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).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.Since the outbreak of corona virus disease (COVID-19), main treatment modalities have been antivirals, interferons, glucocorticoids, anti-coagulants and supportive treatment in addition to traditional Chinese medicine. There are also clinical trials exploring hydroxyquinoline / chloroquine sulphate, azithromycin, immunoglobulins, Vitamin-C, washed microbiota, nebulized interferon, teicoplanin as well as Mesenchymal stem cells. However, most of these trials were small and remain in the experimental phase with currently no effective / specific antiviral with robust scientific evidence as regards the mortality reduction in COVID-19.In an attempt to treat COVID-19, investigator will use different investigational treatment either alone or in combination to see mortality and morbidity benefit on the basis of limitted evidence available so far. These investigational modalities include Therapeutic plasma exchange (TPE), Convalescent Plasma (CP), Remdesivir, Tocilizumab and Mesenchymal stem cell (MSC) therapy in addition to standard supportive treatment.

Long title: Role of different investigational treatments alone or in combination to treat moderate, severe and critical COVID-19 in addition to standard treatment; An Open label, Phase 2 Study Clinical Phase: multi arm, Phase 2 Open Label Conducted by: Department of Pulmonology and Critical Care; Pak Emirates Military Hospital. Sample Size: 600 Study Population: Hospitalized COVID-19 patients aged ≥18 years to 80 years of with Moderate- severe-critical disease Study Duration: 1st April, 2020 to 31st July 2020 Study Design: This open label phase 2 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 3. Therapeutic Plasma exchange in combination with Convalescent Plasma in addition to standard treatment 4. Tocilizumab in addition to standard treatment 5. Remdesivir alone or in combination with Therapeutic plasma exchange in addition to standard treatment 6. Mesenchymal stem cell therapy in combination with other investigational treatments 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.

Inclusion Criteria:

• PCR positive confirmed COVID-19
• Admitted in hospital
• willing patients to participate in trial
• Day of illness less than 14 days
• no contraindications to invasive procedure or novel therapies

Exclusion Criteria:

• co morbidities with life expectancy less than 6 months
• Multi organ failure
• Septic shock before initiation of treatment
• Congestive cardiac failure (EF<20%) (4)
• Those receiving immunotherapy, Anti-thymocyte globulin or hematopoietic stem cell transplant in recent past
• Patients of hematological or solid organ malignancies

data can be shared on demand in SPSS sheet

6 months from completion of study

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