also decreased over time in controls, as would be expected in any patient that recovers. Another potential limitation of our study is that the intervention was unblinded (open label); hence, no enrollment concealment was expedited.

However, the lack of allocation concealment was mitigated by different measures described in appendix 1.

This study was terminated early because of waning SARS-CoV-2 numbers. Accordingly, it may be underpowered to detect a survival benefit. This study was also open-label, and single center, and physicians had some discretion [15, 26, 27, 30, 45, 46] . Notwithstanding, our primary outcome (mortality) was not disputable, co-interventions were largely standardized, and we incorporated an independent blinded investigator.

The definition of COVID-19 associated CRS remains up for debate [82] . Moreover, our work will be less generalizable if practices and laboratory methods differ elsewhere. Although this was a randomized control trial, the administration of dexamethasone might have meant additional anti-inflammation and altered viral clearance, even if the median time to negative RT-PCR was comparable between groups [83] [84] [85] . In short, while our data is encouraging, TPE is no panacea.

It is also costly and requires trained staff. TPE requires close monitoring, preferably in a highdependency unit, and risks viral exposure [19-27, 54, 55] . Finally, there was an imbalance between the groups in our study: The TPE-group had lower lymphocyte counts and ADAMTS-13 activity and increased LDH, ferritin, D-dimers, and IL-6 and higher incidence of pulmonary embolus compared to controls. These values potentially indicate a more severely ill group of patients in the TPE group that can contradict the potential beneficial effect of the intervention. In addition, other unaccounted confounders might exist in the more severely ill group of patients.

Despite limitations, we have shown that early TPE administration is feasible and associated with biochemical and clinical recovery in profoundly sick COVID-19 patients with ARDS, sepsis, thromboinflammation, and few therapeutic options. Our finding is in line with our previous report suggesting that applying TPE should be done early at the fulminant stage of COVID-19 infection, mainly because at this stage, dysregulated immune system pathobiology is equally important as viral replication [86] . Table 3 . Changes in clinical and laboratory parameters from baseline to end-of-therapy within the two groups of COVID-19 patients.

Before therapy End-of-therapy Before therapy End-of-therapy (n=44) (n=39) ⱡ (n=43) (n=34) ⱡ Evaluation II score; SOFA score = Sequential Organ Function Assessment score; PaO2/FiO2 ratio = partial arterial pressure of oxygen to fractional inspired concentration of oxygen; CRS= cytokine release syndrome; HR = hazards ratio; CI = confidence intervals. 

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention

China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China

COVID-19 Lombardy ICU Network. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical characteristics of refractory COVID-19 pneumonia in

Thrombotic and hemorrhagic events in critically ill COVID-19 patients: a French monocenter retrospective study

Deep Vein Thrombosis in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19) in Wuhan, China: Prevalence, Risk Factors, and Outcome

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

Cytokine release syndrome in severe COVID-19

HLH Across Specialty Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression

Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial

Association of treatment dose anticoagulation with in-Hospital survival among hospitalized patients with COVID-19

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

Historically controlled comparison of glucocorticoids with or without tocilizumab versus supportive care only in patients with COVID-19-associated cytokine storm syndrome: results of the CHIC study

Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 -Preliminary Report

Use of therapeutic plasma exchange as a rescue therapy in 2009 pH1N1 influenza A--an associated respiratory failure and hemodynamic shock

Early therapeutic plasma exchange in septic shock: a prospective open-label nonrandomized pilot study focusing on safety, hemodynamics, vascular barrier function, and biologic markers

The therapeutic efficacy of adjunct therapeutic plasma exchange for septic shock with multiple organ failure: a single-center experience

Therapeutic Plasma Exchange: A potential Management Strategy for Critically Ill COVID-19 Patients

Therapeutic Plasma Exchange in Adults with Severe COVID-19 Infection

The Berlin definition of ARDS: an expanded rationale, justification, and supplementary material

ICU severity of illness scores: APACHE, SAPS and MPM

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock

The Surviving Sepsis Campaign Bundle: 2018 update

Dysregulation of immune response in patients with COVID-19 in

Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19

Comment on Hu et al: The cytokine storm and COVID-19

Therapeutic plasma exchange in life-threatening COVID-19 and associated cytokine release syndrome

Improved Molecular Diagnosis of COVID-19 by the Novel, Highly Sensitive and Specific COVID-19-RdRp/Hel Real-Time Reverse Transcription-PCR Assay Validated In Vitro and with Clinical Specimens

Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases. Interim guidance

Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

Helical CT for the evaluation of acute pulmonary embolism

Kidney Disease: Improving Global Outcomes (KDIGO) Chronic Kidney Disease-Mineral and Bone Disorder

Guideline Update Implementation: Asia Summit Conference Report

Efficacy and safety of plasma thrombotic microangiopathy: The first French experience in a single center

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Establishment of the WHO 1st International Standard ADAMTS13, plasma (12/252): communication from the SSC of the ISTH

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

ADAMTS-13 in critically Ill patients with septic syndromes and noninfectious systemic inflammatory response syndrome

Effect of therapeutic plasma exchange on endothelial activation and coagulation-related parameters in septic shock

Clinical Characteristics and Predictors of 28-Day Mortality in 352 Critically Ill Patients with COVID-19: A Retrospective Study

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

COVID-19 patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis

Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study

Association Between Hypoxemia and Mortality in Patients With COVID-19

Risk Factors Associated with Clinical Outcomes

Hospitalized Patients in Wuhan, China

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study

Early predictors of clinical outcomes of COVID-19 outbreak in

Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study

Clinical course and predictors of 60-day mortality in 239 critically ill patients with COVID-19: a multicenter retrospective study from Wuhan, China. Crit Care

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Tocilizumab treatment in COVID-19: A single center experience

Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia

Tocilizumab in patients with severe COVID-19: a retrospective cohort study

Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study

Tocilizumab for treatment of mechanically ventilated patients with COVID-19

BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19

Tocilizumab in the treatment of rapidly evolving COVID-19 pneumonia and multifaceted critical illness: A retrospective case series

Is a "Cytokine Storm" Relevant to COVID-19?

Positive RT-PCR Test Results in Patients Recovered From COVID-19

SARS-CoV-2 viral load in upper respiratory specimens of infected patients

Estimated SARS-CoV-2 Seroprevalence in the US as of

Plasma exchange in the treatment of complex COVID-19-related critical illness: controversies and perspectives

Abbreviations: TPE = therapeutic plasma exchange

APACHE II score = Acute Physiology and Chronic Health Evaluation II score; SOFA score = Sequential Organ Function Assessment score

PaO2/FiO2 = partial arterial pressure of oxygen to fractional inspired concentration of oxygen; CRRT= continuous renal replacement therapy; values are median with interquartile ranges, and other data are presented as numbers and percentages

Prothrombin time (sec

ADAMTS-13 activity (%, normal range: 53-205%) 19%

ADAMTS-13 activity (%, normal range: 53-205%)

32% (22-48%)* 17%

Abbreviations: SOFA score = Sequential Organ Function Assessment score

PaO2/FiO2 = partial arterial pressure of oxygen to fractional inspired concentration of oxygen ⱡ Survivors at end-of-therapy (day 35, post-ICU admission); values are medians with interquartile ranges; * p values < 0.05 were statistically significant by Wilcoxon signed rank test for non-parametric data within the two groups of patients before and after the completion of therapy

We wish to thank all health-care workers involved in the diagnosis and treatment of COVID-19 patients in Riyadh, Saudi Arabia.

All authors contributed to data acquisition, analysis, and interpretation. All authors reviewed and approved the final version.