key: cord-0833661-ngendkj2
authors: Jaiswal, Vinod; Nasa, Prashant; Raouf, May; Gupta, Megha; Dewedar, Hany; Mohammad, Hozaifah; Al Rais, Zeyad; Ali Baqer, Mohamed; Alsabbah, Asad; Ibrahim, Yasser; Salem, Mohamed; Shammass, Demme; Marashi, Mahmoud
title: Therapeutic Plasma Exchange followed by Convalescent Plasma transfusion in critical COVID-19- an exploratory study
date: 2020-11-03
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2020.10.085
sha: c414b36dd6bb142fba5360b92bdc52a7f5fcf3ad
doc_id: 833661
cord_uid: ngendkj2

The pathophysiology of critical coronavirus disease 2019 (COVID-19) is primarily a host immune interplay to virus invasion. The therapeutic options have been explored either against hyperinflammation from dysregulated adaptive immunity or direct virus neutralization using antibodies from convalescent plasma (CP) of a recovered patient. The therapeutic plasma exchange (TPE) for removal of excessive inflammatory cytokines have been tried with success in COVID-19. We undertook this exploratory study to evaluate safety and efficacy of TPE followed by CP transfusion in 14 patients with critical COVID-19 requiring invasive mechanical ventilation (IMV). All patients showed improvement in symptoms and decrease of inflammatory markers especially CRP (p = 0.03). 10 patients were liberated from IMV after median of 5.5 (3-36) days, post sequential therapy. Day 7 and Day 28 mortality was 21.4% and 28.6% respectively. The median duration ICU and hospital LOS were 12 (5-42) days and 18 (12-47) days respectively. No patient developed transfusion-associated complications, but three patients developed secondary bacterial sepsis within 14 days of therapy and, one died. This case series demonstrated the sequential use of TPE followed by CP transfusion as a therapeutic option in critical COVID-19.

 The sequential treatment with therapeutic plasma exchange (TPE) and convalescent plasma (CP) can be tried as a therapeutic option for critical  Case mortality at day 7 and day 28 was 21.4% and 28.6% respectively with sequential therapy of TPE and CP.

 There were no significant immediate complications but, three patients developed secondary bacterial sepsis due to ventilator associated pneumonia and one died.

The pathophysiology of critical coronavirus disease 2019 (COVID-19) is primarily a host immune interplay to virus invasion. The therapeutic options have been explored either against hyperinflammation from dysregulated adaptive immunity or direct virus neutralization using antibodies from convalescent plasma (CP) of a recovered patient. The therapeutic plasma exchange (TPE) for removal of excessive inflammatory cytokines have been tried with success in COVID-19. We undertook this exploratory study to evaluate safety and efficacy of TPE followed by CP transfusion in 14 patients with critical COVID-19 requiring invasive J o u r n a l P r e -p r o o f Introduction The immune system plays a critical part in pathogenesis of severe coronavirus diseases 2019 (COVID-19) (Vabre et al., 2020) . Proposed mechanisms include host immune dysregulation causing excessive cytokines release and/or defective B-cell response with ineffective neutralizing antibodies (Vabre et al., 2020) . The success story of corticosteroids in severe COVID-19 signal towards hyperinflammation and immunomodulation (WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group et al., 2020).

Convalescent plasma for viral neutralization had been tried with varying success in COVID-19 (Li et al., 2020 , Liu et al., 2020 . Therapeutic plasma exchange (TPE) to remove inflammatory cytokines also been tried in severe COVID-19 in smaller case series (Khamis et J o u r n a l P r e -p r o o f al., 2020, Shi et al., 2020 , Zhang et al., 2020 . We used a sequential therapy with TPE followed by CP transfusion in 14 severe COVID-19 patients who were on invasive mechanical ventilation (IMV) to evaluate its effectiveness and safety.

This prospective case-cohort study was conducted in two tertiary care hospitals of Dubai 

The enoxaparin at 1mg/kg subcutaneous 12 hourly and injection methylprednisolone at 1 mg/kg/day was used in all patients.

The clinical and laboratory data on baseline demographics, co-morbidities, symptoms, interval between symptoms to sequential therapy, and negative RT-PCR was collected. The outcome measured were day 7 and day 28 mortality, length of stay (LOS) on IMV, intensive care unit (ICU) or hospital and time to tracheal extubation after therapy. PaO2/FiO2 ratio and inflammatory markers (C-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) and D-dimer) were also collected before, 12 hours, 24 hours and till seven days after sequential therapy. All patients were observed for any immediate complications during TPE or CP and any secondary infection till 14 days after sequential therapy.

Student's unpaired t test was used for comparison of variables before and after sequential therapy.

To our knowledge this is first case series on sequential use of TPE and CP for the management of critical COVID-19.

