Convalescent plasma therapy in COVID-19 critically ill patients during advanced phases of clinical trials and their preliminary results

Fernando Anselmo de Oliveira; Mariana Penteado Nucci; Gabriel Nery de Albuquerque Rego; Arielly da Hora Alves; Luciana Cavalheiro Marti; Leopoldo Penteado Nucci; Javier Bustamante Mamani; Lionel Fernel Gamarra

doi:10.31744/einstein_journal/2021RW6186

. 2021 Apr 9;19:eRW6186. doi: 10.31744/einstein_journal/2021RW6186

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Convalescent plasma therapy in COVID-19 critically ill patients during advanced phases of clinical trials and their preliminary results

Fernando Anselmo de Oliveira ¹, Mariana Penteado Nucci ², Gabriel Nery de Albuquerque Rego ¹, Arielly da Hora Alves ¹, Luciana Cavalheiro Marti ¹, Leopoldo Penteado Nucci ³, Javier Bustamante Mamani ¹, Lionel Fernel Gamarra ^1,^✉

PMCID: PMC8034864 PMID: 33886937

ABSTRACT

The objective of this study was to highlight the global scientific effort to fight the SARS-CoV-2, addressing the preliminary results of passive immunization through convalescent plasma. We performed a search at the major databases of interventional clinical trial protocols about the transfusion of convalescent plasma in patients with COVID-19, as well as, published articles (n≥25), using the following search strategy: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND (Convalescent plasma OR Plasma exchange) AND (Treatment OR Therapy)]. A total of 24 interventional clinical trial protocols (advanced in phases II-III, III, and IV) were included in this review, as well as three studies that had enough outcomes to evaluate the efficacy of convalescent plasma therapy for patients with COVID-19. All interventional clinical trial protocols applied approximately 500mL of convalescent plasma (from single or more donations) in hospitalized patients, mainly in patients with severe disease associated with standard therapy for COVID-19, and compared to placebo or standard therapy plus specific drugs. Most of interventional clinical trial protocols are multicenter, and the phase IV studies are recruiting at intercontinental centers of North America, Oceania, Europe, but most are recruiting center inside their own county. The three studies published reported similar approach of convalescent plasma intervention with decrease in length of stay, mortality, with less than 4% of adverse events, mainly for treating critical cases with life-threatening disease. All advanced clinical trials focused on convalescent plasma therapy in patients with COVID-19 hospitalized in severe conditions, and the preliminary results provide strong evidence for therapy for the COVID-19 patients.

Keywords: COVID-19; Coronavirus infections; SARS-CoV-2; Betacoronavirus; Immunization; Immunization, passive; Plasma; Convalescent plasma

INTRODUCTION

At the end of 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged, resulting in the coronavirus disease 2019 (COVID-19), which caused an unprecedented health emergency and declared a pandemic by the World Health Organization (WHO) on March 11, 2020.⁽¹⁾ Up to September 2020, this pandemic had affected approximately 28 million and killed roughly 920 thousand people worldwide.⁽²⁾ In Brazil, more than 5 million cases and more than 130 thousand deaths have occurred so far.⁽³⁾

New approaches to the development of immunity transfer were quickly implemented in preclinical studies, and currently interesting results of clinical trials are beginning to emerge, aiming to improve the symptoms of COVID-19, a heterogeneous disease caused by SARS-CoV-2.⁽²⁾ Simultaneously, different vaccines are being developed and tested for effective disease prevention.⁽⁴⁾

Before SARS-CoV-2, the use of convalescent plasma (CP) had been investigated, with positive outcomes, in outbreaks of other viral infections,⁽⁵⁾ such as the pandemic influenza A (H1N1), in 2009,⁽⁶⁾ avian influenza A (H5N1),⁽⁷⁾ among others. Furthermore, some studies have demonstrated that CP antibodies can limit virus proliferation during the infection and support viral clearance, which is favorable for fast recovery of the disease.⁽⁸⁾

A recent review on plasma therapy in COVID-19 patients reported low frequency of severe adverse event, and improvement in clinical symptoms in some participants after plasma therapy, but the authors judged the risk of reporting bias.⁽⁹⁾

The high or low titers of neutralizing antibodies against COVD-19 can be managed to reduce patient’s symptoms and mortality. There are 24 advanced clinical trials in phases II-III, III, and IV reported in several countries using CP to treat these patients, and answer this question.⁽¹⁰^–³³⁾ Although passive immunization has been used for over a century to treat infectious diseases, the recent results pose challenges to set the best time of plasma extraction and donor choice, in addition to the cost of this whole procedure. This lack of information empowers the movements of antivaccine and antiplasma groups.⁽³⁴⁾

OBJECTIVE

To highlight the global scientific effort in the fight against SARS-CoV-2, addressing passive immunization through convalescent plasma and their preliminary results.

METHODS

A search was performed until 14 September 2020 at ClinicalTrials.gov (https://clinicaltrials.gov/), Chinese Clinical Trial Registry (http://www.chictr.org.cn/abouten.aspx) and EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) for interventional clinical trials on CP transfusion, in patients with COVID-19, using the following search strategy: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND (Convalescent Plasma OR Plasma Exchange) AND (Treatment OR Therapy)]. Then, the same strategy was used to search for studies in PubMed^® and Scopus databases about the efficacy of CP therapy to treat patients with COVID-19.

Inclusion and exclusion criteria

This review included clinical trial protocols (CTP) phases III and IV that addressed the development of therapies based on CP to treat COVID-19 patients by passive immunization, and studies that showed the efficacy of CP therapy applied in more than 25 COVID-19 patients. The reasons for excluding studies were as follows: CTP for observational studies, CTP involving vaccines, and CTP canceled, or not approved, until the searching date in the databases.

Study eligibility, data extraction, data collection, and risk of bias assessment

The study eligibility followed the Preferred. Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.⁽³⁵⁾

Data analysis

All results were described and presented using the percentage distribution for all variables analyzed in the tables.

RESULTS

Study selection

After applying the search strategies in the databases, 170 CTP were identified (153 protocols at ClinicalTrials.gov, 14 at Chinese Clinical Trial Registry, and three at the EU Clinical Trials Register). The search strategy used the PRISMA.⁽³⁵⁾

Based on established inclusion and exclusion criteria, of 170 protocols identified, 146 clinical trials were excluded after screening (130 protocols were phases I and II and 16 were observational), remaining 24 protocols selected from these databases. In total, 24 CTP were included in the present work for passive immunization for COVID-19 through CP therapy.⁽¹⁰^–¹³^,¹⁵^–³³⁾

Of the selected studies published in the databases mentioned above, only three studies had enough data that allow statistical analysis of the outcomes, to evaluate the CP therapy efficacy due to the number of patients with COVID-19 (n≥25).⁽³⁶^–³⁸⁾

Overview of clinical trial protocols for passive immunization for COVID-19

Of 24 more advanced clinical trials on CP therapy for COVID-19 inpatients, only one (4.2%) was in phase IV, with 58% of study progress rate (SPR), recruiting individuals in different countries by Netherlands sponsor (green bar of figure 1).⁽¹⁰⁾ The phase III studies (54.2%),⁽¹¹^–¹³^,¹⁵^–¹⁹⁾ almost half of CTP had more than 40% of SPR, mainly in Mexico⁽¹⁵^,¹⁹⁾ and the United States (blue bars of figure 1),⁽¹⁸^,²¹⁾ and the phase II-III studies (41.7%),⁽²⁴^–³³⁾ one CTP has 100% of SPR in the Netherlands,⁽²⁴⁾ and almost half of CTP have more than 40% of SPR (red bars of figure 1), as shown in figure 1 and table 1.

Table 1. Study design, arms, interventions, and study time progress.

