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Convalescent Plasma to Treat COVID-19 - Possibilities and Challenges
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Editorial
March 27, 2020
https://jamanetwork.com/journals/jama/fullarticle/2763982
In this issue of JAMA, Shen et al report findings from a preliminary study of 5 severely ill patients with coronavirus disease 2019 (COVID-19) who were treated in the Shenzhen Third People's Hospital, China, using plasma from recovered individuals.1 All patients had severe respiratory failure and were receiving mechanical ventilation; 1 needed extracorporeal membrane oxygenation (ECMO) and 2 had bacterial and/or fungal pneumonia. Four patients without coexisting diseases received convalescent plasma around hospital day 20, and a patient with hypertension and mitral valve insufficiency received the plasma transfusion at day 10. The donor plasma had demonstrable IgG and IgM anti–SARS-CoV-19 antibodies and neutralized the virus in in vitro cultures. Although these patients continued to receive antiviral treatment primarily with lopinavir/ritonavir and interferon, the use of convalescent plasma may have contributed to their recovery because the clinical status of all patients had improvement approximately 1 week after transfusion, as evidenced by normalization of body temperature as well as improvements in Sequential Organ Failure Assessment scores and Pao2/Fio2 ratio. In addition, the patients’ neutralizing antibody titers increased and respiratory samples tested negative for SARS-CoV-2 between 1 and 12 days after transfusion.
Even though the cases in the report by Shen et al are compelling and well-studied, this investigation has important limitations that are characteristic of other “anecdotal” case series. The intervention, administration of convalescent plasma, was not evaluated in a randomized clinical trial, and the outcomes in the treatment group were not compared with outcomes in a control group of patients who did not receive the intervention. Therefore, it is not possible to determine the true clinical effect of this intervention or whether patients might have recovered without this therapy. In addition, patients received numerous other therapies (including antiviral agents and steroids), making it impossible to disentangle the specific contribution of convalescent plasma to the clinical course or outcomes. Moreover, convalescent plasma was administered up to 3 weeks after hospital admission, and it is unclear whether this timing is optimal or if earlier administration might have been associated with different clinical outcomes. Despite these limitations, the study does provide some evidence to support the possibility of evaluating this well-known therapy in more rigorous investigations involving patients with COVID-19 and severe illness.
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, in 2005, Cheng et al reported outcomes of patients who received convalescent plasma in Hong Kong during the 2003 SARS outbreak.2 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.3-5 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.6
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.4 Shen et al used apheresis products produced in the hospital.1
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.3 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,7 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.
Both academic4 and industry groups are beginning to investigate the efficacy of passive antibody therapies for COVID-19 infection. If substantial, robust evidence from rigorously conducted clinical trials clearly establishes effectiveness, and if tests could identify patients who could benefit from passive immunity, the US and other countries could consider a national campaign to provide such treatment. Although a logistical challenge, this may be one approach to protect high-risk populations and could synergize with parallel efforts to develop vaccines and antiviral drugs. However, just as executive direction was critical for rapid implementation of COVID-19 tests, so it will be important to accelerate this effort.
Specifically, guidance would be needed to direct blood centers and plasma fractionators to begin prioritizing collections from COVID-19-convalescent donors; expedite the availability of these products for therapeutic use; create a data collection, analysis, and regulatory infrastructure to identify factors that predict therapeutic efficacy and to inform the relative levels of convalescent plasma vs H-Ig production; and remove regulatory barriers that, for example, currently limit the use of pathogen reduction technology for convalescent plasma collections or that require several-month inventory holds on H-Ig pharmaceuticals.
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Preliminary Communication
March 27, 2020
Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma
In the current study, SARS-CoV-2 was still detectable in all 5 patents even though antiviral treatment had been given for at least 10 days, although viral load decreased and became undetectable soon after convalescent plasma treatment.
In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in the patients’ clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.
JAMA. Published online March 27, 2020.
https://jamanetwork.com/journals/jama/fullarticle/2763983
Key Points
Question
Could administration of convalescent plasma transfusion be beneficial in the treatment of critically ill patients with coronavirus disease 2019 (COVID-19)?
Findings
In this uncontrolled case series of 5 critically ill patients with COVID-19 and acute respiratory distress syndrome (ARDS), administration of convalescent plasma containing neutralizing antibody was followed by an improvement in clinical status.
Meaning
These preliminary findings raise the possibility that convalescent plasma transfusion may be helpful in the treatment of critically ill patients with COVID-19 and ARDS, but this approach requires evaluation in randomized clinical trials.
Abstract
Importance Coronavirus disease 2019 (COVID-19) is a pandemic with no specific therapeutic agents and substantial mortality. It is critical to find new treatments.
