March 30, 2020

Convalescent plasma possibly helpful in the treatment of 5 critically ill patients with COVID-19

By Denise Baez

NEW YORK -- March 30, 2020 -- In a preliminary uncontrolled case series of 5 critically ill patients with laboratory-confirmed coronavirus disease 2019 (COVID-19) and acute respiratory distress syndrome (ARDS), published in JAMA, administration of convalescent plasma containing neutralising antibody was followed by improvement in their clinical status.

“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 randomised clinical trials,” reported Yingxia Liu, MD, Shenzhen Third People’s Hospital, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen, China, and colleagues.

All 5 patients (aged 35-65 years) were receiving mechanical ventilation at Shenzhen Third People’s Hospital at the time of treatment and all had received methylprednisolone and antiviral agents, including interferon and lopinavir/ritonavir. Of the patients, only 1 had a pre-existing medical condition and none were smokers.

Following plasma transfusion, body temperature normalised within 3 days in 4 of 5 patients, the Sequential Organ Failure Assessment (SOFA) score decreased, and Pao2/Fio2 increased within 12 days. Viral loads also decreased and became negative within 12 days after the transfusion, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific enzyme-linked immunosorbent assay (ELISA) and neutralising antibody titres increased following the transfusion. 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 and 2 are in stable condition at 37 days after transfusion (final follow-up date was March 25, 2020).

All 5 patients had severe pneumonia with rapid progression and continuously high viral load despite antiviral treatment. All patients received transfusion with convalescent plasma with a SARS-CoV-2–specific antibody (IgG) binding titre >1:1000 (end point dilution titre, by ELISA) and a neutralisation titre >40 (end point dilution titre) that had been obtained from 5 patients who recovered from COVID-19. Each patient received 2 consecutive transfusions of 200 to 250 mL of ABO-compatible convalescent plasma (400 mL of convalescent plasma in total) on the same day it was obtained from the donor, which helps preserve the natural activity of the plasma.

Convalescent plasma was administered between 10 and 22 days after admission. The patients received antiviral agents continuously until the SARS-CoV-2 viral loads became negative.

The cycle threshold (Ct) value at the time of admission ranged from 18.9 to 38.0, and on the day of plasma transfusion, ranged from 22.0 to 35.9. It increased (improved) within 1 day after transfusion. The Ct value of patient 5 became negative on post-transfusion day 1, patient 3 and patient 4 became negative on day 3, and patient 1 and patient 2 became negative on day 12 after the transfusion.

The SOFA score ranged from 2 to 10 prior to plasma transfusion, and decreased to a range of 1 to 4 at 12 days following transfusion. The Pao2/Fio2 ranged from 172 to 276 prior to transfusion, and increased (improved) for 4 of 5 patients within 7 days after transfusion (overall range, 206-290), and increased substantially (range, 284-366) on the 12th day after the plasma treatment. Body temperature ranged from 37.6 to 39.0 degrees Celsius before plasma transfusion and declined to the normal range on the third day after the transfusion.

Lung CT scans showed improvement of the pulmonary lesion of patient 1 on the third day after the plasma transfusion and gradual resolution of pulmonary lesions of the other patients at 3 days after the plasma treatment.

Patients 3, 4, and 5 were weaned from mechanical ventilation. Patient 2, who was receiving extracorporeal membrane oxygenation (ECMO) at the time of plasma treatment, did not require ECMO on day 5 after transfusion. Patients 3, 4, and 5 were discharged from the hospital (length of stay: 53, 51, and 55 days, respectively). As of March 25, 2020, patients 1 and 2 remained hospitalised, with lengths of stay of 37 days each.

“All plasma from the donors had high virus-specific IgG and IgM ELISA titres,” the authors wrote. “Moreover, the neutralising antibody titres -- 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. 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.”

In addition to the small sample size, the current study had several limitations. According to the authors, it is unclear if the patients would have improved without transfusion of convalescent plasma, although the change in Ct and Pao2/Fio2 represent encouraging findings. In addition, all patients were being treated with multiple agents and it is not possible to determine whether the improvement observed could have been related to therapies other than convalescent plasma, or whether a different timing of administration would have been associated with different outcomes.

The 5 donors of convalescent plasma were aged 18 to 60 years, had been previously diagnosed with laboratory-confirmed COVID-19, and subsequently tested negative for SARS-CoV-2 and other respiratory viruses, as well as for hepatitis B virus, hepatitis C virus, HIV, and syphilis at the time of blood donation. The donors had been asymptomatic for at least 10 days, with a serum SARS-CoV-2-specific ELISA antibody titre higher than 1:1000 and a neutralising antibody >40.

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