Identity number	Phase	Patient features	Intervention by arm	CP dose (day)	Age range (years)	Start date	Completion date	Progress (%)	Recruitment status
NCT02735707⁽¹⁰⁾	IV	Severe acute respiratory illness and severe community acquired pneumonia	Corticosteroid versus antibiotics versus macrolide versus Influenza antiviral versus LPV/Rit versus HydChl versus IFN-β1a versus Anak versus Tmab versus Smab versus Vit C versus heparin versus simvastatin versus CP versus ST	1 or 2 units within 48 hours	>18	4/11/16	12/1/23	58	Recruitingz
NCT04391101⁽¹¹⁾	III	Severe patients treated in ICU	CP associated with ST versus ST	400-500mL	>18	6/1/20	12/1/21	19.2	Not yet recruiting
NCT04372979⁽¹²⁾	III	Early care of hospitalized patients	CP associated with ST versus SP associated with ST	200-230mL	18-80	5/1/20	5/1/21	37.3	Not yet recruiting
NCT04418518⁽¹³⁾	III	Early care for patients hospitalized	CP associated with ST versus ST	500mL of single-donor or 2 units of 250mL from 1-2 donations	18-70	6/24/20	12/1/21	15.6	Recruiting
NCT04355767⁽¹⁴⁾	III	Severe/critical hospitalized patients	CP (antibodies titers ≥1:160) versus placebo	CP: 1-unit versus placebo: saline with multivitamin	>18	8/11/20	12/1/22	4.0	Not yet recruiting
NCT04432103⁽¹⁵⁾	III	Severe/critical hospitalized patients	CP from IgG (severe patients versus critical patients) associated with ST	NR	>19	6/19/20	9/30/20	84.5	Not yet recruiting
NCT04348656⁽¹⁶⁾	III	Early care for patients hospitalized	CP versus ST	500mL of single-donor or 2 units of 250mL from 1-2 donations	>20	5/14/20	12/31/20	53.2	Recruiting
NCT04425915⁽¹⁷⁾	III	Severe/critical hospitalized patients	CP associated with ST versus ST	2 doses of 250mL on consecutive day started by day 3 of symptom onset	>21	6/14/20	5/30/21	26.3	Recruiting
NCT04362176⁽¹⁸⁾	III	Patients hospitalized or in ICU	Pathogen reduced CP versus placebo	CP: 500mL within 12 hours (day 0) versus placebo: 250mL of Lactate Ringers associated with multivitamins (day 1)	>22	4/24/20	4/1/21	41.8	Recruiting
NCT04381858⁽¹⁹⁾	III	Severe respiratory failure with invasive mechanical ventilation	CP (antibodies titers >1:164) versus HIg	CP: 400mL (2 units) versus HIg: 0.3g/kg/day (5 doses)	16-18	5/6/20	9/30/20	89.1	Recruiting
NCT04361253⁽²⁰⁾	III	Patients hospitalized	CP (high-titer) versus SP (FFP or FP 24)	HT-CP: 2 doses of 250mL of single donor within 24 hours; FFP: 2 units of 200-275mL	>1	04/30/20	12/1/21	23.6	Recruiting
NCT04376034⁽²¹⁾	III	Mild, moderate and severe/critical severity	CP associated with ST versus ST	Adult: 200 to 250mL; children: 10mL/kg; 2 units severe patients or critical condition	>30 days	4/16/20	3/30/21	43.4	Recruiting
NCT04483960⁽²²⁾	III	No severe patients	LPV/Rit versus HydChl versus CP	1 unit on day 1 and day 2	>18	7/21/20	6/12/22	8.0	Recruiting
NCT0434528 9⁽²³⁾	III	Mild, moderate and severe/critical hospitalized patients	CP associated with ST (Smab versus baricitinib versus HydChl) versus ST associated with injective placebo	CP: (twice 300mL) and single dose of 600mL; placebo: (twice 300mL) and single dose of 600mL IV saline oral placebo: three times/day (7 days)	>18	5/1/20	6/15/21	33.2	Recruiting
NCT04342182⁽²⁴⁾	II-III	Hospitalized patients	CP associated with ST versus ST	300mL (according to the Erasmus MC KIS protocol)	>18	4/8/20	7/1/20	100	Recruiting
NCT04388410⁽²⁵⁾	II-III	Hospitalized patients with severe disease or at risk for severe disease.	CP versus placebo	CP: 2 units of 200mL within 24-72 hours); placebo: 200mL of saline	>18	8/25/20	12/31/20	15.6	Not yet recruiting
NCT04374526⁽²⁶⁾	II-III	Hospitalized patients	CP associated with ST versus ST	200mL/day for 3 days	>65	5/27/20	6/30/21	27.6	Recruiting
NCT04384588⁽²⁷⁾	II-III	Oncological and non-oncological patients with severe disease	CP associated with ST versus ST	1 or more units	>15	4/7/20	4/6/21	44.0	Recruiting
NCT04425837⁽²⁸⁾	II-III	Hospitalized patients at high risk of severe disease or in ICU	CP (antibodies titers of ≥1:160) associated with ST versus ST	2 doses of 200mL in a day	>18	7/1/20	2/1/21	34.9	Not yet recruiting
NCT04395170⁽²⁹⁾	II-III	Early care for patients hospitalized	CP associated with ST versus anti-COVID-19 HIg versus ST	CP: 200-250mL (day 1 and 3); 10% IgG solution: 50mL (patient ≥50kg); 1 mL/Kg (patient <50Kg), on days 1 and 3	>18	9/1/20	6/1/21	4.8	Not yet recruiting
NCT04380935⁽³⁰⁾	II-III	Hospitalized patients in ICU (using mechanical ventilation)	CP associated with ST versus ST	NR	>18	5/18/20	10/31/20	71.7	Not yet recruiting
NCT04332835⁽³¹⁾	II-III	Moderate and severe/critical severity	CP associated with ST versus HyChl associated with ST	250mL on days 1 and 2	18-60	8/8/20	10/31/20	44.0	Not yet recruiting
NCT04385043⁽³²⁾	II-III	Severe/critical hospitalized patients	CP associated with ST versus ST	NR	18-60	5/1/20	5/15/21	35.9	Recruiting
NCT04381936⁽³³⁾	II-III	Hospitalized patients at high-risk of severe disease	LPV/Ritversus corticosteroid versus HyChl versus Azi versus Tmab associated with ST versus CP associated with ST	275mL±75mL on days 1 and 2	all	3/19/20	12/1/31	4.2	Recruiting

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Passive immunotherapy occurs through the infusion of plasma from convalescent individuals, hence the use of the term convalescent plasma which can also be called hyperimmune plasma or ABO-compatible convalescent plasma.

CP: convalescent plasma; LPV: lopinavir; Rit: ritonavir; HydChl: hydroxychloroquine; IFN-β1a: interferon-β1a; Anak: anakinra; Tmab: tocilizumab; Smab: sarilumab; Vit C: vitamin C; ST: standard therapy; ICU: intensive care unit; SP: standard plasma; IgG: immunoglobulin G; NR: not report; HIg: human immunoglobulin; FFP: fresh frozen plasma; FP24: plasma frozen within 24 hours after phlebotomy; HT-CP: high-titer convalescent plasma; IV: intravenous; Azi: azithromycin.

Convalescent plasma intervention

The CP intervention applied in all CTP was for inpatients with different degrees of disease impairment, especially for severe cases admitted to the ICU (58.3%) with or without invasive mechanical ventilation, and all patients received the ST for COVID-19. The intervention arms applied in these inpatients normally compared the CTP of plasma therapy plus ST versus only ST associated or not with some selected drugs, such as corticosteroid, antibiotics, antimalarials (hydroxychloroquine), anticoagulants, human immunoglobulin, antiviral drugs, among others.⁽¹⁰^,²²^,²³^,²⁹^,³¹^,³³⁾ The CP therapy was applied mainly as single dose, with different volume of transfusion (45.8%), and the volume more frequently used was 500mL, in 20.8%,⁽¹³^,¹⁶^,¹⁸^,³⁹⁾ following by doses of 200 to 250mL in 8.3%,⁽¹²^,²¹⁾ 400mL in 8.3%,⁽¹⁹^,³⁹⁾ 300mL in 4.2%,⁽²⁴⁾ and 600mL in 4.2%.⁽²³⁾ In the cases using more than one dose, the volume was two doses of 250mL,⁽¹³^,¹⁶^,¹⁷^,²⁰^,²⁹^,³¹^,³³⁾ used in most of CTP, following by 2x200mL⁽¹⁹^,²⁵^,²⁸^,²⁹^,³³⁾ and 2x300mL.⁽²³^,³³⁾ Plasma doses were derived from a single donor,⁽¹³^,¹⁶^,²⁰^,²³⁾ or until two different donors in some CTP.⁽¹³^,¹⁶⁾ Almost all CTP test the intervention in individuals aged over 18 years, with exception of two CTP (Table 1).

