Early high-titer convalescent plasma prevents 75% of extreme COVID-19 in aged

The ongoing COVID-19 pandemic has caused over 1.39 million deaths worldwide. Many of these deaths have occurred among the elderly, experiencing disproportionate rates of severe illness, hospitalization, and death, especially if they have chronic underlying diseases such as diabetes, hypertension, and kidney disease.

A promising new clinical study published on the preprint server medRxiv* reports that if convalescent plasma with a high titer of antibodies is given early in the course of COVID-19 in elderly patients, the risk of severe illness is reduced by 73%. This could promote the use of this safe, cost-effective prophylactic intervention to prevent hospital overwhelm and save lives in multiple ways.

Few effective drugs have been approved so far against COVID-19. Among those therapies which show some promise is the use of convalescent plasma (CP), which makes use of serum obtained from the blood of individuals who have had SARS-CoV-2 infection, typically in a mild form, and have recovered. Their blood is therefore deemed to be rich in antibodies specifically targeting the virus, preventing its entry into and infection of host cells.

CP has been used earlier to treat a number of diseases, but much depends on the timing of administration and the titer of specific antibodies. Several earlier studies have failed to show convincing evidence of clinical benefit in COVID-19 patients.

Several early studies cast doubt on the role of convalescent plasma (CP) in COVID-19. However, this could well have been due to the late administration of this modality. The current study aimed at testing the ability of CP to prevent the progression of COVID-19 to severe disease if given in the first 72 hours after the onset of symptoms.

The researchers conducted a randomized double-blinded controlled trial between June 4 and October 25, 2020, using CP with a high titer of anti-SARS-CoV-2 antibodies in elderly patients within this period after the development of mild symptoms. Their objective was to assess the reduction in severe respiratory disease, as defined by a respiratory rate ≥30 or an oxygen saturation below 93% in room air.

While the original intention was to study 210 patients, there was a steep climb in the number of severe cases in late July, which drained both doctors and hospital capacity from the trial. Coupled with a dramatic fall in the number of patients available for screening towards the latter part of the study, this meant that the original target would have been challenging to meet without unduly prolonging the study period. Thus, the study was prematurely terminated to analyze the data obtained so far.

The study group eventually included 160 patients, all 75 years old or more, or between 65 and 74 years but with one or more comorbid conditions. The mean age was 77 years, and ~63% were female.

All had one symptom at least from each of two categories, for at least 48 hours, when tested for the virus by reverse transcriptase-polymerase chain reaction (RT PCR).

The first category included nonspecific symptoms like fever, sweating and chills, while the second included more suspicious symptoms such as tiredness, shortness of breath, dry cough, sore throat, alterations of taste or smell, and muscle pain. None of the patients had pre-existing severe respiratory disease.

Once diagnosed, the patients were hospitalized and randomly assigned to receive CP with anti-SARS-CoV-2 spike IgG titers of over 1:1,000 or placebo over 1.5 to 2 hours. Thus, 80 received plasma and 80 a placebo. The minimum clinically significant reduction in risk of severe respiratory distress was set at 40%, which meant that the expected risk of 50% in the control group would have to be reduced to 30% in the intervention group for the CP infusion to be seen as effective.

The researchers found that only ~16% of the plasma recipient group had progressive disease vs. ~31% of the placebo group. Thus, the early use of CP reduced the risk by 48%. The time to development of severe disease in the CP group was delayed relative to the control group. In the age group above 75 years, the relative risk was reduced by 65%.

However, when 6 of the participants who developed severe respiratory distress after being randomized but before receiving the CP were excluded from the analysis, the reduction of the risk of severe outcomes in the remaining members of the group was even higher, at 60%, confirming the efficacy of this intervention.

The investigators also found a dose-dependent response to the CP, with the dividing line being at 1:3,200 (the median IgG titer). If the CP that was used contained IgG at high doses above this titer, it produced better responses, reducing the risk of severe outcomes by 73%. For every one patient who recovered without developing severe disease, four patients would have to be infused.

The scientists suggest that fostering local donations from a community drive, and selecting super-donors with IgG titers above 1:12,800, could help each donor to provide CP for over 20 sick patients, each with just 750 mL of donated blood. Repeated donations could be made since IgG levels have been shown to remain high for months. Most of the high-titer CP donors in this study had a history of COVID-19 illness requiring hospitalization.

The researchers comment, “Enhancing early symptom awareness in seniors will be vital, now that there is a time-limited effective intervention available. Plasma against COVID-19 is conceptually like health insurance. It should be in-hand when it intuitively seems unnecessary.”

This intervention is simple and cheap, but can be life-saving in the majority of high-risk cases. This would reduce mortality due to COVID-19 while simultaneously preventing healthcare overwhelm, allowing some measure of control until other effective drugs or a vaccine becomes widely available.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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