Therapeutic plasma exchange in the treatment of COVID-19 induced … – BMC Infectious Diseases

In our study, a statistically significant improvement of clinical (SpO2 and PaO2/FiO2 ratio) and biological (Lymphocytes, CRP, IL-6, Ferritin, D-dimers, Fibrinogen) parameters was attributed to the use of therapeutic plasma exchange in the first group. Additionally, a statistically significant difference was observed comparing clinical (SpO2 and PaO2/FiO2 ratio) and biological (WBC, D-dimers, Fibrinogen) between both groups included in this study, as well as a higher extubation rate, a lower ICU length of stay and mortality in group 1.

Beyond its pulmonary tropism, COVID-19 is a systemic disease with multi-organ involvement attributed to an excessive immune response to the virus [20, 21]. In fact, this hyperinflammatory induced state has been well documented and corresponds to the "cytokine storm" syndrome previously described in various conditions [8, 9].

Serum cytokine levels that are elevated in patients with COVID-19-associated cytokine storm include interleukin-1, interleukin-6, IP-10 (Interferon gamma-induced protein 10), TNF (Tumor Necrosis Factor), interferon-, MIP-1 and 1 (Macrophage Inflammatory Protein-1 Alpha and 1 Beta) proteins, and VEGF (Vascular Endothelial Growth Factor) [10, 21]. Higher levels of interleukin-6 are strongly associated with shorter survival [11]. Circulating activated CD4+and CD8+(Cluster Of Differentiation 4 and 8) T cell and plasmablast levels are also increased in COVID-19 [12].

In addition to elevated systemic cytokine levels and activated immune cells, several clinical and laboratory abnormalities, such as elevated CRP and d-dimer levels, hypoalbuminemia, renal dysfunction, and effusions, are also observed in COVID-19. These organ failures and biological abnormalities reflect the degree of hyperinflammation and tissue damage and can predict the prognosis of COVID-19 [13].

Pre-existing comorbidities such as hypertension, diabetes, and obesity are associated with more severe forms of COVID-19 [14], perhaps due to the pre-existing chronic inflammatory state or a lower threshold for the development of organ dysfunction due to the immune response [5].

Naturally, therapies targeting hyperinflammation, such as immunosuppressants [15], and therapeutic plasma exchange therapy (given their proven role in blood purification by eliminating high molecular weight circulating substances and restoring homeostasis in many dysregulated biological pathways [16]), have a valuable place in the therapeutic arsenal against COVID-19.

In a multicenter case-control study was conducted by Gucyetmez et al. [17] to determine the effectiveness of TPE in patients with COVID-19 admitted to five ICUs in Turkey. The patients were divided into two groups: group 1 consisted of 18 patients who received three consecutive TPE sessions, and group 2 consisted of 35 patients who only received standard therapeutic protocol. The mean SpO2 in group 1 was 917% vs. 895% in group 2. The same study also reported a mean pre-TPE WBC count of 9.084.1103/L compared to a mean post-TPE WBC count of 9.143.5103/L. To date, the study by Gucyetmez et al. and ours are the only ones to have included SpO2 and WBC count as variables to study the effectiveness TPE in COVID-19.

Similarly, to our findings, a randomized control trial including 87 patients divided into two groups [18], depending on who benefited from TPE on top of the standard therapeutic protocol or just the latter, and in which significant improvement in PaO2/FiO2 ratio, CRP, IL-6, Ferritine, and D-dimers were noted before and after TPE sessions. The same study reported better clinical and biological parameters in the intervention group comparted to the control group.

While the efficiency of TPE has extensively documented, the diversity of methods used by each center has been well documented, particularly in the literature review conducted by Krzych et al. [6] and later by Beraud et al. [19], the latter of which included 34 articles (1 randomized controlled trial, 4 casecontrol studies, 15 case series, and 14 case reports, totaling 267 patients treated with plasma TPE).

We highlighted three major differences. First, the number of sessions varied from 1 to 9 sessions depending on the case series in question. Second, there was a variability in the choice of replacement fluid, with Fresh Frozen Plasma (FFP) being the most commonly used, followed by 5% albumin. Finally, there was a predominance of regional citrate anticoagulation (RCA) [6, 19].

In the absence of guidelines regarding the practical aspects of TPE and following the departments procedural habits, we opted for a number of 5 consecutives TPE sessions using FFP as a substitution fluid and heparin for anticoagulation given that RCA is not available. The therapy was provided to patients based on the informed consent of either the patient or a proxy, and also based on the therapys availability given the limited number of machines, consumables, and FFP.

Taking into account the therapys procedural diversity, a multinational team of the International Society of Blood Transfusion (ISBT) conducted a literature review relying on the recommendations of the American Society for Apheresis (ASFA) to formulate preliminary clinical practice recommendations related to the performance of plasma exchanges in COVID-19 [22], which concluded up to the date of its publication that the use of TPE in COVID-19-induced cytokine storm is categorized as Class III, Grade 2B, meaning that its optimal role is not established, and that the quality of evidence evaluated at that time supported only a weak overall recommendation for this approach, indicated in critically-ill COVID-19 patients with virtually no absolute contraindications, initiated early in the disease progression, using FFP or ideally convalescent plasma for substitution, and RCA for anticoagulation. The recommended exchange volume is 1 to 1.5 times the patients TPV (Total Plasma Volume), for virtually as many sessions as necessary.

The results of our cohort are in line with those widely reported by several studies already in the literature, advocating for the effectiveness of plasma exchange in COVID-19, especially in severely ill patients requiring ICU care.

The COVID-19 pandemic proved to be a unique experience, opening the door to an unlimited potential of research and experimentation. While our study could have been better led, with more clinical and biological parameters monitored, it offers ad significant sample size, with valuable results.

That said, further studies are needed to first describe more specifically and closely delineate the clinical-biological spectrum of the cytokine storm induced by COVID-19, particularly its often-neglected extrapulmonary manifestations, but also to support the safety and efficacy of plasma exchange in COVID-19.

In this sense, it would be preferable to evaluate the use of plasma exchange alone, or in combination with other therapies, for COVID-19 patients in the context of prospective, randomized, and controlled clinical trials. This approach could yield fruitful results in saving lives and paving the way for future consideration of plasma exchange in similar diseases.

Our study has a number of strengths including a specific focus on the use of TPE in critically-ill patients, joining only a limited number of studies published to this day, as well as comparative approach comparing outcomes before and after TPE sessions within Group 1 and conducting an event-based comparison between both groups, enhancing the depth of the analysis. This Event-Based Comparison provides a meaningful endpoint, aligning with practical clinical outcomes. This study also carries certain weaknesses such as its retrospective and single-center design. Also, a longitudinal data analysis comparing parameters and outcomes at various time points, accounting for individual variations would have been more informative, specifically on the efficiency of TPE with less than 5 sessions.

Here is the original post:

Therapeutic plasma exchange in the treatment of COVID-19 induced ... - BMC Infectious Diseases