Regarding study design characteristics of these CTP, figure 2 shows the intervention was mostly (87.5%) randomized and few CTP used some type of masking (33.3%), such as: 4.2% single blinding (participant), 12.5% double-blinding (participant and outcome evaluator), 8.3% triple-blinding (participant, care provider and outcome evaluator), and 8.3% quadruple-blinding (participant, care provider, investigator and outcome evaluator). Although 12.5% of CTP have not adopted any technique used to minimize the bias in allocations and blinding, keeping it open-label. The estimated enrollment of clinical trial in phase IV is 7,100 individuals,⁽¹⁰⁾ in phase III from 36 to 2,400 individuals,⁽¹¹^–²³⁾ and phase II-III from 60 to 15,000.⁽²⁴^–³³⁾ The number of volunteers estimated in each protocol was represented by the color scale bar in figure 2.

Global research network in clinical trial protocol

Among the CP multicenter CTP,⁽¹⁰^,¹²^,¹³^,¹⁶^,¹⁷^,²²^–²⁴^,²⁶^,³⁰^,³²⁾ the CTP phase IV⁽¹⁰⁾ is the only one with intercontinental collaborations represented by the dashed black lines on the world map (Figure 3), with 87 recruitment centers (green cylinders) distributed in North America, Europe, and Oceania. The CTP phase III also have collaborations among countries and involve 48 recruitment centers (yellow cylinders) in the USA and Canada.⁽¹⁶⁾ The other multicenter CTP involve a varied number of recruitment centers within the same country, such as: Australia with 79 centers (purple cylinders),⁽²²⁾ the Netherlands with 18 centers (blue cylinders),⁽²⁴⁾ Denmark with 12 centers (dark gray cylinders),⁽²³⁾ Italy with six centers (orange cylinders),⁽³²⁾ highlighted in figure 3, with the enlarged image for better visualization of the collaboration centers, and others with approximately three centers.⁽¹²^,¹⁷^,²⁶^,³⁰⁾ The single center CTP concentrate mainly in North America⁽¹⁵^,¹⁸^–²¹⁾ and South America.⁽¹¹^,²⁷^–²⁹^,³¹⁾

Plasma therapy outcome in COVID-19 patients

The three studies that evaluate the efficacy of plasma therapy also prioritize the evaluation of COVID-19 in severely ill patients or those in life-threatening situation, such as the advanced clinical trials mentioned above. The CP therapy intervention varied a lot among studies, without a consensus about the best CP pattern of application. Regarding the results, the studies showed a reduction by 53% in disease severity (not needing intensive care),⁽³⁸⁾ 26% in length of hospital stay,⁽³⁶⁾ and from 35% to 50% in mortality rate,⁽³⁶^–³⁸⁾ reporting adverse effects in less than 4% of patients after treatment with CP in different doses and volumes associated with standard therapy for COVID-19,⁽³⁶^–³⁸⁾ as shown in table 2.

Table 2. Studies that evaluation the efficacy of plasma therapy in COVID-19 patients.

References	n/CP sample	Antibody titer	CP dose (mL)	Viral charge (x10 ^/dL)	Previous treatments	Hospitalization (variation)	Adverse events (n)	Mortality rate reduction
Abolghasemi et al.⁽³⁶⁾	189/115 CP versus 74 ST	Plasma antibody titer cut off index >1.1	2x500mL	NI	ST + antiviral (LPV/Rit), HydChl and anti-inflammatory agent	9.54 days CP versus 12.88 days ST CP reduced length of stay by ~26%	~1% CP Transient mild fever and chills following infusion of the plasma (n=1)	14.8% CP versus 24.3% ST ~40%
Li et al.⁽³⁷⁾	103/52 CP (23 severe + 29 life-threatening) versus 51 ST (22 severe + 29 life-threatening)	1:350 (6 donors)	4-13mL/kg	Reduction in severe patients: 44.7% (24 hours), 68.1% (48 hours) and 87.2% (72 hours) virus-free Life-threatening patients: 53.8% (24 hours); 73.1 (48 hours) and 84.6% (72 hours) virus-free	Antiviral (41/46; 89.1%); antibacterial (38/46; 82.6%); Chinese herbal medicine (26/46; 56.5%); steroids (21/46 45.7%); antifungal (15/46; 32.6%); HIg (13/46; 28.3%); interferon (12/46; 26.1%)	Severe: 32.00 (26.00-40.00); life-threatening: indeterminate (46.00-indeterminate)	~4% CP Chills and rashes within 2 hours (n=1); shortness of breath, cyanosis and severe dyspnea within 6 hours (n=1)	15.7% CP versus 24.0% ST ~35%
Xia et al.⁽³⁸⁾	1,568/138	Not significantly higher in rapid responders than in moderate responders	200-1,200mL	20/25 (80%) became virus-free after 14 days	NI	2.4% CP versus 5.1% ST CP reduced admitted to the ICU by ~53%	~2% CP Pruritus or erythema during transfusion (n=3)	2.2% CP versus 4.1% ST ~50%

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CP: convalescent plasma; ST: standard treatment; NI: not informed; LPV: lopinavir; Rit: ritonavir; HydChl: hydroxychloroquine; HIg: human immunoglobulin; ICU: intensive care unit.

DISCUSSION

In the absence of effective treatment for patients with COVID-19, many studies have sought alternatives to treat patients and enhance patient’s immune defense, such as the use of CP therapy. The recovery trial⁽⁴⁰⁾ provides evidence to support some treatments (for instance, dexamethasone) and improve immunity in critical condition cases, and this trial uses CP therapy as one therapeutic arm. However, many aspects of this therapy are still being explored, such as a timeout/collection interval for COVID-19, or immunoglobulin G/immunoglobulin M (IgG/IgM) titers from donors, the therapy clinical improvement and efficacy in critical or non-critical patients and adverse effects. Among 170 CTP identified, only 24 CTP were in advanced phase (III/IV) with 33,000 individuals, concentrated in the regions of America, showing the pivotal questions on efficient use of the CP still uncertain or fragile to justify an increased use in critical or non-critical hospital care. In addition, no country, including the United States, has licensed CP as a treatment for COVID-19. The Food and Drug Administration (FDA) judged eligible for wider use under an emergency use authorization,⁽⁴¹⁾ although other countries have granted approval for use on an individual patient basis.

One of the first CP clinical trials that analyzed 103 patients with severe and life-threatening COVID-19 (median age 70 years),⁽³⁷⁾ showed no statistically significance in clinical improvement after 28 days or reduced mortality. However, there was evidence of notable therapeutic effects and possible antiviral activity in group of 60 to 80-year-old patients, at the final stage of the disease course, after 14 days of symptoms, using only units with a very high antibody titers (IgG over 1:50) specific for spike (S)- and receptor-binding domain (RBD). Another study on CP therapy in severe COVID-19 patients⁽⁴²⁾ showed significant improvement of clinical symptoms, with an increase in oxyhemoglobin saturation after the third day of transfusion, reduction of pulmonary lesions, amelioration of routine laboratory criteria, and pulmonary function accompanied by rapid neutralization of viremia, using 200mL of CP derived from recently recovered donors with the neutralizing antibody titers between 1:160-640, approximately 16.5 days after onset of symptoms, associated to standard care and antiviral agents. Only three CTP⁽¹⁴^,¹⁹^,²⁸⁾ mentioned the antibody titers used in the CP therapy (over 1:160), and the studies by Abolghasemi et al.,⁽³⁶⁾ and Li et al.,⁽³⁷⁾ also reported the use of antibody titers above 1.1 in CP therapy associated with clinical improvement and reduction in mortality.

