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23rd August 2021
The use of convalescent plasma (CP) in patients with COVID-19 is based on the notion that the administered plasma, by containing therapeutic antibodies to the virus, enables recovery. However, to date, results with this therapy have been disappointing, prompting the RECOVERY trial in the UK to halt recruitment to the CP arm in January 2021. In fact, studies have shown how the use of CP in those with severe COVID-19 infection, did not result in any improvements compared to standard care. Nevertheless, in these studies, CP was administered to patients late in their disease. Furthermore, and there is some evidence from a small study in 80 older patients that when CP was given within 72 hours of the onset of mild COVID-19, it did result in reduced illness progression.
In an attempt to provide more robust evidence for the benefit of early use of CP in those with COVID-19, a team from Michigan State University, US, decided to undertake a randomised, multi-centre, single-blind trial in patients who presented at an emergency department within seven days of developing COVID-19 symptoms. The researchers wanted to examine if the early administration of CP was able to halt disease progression. All participants had PCR confirmed COVID-19 infection and were aged 50 years or older and with one or more known risk factors for disease progression. Individuals were randomised in a 1:1 fashion to either one unit of convalescent plasma or saline (placebo) which was coloured to resemble the plasma. The primary outcome of the study was disease progression within 15 days of randomisation and which was defined by a composite of hospital admission, seeking emergency/urgent care or death without hospitalisation.
A total of 511 patients underwent randomisation, 257 to plasma with a mean age of 54 years (52.5% female). Risk factors included a body mass index greater than 30 (59.1%), hypertension (40.9%) and diabetes (29.6%). In fact, overall, 54.9% of those assigned to convalescent plasma had three or more COVID-19 risk factors. The primary outcome occurred in 30% of those given CP and 31.9% of those given saline. Furthermore, subgroup analysis, i.e., by body mass index, age, ethnicity etc, also showed no important differences. Within 30 days of administration of either treatment, death occurred in 1.9% of those given plasma and 0.4% given saline.
In their discussion, the authors noted that there was a potentially sound rational for giving early convalescent plasma, i.e., that it would boost the level of neutralising antibodies before an individual could develop their own sufficient antibody response. Despite this obvious possible benefit, the authors concluded that even that even among those with a number of risk factors for COVID-19 disease progression, early use of convalescent plasma had no impact on clinical outcomes.
Korley FK et al. Early Convalescent Plasma for High-Risk Outpatients with Covid-19. New Eng J Med 2021
18th January 2021
The use of convalescent plasma (CP) to treat respiratory infections has a long history having been used for over a century. During the current pandemic, interest in this therapeutic modality has picked up although the efficacy signals from this approach are still preliminary and require further study. As a result, a team led by researchers from the Department of Anaesthesiology and Peri-operative Medicine, Rochester, Minnesota, in the US, retrospectively studied the results obtained from an expanded-access programme to CP across a range of hospitals. Eligible patients were 18 years and over, hospitalised with a laboratory confirmed positive COVID-19 test and deemed at high risk for progression to severe or life-threatening COVID-19.
Treatment consisted of CP given intravenously although the corresponding IgG COVID-19 antibody levels within these samples were unknown. The researchers therefore collected and quantitively analysed, remnant aliquots of serum retained from the donation process for IgG antibody levels. These which were divided into low (<4.62), medium (4.62 to 18.45) and high (>18.45) titre levels. The primary outcome for the study was mortality at 30 days after transfusion of CP.
The patient cohort consisted of 3082 individuals of whom, 61% were male and 69% were younger than 70 years of age. In total, two-thirds received CP prior to mechanical ventilation. Death within 30 days after CP occurred in a 26.9% of all patients. Furthermore, the outcome occurred in 29.6%, 27.4% and 22.3% of those in the low, medium and high, IgG titre ranges respectively. The risk of death among those with higher antibody titre levels was reduced by 46% compared to the lowest antibody titre (relative risk, RR = 0.66, 95% CI 0.48-0.91) in patients who were not mechanically ventilated. However, there was no effect of antibody titre levels on death rates among patients who required mechanical ventilation.
The authors concluded that their data support the notion that the benefits of CP are largely dependent on the levels of antibody present within samples.
Joyner MJ et al. Convalescent plasma antibody levels and the risk of death from COVID-19. N Engl J Med 2021
23rd October 2020
To date only two clinical trials have examined the value of convalescent plasma therapy (CP) in patients with COVID-19 though both were stopped early and did not appear to show any significant benefit. For this new study, researchers from the Indian Council of Medical Research have undertaken a randomised trial in over 400 patients but the results also suggest that CP is of limited value. The study recruited 464 adult patients (aged 18 and over) with a median age of 52 years (75% male) from 39 public and private hospitals across India who were admitted to hospital with confirmed moderate COVID-19, based on a positive PCR test. Included patients had a partial pressure of oxygen in arterial blood/fraction of inspired oxygen (Pa02/FiO2) ratio between 200mmHg and 300mmHg, or a respiratory rate of more than 24/minute and an oxygen saturation < 93%. Eligible CP donors were required to have had a PCT positive test for COVID-19 and symptom resolution for 28 consecutive days before donation or a 14-day period which included two negative PCR tests collected 24 hours apart.
Patients were randomised to either CP and best standard of care (intervention group) or care lone (the control group) and intervention patients received two doses of 200ml CP transfused 24 hours apart. The primary outcome as a composite of progression to severe disease Pa02/FiO2 ratio < 100mmHg, anytime within 28 days of enrolment or mortality at 28 days.
Progression to severe disease occurred in 19% vs 18% (intervention vs control) and 28 day mortality occurred in 15% vs 14% (intervention vs control) of patients. There was a statistically significant higher proportion of patients receiving CP with a resolution of shortness of breath after 7 days (76% vs 66%) and fatigue (73% vs 60%), there was no difference for fever or cough. In addition, significantly more patients (68% vs 55%) had a negative PCR test at day 7. The authors concluded that as a treatment for COVID-19, CP appeared to be of limited value.
Agarwal A et al. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ 2020;371:m3939.