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.
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.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).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.In this study, collection and transfusion of the plasma were done as previously reported.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.Fatal outcome of human influenza A(H5N1) has been associated with high viral load and hypercytokinemia. 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.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.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.
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.
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.
Reference & Source information: https://jamanetwork.com/
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