To reduce the variability in therapeutic response of patients, the WHO recommends some care and standardization in the selection of CP donors.⁽⁴³⁾ Eligibility criterion in relation to donor age does not vary widely: 18-67 years.⁽³⁶^,⁴⁴⁾ The donors were patients who recovered from COVID-19 and showed no detection of SARS-CoV-2 by real-time Quantitative polymerase chain reaction (qRT-PCR) or any related symptoms after a period that varied among studies. In one study, donors could have recovered after one week, and the short recovery period might have contributed to the death of 5 out of 6 patients.⁽⁴⁵⁾ Longer recovery period allowed reports of therapeutic efficacy. This period could be 10 days, with collection performed twice, with a difference of 24 hours,⁽⁴⁶⁾ at least 14 days,⁽³⁶^,⁴⁷⁾ and more than two weeks.⁽³⁶^,⁴²^,⁴⁴⁾ In some cases, qRT-PCR from nasopharyngeal swabs must be tested negative twice, and an interval of 24 hours between tests.⁽³⁶^,⁴²⁾

Regarding the quantification of antibodies, S-RBD-specific IgG titers vary from donor to donor. One study demonstrated that ten out of 25 collected plasma displayed the titer of 1:450, 6/25 1:350, while in the others vary from 1:1 to 1:150.⁽⁴⁴⁾ Most of studies employed a CP volume of roughly 500mL, in a single dose or divided into two doses, derived from a single donor,^{(12,16,20,23)} or two different donors.⁽¹²^,¹⁶⁾ Therefore, this lack of standardization regarding donor selection, quality control of the CP, and recipient patients could explain the varied therapeutic effects.

Some possible adverse effects with the use of CP can be avoided, such as CP free of antigens, which could cause transfusion-related acute lung injury (TRALI), such as human leukocyte antigens that protect the embryo.⁽³⁶⁾ In a multicenter clinical trial, the use of CP was not allowed in pregnant women, aiming to prevent TRALI.⁽³⁶⁾

The severity of patient’s disease transfused with CP varied from mild, moderate, severe to critical. A CTP with severe patients divided the study groups in severe acute respiratory illness and severe community acquired pneumonia.⁽¹⁰⁾ Another CTP compared the effects of the treatment in oncological and non-oncological COVID-19 patients.⁽²⁷⁾ Admission in the intensive care unit is related in some CTP,⁽¹¹^,¹⁸^,²⁸^,³⁰⁾ although it is presumed that it is applied to all severe patients. In some CTP, the CP treatment was compared to other treatments, such as corticoids, antibiotics, monoclonal antibodies, and anti-viral drugs.⁽¹⁰^,²²^,²³^,³³⁾

Some published results allowed evaluation of different parameters concerning the efficacy of treatment. In a study in which CP was applied, 6 out of 17 patients required mechanical ventilation, mainly elderly patients.⁽⁴⁷⁾ In a multicenter study, the mortality rate was 14.8% of the patients (n=115).⁽³⁶⁾ Similar results were found in another multicenter study (15.7%).⁽³⁶⁾ Another investigation reported a mortality rate of only 2.2%.⁽³⁸⁾ A study employed this therapy in patients with hypertension, diabetes or cardiovascular disease, but it was not clear the effect of these comorbidities in the CP treatment effect.⁽³⁶⁾

The transfusion of CP therapy for COVID-19 must follow some pre-established conditions, such as availability of a population of donors who have recovered from the disease and can donate convalescent serum; blood banks to process serum donations; availability of assays, including serological tests, to detect SARS-CoV-2 in serum and virological assays to measure viral neutralization; laboratory support for virology to carry out these tests; and standardization of phase and condition of COVID-19 patient.⁽⁴⁸⁾

The main limitations of the multicenter studies were the reduced number of patients in the control groups compared to the treatment group, usually due to lack of blood group CP match, and concomitant or previous use of another treatment.⁽³⁶⁾ Another limitation is the lack of standard protocols and training for the study staff, as well as diversity in patients monitoring.⁽⁴⁹⁾ In turn, the main limitation of our study is the impossibility of carrying out a meta-analysis, due to the lack of a robust number of studies reporting conclusive therapeutic effects of this modality, such as decrease in SARS-CoV-2 titers. However, few articles published on multicenter studies demonstrated that CP could be a promising therapeutic modality.

CONCLUSION

Currently, there are no reliable therapeutic options for critically-ill COVID-19 patients. Based on the few consolidated multicenter clinical data results available, we concluded the convalescent plasma therapy studies provided relevant results in severe/critical cases of COVID-19 patients, reducing length of hospital stay, disease severity, and mortality, with low frequency of adverse events in a considerable number of patients. However, it is not possible to state, in a conclusive fashion, about the real relevance of this treatment, considering the lack of data that enable a robust statistics analysis, such as a meta-analysis.

ACKNOWLEDGEMENTS

Lionel Fernel Gamarra was supported by the Sistema Nacional de Laboratórios em Nanotecnologias (SisNANO) 2.0 (Conselho Nacional de Desenvolvimento Científico e Tecnológico/Ministério da Ciência, Tecnologia, Inovações e Comunicações, process 442539/2019-3).

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Einstein (Sao Paulo). 2021 Apr 9;19:eRW6186. [Article in Portuguese]

Terapia com plasma convalescente em pacientes graves com COVID-19 nas fases avançadas dos ensaios clínicos e seus resultados preliminares

RESUMO

O objetivo deste estudo foi destacar o esforço científico global para combater o SARS-CoV-2 abordando os resultados preliminares da imunização passiva por plasma convalescente. Foi realizada uma busca nas principais bases de dados dos protocolos de ensaios clínicos intervencionistas sobre transfusão de plasma convalescente em pacientes com COVID-19, bem como artigos publicados (n≥25), utilizando a seguinte estratégia de busca: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND (Convalescent plasma OR Plasma exchange) AND (Treatment OR Therapy)]. Um total de 24 protocolos de ensaios clínicos intervencionistas (avançados nas fases II-III, III e IV) foi incluído nesta revisão, assim como três estudos que tiveram resultados suficientes para avaliar a eficácia da terapia com plasma convalescente para pacientes com COVID-19. Todos os protocolos de ensaios clínicos intervencionistas aplicaram cerca de 500mL de plasma convalescente (de uma ou mais doações) em pacientes hospitalizados, principalmente naqueles com grau grave de doença associada à terapia-padrão para COVID-19 em comparação com placebo ou terapia-padrão mais medicamentos específicos. A maioria dos protocolos de ensaios clínicos intervencionistas é multicêntrica, e os estudos de fase IV estão recrutando em centros intercontinentais da América do Norte, Oceania e Europa, mas a maior parte dos centros de recrutamento está dentro de seu próprio país. Os três estudos publicados relataram abordagem semelhante de intervenção para plasma convalescente com redução do tempo de internação, mortalidade e menos de 4% de eventos adversos, principalmente para o tratamento de casos críticos com risco de vida. Todos os ensaios clínicos avançados focaram na terapia com plasma convalescente em pacientes com COVID-19 hospitalizados em condições graves, e os resultados preliminares fornecem fortes evidências para a terapia para esses pacientes com COVID-19.

Descritores: COVID-19, Infecções por coronavírus, SARS-CoV-2, Betacoronavírus, Imunização, Imunização passiva, Plasma, Plasma convalescente

INTRODUÇÃO

No final de 2019, surgiu o coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2), resultando na doença pelo coronavírus 2019 (COVID-19), que causou uma emergência sanitária sem precedentes, sendo declarada pandemia pela Organização Mundial de Saúde (OMS) em 11 de março de 2020.⁽¹⁾ Até setembro de 2020, essa pandemia afetara cerca de 28 milhões pessoas, com cerca de 920 mil mortes em todo o mundo.⁽²⁾ No Brasil, até agora, já ocorreram mais de 5 milhões de casos com mais de 130 mil mortes.⁽³⁾

Novas abordagens para o desenvolvimento de transferência de imunidade foram rapidamente implementadas em estudos pré-clínicos, e, atualmente, surgem resultados interessantes de ensaios clínicos, com o objetivo de melhorar os sintomas da COVID-19, uma doença heterogênea.⁽²⁾ Ao mesmo tempo, diversas vacinas estão sendo desenvolvidas e testadas para a prevenção efetiva da doença.⁽⁴⁾

Antes da SARS-CoV-2, já tinha sido investigado o uso de plasma convalescente (PC), com desfechos positivos, em surtos de outras infecções virais,⁽⁵⁾ como a pandemia de gripe A (H1N1), em 2009,⁽⁶⁾ e a gripe aviária A (H5N1),⁽⁷⁾ entre outras. Além disso, há estudos que demonstram que os anticorpos do PC podem limitar a proliferação do vírus durante a infecção e promover a eliminação viral, favorecendo uma recuperação rápida da doença.⁽⁸⁾

Revisão recente sobre a terapia com plasma em pacientes com COVID-19 relatou baixa frequência de eventos adversos graves e melhora nos sintomas clínicos em alguns participantes após a terapia com plasma, mas os autores julgaram existir risco de viés de relatório.⁽⁹⁾

Os títulos altos ou baixos de anticorpos neutralizantes contra a COVID-19 podem ser manejados para reduzir os sintomas e a mortalidade do paciente. Existem 24 ensaios clínicos avançados nas fases II-III, III e IV relatados em vários países usando PC para tratar esses pacientes e responder a essa pergunta.⁽¹⁰^–³³⁾ Embora a imunização passiva seja utilizada há mais de um século no tratamento de doenças infecciosas, resultados recentes apresentam desafios na definição do melhor momento de extração do plasma e na escolha do doador, além do custo de todo esse procedimento. Essa falta de informação potencializa os movimentos de grupos antivacina e antiplasma.⁽³⁴⁾

OBJETIVO

Destacar o esforço científico global na luta contra o SARS-CoV-2, abordando a imunização passiva por plasma convalescente e seus resultados preliminares.

