key: cord-0685924-b396reyr
authors: Mousavi‐Roknabadi, Razieh Sadat; Haddad, Fatemeh; Fazlzadeh, Aylar; Kheirabadi, Dorna; Dehghan, Hamidreza; Rezaeisadrabadi, Mohammad
title: Investigation of plasma exchange and hemoperfusion effects and complications for the treatment of patients with severe COVID‐19 (SARS‐CoV‐2) disease: A systematic scoping review
date: 2021-07-13
journal: J Med Virol
DOI: 10.1002/jmv.27182
sha: 8fad4410d8e21079dc6690b34ba80fe1bad6129a
doc_id: 685924
cord_uid: b396reyr

Some previous studies suggested that the plasma exchange (PE) and hemoperfusion (HP) played a cardinal role in the treatment of severe coronavirus disease 2019 (COVID‐19) cases by diminishing the cytokine storm. This study aimed to assess the effects of PE and HP on cytokine storms in patients with severe COVID‐19 through a systematic scoping review. Four Electronic databases (Medline [accessed from PubMed], Scopus, Science Direct, and Cochrane library) were searched systematically on February 2, 2021, using MESH terms and related keywords in the English language. Considering the titles and abstracts, unrelated studies were excluded. The full texts of the remained studies were evaluated by authors, independently. Then, their findings were assessed and reported. A total of 755 articles were obtained within the first step of searching, and 518 remained after removing the duplications. Through the title and abstract screening, 438 were removed. Of the rest, 59 papers were excluded. Finally, after reading the full text of the remained articles, 21 were included in data extraction. Most of the previously reported evidence were case reports and case series. Findings were summarized in two categories. The first category encompassed nine studies regarding HP and continuous renal replacement therapy, and the second category included twelve studies about PE. The results revealed that HP and PE within the cytokine storm phase would be beneficial with a high probability in the treatment of severely ill COVID‐19 patients. Highlights Some studies showed that plasma exchange (PE) and hemoperfusion (HP) played an important role in the treatment of patients with severe COVID‐19 disease. The results of this systematic scoping review revealed that HP and PE within the cytokine storm phase would be beneficial with a high probability in the treatment of severely ill COVID‐19 patients.

According to a recent World Health Organization report, 110,749,023 definite cases of COVID-19, including 2,455,131 deaths, were observed until February 21, 2021. Currently, the mortality rate of COVID-19 is estimated from 1.36% to 15%. [1] [2] [3] Individuals can be infected with SARS-COV-2 for the second time as well. 4 COVID-19 has no definitive treatment. Remdesivir, favipiravir, and corticosteroids have been suggested for moderate to severe cases to date. 5 Recent evidence suggests that an immune response in severely ill individuals is responsible for acute respiratory distress syndrome and multiple organ failures. 6, 7 A cytokine surge, also called hypercytokinemia is also the main cause of death in SARS, MERS, H5N1, and H7N9 infections. 6 and COVID-19, have different cytokine profiles and coagulopathy presentations, with microvascular thrombosis and superficial microcoagulation known as the most common pathologies, respectively. Therefore, timely control of cytokine storms and decreasing inflammatory cell infiltration in the lungs is key to reducing COVID-19-associated mortality. 9 Treatment strategies with antibodies, such as tocilizumab, sarilumab, siltuximab, and blood-purification techniques, including therapeutic plasma exchange (PE), absorption, perfusion, and blood plasma filtration, are likely to be more beneficial for COVID-19. 10-13 PE replaces patient's plasma with another fluid, such as allogeneic plasma maintaining homeostasis by eliminating excess cytokines and modifying the coagulation factors. This is a standard treatment for a subtype of thrombotic microangiopathy, thrombocytopenic purpura, through the elimination of ADAMTS-13 inhibitors. 14 PE has also shown some degrees of success in disseminated intravascular coagulation (DIC), 15, 16 which can occur as a complication of COVID- 19 . It has been reported that PE can prevent the progression of the disease. 17 Although there are vaccines available in many countries, there are some limitations in other regions due to some issues. 18 Hence, physicians are still dealing with severe COVID-19 patients who need more complex treatments. Based on a preliminary search in PubMed and Cochrane Database of Systematic Reviews, there is no systematic review regarding the treatment of COVID-19 with "hemoperfusion," or "plasma exchange," or "plasmapheresis." Hence, this review was aimed to evaluate the effects of PE and hemoperfusion (HP) on cytokine storm in patients with severe COVID-19. The findings would help physicians to find guidance in the appropriate COVID-19 treatment strategy in the cytokine storm phase.

