Convalescent Plasma Use in the United States was inversely correlated with COVID-19 Mortality: Did Convalescent Plasma Hesitancy cost lives?
Summary (2 min read)
Introduction
- In the Spring of 2020, the United States embarked on a historic and unprecedented deployment of plasma derived from patients who survived COVID-19 (COVID-19 Convalescent Plasma (CCP)) for treatment of the disease, and one-year into this effort more than 500,000 individuals have been treated.
- The demonstration by the summer of 2020 that CCP was safe 3,4, that antibody in plasma correlated with survival in people treated before ventilation 5 along with initial suggestions of efficacy 6-8, fueled interest in and use of this product.
- The interpretation of the potential efficacy of CCP is complex as many of the positive findings arose through post hoc examinations and subgroup comparisons.
- Later in the pandemic several larger RCTs reported no mortality benefit 10-12, raising doubts as to CCP efficacy.
- On March 13, 2021 the New York Times reported that COVID-19 mortality remained high with nearly 1,500 daily deaths despite a drop in the number of new infections since earlier in the year 18.
Materials and Methods
- CCP usage was inferred from the distribution of plasma units to hospitals in the USA from data obtained from Blood Centers of America (BCA, West Warwick, RI).
- Units transfused in the EAP were reported by providers as part of the official case report forms and each transfusion could comprise one or two units.
- For the analysis, which was based on weekly aggregated data, a two-week shift was selected to align the mortality with the median and upper quartile estimates in these reports.
- In scenario 2 a constant 50% CCP utilization ratio was set over the entire study period.
- A final scenario estimated the CFR that may have been observed had CCP not been used at all (i.e., the y-intercept from the model).
Results
- The FDA first allowed compassionate use of CCP on a case-by-case basis in late March 2020, but very quickly initiated the Expanded Access Program in early April 2020.
- The comparison of curves showed a trough in deaths per admission coinciding with the peak of CCP usage per admission.
- A comparison of this number with that from USA studies shows reasonable agreement between with the average mortality of 23.5% in patients not receiving CCP (Table S3).
- Nevertheless, it is possible to use these efficacy numbers to estimate what the effect on deaths would have been had the United States continued to use CCP at the height of its usage in early Fall 2020, when more than 40% of all patients received plasma therapy.
- The two-week lagged mortality ratio for hospitalized patients was 18.16%.
Discussion
- The use of CCP in hospitalized patients peaked from mid-September to the end of October 2020 shortly after the FDA allowed its widespread use under the EUA of August 23, 2020.
- Of concern, the drop in per capita CCP utilization appeared to be associated with an increase in mortality among hospitalized COVID-19 patients.
- Convalescent plasma has proven effective in individuals with defective humoral immunity and B cell defects 30,31.
- Patients treated with CCP manifest reduced inflammatory markers 35-37 that can lead to host damage.
- This inference is strengthened by the fact that mortality from COVID-19 among hospitalized patients decreased substantially over most of 2020, consistent with worldwide trends 19, but then began to rise in late November and early December 2020, a period that coincided with precipitous reduction in CCP/admission.
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Frequently Asked Questions (13)
Q2. How was the mortality adjusted for the time lag between admission and death?
Since the overwhelming majority of COVID-19 deaths occur in hospitals 20,21, since CCP is only authorized for use in hospitals, and since death generally occurs a few days to weeks after admission, mortality was adjusted for the time lag between admission and death.
Q3. What was the reason for the rapid rise in use of CCP?
the use of CCP rose rapidly without the ideal evidence base of efficacy from randomized controlled clinical trials (RCT), since early RCTs though generally trending positively, were unsatisfactory, mostly due to small size or premature termination as the epidemic abated in the early surge regions 9.
Q4. How many deaths would be expected to be caused by CCP?
Had the rate of CCP utilization observed during August through October 2002 carried over for the remaining months, the expected number of deaths was 327,516 (95%: CI: 293,811 to 361,221), which would result in 29,018 (95% CI: 3535 to 54,501) fewer deaths than observed.
Q5. How did the FDA reaffirm the EUA status of CCP?
The authors note that the FDA reaffirmed the EUA status of CCP in February 2021 2 by permitting its continued use in hospitalized patients if used early in COVID-19 and with units that have a sufficient content of specific antibody.
Q6. What is the effect of CCP on patients with COVID-19?
In addition, interim guidelines for American Association of Blood Banks 48 and Brazil 49 emphasize that CCP is more likely to be effective when used in early COVID-19 with units having high content of specific antibody.
Q7. What was the reason for the decision to stop offering CCP?
A poll by the American Association of Blood Banks revealed a 50% increase in the number of institutions planning to stop offering CCP between February and March 2021, which cited lack of stronger efficacy data as the major reason for this decision 28.
Q8. What is the definition of a hesitancy?
In this regard, the authors note that both the vaccines being administered in the USA and CCP are being used under a EUA regulatory framework, since neither has full approval status and that these hesitancies lead to avoidance behaviors based on the interpretation of available data by the public and health care providers, respectively.
Q9. What was the EAP's effect on the distribution of CCP to hospitals?
Distribution of CCP to hospitals rose to 25,000 - 30,000 weekly units by the December 2020 to January 2021 time period, but this rise in plasma distribution largely reflected the great increase in hospital admissions for COVID in those months.
Q10. How many cases of SARS-CoV-2 were reported in the United States?
This variant was identified in the United States in early winter 2021 but as of January only 76 cases had been described in 12 states, which was estimated to be <0.5% of the infections at the time 42.
Q11. What was the first time the FDA allowed compassionate use of CCP?
The FDA first allowed compassionate use of CCP on a case-by-case basis in late March 2020, but very quickly initiated the Expanded Access Program in early April 2020.
Q12. How long did the CDC estimate that the increased mortality from SARS-CoV-2 would?
Even as late as mid-March 2021 the CDC estimated that B.1.1.17 variant comprised only 25% of US isolates and increased mortality from these infections would not manifest itself until times later than their analysis 43.
Q13. How many deaths would be expected to be caused by CCP in the United States?
it is possible to use these efficacy numbers to estimate what the effect on deaths would have been had the United States continued to use CCP at the height of its usage in early Fall 2020, when more than 40% of all patients received plasma therapy.