Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a rapid review

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ABSTRACT

Background:
Convalescent plasma and hyperimmune immunoglobulin can reduce mortality in patients with diseases caused by respiratory viruses. It is currently being investigated in trials as a possible treatment for coronavirus disease 2019 (COVID‐19). A deep understanding of the current body of evidence on benefits and risks is required.

Objectives:
To evaluate whether transfusion of convalescent plasma or hyperimmune immunoglobulins is effective and safe in the treatment of people with COVID-19.

Search methods:
The protocol was pre-published with the Center for Open Science and can be consulted here: osf.io/dwf53
We searched the World Health Organization (WHO) COVID‐19 Global Research Database, MEDLINE, Embase, the Cochrane COVID‐19 Study Registry, the Research Articles Database. from the Centers for Disease Control and Prevention (CDC) and in trial registries to identify ongoing studies and results of studies completed on April 23, 2020 for case series, cohorts, trials prospective controlled trials and randomized controlled trials (RCTs).

Selection criteria:
Standard Cochrane methodology was followed and all steps for study selection were performed in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Review Methods Group).
Studies evaluating convalescent plasma or hyperimmune immunoglobulin from people with COVID‐19 were included, regardless of disease severity, age, sex, or ethnicity.
Studies that included populations with other coronavirus diseases, such as severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), and studies evaluating standard immunoglobulins were excluded.

Data collection and analysis:
The recommendations of the Cochrane Rapid Review Methods Group were followed for data extraction and evaluation.
To assess bias in the included studies, we used the assessment criteria tool for observational studies, provided by the Cochrane Childhood Cancer Group. The certainty of evidence was graded using the GRADE method for the following outcomes: all-cause mortality at hospital discharge, improvement in clinical symptoms (7, 15, and 30 days after transfusion), grade-grade adverse events. 3 and 4, and serious adverse events.

MAIN RESULTS:
Eight studies were included (seven case series, one prospectively planned, single-arm intervention study) with 32 participants, and a further 48 ongoing studies were identified evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomized.
The overall risk of bias of the eight included studies was high due to: study design; the small number of participants; poor information within studies; and the variety of type of participants with different degrees of disease severity, comorbidities, and types of prior or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine, and respiratory support.
All results were rated as very low certainty, and numerical data could not be summarized in any meaningful way. As only case series studies were identified, results were reported narratively.

Effectiveness of convalescent plasma for people with COVID-19:
All results reported below could be related to the underlying natural course of the disease or other concomitant treatment, rather than convalescent plasma.

All-cause mortality at hospital discharge
All studies reported mortality. All participants were alive at the end of the reporting period, but not all participants had been discharged from the hospital by the end of the study (15 participants discharged, six still hospitalized, 11 unclear). The duration of follow-up ranged from three to 37 days after transfusion. It is unknown whether treatment with convalescent plasma affects mortality (very low-certainty evidence).

Improvement of clinical symptoms (assessed by respiratory support)
Six studies, including 28 participants, reported the level of respiratory support required. Most participants required respiratory support at baseline. All studies reported improvement of clinical symptoms in at least some participants. It is unknown whether treatment with convalescent plasma improves clinical symptoms (very low-certainty evidence).

Time until hospital discharge:
Six studies reported time to hospital discharge for at least some participants, which ranged from four to 35 days after convalescent plasma treatment.

Admission to the Intensive Care Unit (ICU):
Six studies included severely ill patients. At the end of follow-up, most of these patients were no longer in the ICU or no longer required mechanical ventilation.

Length of stay in ICU:
Only one study (one participant) reported length of ICU stay. The patient was discharged from the ICU 11 days after the plasma transfusion.

Safety of convalescent plasma for people with COVID-19

Grade 3 or 4 adverse events:
The studies did not report the extent of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, which were presumably grade 3 or 4. One case study reported a participant who had a moderate fever (38,9°C). One case of severe anaphylactic shock was reported in another study (three participants). Four studies reported the absence of moderate or severe adverse events (19 participants). We are uncertain whether treatment with convalescent plasma influences the risk of moderate or severe adverse events (very low-certainty evidence).

Serious adverse events:
One study (three participants) reported one serious adverse event. As described above, this person suffered severe anaphylactic shock after receiving convalescent plasma. Six studies reported no serious adverse events. We are uncertain whether treatment with convalescent plasma influences the risk of serious adverse events (very low-certainty evidence).

Authors' conclusions:
Eight studies were identified (seven case series and one prospectively planned single-arm intervention study) with a total of 32 participants (range 1 to 10). Most studies assessed the risks of the intervention; They reported two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. It is not clear that convalescent plasma is effective for people admitted to hospital with COVID‐19, as studies reported results inconsistently, making it difficult to compare results and draw conclusions. We identified very low‐certainty evidence on the efficacy and safety of convalescent plasma treatment for people with COVID‐19. All studies had a high risk of bias and reporting quality was low.

No RCTs or non-randomized controlled studies evaluating the benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs and one is a trial evaluating hyperimmune immunoglobulin. This review will be updated as a living systematic review based on monthly searches of the aforementioned databases and registries. These updates will likely show different results than those described here.