MÉTODOS

Foi realizada uma pesquisa até 14 de setembro de 2020 em ClinicalTrials.gov (https://clinicaltrials.gov/), Chinese Clinical Trial Registry (http://www.chictr.org.cn/abouten.aspx) e EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) para ensaios clínicos de intervenção sobre transfusão de PC, em pacientes com COVID-19, usando a seguinte estratégia de pesquisa: [(COVID-19 OR SARS-CoV-2 OR nCoV-2019) AND (Convalescent Plasma OR Plasma Exchange) AND (Treatment OR Therapy)]. Em seguida, a mesma estratégia foi usada para pesquisar estudos nas bases de dados PubMed^® e Scopus sobre a eficácia da terapia com PC para tratar pacientes com COVID-19.

Critérios de inclusão e exclusão

Esta revisão incluiu protocolos de ensaios clínicos (PEC) nas fases III e IV que abordassem o desenvolvimento de terapias baseadas em PC para tratamento de pacientes com COVID-19 por imunização passiva e estudos que mostrassem a eficácia da terapia com PC aplicada em mais de 25 pacientes com COVID-19. Os motivos para exclusão de estudos foram os seguintes: PEC de estudos observacionais, PEC envolvendo vacinas e PEC cancelados ou não aprovados até a data da pesquisa nas bases de dados.

Elegibilidade dos estudos, extração de dados, coleta de dados e avaliação de risco de viés

A elegibilidade dos estudos seguiu as diretrizes Preferred. Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).⁽³⁵⁾

Análise dos dados

Todos os resultados foram descritos e apresentados por meio de distribuição percentual para todas as variáveis analisadas nas tabelas.

RESULTADOS

Seleção de estudos

Após a aplicação das estratégias de busca nas bases de dados, 170 PEC foram identificados (153 protocolos no ClinicalTrials.gov, 14 no Chinese Clinical Trial Registry e três no EU Clinical Trials Register). A estratégia de busca utilizou o PRISMA.⁽³⁵⁾

Com base nos critérios de inclusão e exclusão estabelecidos, dentre os 170 protocolos identificados, 146 ensaios clínicos foram excluídos após a triagem (130 protocolos eram fases I e II, e 16 eram observacionais), restando 24 protocolos selecionados dessas bases de dados. No total, 24 PEC foram incluídos neste trabalho sobre imunização passiva para COVID-19 por meio de terapia com PC.⁽¹⁰^–¹³^,¹⁵^–³³⁾

Dentre os estudos selecionados publicados nas bases de dados citadas, apenas três estudos apresentaram dados suficientes que permitiam uma análise estatística dos desfechos, para avaliar a eficácia da terapia com PC devido ao número de pacientes com COVID-19 (n≥25).⁽³⁶^–³⁸⁾

Visão geral dos protocolos de ensaios clínicos sobre imunização passiva para COVID-19

Dos 24 ensaios clínicos mais avançados sobre terapia com PC para pacientes hospitalizados com COVID-19, apenas um (4,2%) estava na fase IV, com taxa de progresso do estudo (TPE) de 58%, recrutando indivíduos em diferentes países pelo patrocinador holandês (barra verde da figura 1).⁽¹⁰⁾ Nos estudos de fase III (54,2%),⁽¹¹^–¹³^,¹⁵^–¹⁹⁾ quase metade dos PEC tinha TPE de mais de 40%, principalmente no México⁽¹⁵^,¹⁹⁾ e nos Estados Unidos (barras azuis da figura 1),⁽¹⁸^,²¹⁾ e, nos estudos de fase II-III (41,7%),⁽²⁴^–³³⁾ um PEC tinha TPE de 100% na Holanda,⁽²⁴⁾ e quase metade dos PEC tinha TPE de mais de 40% (barras vermelhas da figura 1), conforme mostrado na figura 1 e na tabela 1.

Tabela 1. Desenho do estudo, braços, intervenções e progresso do tempo de estudo.

