Therapeutic Plasma Exchange in Resistant Cytokine Storm of COVID 19

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

Detailed Description
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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.

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

Conditions
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COVID 19

Intervention / Treatment
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* Procedure: Therapeutic Plasma Exchange (TPE)


Participation Criteria
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Eligibility Criteria
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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: Persistent high IL-6 and CRP. Persistent worsening of respiratory symptoms ( dyspnea, tachypnea, increased oxygen (O2) requirements or even need for mechanical ventilation). Partial arterial pressure of oxygen to fractional inspired concentration of oxygen (PaO2/FiO2) ratio < 150. 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).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic Plasma Exchange (TPE)<br>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)<br>* Treatment with Therapeutic Plasma Exchange (TPE)<br>* Other names: plasmapheresis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| mortality | 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 | to calculate the mean time with oxygen therapy | through study completion, and average of 1 month | 
| the mean time with Non-invasive mechanical ventilation | to calculate the mean time with Non-invasive mechanical ventilation | through study completion, and average of 1 month | 
| the mean time of intubation | to calculate the mean time of intubation | through study completion, and average of 1 month | 
| respiratory function parameters | To calculate the mean of PaO2/FiO2 | through study completion, and average of 1 month | 
| respiratory function parameters | To calculate the mean of levels of oxygen saturation | through study completion, and average of 1 month | 
| radiological lung extension | to evaluate the lung extension of pneumonia | through study completion, and average of 1 month | 
| mean duration of hospitalization and ICU use | 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 | Percentage of patients with dialysis | through study completion, and average of 1 month | 
| the levels of IL-6 | 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 | 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 | To evaluate the time to RT-PCR virus negativity | through study completion, and average of 1 month | 
| the levels of CRP | 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) | 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 | To evaluate the effect of TPE on the serum levels of inflammatory markers | through study completion, and average of 1 month | 
| levels of ferritin | To evaluate the effect of TPE on the serum levels of inflammatory markers | through study completion, and average of 1 month |