A novel scoring system for selecting the target patients of COVID-19 convalescent plasma therapy: A hypothesis.

The primary cause of mortality in patients of coronavirus disease 2019 (COVID-19) is the cytokine storm and not directly due to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Therefore, it is being stressed by transfusion medicine specialists to use COVID-19 convalescent plasma (CCP) therapy early in the course of the disease, preferably within 72h of diagnosis. The authors herein, propose a scoring system for the rapid assessment of the patients who have tested positive for SARS-CoV-2. Therefore, a systematic approach may be followed where the patients are categorised into two groups, namely, the low-risk group [LRG; score<5] and the high-risk group [HRG; score ≥ 5] based on this scoring system. Those classified as an HRG should be administered CCP therapy within 72h of a confirmed diagnosis of COVID-19 to neutralise the SARS-CoV-2 virus and prevent the occurrence of the cytokine storm. This in turn could help reduce the overall mortality in the recipients.

Introduction

With the evolving understanding of coronavirus disease 2019 (COVID-19) [1], the COVID-19 convalescent plasma (CCP) therapy has emerged as an important investigational therapy being used in the management of the same [2]. It is now well established that the mortality in COVID-19 patients is due to the SARS-CoV-2 virus-induced cytokine storm and systemic inflammatory response syndrome and not directly due to the SARS-CoV-2 virus [3]. The autopsy findings in patients with COVID-19 have confirmed the presence of cytokine release syndrome (CRS) characterized by hypercytokinemia and multi-organ damage [4]. Furthermore, there is a window of opportunity of few days between the entry of SARS-CoV-2 inside the body and the development of CRS [5]. Therefore, early CCP therapy can result in SARS-CoV-2 neutralisation and prevent the occurrence of cytokine storm [6]. However, practically it has been observed that clinicians have been using CCP even in severe COVID-19 patients as a compassionate therapy and in whom the CRS has already occurred. Therefore, it is highly unlikely that CCP will be effective in such cases [7]. The authors have conceptualised a novel scoring system for identifying the high-risk patients who are likely to develop severe COVID-19 and remain ideal candidates for early CCP therapy. However, even before the authors could test the hypothesis, the CCP therapy was dropped from the treatment protocol for COVID-19 patients in India largely due to the unscientific and indiscriminate use of CCP in the country [8].

Proposing the hypothesis

The authors herein propose a novel Rapid CCP [RCCP] scoring system for the early assessment of patients who have tested positive for SARS-CoV-2. The scoring system has a total of twelve parameters and can be used to identify those who are at a high risk of developing severe COVID-19 infection (Table 1 ). The parameters selected are based on the conditions which have been found to have a significant co-relation of developing severe COVID-19 infection based on the published research [9], [10], [11], [12], [13], [14], [15]. Therefore, a systematic approach may be followed and the patients can be categorised into two groups, namely, the low-risk group [LRG; score < 5] and the high-risk group [HRG; score ≥ 5] based on this scoring system (Fig. 1 ). Those classified as an HRG should be administered CCP therapy within 72 h of a confirmed diagnosis of COVID-19 to neutralise the SARS-CoV-2 virus and prevent the occurrence of the CRS. This in turn could help reduce the overall mortality in the recipients.

Table 1

Rapid COVID-19 convalescent plasma therapy (RCCP) scoring system.

Parameter	Score
	0	1
Age	< 60 years	≥ 60 years
Core body temperature > 37 °C	No	Yes
Cough	No	Yes
Smoking history	No	Yes
Hypertension	No	Yes
Diabetes	No	Yes
Cardiovascular disease	No	Yes
Hematological and/or non-hematological malignancies	No	Yes
Chronic liver diseases	No	Yes
Chronic renal diseases	No	Yes
Breathlessness	No	Yes
Oxygen saturation	> 94%	≤ 94%
Total scoreScore 0-4: No intervention [Baseline standard care & hospital management]Score ≥5: Early convalescent plasma therapy preferably within 72 h

Fig. 1

CCP therapy using RCCP scoring system (CCP: COVID-19 convalescent plasma; RCCP: Rapid COVID-19 convalescent plasma therapy; LRG: Low-risk group; HRG: High-risk group).

Support for the hypothesis

CCP therapy as an experimental treatment is being used as early as January 2020 [16]. Initial studies gave conflicting results about its safety and efficacy in the treatment of COVID-19. The majority of this data was either case reports or institutional experiences [17], [18], [19]. In fact, the PLACID trial [a multi centre clinical trial] from India concluded that the CCP was successfully able to neutralise the SARS-CoV-2 virus, however, it did not result in a decreased patient mortality [20]. This result could be explained by the fact that the primary cause of mortality in patients of COVID-19 is a SARS-CoV-2 virus-induced cytokine storm and not the SARS-CoV-2 virus itself. The most probable reason for the ineffectiveness of CCP therapy in reducing the patient mortality could be attributed to the transfusion of CCP in patients who had already developed severe COVID-19 symptoms compounded with a CRS. Moreover, the convalescent plasma contains non-neutralising antibodies which can assist the virus to gain entry into the macrophages. The virus undergoes rapid proliferation in the macrophages, establishing a pro-inflammatory environment, resulting in the aggravation of the cytokine storm [21]. This was observed in a case report wherein, the use of the convalescent plasma therapy in a patient with Ebola virus disease resulted in acute respiratory distress syndrome (ARDS) [22]. Therefore, in patients having severe COVID-19 infection, where cytokine storm has already occurred, the use of the CCP therapy is not only unjustified rather it merits a clinical reconsideration.

If the CCP therapy is given within the first few days of the diagnosis, the passive IgG anti-SARS-CoV-2 antibodies can neutralise the virus and prevent the occurrence of this CRS in the patients. Early treatment with CCP had resulted in a better outcome in patients having severe symptoms during the 2002-04 SARS epidemic [23], [24]. In a recent study, early administration of convalescent plasma (i.e. within 72 h of the onset of mild COVID-19 symptoms) resulted in the decreased progression to severe COVID-19 infection in elderly patients [25]. Similar results have been observed in another study wherein there was a decreased mortality seen in COVID-19 patients when they were administered the CCP within seven days of hospitalisation [26].

Conclusion

CCP therapy must be used judiciously in a specific patient population where it is likely to be effective. The HRG patients can be identified by using the proposed RCCP scoring system which could be easily utilised in hospital settings and or screening centres. Multicentre prospective interventional studies need to be done to be able to understand the effectiveness of CCP therapy in reducing the mortality rate when administered within the first 72 h of diagnosis especially in those susceptible to develop severe COVID-19 infection.

Author contributions

Source of funding

None.

Disclosure of interest

The authors declare that they have no competing interest.

S.No.	Category of contribution	Author 1Naveen Bansal	Author 2Manish Raturi	Author 3Yashik Bansal	Author 4Pushpendra Singh
1.	Conceptual design	Yes	No	No	No
2.	Literature search	Yes	Yes	Yes	No
3.	Data compilation	Yes	Yes	Yes	Yes
4.	Manuscript preparation and editing	Yes	Yes	Yes	Yes
5.	Manuscript review and final approval	Yes	Yes	Yes	Yes
6.	Final guarantor of the entire manuscript	No	Yes	No	No