The median age was 51 (range 28-65) years; 78.6% were male ( Table 1 ). The patients were obese with median body mass index (BMI) of 32.5 (24-41) kg/m 2 . Co-morbidities were present in 10 (71.4%) patients with hypertension (64.2%) being most common. All patients were on IMV with mean PaO2/FiO2 ratio of 138.89 (±41.90) mm of Hg before sequential therapy. The therapy was administered 9 (6-21) days from the onset of symptoms. The improvement in symptoms (resolution of fever) and decrease in inflammatory markers (CRP, LDH, D-dimer and ferritin) was observed in all 14 patients with significant decrease in CRP (p=0.03) ( Table 1 ). Day 7 and Day 28 mortality was 21.4% and 28.6% respectively. The time from sequential therapy to negative RT-PCR was 8 (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) days. 10 patients were liberated J o u r n a l P r e -p r o o f from IMV with median duration of 8 (6-36) days and 5.5 days post sequential therapy.

Median ICU and hospital LOS were 12 days and 18 (Khamis et al., 2020 , Shi et al., 2020 , Zhang et al., 2020 . FFP as replacement fluid of TPE may help in modulating the circulating inflammatory cytokines and hypercoagulable state, by replacing ADAMTS13 enzyme. (Focosi, et al., 2020) . Khamis et al. (2020) in a case series of 31 patients with moderate to severe COVID-19, found use of TPE was associated with significantly lower day 14 and day 28 mortality.

The prolonged replication and shedding of SARS-CoV-2 virus has been demonstrated in critically ill patients with COVID-19 (Vabre et al., 2020 , Focosi et al., 2020 . CP from recovered donors can help in inactivation of the virus by neutralizing antibodies (Focosi et al., 2020) . The randomized controlled trials (RCTs) using CP in severe COVID-19 showed variable success (Li et al., 2020 , Liu et al., 2020 . Liu et al. (2020) in a retrospective RCT found use of CP was associated with reduced oxygen requirement and mortality benefit in J o u r n a l P r e -p r o o f non-intubated patients [Hazard ratio (HR)= 0.19]. In another prospective RCT, which was stopped prematurely, day 28 mortality was significantly lower in patients with severe COVID-19 but, not for life-threatening disease (Li et al., 2020) .

The sequential use of TPE and CP as a therapeutic option in severe COVID-19 by removal of inflammatory cytokines followed by transfusion of neutralizing antibodies had never been explored (Kesici et al., 2020 , Focosi et al., 2020 .

We used sequential TPE and CP early in the disease course with median of 9 (6-21) days from symptoms onset. The day 28 mortality in these patients was only 28.6%. Armstrong et al., 2020 

This case series demonstrated the sequential use of TPE followed by CP transfusion as a therapeutic option in critical COVID-19 patients with ARDS. We propose RCTs to further explore this sequential treatment in severe to critical COVID-19.

J o u r n a l P r e -p r o o f

Outcomes from intensive care in patients with COVID-19: a systematic review and meta-analysis of observational studies

Convalescent Plasma Therapy for COVID-19: State of the Art

Get rid of the bad first: Therapeutic plasma exchange with convalescent plasma for severe COVID-19

Therapeutic plasma exchange in adults with severe COVID-19 infection

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

Convalescent plasma treatment of severe COVID-19: a propensity score-matched control study

Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19

Incidence of ARDS and outcomes in hospitalized patients with COVID-19: a global literature survey

Immunology of COVID-19: Current State of the Science Immunity

WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group

Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

Efficacy of therapeutic plasma exchange in severe COVID-19 patients

Median(range)

Demographics Age (years) Mean-49.14 (±12.50), Median-51

Female-3(21.4%)

BMI (kg/m 2 ) Mean-29.66 (±4.99), Median

Mean=16.93 (±9.40)

Treatment Anti-viral agent HCQ -35.7%, Favipiravir-42.9%, Lopinavir/ritonavir-71%

Interval between sequential therapy and negative RT-PCR for SARS-CoV-2 (days)

Interval between sequential therapy and removal of IMV (days) Mean -18.63 (±17.85)

ICU-Length of stay (days) Mean=26.43 (±17.77), Median

IMV-Length of stay (days) Mean=28.86 (±18.45), Median

Hospital-Length of stay (days) Mean=35.64 (±16.98), Median

Before therapy, Mean ± SD p value less than 0.05 is significant.BMI-body mass index, CRP-C-reactive protein, HCQ-hydroxychloroquine, ICU-intensive care unit, IMV-Invasive mechanical ventilation, LDH-lactate dehydrogenase, RT-PCRreverse transcriptase polymerase chain reaction, SARS-CoV-2-severe acute respiratory syndrome coronavirus 2, SD-standard deviation.