Therapeutic Plasma Exchange for Coronavirus Disease-2019 Triggered Cytokine Release Storm;
Condition: COVID-19; Cytokine Release Syndrome
MeSH terms: COVID-19; Cytokine Release Syndrome
Study type: Interventional

Summary: 
      Background:

      investigators have seen recently from experience in Western countries with best health care
      systems that pandemics cannot be managed in hospitals. Investigators have seen ICUs crowded
      to capacity, healthcare workers being exposed and going to quarantine or dying after exposure
      to large doses of viral inoculums. Investigators recommend that institutions should register
      for Clinical trials and consider emergency use of TPE. In Pandemics, time is of essence to
      avoid mortality by intervening early with available evidence, preferably as part of clinical
      trial.

      Scientific rationale:

      Beyond supportive care, there are currently no proven treatment options for coronavirus
      disease (COVID-19) and related pneumonia, caused by Severe Acute Respiratory Syndrome
      Coronavirus 2 (SARS-CoV-2). However, literature review has shown that most common cause of
      death in severe SARS-COV-2 is Cytokine release syndrome and Hemophygocytic Lymphohistocytosis
      (HLH). In this context, Investigators seek to treat patients who are sick enough to warrant
      hospitalization prior to the onset of overwhelming disease including a systemic inflammatory
      response, sepsis, and/or Acute Respiratory Distress Syndrome (ARDS).
    

Detailed description: 
      PROTOCOL SUMMARY:

      Therapeutic plasma exchange for coronavirus disease-2019 triggered cytokine release storm; a
      retrospective propensity matched control study

      Clinical Phase: Two arms, Phase 2 Open Label

      Conducted by: Department of Pulmonology and Critical Care; Pak Emirates Military Hospital.

      Sample Size: 280

      Study Population: Hospitalized COVID-19 patients aged ≥18 years to 80 years of with Moderate-
      severe-critical disease and evidence of Cytokine release storm (CRS)

      Study Duration: 1st April, 2020 to 31st July 2020

      Study Design: A retrospective propensity matched control trial will assess the efficacy and
      safety of following treatment options

        1. Standard treatment including steroids

        2. Therapeutic plasma exchange in addition to standard treatment

      Operational Definitions

        1. Moderate disease:

           COVID-19 positive case with lung infiltrates < 50% of total lung fields on Chest X-ray /
           peripheral ground glass opacities (GGOs) on High Resolution Computerized Tomography
           (HRCT)chest but no evidence of hypoxemia.

        2. Severe disease:

           COVID-19 pneumonia with evidence of hypoxemia (RR > 30/minute or PaO2 on ABGs < 80mmHg
           or PaO2/FiO2 (PF ratio) < 300 or lung infiltrates > 50% of the lung field).

        3. Critical illness:

           COVID-19 pneumonia with evidence of either respiratory failure (PaO2 < 60mmHg) or
           multiorgan dysfunction syndrome (MODS) measured by Sequential Organ Failure assessment
           (SOFA score) > 10 or septic shock (Systolic BP less than 90 or less than 40mm Hg of
           baseline in hypertensive or Urine output < 0.5 ml/kg/hour).Age, sex, comorbidities, date
           of symptoms, source of infection, type of admission SOFA score, Clinical status, vital
           signs including temperature, respiratory rate, oxygen saturation, oxygen requirement,
           Complete Blood counts (CBC) with neutrophil counts, lymphocytes count, C-reactive
           Proteins (CRP), chest imaging (CT or X-ray), location and status in hospital

        4. Cytokine release storm (CRS):

      Diagnostic criteria of Cytokine release syndrome (CRS) CRS is defined as fever of equal to or
      more than 100 F persisting > 48 hours in absence of documented bacterial infection and ANY of
      the following in the presence of moderate, severe or critical disease

        1. Ferritin >1000 mcg/L and rising in last 24 hours

        2. Ferritin >2000 mcg/L in patient requiring high flow oxygen or ventilation

        3. Lymphopenia < 800 cells/ul or lymphocyte percentage <20% and two of the following

             1. Ferritin >700 mcg/mL and rising in the last 24 hours

             2. LDH > 300 IU (reference 140-250 IU/L) and rising in the last 24 hours

             3. D-Dimer >1000ng/mL (or >1mcg/ml) and rising in the last 24 hours

             4. CRP >70 mg/L (or >10 hsCRP) and rising in the last 24 hours, in absence of
                bacterial infection

             5. If any 3 of above presents on admission no need to document rise

      5. Standard treatment:

      As per Institutional COVID-19 Management Guidelines all patients of moderate, severe and
      critical COVID-19 received standard protocol of aspirin, anticoagulation, ulcer prophylaxis,
      awake Proning (if PaO2 < 80mmHg) and corticosteroids. All patients of CRS received
      Methylprednisolone 1 mg/kg irrespective of disease severity.

      6. Therapeutic Plasma exchange (TPE)

      Therapeutic plasma exchange: 1-1.5 plasma exchange daily (1-5 sessions) with replacement
      fluid Fresh frozen Plasma (FFP) (whole volume) to 70 willing patients of moderate, severe and
      critical disease with evidence of CRS after explaining the investigational role of this
      therapy. TPE will be given in addition to standard treatment to 70 patients randomly. TPE
      related complications to be documented

      7. Recovery Recovery to be defined by de-escalation of patients condition from severe to
      moderate, or from moderate to mild, plus at least 2 of the following; serum Ferritin < 1000
      ug/ml (and decreasing trend on two consecutive days), serum LDH normalization, C-reactive
      protein > 50% fold reduction (and decreasing trend in on two consecutive days),), ALC > 1000
      and PT/APTT normalization.
    

Intervention name(s): Therapeutic Plasma Exchange
Intervention type(s): Procedure
Intervention description(s): a. 1-1.5 plasma volume exchange, 2/3rd plasma should be replacing with FFP to avoid coagulopathy, adequate dieresis to prevent volume overload, 1-5 sessions in total, 1 session daily
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: It was an interventional retrospective Propensity score matched (PSM) single centre based cohort study in Pak Emirates Military Hospital Rawalpindi (PEMH), Pakistan from 1st April to 30th June 2020. This study was carried out at the Department of Pulmonology and Critical care. PEMH is the largest Covid-19 designated hospital in the country. Data of all hospitalized patients is maintained by PEMH Covid-19 Research and evaluation cell. The study was approved by Institutional Review Board.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Therapeutic Plasma exchange; Cytokine release storm; COVID-19; ARDS; Critical disease