What's new in critical illness and injury science? Convalescent plasma for coronavirus disease-2019 patients with severe or critical illness

Since emerging in December 2019, the coronavirus disease-2019 (COVID-19) pandemic caused by the beta-coronavirus severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) virus has resulted in over 118 million cases worldwide and over 2.62 million deaths (as of 11 March 2021). Roughly 20% of patients require hospitalization, with one-quarter of those necessitating intensive care unit (ICU) admission for reasons including refractory hypoxemia, shock, or multiple organ failure.[1,2] The paucity of therapeutics with demonstrable efficacy has led many to employ less substantiated treatments supported by case series, small nonrandomized studies, or even intellectual intuition. Recently, we discussed the use of intravenous immunoglobulin.[3] This editorial focuses on convalescent plasma (CP) to treat COVID-19 patients with a severe or critical illness.

CP refers to plasma that is collected from individuals, following resolution of infection and development of antibodies.[4] It has been hypothesized that infusion of the SARS-CoV-2 neutralizing antibodies contained within this serum may improve patient outcomes. CP has been utilized to treat other infectious diseases with variable results, including outbreaks of other beta-coronaviruses (SARS-CoV-1, Middle East respiratory syndrome),[5] Ebola,[6] and influenza;[7] however, the efficacy of CP in critically ill patients with SARS-CoV-2 infection remains unclear.

Several nonrandomized studies indicated that CP treatment for patients with COVID-19 may be safe,[4,8,9] with variable results regarding mortality and clinical markers of critical illness.[10,11,12] Moreover, when combined with remdesivir, CP did not improve outcomes over remdesivir alone.[13] Despite this modest evidence, the United States Food and Drug Administration has approved the use of experimental CP therapy in clinical trials and critical COVID-19 patients without other treatment options.[14]

A listing of randomized controlled trials in adult patients with severe or critical illness due to COVID-19 is presented inTable 1.[15,16,17,18,19] Four studies were excluded for including patients other than those with a severe or critical illness.[20,21,22,23] Risk of bias was assessed for each study using the Cochrane risk-of-bias tool [Table 2], and evidence was graded according to the GRADE rating system.

Table 1.

The characteristics of the included studies assessing convalescent plasma for management of coronavirus disease-2019 patients with severe or critical illness

Author (year)	Design, Country, (n)	Intervention (n)	Comparison (n)	Primary endpoint (s)	Select secondary endpoint (s)a
AlQahtanib	RCT, 2 centers, Bahrain (n=40)	CP 200 ml, transfused 24 h apart for 2 doses (n=20)	Conventional therapy (n=20)	Requirement and duration of invasive or noninvasive ventilation	28 days mortality; laboratory parameters
Bajpaib	RCT, 1 center, India (n=29)	CP 250 ml daily × 2, (n=14) c, d	FFP 250 ml daily ×2, (n=15)c,d	Proportion of patients free of MV on day seven	Mortality (day 7 and 28), PaO2/FiO2 improvement, SOFA score reduction (48 h and day 7), hospital LOS, ICU LOS, vasopressor requirements, dialysis-free days (at 28 days)
Li (2020)	RCT, 7 centers, China (n=103)	CP 4-13 mL/kg × 1 (n=52)	Conventional therapy (n=51)a,c,e,f	Composite time to clinical improvement: survival to discharge or 2-point reduction disease severity scale at 28 days	28 days mortality, hospital LOS; viral seroconversion rate at 72 h
Rasheed (2020)	RCT, 3 centers, Iraq (n=49)	CP 400 mL IV over 2 h, one time (n=21)	Conventional therapyc,d,e (n=28)	Safety of CP therapy	Time to seroconversion; RTCI; hospital mortality
Simonovich (2021)	RCT, 12-centers, Argentina (n=333)	CP 5-10 ml/kg once (n=228)	Placebo (normal saline) plus conventional therapy (n=105)	30 days clinical status according to the WHO clinical scale	Hospital LOS; ICU LOS; time to improve in at least 2 WHO clinical scale categories; clinical status on WHO clinical scale (days 7 and 14); time to death; time to full functional recovery

^aTreatment with systemic antiviral therapy (e.g., remdesivir, lopinavir, etc.) permitted, ^bPreprint, ^cTreatment with systemic antibiotics permitted, ^dTreatment with hydroxychloroquine permitted, ^eTreatment with systemic corticosteroids permitted, ^fTreatment with intravenous immunoglobulin permitted. COVID-19: Coronavirus disease-2019, CP: Convalescent plasma, PaO2/FiO2: Ratio of arterial oxygen partial pressure to fractional inspired oxygen, SOFA: Sequential organ failure assessment, IV: Intravenous, LOS: Length of stay, WHO: World Health Organization, FFP: Fresh frozen plasma, MV: Mechanical ventilation, ICU: Intensive care unit, HFNC: High-flow nasal canula, RCT: Randomized controlled trial. May delete: RTCI: Recovery time from critical illness, SaO2: Oxygen saturation

Table 2.

