Plasma from people who have recovered from COVID-19 to treat individuals with COVID-19

Background

Coronavirus (COVID-19) is a highly infectious respiratory illness caused by a new strain of virus. The outbreak has spread rapidly on a global scale. People infected with this virus may not show signs of the disease, others may develop symptoms, including fever, cough, shortness of breath and sore throat. In some people the infection is more severe and can cause severe breathing difficulties, leading to hospitalisation, admission to intensive care or death. Currently, no vaccine or specific treatment is available.

People who have recovered from COVID-19 develop natural defences to the disease in their blood (antibodies). Antibodies are found in part of the blood called plasma. Plasma from blood donated from recovered patients, which contains COVID-19 antibodies, can be used to make two preparations. Firstly, convalescent plasma, which is plasma that contains these antibodies. Secondly, hyperimmune immunoglobulin, which is more concentrated, and therefore contains more antibodies.

Convalescent plasma and hyperimmune immunoglobulin have been used successfully to treat other respiratory viruses. These treatments (given by a drip or injection) are generally well-tolerated, but unwanted effects can occur.

What did we want to find?

We wanted to know whether plasma from people who have recovered from COVID-19 is an effective treatment for people with COVID-19, and whether this treatment causes any unwanted effects.

Our methods

We searched major medical databases for clinical studies on treatment with convalescent plasma or hyperimmune immunoglobulin for people with COVID-19. Studies could be conducted anywhere in the world and include participants of any age, gender or ethnicity, with mild, moderate or severe COVID-19.

COVID-19 is spreading rapidly, so we needed to answer this question quickly. This meant that we shortened some steps of the normal Cochrane Review process - only one review author extracted data from studies and assessed study quality; normally two review authors would do this.

Key results

We included eight completed studies, with 32 participants who received convalescent plasma. None of the studies randomly allocated participants to different treatments (randomised trials produce the best evidence). None of the studies included a group of people who did not receive convalescent plasma, as a comparison group.

All participants in the studies were alive at the end of follow-up, but not all had been discharged from hospital. Follow-up varied from 3 to 37 days after treatment with convalescent plasma.

Six studies used the level of breathing support that participants required as a measure of recovery. Breathing support included oxygen therapy, mechanical ventilation and the need for a special machine that oxygenates the blood. All six studies reported clinical improvement in at least some of their participants, but it remains uncertain whether this improvement was related to convalescent plasma, another treatment, or the natural progression of the disease.

Six studies reported time to discharge from hospital for some of their participants, all of whom received convalescent plasma. The time to discharge ranged from 4 to 35 days after convalescent plasma treatment.

Six studies included participants with severe COVID-19. Most had improved at final follow-up, but this improvement may have been due to another treatment, the natural progression of the disease or convalescent plasma treatment.

Two participants reported unwanted effects related to convalescent plasma. One participant developed a fever, and a second participant experienced anaphylactic shock (severe allergic reaction) early on in the transfusion.

Certainty of the evidence

Our certainty (confidence) in the evidence was very limited because the studies were not randomised and did not use reliable methods to measure their results. Furthermore, they had only a small number of participants, who received various treatments alongside convalescent plasma, and some had underlying health problems.

Conclusion

We are very uncertain whether plasma from people who have recovered from COVID-19 is an effective treatment for people with COVID-19. The completed studies we found were poor quality and their results could be related to the natural progression of the disease, other treatments that the participants received, or to convalescent plasma. However, our searches found 48 ongoing studies: 47 evaluating convalescent plasma and 1 evaluating hyperimmune immunoglobulin, of which 22 are randomised. We will update this review with their results when these studies are completed.

Authors' conclusions: 

We identified eight studies (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; reporting two adverse events (potentially grade 3 or 4), one of which was a serious adverse event. We are very uncertain whether convalescent plasma is effective for people admitted to hospital with COVID-19 as studies reported results inconsistently, making it difficult to compare results and to draw conclusions. We identified very low-certainty evidence on the effectiveness and safety of convalescent plasma therapy for people with COVID-19; all studies were at high risk of bias and reporting quality was low.

No RCTs or controlled non-randomised studies evaluating benefits and harms of convalescent plasma have been completed. There are 47 ongoing studies evaluating convalescent plasma, of which 22 are RCTs, and one trial evaluating hyperimmune immunoglobulin. We will update this review as a living systematic review, based on monthly searches in the above mentioned databases and registries. These updates are likely to show different results to those reported here.