Número de identidade	Fase	Características do paciente	Intervenção por braço	Dose PC (dia)	Faixa etária (anos)	Data de início	Data de conclusão	Progresso (%)	Situação de recrutamento
NCT02735707⁽¹⁰⁾	IV	Doença respiratória aguda grave e pneumonia adquirida na comunidade grave	Corticosteroides versus antibióticos versus macrolídeo versus antiviral para gripe versus LPV/Rit versus HCQ versus IFN-β1a versus Anak versus Tmab versus Smab versus Vit C versus heparina versus sinvastatina versus PC versus TP	1 ou 2 unidades em 48 horas	>18	11/4/2016	1/12/2023	58	Recrutamento
NCT04391101⁽¹¹⁾	III	Pacientes graves tratados na UTI	PC associado a TP versus TP	400-500mL	>18	1/6/2020	1/12/2021	19,2	Ainda sem recrutamento
NCT04372979⁽¹²⁾	III	Atendimento precoce de pacientes hospitalizados	PC associado a TP versus PP associado a TP	200-230mL	18-80	1/5/2020	1/5/2021	37,3	Ainda sem recrutamento
NCT04418518⁽¹³⁾	III	Atendimento precoce a pacientes hospitalizados	PC associado a TP versus TP	500mL de doador único ou 2 unidades de 250mL de 1-2 doações	18-70	24/6/2020	1/12/2021	15,6	Recrutamento
NCT04355767⁽¹⁴⁾	III	Pacientes graves/críticos hospitalizados	PC (títulos de anticorpos ≥1:160) versus placebo	PC: 1 unidade versus placebo: solução fisiológica com multivitamínico	>18	11/8/2020	1/12/2022	4,0	Ainda sem recrutamento
NCT04432103⁽¹⁵⁾	III	Pacientes graves/críticos hospitalizados	PC de IgG (pacientes graves versus pacientes críticos) associado a TP	NR	>19	19/6/2020	30/9/2020	84,5	Ainda sem recrutamento
NCT04348656⁽¹⁶⁾	III	Atendimento precoce a pacientes hospitalizados	PC versus TP	500mL de doador único ou 2 unidades de 250mL de 1-2 doações	>20	14/5/2020	31/12/2020	53,2	Recrutando
NCT04425915⁽¹⁷⁾	III	Pacientes graves/críticos hospitalizados	PC associado a TP versus TP	2 doses de 250mL em dias consecutivos iniciadas no dia 3 do início dos sintomas	>21	14/6/2020	30/5/2021	26,3	Recrutando
NCT04362176⁽¹⁸⁾	III	Pacientes hospitalizados ou em UTI	Patógeno reduzido PC versus placebo	PC: 500mL em 12 horas (dia 0) versus placebo: 250mL de Ringer lactato associado a multivitaminas (dia 1)	>22	24/4/2020	1/4/2021	41,8	Recrutando
NCT04381858⁽¹⁹⁾	III	Insuficiência respiratória grave com ventilação mecânica invasiva	PC (títulos de anticorpos > 1:164) versus HIg	PC: 400mL (2 unidades) versus HIg 0,3g/kg/dia (5 doses)	16-18	6/5/2020	30/9/2020	89,1	Recrutando
NCT04361253⁽²⁰⁾	III	Pacientes hospitalizados	PC (título alto) versus PP (PFC ou PC 24)	PC-AT 2 doses de 250mL de doador único em 24 horas; PFC: 2 unidades de 200-275mL	>1	30/4/2020	1/12/2021	23,6	Recrutando
NCT04376034⁽²¹⁾	III	Gravidade leve, moderada e grave/crítica	PC associado a TP versus TP	Adultos: 200 a 250mL; crianças: 10mL/kg; 2 unidades de pacientes graves ou em condição crítica	>30 dias	16/4/2020	30/3/2021	43,4	Recrutando
NCT04483960⁽²²⁾	III	Sem pacientes graves	LPV/Rit versus HCQ versus PC	1 unidade no dia 1 e no dia 2	>18	21/7/2020	12/6/2022	8,0	Recrutando
NCT04345289⁽²³⁾	III	Pacientes hospitalizados com doença leve, moderada e grave/crítica	PC associado a TP (Smab versus baricitinibe versus HCQ) versus TP associado a placebo injetável	PC: (2 vezes de 300mL) e dose única de 600mL; placebo: (2 vezes de 300mL) e dose única de 600mL de solução fisiológica IV por placebo: 3 vezes ao dia (7 dias)	>18	1/5/2020	15/6/2021	33,2	Recrutando
NCT04342182⁽²⁴⁾	II-III	Pacientes hospitalizados	PC associado a TP versus TP	300mL (de acordo com o protocolo Erasmus MC KIS)	>18	8/4/2020	1/7/2020	100	Recrutando
NCT04388410⁽²⁵⁾	II-III	Pacientes hospitalizados com doença grave ou risco de doença grave	PC versus placebo	PC: 2 unidades de 200mL dentro de 24-72 horas; placebo: 200mL de soro fisiológico	>18	25/8/2020	31/12/2020	15,6	Ainda sem recrutamento
NCT04374526⁽²⁶⁾	II-III	Pacientes hospitalizados	PC associado a TP versus TP	200mL/dia por 3 dias	>65	27/5/2020	30/6/2021	27,6	Recrutando
NCT04384588⁽²⁷⁾	II-III	Pacientes oncológicos e não oncológicos com doença grave	PC associado a TP versus TP	1 ou mais unidades	>15	7/4/2020	6/4/2021	44,0	Recrutando
NCT04425837⁽²⁸⁾	II-III	Pacientes hospitalizados com alto risco de doença grave ou em UTI	PC (títulos de anticorpos ≥1:160) associado a TP versus TP	2 doses de 200mL por dia	>18	1/7/2020	1/2/2021	34,9	Ainda sem recrutamento
NCT04395170⁽²⁹⁾	II-III	Atendimento precoce a pacientes hospitalizados	PC associado a TP versus anti-COVID-19 HIg versus TP	PC: 200-250mL (dias 1 e 3); Solução IgG a 10%: 50mL (paciente ≥50kg); 1mL/kg (paciente <50Kg), nos dias 1 e 3	>18	1/9/2020	1/6/2021	4,8	Ainda sem recrutamento
NCT04380935⁽³⁰⁾	II-III	Pacientes hospitalizados na UTI (usando ventilação mecânica)	PC associado a TP versus TP	NR	>18	18/5/2020	31/10/2020	71,7	Ainda sem recrutamento
NCT04332835⁽³¹⁾	II-III	Gravidade moderada e grave/crítica	PC associado a TP versus HCQ associado a TP	250mL nos dias 1 e 2	18-60	8/8/2020	31/10/2020	44,0	Ainda sem recrutamento
NCT04385043⁽³²⁾	II-III	Pacientes graves/críticos hospitalizados	PC associado a TP versus TP	NR	18-60	1/5/2020	15/5/2021	35,9	Recrutando
NCT04381936⁽³³⁾	II-III	Pacientes hospitalizados com alto risco de doença grave	LPV/Rit versus corticosteroide versus HCQ versus Azi versus Tmab associado a TP versus PC associado a TP	275mL±75mL nos dias 1 e 2	Todos	19/3/2020	1/12/2031	4,2	Recrutamento

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A imunoterapia passiva ocorre por meio da infusão de plasma de indivíduos convalescentes, por isto o uso do termo plasma convalescente que também pode ser denominado plasma hiperimune ou plasma convalescente compatível com ABO (tipo sanguíneo).

PC: plasma convalescente; LPV: lopinavir; Rit: ritonavir; HCQ: hidroxicloroquina; IFN-β1a: interferon beta-1a; Anak: anakinra; Tmab: tocilizumabe; Smab: sarilumabe; Vit C: vitamina C; TP: tratamento padrão; UTI: unidade de terapia intensiva; PP: plasma padrão; IgG: imunoglobulina G; NR: não reportar; HIg: imunoglobulina humana; PFC: plasma fresco congelado; PC24: plasma congelado em 24 horas após a flebotomia; PC-AT plasma convalescente de alto título; IV: intravenoso; Azi: azitromicina.

Intervenção com plasma convalescente

A intervenção com PC aplicada em todos os PEC foi para pacientes hospitalizados com diferentes graus de comprometimento da doença, principalmente para os casos graves internados em UTI (58,3%) com ou sem ventilação mecânica invasiva, e todos os pacientes receberam o TP para COVID-19. Os braços de intervenção aplicados nesses pacientes hospitalizados normalmente comparavam o PEC da terapia com plasma mais TP em relação a somente TP associado ou não a alguns medicamentos selecionados, como corticosteroides, antibióticos, antimaláricos (hidroxicloroquina), anticoagulantes, imunoglobulina humana, medicamentos antivirais, entre outros.⁽¹⁰^,²²^,²³^,²⁹^,³¹^,³³⁾ A terapia com PC foi aplicada principalmente por meio de dose única com diferentes volumes de transfusão (45,8%). O volume mais utilizado foi de 500mL, em 20,8%,⁽¹³^,¹⁶^,¹⁸^,³⁹⁾ seguido de doses de 200 a 250mL em 8,3%,⁽¹²^,²¹⁾ 400mL em 8,3%,⁽¹⁹^,³⁹⁾ 300mL em 4,2%,⁽²⁴⁾ e 600mL em 4,2%.⁽²³⁾ Nos casos com mais de uma dose, o volume foi de duas doses de 250mL,⁽¹³^,¹⁶^,¹⁷^,²⁰^,²⁹^,³¹^,³³⁾ utilizadas na maioria dos PEC, seguidas de 2x200mL⁽¹⁹^,²⁵^,²⁸^,²⁹^,³³⁾ e 2x300mL.⁽²³^,³³⁾ As doses de plasma foram derivadas de um único doador⁽¹³^,¹⁶^,²⁰^,²³⁾ ou de até dois doadores diferentes em alguns PEC.⁽¹³^,¹⁶⁾ Quase todos os PEC testaram a intervenção em indivíduos com mais de 18 anos, com exceção de dois PEC (Tabela 1).

Em relação às características do desenho do estudo desses PEC, a figura 2 mostra que a intervenção foi randomizada em sua maioria (87,5%), e poucos PEC utilizaram algum tipo de mascaramento (33,3%), como 4,2% com cegamento simples (participante), 12,5% com cegamento duplo (participante e avaliador dos desfechos), 8,3% com cegamento triplo (participante, prestador de cuidados e avaliador dos desfechos) e 8,3% com cegamento quádruplo (participante, prestador de cuidados, investigador e avaliador dos desfechos). No entanto, 12,5% dos PEC não adotaram nenhuma técnica utilizada para minimizar o viés nas alocações e no cegamento, mantendo-se open-label. A inscrição estimada em ensaios clínicos em fase IV é de 7.100 indivíduos,⁽¹⁰⁾ em fase III é de 36 a 2.400 indivíduos⁽¹¹^–²³⁾ e, em fase II-III, de 60 a 15 mil indivíduos.⁽²⁴^–³³⁾ O número estimado de voluntários em cada protocolo está representado pela barra de escala colorida na figura 2.