The present systematic scoping review was conducted based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews statement. 19 As shown in Figure 1 , a multi-step search strategy was performed. The electronic literature searches were conducted to identify all studies in the field of treatment of COVID-19 with "hemoperfusion" or "plasma exchange," or "plasmapheresis." Hence, Medline (accessed from PubMed), Scopus, Science Direct, and Cochrane library were four databases taken into account for systematic searching till February 2, 2021, by two authors (RSM, MR). Google search engine was also reviewed manually to explore the gray literature (RSM). Table 1 Studies, which were not relevant to the study's aim, written in non-English language, or considered other coronaviruses except COVID-19, studies without any specific patient's data, as well as not available fulltext were excluded, through reading the title and the abstract (MR, AF, FH). Also, we excluded the studies that evaluated renal replacement therapy in patients with raised creatinine or acute kidney injury.

Then, two authors evaluated the full texts of the obtained studies, independently, and they decided whether these papers met the inclusion criteria or not (MR, AF). Disagreements were resolved by discussion between all authors, and eventually, the articles were selected based on consensus. None of the authors was blind to the titles of the journals or to the authors or institutions of the studies. Then, the level of evidence of each study was determined. 20 The following data were extracted from the included studies: study authors, time of publishing, study designs, population and sample size, treatment, main findings, complications, and limitations. A data extraction form was designed in a Microsoft Excel sheet 2013, and two authors extracted the data, independently (AF, FH, DK). The discrepancies were resolved, and then the obtained results were summarized (RSM).

Ethical issues (including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors. level. Eventually, after reading the full text of these articles, 21 articles were included for the final data extraction. 13, [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] Inter-rater agreement following the first round of screening between the two investigators was 94.26% (Cohen's k = 0.55). Within the second round of screening, inter-rater agreement rose to 100%. Our investigation illustrated that the most of available reported evidence was basically case reports and case series, and they did not have high quality. Also, the studies used various methods and did not have enough data homogeneity for meta-analysis. For instance, the number of sessions and hours per session for each of both treatments were different in available studies. Furthermore, the filters used in the HP treatments were also different. Results were summarized in two categories: (1) HP and continuous renal replacement therapy (CRRT); (2) PE.

With respect to HP and CRRT treatments for COVID-19 patients with severe conditions, nine studies were enrolled, in which 1/8 was a controlled trial, 21 increased significantly following the intervention (from 89.6% ± 3.94% to 92.13% ± 3.28%), but the mode of oxygen therapy was not effective. In addition, C-reactive protein (CRP) decreased significantly but the reduction of serum interleukin-6 (IL-6)

was not significant. Finally, 6/10 patients improved after the inter- In another case series by Shadvar et al., 27 

Twelve studies were enrolled in this category and PE was introduced as a therapeutic strategy for critically ill patients with COVID-19.

This category included 1/12 clinical trial, 24 1/12 cohort, 26 1/12 case-control, 22 

As it was confirmed through previous evaluations, the cytokine storm phase can play an important role in severe COVID-19.

Scientists tried to find therapeutic protocols for the purification of the blood from harmful cytokines, and if they control it, many lives can be saved. 13, 24, 32 Invasive therapeutic strategies are categorized into two, including PE and HP. Because of the lack of available clinical and analytical investigations on PE and HP, we decided to evaluate these two invasive treatments by a systematic scoping review.

Studies have shown that the use of PE can be effective for patients having very poor general conditions and experiencing decreased oxygen saturation due to severe lung involvement.

Investigations showed that PE could increase the lymphocyte level and decrease the levels of TNF-α, IL-6, ferritin, D-dimer, and CRP.

This therapeutic manner could also improve clinical features like PaO 2 /FiO 2 ratio, oxygen demand, and length of admission, especially in ICU. Plasmapheresis was able also to lessen noninvasive or ventilator demand. Studies that have used PE did not report any lifethreatening side effects, especially severe thrombosis. [22] [23] [24] [25] [26] 28, 35 HP also was known as a method for removing harmful interleukins and acute phase reactants. In some studies, this manner caused improving P/F, and the patients announced better condition after administrating it. For more safety, using heparin was advised by different protocols. 21, 27, 29, 34, 36 As was mentioned above, using either HP or plasmapheresis is a good way to reduce cytokines and improve oxygenation in patients with severe COVID-19. For more safety and decreasing the chance of thrombosis, using heparin was recommended in HP, while FFP or immunoglobulins were recommended in some PEs.

It is worthy to mention that according to the current findings, PE and HP should be planned when the patient with COVID-19 is in the cytokine storm phase, which means the presence of high levels of ferritin, CRP, and IL-6 in the bloodstream, as well as severe hypoxic condition (P/E < 100).

Due to the insufficient high-quality studies, it is recommended that more controlled clinical trials be done, and a specific therapeutic protocol, as well as its advantages and disadvantages, be defined. 

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The authors would like to thank all the healthcare providers who are fighting the COVID-19 around the world.

The authors declare that there are no conflict of interests. 

The data that support the findings of this study are available in the references.

The review protocol was not previously registered.