Objective
To determine whether convalescent plasma transfusion may be beneficial in the treatment of critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
Design, Setting, and Participants
Case series of 5 critically ill patients with laboratory-confirmed COVID-19 and acute respiratory distress syndrome (ARDS) who met the following criteria: severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment; Pao2/Fio2 <300; and mechanical ventilation. All 5 were treated with convalescent plasma transfusion. The study was conducted at the infectious disease department, Shenzhen Third People's Hospital in Shenzhen, China, from January 20, 2020, to March 25, 2020; final date of follow-up was March 25, 2020. Clinical outcomes were compared before and after convalescent plasma transfusion.
Exposures
Patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titer greater than 1:1000 (end point dilution titer, by enzyme-linked immunosorbent assay [ELISA]) and a neutralization titer greater than 40 (end point dilution titer) that had been obtained from 5 patients who recovered from COVID-19. Convalescent plasma was administered between 10 and 22 days after admission.
Main Outcomes and Measures
Changes of body temperature, Sequential Organ Failure Assessment (SOFA) score (range 0-24, with higher scores indicating more severe illness), Pao2/Fio2, viral load, serum antibody titer, routine blood biochemical index, ARDS, and ventilatory and extracorporeal membrane oxygenation (ECMO) supports before and after convalescent plasma transfusion.
Results
All 5 patients (age range, 36-65 years; 2 women) were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. Following plasma transfusion, body temperature normalized within 3 days in 4 of 5 patients, the SOFA score decreased, and Pao2/Fio2 increased within 12 days (range, 172-276 before and 284-366 after). Viral loads also decreased and became negative within 12 days after the transfusion, and SARS-CoV-2–specific ELISA and neutralizing antibody titers increased following the transfusion (range, 40-60 before and 80-320 on day 7). ARDS resolved in 4 patients at 12 days after transfusion, and 3 patients were weaned from mechanical ventilation within 2 weeks of treatment. Of the 5 patients, 3 have been discharged from the hospital (length of stay: 53, 51, and 55 days), and 2 are in stable condition at 37 days after transfusion.
Conclusions and Relevance
In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.
Discussion
In this case series, 5 patients who were critically ill with COVID-19 were treated with convalescent plasma. As assessed by Ct, viral load declined within days of treatment with convalescent plasma, and the clinical conditions of these patients improved, as indicated by body temperature reduction, improved Pao2/Fio2, and chest imaging. Four patients who had been receiving mechanical ventilation and ECMO no longer required respiratory support by 9 days after plasma transfusion.
Previous studies have reported the use of convalescent plasma transfusion in the treatment of various infections.6,10,16 For example, patients (n = 50) with SARS had a significantly higher discharge rate by day 22 following onset of illness (73.4% vs 19.0%; P<.001) and lower case-fatality rate (0% vs 23.8%; P = .049) in the convalescent plasma treatment group (n = 19 patients) when compared with steroid treatment group (n = 21).17 In another study of 93 patients with influenza A(H1N1), patients who received convalescent plasma treatment (n = 20) compared with those in the control group (n = 73) had significantly fewer deaths (20% vs 54.8%; P = .01) and a lower median lymphocyte count on ICU admission.10
In this study, collection and transfusion of the plasma were done as previously reported.10 In addition, plasma was obtained from the donors and transfused in the recipients on the same day, which helps preserve the natural activity of the plasma.
Studies have shown that viral loads are highly correlated with disease severity and progression.18 Fatal outcome of human influenza A(H5N1) has been associated with high viral load and hypercytokinemia.19 Apart from antiviral treatment, virus-specific neutralizing antibody, which could accelerate virus clearance and prevent entry into target cells, serves as the main mechanism for the restriction and clearance of the viruses by the host.20-22 In the current study, SARS-CoV-2 was still detectable in all 5 patents even though antiviral treatment had been given for at least 10 days, although viral load decreased and became undetectable soon after convalescent plasma treatment. As determined by ELISA, all plasma from the donors had high virus-specific IgG and IgM ELISA titers. Moreover, the neutralizing antibody titers, vital for the restriction of viral infection of the 5 recipients, significantly increased after plasma transfusion. The results highlight the possibility that antibodies from convalescent plasma may have contributed to the clearance of the virus and also the improvement of symptoms. In addition to viral neutralizing antibodies, acceleration of infected cell clearance by antibodies has also been found in an in vivo study of HIV-1 virus.23 In the current study, all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, which also may have contributed to the viral clearance observed.
Limitations
This study has several limitations. First, this was a small case series that included no controls. Second, it is unclear if these patients would have improved without transfusion of convalescent plasma, although the change in Ct and Pao2/Fio2 represent encouraging findings. Third, all patients were treated with multiple other agents (including antiviral medications), and it is not possible to determine whether the improvement observed could have been related to therapies other than convalescent plasma. Fourth, plasma transfusion was administered 10 to 22 days after admission; whether a different timing of administration would have been associated with different outcomes cannot be determined. Fifth, whether this approach would reduce case-fatality rates is unknown.
Conclusions
In this preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in the patients’ clinical status. The limited sample size and study design preclude a definitive statement about the potential effectiveness of this treatment, and these observations require evaluation in clinical trials.
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