Rede global de pesquisa em protocolos de ensaios clínicos

Entre os PEC multicêntricos sobre PC,⁽¹⁰^,¹²^,¹³^,¹⁶^,¹⁷^,²²^–²⁴^,²⁶^,³⁰^,³²⁾ o de fase IV⁽¹⁰⁾ é o único com colaborações intercontinentais representadas pelas linhas pretas tracejadas no mapa-múndi (Figura 3), com 87 centros de recrutamento (cilindros verdes) distribuídos na América do Norte, na Europa e na Oceania. Os PEC de fase III também têm colaboração entre países e envolvem 48 centros de recrutamento (cilindros amarelos) nos Estados Unidos e no Canadá.⁽¹⁶⁾ Os outros PEC multicêntricos envolvem um número variado de centros de recrutamento dentro do mesmo país, como Austrália com 79 centros (cilindros roxos),⁽²²⁾ Holanda com 18 centros (cilindros azuis),⁽²⁴⁾ Dinamarca com 12 centros (cilindros cinza escuro),⁽²³⁾ Itália com seis centros (cilindros laranja),⁽³²⁾ destacados na figura 3, com a imagem ampliada para melhor visualização do centros de colaboração e outros com cerca de três centros.⁽¹²^,¹⁷^,²⁶^,³⁰⁾ Os PEC de centro único concentram-se principalmente na América do Norte⁽¹⁵^,¹⁸^–²¹⁾ e América do Sul.⁽¹¹^,²⁷^–²⁹^,³¹⁾

Desfecho da terapia com plasma em pacientes COVID-19

Os três estudos que avaliam a eficácia da terapia com plasma também priorizam a avaliação da COVID-19 em pacientes gravemente doentes ou com risco de vida, como os ensaios clínicos avançados mencionados. A intervenção da terapia com PC variou muito entre os estudos, sem um consenso sobre o melhor padrão de aplicação de PC. Em relação aos resultados, os estudos mostraram redução de 53% na gravidade da doença (dispensando terapia intensiva),⁽³⁸⁾ de 26% no tempo de internação⁽³⁶⁾ e de 35% a 50% na mortalidade,⁽³⁶^–³⁸⁾ relatando efeitos adversos em menos de 4% dos pacientes após tratamento com PC em diferentes doses e volumes associados à terapia padrão para COVID-19,⁽³⁶^–³⁸⁾ conforme mostrado na tabela 2.

Tabela 2. Estudos que avaliam a eficácia da terapia com plasma em pacientes com COVID-19.

Referências	Amostra n/PC	Título de anticorpos	Dose PC (mL)	Carga viral (x10 ^/dL)	Tratamentos anteriores	Hospitalização (variação)	Eventos adversos (n)	Redução da taxa de mortalidade
Abolghasemi et al.⁽³⁶⁾	189/115 PC versus 74 TP	Índice de corte de título de anticorpos plasmáticos >1,1	2×500mL	NI	TP + antiviral (LPV/Rit), HCQ e agente anti-inflamatório	9,54 dias PC versus 12,88 dias TP PC reduziu o tempo de hospitalização em aproximadamente 26%	Aproximadamente 1% PC Febre leve transitória e calafrios após infusão do plasma (n=1)	14,8% PC versus 24,3% TP Aproximadamente 40%
Li et al.⁽³⁷⁾	103/52 PC (23 graves + 29 com risco de vida) versus 51 TP (22 graves + 29 com risco de vida)	1:350 (6 doadores)	4-13mL/kg	Redução em pacientes graves: 44,7% (24 horas), 68,1% (48 horas) e 87,2% (72 horas) livre de vírus Pacientes com risco de vida: 53,8% (24 horas); 73,1 (48 horas) e 84,6% (72 horas) livre de vírus	Antiviral (41/46; 89,1%); antibacteriano (38/46; 82,6%); fitoterapia chinesa (26/46; 56,5%); corticoides 21/46; 45,7%); antifúngico (15/46; 32,6%); HIg (13/46; 28,3%); Interferon (12/46; 26,1%)	Graves: 32,00 (26,00-40,00); com risco de vida: indeterminado (46,00 - indeterminado)	Aproximadamente 4% PC Calafrios e erupções cutâneas em 2 horas (n=1); falta de ar, cianose e dispneia intensa em 6 horas (n=1)	15,7% PC versus 24,0% TP Aproximadamente 35%
Xia et al.⁽³⁸⁾	1.568/138	Não significativamente maior nos que responderam de forma rápida ao tratamento do que nos que responderam de forma moderada	200-1.200mL	20/25 (80%) ficaram livres de vírus após 14 dias	NI	2,4% PC versus 5,1% TP PC reduziu o número de internados na UTI em aproximadamente 53%	Aproximadamente 2% PC Prurido ou eritema durante a transfusão (n=3)	2,2% PC versus 4,1% TP Aproximadamente 50%

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PC: plasma convalescente; TP: tratamento padrão; NI: não informado; LPV: lopinavir; Rit: ritonavir; HCQ: hidroxicloroquina; HIg: imunoglobulina humana; UTI: unidade de terapia intensiva.

DISCUSSÃO

Na ausência de um tratamento efetivo para pacientes com COVID-19, muitos estudos têm buscado alternativas para tratar os pacientes e melhorar sua defesa imune, como é o caso do uso da terapia com PC. O ensaio de recuperação⁽⁴⁰⁾ fornece evidências para apoiar algumas formas de tratamento (por exemplo, dexametasona) e de melhora da imunidade em pacientes em condições críticas, e esse ensaio utiliza a terapia com PC como braço terapêutico. No entanto, muitos aspectos dessa terapia ainda estão sendo explorados, como o intervalo de tempo limite e o momento ideal de coleta para a COVID-19, ou os títulos de imunoglobulina G/imunoglobulina M (IgG/IgM) dos doadores, a melhora clínica proporcionada pela terapia, sua eficácia em pacientes críticos ou não críticos e seus efeitos adversos. Dentre os 170 PEC identificados, apenas 24 PEC estavam em fase avançada (III/IV) com 33 mil indivíduos, concentrados nas regiões da América, mostrando as principais questões referentes à eficácia do uso do PC ainda incertas ou frágeis para justificar a ampliação de seu uso no atendimento hospitalar de pacientes críticos ou não críticos. Além disso, nenhum país, incluindo os Estados Unidos, licenciou o PC como tratamento para a COVID-19. A Food and Drug Administration (FDA) o considerou elegível para uso mais amplo sob uma autorização de uso de emergência,⁽⁴¹⁾ embora outros países tenham concedido aprovação para seu uso em alguns pacientes.

Um dos primeiros ensaios clínicos com PC que analisou 103 pacientes com COVID-19 grave e risco de vida (idade mediana de 70 anos)⁽³⁷⁾ não mostrou significância estatística na melhora clínica após 28 dias ou redução da mortalidade. No entanto, houve evidências de efeitos terapêuticos notáveis e possível atividade antiviral em grupos de pacientes de 60 a 80 anos, no estágio final da evolução da doença, após 14 dias de sintomas, utilizando apenas unidades com títulos de anticorpos muito altos (IgG superior a 1:50) específicos para spike (S) e domínio de ligação ao receptor (RBD). Outro estudo sobre o tratamento com PC em pacientes com COVID-19 grave⁽⁴²⁾ mostrou melhora significativa dos sintomas clínicos, com aumento da saturação da oxi-hemoglobina após o terceiro dia de transfusão, redução das lesões pulmonares, melhora dos critérios laboratoriais de rotina e da função pulmonar acompanhada por rápida neutralização da viremia, utilizando 200mL de PC proveniente de doadores recentemente recuperados com títulos de anticorpos neutralizantes entre 1:160-640, cerca de 16,5 dias após o início dos sintomas, associados ao tratamento padrão e agentes antivirais. Apenas três PEC⁽¹⁴^,¹⁹^,²⁸⁾ mencionaram os títulos de anticorpos usados na terapia com PC (acima de 1:160), e os estudos de Abolghasemi et al.,⁽³⁶⁾ e Li et al.,⁽³⁷⁾ também relataram o uso de títulos de anticorpos acima de 1.1 na terapia com PC associados à melhora clínica e à redução da mortalidade.

