Convalescent plasma to treat COVID-19

The use of convalescent plasma is not new; it was used for severe acute respiratory syndrome ( SARS ), pandemic 2009 influenza A ( H1N1 ), avian influenza A ( H5N1 ), several hemorrhagic fevers such as Ebola, and other viral infections.

For instance, Cheng et al [ J Clin Microbiol Infect Dis 2005 ] reported outcomes of patients who received convalescent plasma in Hong Kong during the 2003 SARS outbreak.
Although this investigation was not a randomized trial, of 1775 patients, the 80 who received convalescent plasma had a lower mortality rate ( 12.5% ) compared with the overall SARS-related mortality for admitted patients ( n = 299 [ 17% ] ).
The antibody titers and plasma transfusion volumes varied and did not appear to correlate with clinical response; however, patients receiving transfusion within 14 days of symptom onset ( n = 33 ) had better outcomes. No adverse events were reported among patients receiving convalescent plasma.

Despite the potential utility of passive antibody treatments, there have been few concerted efforts to use them as initial therapies against emerging and pandemic infectious threats.
The absence of large trials certainly contributes to the hesitancy to employ this treatment.
Also, the most effective formulations ( convalescent plasma or hyperimmune globulin, H-Ig ) are unknown.

Convalescent plasma has the advantage that while its antibodies limit viral replication, other plasma components can also exert beneficial effects such as replenishing coagulation factors when given to patients with hemorrhagic fevers such as Ebola.
On the other hand, individual convalescent plasma units demonstrate donor-dependent variability in antibody specificities and titers.
H-Ig preparations, in contrast, contain standardized antibody doses, although fractionation removes IgM, which may be necessary against some viruses.
Nonetheless, the construction of a strategic stockpile of frozen, pathogen-reduced plasma, collected from Ebola-convalescent patients with well-characterized viral neutralization activities, is one example of how to proceed despite existing unknowns.

Deploying passive antibody therapies against the rapidly increasing number of COVID-19 cases provides an unprecedented opportunity to perform clinical studies of the efficacy of this treatment against a viral agent.
If the results of rigorously conducted investigations, such as a large-scale randomized clinical trial, demonstrate efficacy, use of this therapy also could help change the course of this pandemic.
Shen et al [ JAMA 2020 ] used apheresis products produced in the hospital.

How could this be scaled to meet increased demands ? One approach would be to combine the use of convalescent plasma and H-Ig in a complementary way to treat infected patients in the current COVID-19 pandemic, and subsequent infectious waves, perhaps with the following steps and considerations.

First, blood centers could start collecting plasma from convalescent donors, preferably at the leading edge of the infectious wave; health care workers could encourage COVID-19–infected patients to donate after hospital discharge. Plasma would be tested, frozen, and distributed to hospitals; paired samples would be retained for concurrent investigations.

Second, within days of collection, clinicians could transfuse convalescent plasma to infected patients. This approach would be expected to be most effective in patients before they develop a humoral response to COVID-19; serology tests that detect COVID-19 neutralizing antibodies would be beneficial in identifying the best treatment candidates. Monitoring patient responses by clinical, laboratory, and imaging results could be compared against antibody titers, specificities, and neutralizing activities in paired plasma samples to develop better algorithms for identifying patient and donor factors that predict clinical efficacy.

Third, funding to expand plasma collection capabilities, as well as for academic, industry, and government research initiatives, could mobilize these efforts. However, despite potentially rapid availability, the deployment of convalescent plasma will have limited reach because transfusions are typically performed in hospital settings and may require large infusion volumes. In addition, plasma transfusions are also associated with adverse events ranging from mild fever and allergic reactions to life-threatening bronchospasm, transfusion-related acute lung injury, and circulatory overload in patients with cardiorespiratory disorders, which must be carefully tracked. There is also a small, but nonzero, risk of infectious disease transmission.

Fourth, dynamic modeling of COVID-19 infections and factors that are associated with clinical efficacy could be used to inform the distribution of convalescent plasma ( and donors ) between blood centers and the source plasma industry so the latter can manufacture concentrated COVID-19 H-Ig.

Fifth, within several months, it could be possible for clinicians to begin using small volume H-Ig preparations in ambulatory settings and drive-through clinics, as well as in hospitals. Concentrated H-Ig preparations are an injectable, time-tested treatment for viral ( eg, hepatitis A and B ) and bacterial ( eg, tetanus, diphtheria ) diseases. In principle, each dose delivers antibody preparations with accurately determined specificities, affinities, and titers against COVID-19 and is logistically simpler than plasma to distribute worldwide. As with convalescent plasma, it will be critical to identify factors that predict responses to COVID-19 H-Ig, and also to track adverse events.

While H-Ig ( like plasma ) can be stored for years, a similar pathway may need to be reactivated next season, especially as passive antibody efficacy wanes due to accumulated viral mutations. During each iteration, the investigations performed in parallel to clinical use will drive improvements, for example by guiding the relative amounts of convalescent plasma vs H-Ig that are prepared, or by identifying patients most likely to benefit from these treatments. ( Xagena )

Source: JAMA, 2020



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