Therapeutic Plasma Exchange in Resistant Cytokine Storm of COVID 19

April 13, 2022 updated by: Mohamed Mamdouh Mahmoud Mohamed Elsayed , MD, Alexandria University

Does Therapeutic Plasma Exchange Have A Role in Resistant Cytokine Storm State Of COVID-19 Infection?

This research is planned to illustrate the efficacy of Therapeutic Plasma Exchange (TPE) treatment in COVID-19 patients with resistant cytokine storm state.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

In early December 2019, several pneumonia cases of unknown origin were observed in Wuhan (China). A novel enveloped RNA β coronavirus was isolated and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The new virus rapidly spread across China and worldwide. On March 11th 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a pandemic. As of 19June 2020, COVID-19 has been confirmed in 8,385,440 individuals globally with deaths reaching 450,686 with a morality of 5.37%. Egypt has 50,437 confirmed cases and 1938 deaths.

The virus mainly spreads through respiratory droplets from infected patients.The clinical spectrum of COVID-19 infection ranges from asymptomatic forms to severe pneumonia requiring hospitalization and isolation in critical care units with the need of mechanical ventilation due to acute respiratory distress syndrome (ARDS). Main symptoms include fever, fatigue and dry cough. Common laboratory findings include lymphopenia and elevated lactate dehydrogenase levels. Platelet count is usually normal or mildly decreased. C reactive protein (CRP) and erythrocyte sedimentation rate are usually increased while procalcitonin levels are normal and elevation of procalcitonin usually indicates secondary bacterial infection. Ferritin, D-dimer, and creatine kinase elevation is associated with severe disease. Chest computed tomographic scans show a typical pattern of bilateral patchy shadows or ground glass opacity.

Severe COVID-19 conditions are usually due to an aggressive inflammatory response known as "cytokine storm" that is characterized by the release of a large amount of pro-inflammatory cytokines. Lung injury, multiorgan failure, and unfavorable prognosis of severe COVID-19 infection have been attributed mainly to the cytokine storm state.

Many proinflammatory cytokines elevate in COVID-19 patients including IL-1, IL-6, IL-8, IL-10, tumour necrosis factor α (TNF-α) and interferon Ȣ(IFN-Ȣ) stimulating immune cells to invade sites of infection causing endothelial dysfunction, vascular damage, alveolar damage and ARDS. Cytokine storm has been reported in several viral infections including influenza H5N1 virus, influenza H1N1 virus, and the two coronaviruses highly related to COVID-19; "SARS-CoV" and "MERS-CoV".

Therapeutic approaches to manage the COVID-19 cytokine storm might provide an avenue to decrease the COVID-19 associated morbidity and mortality. Options include immunomodulators, cytokine antagonists and cytokine removal. Tocilizumab (IL-6 antagonist), Anakinra (antagonist of IL-1 β), TNF blockers, ruxolitinib (JAK1/2 inhibitor ), corticosteroids, intravenous immunoglobulins and therapeutic plasma exchange (TPE) have been used with variable efficacy.

Therapeutic plasma exchange can remove inflammatory factors, block the "cytokine storm", to reduce the damage of inflammatory response to the body. This therapy can be used for severe and critical patients in the early and middle stages of the disease. Patel and colleagues utilized TPE during the 2009 H1N1 influenza A outbreak in three pediatric patients presenting in a similar fashion to those seen with fulminant COVID-19 today. All three had full recovery from their illness after receiving rescue TPE. Adeli at al. used TPE as a rescue therapy in patients with severe forms of COVID-19 ( septic shock, ARDS ) with very good results. Out of 8 patients, 7 patients improved and one patient died. Zhang et al. also tried TPE in three COVID-19 patients who despite receiving antiviral treatment developed respiratory distress and levels of IL-6 increased rapidly. All patients improved clinically and radiologically with negative nucleic acid testing and were discharged 10-14 days later.

In Egypt, the first line drug to treat cytokine storm of COVID-19 is tocilizumab with good results. But a considerable percentage of patients do not respond to it leaving physicians with very limited options and usually patients deteriorated rapidly with high mortality. Based on the encouraging results of TPE in severe COVID-19 infections and the familiarity of the procedure, TPE could be a good option in those patients who do not respond to tocilizumab.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Egypt
      • Alexandria, Egypt, 21526
        • Faculty of Medicine, Alexandria University, Egypt

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • COVID-19 positive patients (confirmed by PCR) with cytokine storm state who will not improve after two doses of tocilizumab.

    • Criteria of failure (resistance) to tocilizumab:

      1. Persistent high IL-6 and CRP.
      2. Persistent worsening of respiratory symptoms ( dyspnea, tachypnea, increased oxygen (O2) requirements or even need for mechanical ventilation).
      3. Partial arterial pressure of oxygen to fractional inspired concentration of oxygen (PaO2/FiO2) ratio < 150.
      4. Persistent fever (˃38.5°C) despite normal procalcitonin level.