Risk-of-bias analysis for randomized controlled trails of convalescent plasma for management of coronavirus disease-2019 patients with severe or critical illness

Bias type	Risk of bias per study
	AlQahtani (n=40)a	Bajpai (n=29)a	Li (n=103)	Rasheed (n=49)	Simonovich (n=333)
Selection bias: Random sequence generation	Low	Low	Low	Low	Low
Selection bias: Allocation concealment	Unclear	Low	Low	Unclear	Low
Performance bias: Blinding participants and personnel	Highb	Highb	Highb	Unclear	Low
Detection bias: Blinding outcome assessors	Unclear	Unclear	Low	Unclear	Low
Attrition bias: Incomplete outcome data	Highc	High	Low	Low	Low
Other bias	Highd	Uncleare	Uncleare	Uncleare	Low

^aPreprint, ^bNo blinding of investigators or participants (open study), ^cStudy endpoints not reported in the manuscript: AlQahtani (28 days mortality; Bajpai (dialysis-free days at 28 days), ^dUnderpowered according to the provided sample size calculation. Evidence of pretrial bias, ^eNo sample size calculation. RCT: Randomized controlled trial, RoB: Risk of bias

The results of included studies are summarized in Table 3. When compared to usual care, CP treatment for COVID-19 with severe or critical illness does not show statistically significant benefit on hospital mortality (4 studies,[16,17,18,19]514 patients, CP 37 [11.7%] vs. usual care 33 [16.6%]; odds ratio [OR]: 0.74 [95% confidence interval [CI]: 0.44, 1.24); evidence certainty by GRADE criteria low). Furthermore, the incidence of serious adverse events was not statistically different between the groups (3 studies,[17,18,19]485 patients, CP 55 [18.3%] vs. usual care 19 [10.3%]; OR: 1.44 [95% CI: 0.81, 2.56]; evidence certainty by GRADE criteria low). In addition, treatment with CP does not appear to improve hospital or ICU length of stay (data not presented due to space limitations). Finally, it should be noted that two of the studies are preprints,[15,16] and a number of clinical trials have been undertaken (some abandoned), thus necessitating careful review once additional data are available.

Table 3.

Summary of the clinical effects of convalescent plasma for management of coronavirus disease-2019 patients with severe or critical illness

Variables	Study First author (n)
	AlQahtani (n=40)a	Bajpai (n=29)a	Li (n=103)	Rasheed (n=49)	Simonovich (n=333)
Mortality		CP 3 (21.4%) versus FFP 1 (6.7%), effect size 3.2 (0.4-27.4), P=0.33b	CP 8 (15.7%) versus control 12 (24.0%; OR, 0.59 (95% CI, 0.22-1.59); P=0.30)b	CP 1 (4.8%) versus control 8 (28.6%); P<0.05c	Death rateCP 25 (11%) versus control 12 (11.4%); risk difference −0.46 (95% CI, −7.8-6.8)d
ICU LOS		CP 5 (4-5.7) versus control 5 (4-7); P=0.72			CP ND (8-ND) versus Control ND (6-ND); Subhazard ratio, 0.94 (0.48-1.82)e
Hospital LOS		CP 12.1±4.1 versus control 16.1±5.6; P=0.08			CP 18 (8-30) versus control 12 (7-ND); Subhazard ratio, 1 (0.76-1.32)e
Ventilatory support: Invasive only					CP 19 (8.3) versus control arm 10 (9.5)f
Ventilatory support, composite: Invasive or noninvasive	CP 4 (20%) versus controls 6 (30%); risk ratio 0.67 95% CI 0.22-2.0, P=0.72
Adverse event (severe)			CP 1 (2%) versus control 0	CP 0 versus control 0	CP 54 (23.7) versus control 19 (18.1), OR 1.40 (0.78-2.51)

^aPreprint, ^bAt 28 days, ^cAt any time, ^dAt 30 days, ^eMeasured from time of randomization, ^fP-value not reported. CP: Convalescent plasma, ICU: Intensive care unit, LOS: Length of stay, ND: Not determined, OR: Odds ratio, CI: Confidence interval

In conclusion, available evidence suggests that CP treatment for COVID-19 patients with a severe or critical illness does not decrease hospital mortality or increase rates of serious adverse events. Routine use of CP treatment for severe or critically ill COVID-19 patients without other indications for its use is not advised.