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