Exclusion Criteria:

  • Refractory septic shock:

( It is defined according to surviving sepsis campaign as the presence of hypotension with end organ dysfunction requiring high dose vasopressor support often greater than 0.5 µg/kg/min norepinephrine or equivalent).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Therapeutic Plasma Exchange (TPE)
Each patient will undergo two sessions. TPE will be done through filtration technique using a plasma filter at a dose of (1-1.5) plasma volume/session. Fresh frozen plasma or albumin 5% will be used to replace plasma.
Procedure: Therapeutic Plasma Exchange (TPE)
Treatment with Therapeutic Plasma Exchange (TPE)
Other Names:
  • plasmapheresis

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
mortality
Time Frame: 28 day
Number of patients deaths of the total of patients included
28 day

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
the mean time with oxygen therapy
Time Frame: through study completion, and average of 1 month
to calculate the mean time with oxygen therapy
through study completion, and average of 1 month
the mean time with Non-invasive mechanical ventilation
Time Frame: through study completion, and average of 1 month
to calculate the mean time with Non-invasive mechanical ventilation
through study completion, and average of 1 month
the mean time of intubation
Time Frame: through study completion, and average of 1 month
to calculate the mean time of intubation
through study completion, and average of 1 month
respiratory function parameters
Time Frame: through study completion, and average of 1 month
To calculate the mean of PaO2/FiO2
through study completion, and average of 1 month
respiratory function parameters
Time Frame: through study completion, and average of 1 month
To calculate the mean of levels of oxygen saturation
through study completion, and average of 1 month
radiological lung extension
Time Frame: through study completion, and average of 1 month
to evaluate the lung extension of pneumonia
through study completion, and average of 1 month
mean duration of hospitalization and ICU use
Time Frame: through study completion, and average of 1 month
Days of hospitalization in survivors and/or days at ICU throughout the study
through study completion, and average of 1 month
the requirement of additional organ support
Time Frame: through study completion, and average of 1 month
Percentage of patients with dialysis
through study completion, and average of 1 month
the levels of IL-6
Time Frame: through study completion, and average of 1 month
To evaluate the effect of TPE on the serum levels of inflammatory markers
through study completion, and average of 1 month
Incidence of adverse events
Time Frame: through study completion, and average of 1 month
To calculate the number of adverse events in patients with COVID-19 treated with TPE
through study completion, and average of 1 month
time to reverse-transcriptase polymerase chain reaction (RT-PCR) virus negativity
Time Frame: through study completion, and average of 1 month
To evaluate the time to RT-PCR virus negativity
through study completion, and average of 1 month
the levels of CRP
Time Frame: through study completion, and average of 1 month
To evaluate the effect of TPE on the serum levels of inflammatory markers
through study completion, and average of 1 month
the levels of procalcitonin (PCT)
Time Frame: through study completion, and average of 1 month
To evaluate the effect of TPE on the serum levels of inflammatory markers
through study completion, and average of 1 month
levels of D-dimer
Time Frame: through study completion, and average of 1 month
To evaluate the effect of TPE on the serum levels of inflammatory markers
through study completion, and average of 1 month
levels of ferritin
Time Frame: through study completion, and average of 1 month
To evaluate the effect of TPE on the serum levels of inflammatory markers
through study completion, and average of 1 month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Alexandria University

Investigators

  • Principal Investigator: Mohamed Mamdouh Elsayed, MD, Lecturer of Nephrology & Internal Medicine, Faculty of Medicine, Alexandria university, Egypt
  • Study Chair: montasser M zeid, MD, Professor of Nephrology & Internal Medicine, Faculty of Medicine, Alexandria university, Egypt
  • Study Chair: Akram M Fayed, MD, Professor of Critical Care Medicine, Faculty of Medicine, Alexandria university, Egypt
  • Study Chair: Ehab M El Reweny, MD, Assistant Professor of Critical Care Medicine, Faculty of Medicine, Alexandria university, Egypt
  • Study Chair: Nermine H Zakaria, MD, Professor of Clinical and Chemical Pathology Medicine, Faculty of Medicine, Alexandria university, Egypt
  • Study Chair: Ayman I Baess, MD, Assistant Professor of Chest Diseases, Faculty of Medicine, Alexandria university, Egypt

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 25, 2020

Primary Completion (Actual)

December 29, 2020

Study Completion (Actual)

January 20, 2021

Study Registration Dates

First Submitted

June 30, 2020

First Submitted That Met QC Criteria

July 2, 2020

First Posted (Actual)

July 7, 2020

Study Record Updates

Last Update Posted (Actual)

April 15, 2022

Last Update Submitted That Met QC Criteria

April 13, 2022

Last Verified

April 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • plasma exchange in COVID 19

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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