Para reduzir a variabilidade na resposta terapêutica dos pacientes, a OMS recomenda alguns cuidados e padronização na seleção de doadores de PC.⁽⁴³⁾ O critério de elegibilidade em relação à idade do doador não varia muito: 18 a 67 anos.⁽³⁶^,⁴⁴⁾ Os doadores eram pacientes que se recuperaram de COVID-19 e não mostraram detecção de SARS-CoV-2 por reação em cadeia da polimerase quantitativa em tempo real (qRT-PCR) ou quaisquer sintomas relacionados após um período que variou entre os estudos. Em um estudo, os doadores podem ter se recuperado após 1 semana, e o curto período de recuperação talvez possa ter contribuído para a morte de cinco em seis pacientes.⁽⁴⁵⁾ Recuperação mais longa permitiu relatos de eficácia terapêutica. Esse período pode ser de 10 dias, com a coleta realizada em duas vezes, com diferença de 24 horas,⁽⁴⁶⁾ de pelo menos 14 dias⁽³⁶^,⁴⁷⁾ e de mais de 2 semanas.⁽³⁶^,⁴²^,⁴⁴⁾ Em alguns casos, o qRT-PCR dos swabs nasofaríngeos deve ser testado como negativo duas vezes, com intervalo de 24 horas entre os exames.⁽³⁶^,⁴²⁾

Em relação à quantificação de anticorpos, os títulos de IgG específicos para S-RBD variam de doador para doador. Estudo demonstrou que dez em 25 amostras de plasma coletado exibiram o título de 1:450, 6/25 1:350, ao passo que, nos demais, variaram de 1:1 a 1:150.⁽⁴⁴⁾ A maioria dos estudos utilizou um volume de PC em torno de 500mL, em dose única ou dividido em duas doses, proveniente de um único doador⁽¹²^,¹⁶^,²⁰^,²³⁾ ou de dois doadores diferentes.⁽¹²^,¹⁶⁾ Portanto, essa falta de padronização na seleção dos doadores, no controle de qualidade do PC e nos pacientes receptores poderia explicar os diversos efeitos terapêuticos.

Alguns possíveis efeitos adversos com o uso do PC podem ser evitados, como o uso de PC sem antígenos, que poderia causar lesão pulmonar aguda associada à transfusão (TRALI - transfusion-related acute lung injury), como os antígenos leucocitários humanos que protegem o embrião.⁽³⁶⁾ Em ensaio clínico multicêntrico, não foi permitido o uso de PC em mulheres grávidas, com o objetivo de prevenir a ocorrência de TRALI.⁽³⁶⁾

A gravidade da doença do paciente transfundido com PC variou de leve, moderada, grave a crítica. Um PEC com pacientes graves dividiu os grupos de estudo em pacientes com doença respiratória aguda grave e pneumonia grave adquirida na comunidade.⁽¹⁰⁾ Outro PEC comparou os efeitos do tratamento em pacientes com COVID-19 oncológicos e não oncológicos.⁽²⁷⁾ A admissão na unidade de terapia intensiva está relatada em alguns PEC,⁽¹¹^,¹⁸^,²⁸^,³⁰⁾ embora se presuma que isso se aplique a todos os pacientes graves. Em alguns PEC, o tratamento com PC foi comparado a outros tratamentos, como corticoides, antibióticos, anticorpos monoclonais e medicamentos antivirais.⁽¹⁰^,²²^,²³^,³³⁾

Alguns resultados publicados permitiram a avaliação de diferentes parâmetros quanto à eficácia do tratamento. Em estudo em que foi aplicado o PC, seis de 17 pacientes necessitaram de ventilação mecânica - na maioria pacientes idosos.⁽⁴⁷⁾ Em estudo multicêntrico, a taxa de mortalidade foi de 14,8% dos pacientes (n=115).⁽³⁶⁾ Resultados semelhantes foram encontrados em outro estudo multicêntrico (15,7%).⁽³⁶⁾ Em outro, a mortalidade foi de apenas 2,2%.⁽³⁸⁾ Um estudo utilizou essa terapia em pacientes com hipertensão, diabetes ou doença cardiovascular, mas não ficou claro o efeito dessas comorbidades no resultado do tratamento com PC.⁽³⁶⁾

A transfusão da terapia com PC para COVID-19 deve seguir algumas condições preestabelecidas, como disponibilidade de uma população de doadores que já se recuperou da doença e pode doar soro convalescente; bancos de sangue para processar as doações de soro; disponibilidade de testes, incluindo testes sorológicos, para detectar SARS-CoV-2 em exames séricos e virológicos para medir a neutralização viral; apoio laboratorial de virologia para a realização desses exames e padronização da fase e condição do paciente com COVID-19.⁽⁴⁸⁾

As principais limitações dos estudos multicêntricos foram o número reduzido de pacientes nos grupos de controle em comparação ao grupo de tratamento, geralmente devido à falta de compatibilidade do grupo sanguíneo do PC e ao uso concomitante ou prévio de outro tratamento.⁽³⁶⁾ Outra limitação é a falta de protocolos padronizados e treinamento para a equipe do estudo, além de diversidade no monitoramento dos pacientes.⁽⁴⁹⁾ Por sua vez, a principal limitação do nosso estudo foi a impossibilidade de realizar uma metanálise, devido à falta de um número robusto de estudos que relatassem efeitos terapêuticos conclusivos dessa modalidade, como diminuição dos títulos de SARS-CoV-2. No entanto, alguns artigos publicados sobre estudos multicêntricos demonstraram que o PC pode ser uma modalidade terapêutica promissora.

CONCLUSÃO

Atualmente, não há opções terapêuticas confiáveis para pacientes com COVID-19 em estado crítico. Com base nos poucos resultados de dados clínicos multicêntricos consolidados disponíveis, concluímos que os estudos de terapia com plasma convalescente forneceram resultados relevantes em casos graves/críticos de pacientes com COVID-19, reduzindo o tempo de internação, a gravidade da doença e a mortalidade, com baixa frequência de eventos adversos em um número considerável de pacientes. Porém, não é possível afirmar, de forma conclusiva, qual a real relevância desse tratamento, devido à falta de dados que permitam uma análise estatística robusta, como uma metanálise.

AGRADECIMENTOS

Lionel Fernel Gamarra teve apoio do Sistema Nacional de Laboratórios em Nanotecnologias (SisNANO) 2.0 (Conselho Nacional de Desenvolvimento Científico e Tecnológico/Ministério da Ciência, Tecnologia, Inovações e Comunicações, processo 442539/2019-3).

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PERMALINK

Convalescent plasma therapy in COVID-19 critically ill patients during advanced phases of clinical trials and their preliminary results

Fernando Anselmo de Oliveira

Mariana Penteado Nucci

Gabriel Nery de Albuquerque Rego

Arielly da Hora Alves

Luciana Cavalheiro Marti

Leopoldo Penteado Nucci

Javier Bustamante Mamani

Lionel Fernel Gamarra

ABSTRACT

INTRODUCTION

OBJECTIVE

METHODS

Inclusion and exclusion criteria

Study eligibility, data extraction, data collection, and risk of bias assessment

Data analysis

RESULTS

Study selection

Overview of clinical trial protocols for passive immunization for COVID-19

Figure 1. Analysis of the study progress rate percentile of clinical trial protocols on convalescent plasma therapy for hospitalized patients of COVID-19 distributed by their phases (green bar: phase IV; blue bars: phase III; and red bars: phase II-III) and the corresponding sponsor country.

Table 1. Study design, arms, interventions, and study time progress.

Convalescent plasma intervention

Global research network in clinical trial protocol

Plasma therapy outcome in COVID-19 patients

Table 2. Studies that evaluation the efficacy of plasma therapy in COVID-19 patients.

DISCUSSION

CONCLUSION

ACKNOWLEDGEMENTS

REFERENCES

Terapia com plasma convalescente em pacientes graves com COVID-19 nas fases avançadas dos ensaios clínicos e seus resultados preliminares

Fernando Anselmo de Oliveira

Mariana Penteado Nucci

Gabriel Nery de Albuquerque Rego

Arielly da Hora Alves

Luciana Cavalheiro Marti

Leopoldo Penteado Nucci

Javier Bustamante Mamani

Lionel Fernel Gamarra

RESUMO

INTRODUÇÃO

OBJETIVO

MÉTODOS

Critérios de inclusão e exclusão

Elegibilidade dos estudos, extração de dados, coleta de dados e avaliação de risco de viés

Análise dos dados

RESULTADOS

Seleção de estudos

Visão geral dos protocolos de ensaios clínicos sobre imunização passiva para COVID-19

Tabela 1. Desenho do estudo, braços, intervenções e progresso do tempo de estudo.

Intervenção com plasma convalescente

Rede global de pesquisa em protocolos de ensaios clínicos

Desfecho da terapia com plasma em pacientes COVID-19

Tabela 2. Estudos que avaliam a eficácia da terapia com plasma em pacientes com COVID-19.

DISCUSSÃO

CONCLUSÃO

AGRADECIMENTOS

ACTIONS

PERMALINK

RESOURCES

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