Read the full abstract...
Background: 

Convalescent plasma and hyperimmune immunoglobulin may reduce mortality in patients with respiratory virus diseases, and are currently being investigated in trials as a potential therapy for coronavirus disease 2019 (COVID-19). A thorough understanding of the current body of evidence regarding the benefits and risks is required. 

Objectives: 

To assess whether convalescent plasma or hyperimmune immunoglobulin transfusion is effective and safe in the treatment of people with COVID-19.

Search strategy: 

The protocol was pre-published with the Center for Open Science and can be accessed here: osf.io/dwf53 

We searched the World Health Organization (WHO) COVID-19 Global Research Database, MEDLINE, Embase, Cochrane COVID-19 Study Register, Centers for Disease Control and Prevention COVID-19 Research Article Database and trials registries to identify ongoing studies and results of completed studies on 23 April 2020 for case-series, cohort, prospectively planned, and randomised controlled trials (RCTs).

Selection criteria: 

We followed standard Cochrane methodology and performed all steps regarding study selection in duplicate by two independent review authors (in contrast to the recommendations of the Cochrane Rapid Reviews Methods Group).

We included studies evaluating convalescent plasma or hyperimmune immunoglobulin for people with COVID-19, irrespective of disease severity, age, gender or ethnicity.

We excluded studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)) and studies evaluating standard immunoglobulins.

Data collection and analysis: 

We followed recommendations of the Cochrane Rapid Reviews Methods Group regarding data extraction and assessment.

To assess bias in included studies, we used the assessment criteria tool for observational studies, provided by Cochrane Childhood Cancer. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality at hospital discharge, improvement of clinical symptoms (7, 15, and 30 days after transfusion), grade 3 and 4 adverse events, and serious adverse events. 

Main results: 

We included eight studies (seven case-series, one prospectively planned, single-arm intervention study) with 32 participants, and identified a further 48 ongoing studies evaluating convalescent plasma (47 studies) or hyperimmune immunoglobulin (one study), of which 22 are randomised.

Overall risk of bias of the eight included studies was high, due to: study design; small number of participants; poor reporting within studies; and varied type of participants with different severities of disease, comorbidities, and types of previous or concurrent treatments, including antivirals, antifungals or antibiotics, corticosteroids, hydroxychloroquine and respiratory support.

We rated all outcomes as very low certainty, and we were unable to summarise numerical data in any meaningful way. As we identified case-series studies only, we reported results narratively.

Effectiveness of convalescent plasma for people with COVID-19

The following reported outcomes could all be related to the underlying natural history 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 hospital by the end of the study (15 participants discharged, 6 still hospitalised, 11 unclear). Follow-up ranged from 3 days to 37 days post-transfusion. We do not know whether convalescent plasma therapy 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 in clinical symptoms in at least some participants. We do not know whether convalescent plasma improves clinical symptoms (very low-certainty evidence).

Time to discharge from hospital

Six studies reported time to discharge from hospital for at least some participants, which ranged from four to 35 days after convalescent plasma therapy

Admission on the intensive care unit (ICU)

Six studies included patients who were critically ill. At final follow-up the majority of these patients were no longer on the ICU or no longer required mechanical ventilation.

Length of stay on the ICU

Only one study (1 participant) reported length of stay on the ICU. The individual was discharged from the ICU 11 days after plasma transfusion.

Safety of convalescent plasma for people with COVID-19

Grade 3 or 4 adverse events 

The studies did not report the grade of adverse events after convalescent plasma transfusion. Two studies reported data relating to participants who had experienced adverse events, that were presumably grade 3 or 4. One case study reported a participant who had moderate fever (38.9 °C). Another study (3 participants) reported a case of severe anaphylactic shock. Four studies reported the absence of moderate or severe adverse events (19 participants). We are very uncertain whether or not convalescent plasma therapy affects the risk of moderate to severe adverse events (very low-certainty evidence).

Serious adverse events

One study (3 participants) reported one serious adverse event. As described above, this individual had severe anaphylactic shock after receiving convalescent plasma. Six studies reported that no serious adverse events occurred. We are very uncertain whether or not convalescent plasma therapy affects the risk of serious adverse events (very low-certainty evidence). 

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