COVID: convalescent plasma not help

 A randomized controlled trial in India found that convalescent plasma did not help adults with moderate Covid-19 infections, the PLACID Trial (see covid convales plasma not help bmj2020 in dropbox, or dx.doi.org/10.1136/bmj.m3939) 

 

Details:

--464 adults admitted to one of 39 public and private hospitals across India from April till July, all with PCR=confirmed moderate Covid-19 infection (PaO₂/FiO₂ of 200-300 mmHg or respiratory rate of > 24 per minute with oxygen saturation 93% or less on room air)

-- all received the standard of care, though 235 of them also received convalescent plasma

    -- those receiving convalescent plasma received 200 mL transfused 24 hours apart, for total of 2 doses

    -- the presence and levels of neutralizing antibodies were not measured beforehand, but were at the end of the study

-- 94% of the donors were men, mean age 34, median disease duration was 6 days, and most had mild disease. Recovered patients who had moderate or severe disease were generally reluctant to return to the hospitals for plasma donation

-- Main outcome: the composite of progression to severe disease (PaO₂/FiO₂ <100 mmHg), or all-cause mortality at 28 days

 

Results:

-- progression to severe disease or all-cause mortality: 44 (19%) in the intervention arm vs 41 (18%) in the control arm, nonsignificant difference

-- neutralizing antibody titers: 64% of the donors had a neutralizing antibody titer of >1:20, with a median titer of 1:40; plasma was donated after median of 41 days (31-51) from PCR-confirmed diagnosis of Covid-19

-- the neutralizing antibody titer in both groups was the same at baseline and increased similarly from day 0 to day 3 to day 7, despite the transfusion of convalescent plasma in the intervention arm

-- a higher proportion of patients in the intervention arm had resolution of shortness of breath and fatigue by day 7, though fever and cough did not differ

-- SARS-CoV-2 RNA converted to negative at day 7 more often in the intervention arm (but not at day 3)

-- no difference in duration of respiratory support, proportion receiving invasive ventilation, proportion receiving vasopressors, average fraction of inspired oxygen over 14 days of hospital stay, and the average levels of inflammatory markers (LDH, ferritin, CRP, d-dimer) were no different over a period of 7 days from enrollment. And, the WHO ordinals scale scores for clinical improvement did not differ

-- adverse events associated with transfusion included pain at the infusion site, chills, nausea, bradycardia, and dizziness. Fever and tachycardia were found in 3 patients, dyspnea and blockage of an IV catheter in 2 patients

-- No difference between those who had neutralizing antibody titers of 1:80 or higher vs those receiving the standard care alone 

 

Commentary:

-- this study suggests that there is no benefit for convalescent plasma collected from young survivors of mild Covid-19 infection and administered to elderly patients with moderate to severe disease

    -- there was no effect on inflammatory markers, likely related to the finding of no clinical benefit

--one issue is what is the appropriate neutralizing antibody titer for a potentially effective transfusion?

    -- An early Chinese study of 5 people found that in those with titers of 1:40 to 1:60, titers increased to 1:80 to 1:320 after plasma transfusion, and there appeared to be clinical benefit from the transfusion. but, really small study. http://gmodestmedblogs.blogspot.com/2020/03/covid-using-convalescent-serum-to-treat.html

    -- Also, small studies of influenza A(H1N1) in the 2009 pandemic and another on SARS did find mortality benefits from transfusions (studies cited in this http://gmodestmedblogs.blogspot.com/2020/03/covid-using-convalescent-serum-to-treat.html)

-- But, this PLACID study's results were consistent with 20 prior ones finding that the effectiveness of convalescent plasma in improving mortality or clinical improvement is uncertain, including trials in China, and the Netherlands

-- It is unclear to my reading what the optimal neutralizing antibody titer needs to be to be effective. A study of 101 healthcare providers who were infected in New York City found that 75% had low neutralizing antibody response (titer 1:10 to 1:80), 20% had intermediate neutralization response (titer 1:81 to 1:639), and only about 5% had a high neutralization response (>1:640), all analyzed from 32-57 days after infection. See https://www.biorxiv.org/content/10.1101/2020.08.15.252353v1.full.pdf .  So, not so easy to get high titer neutralizing antibodies to transfuse from those previously infected.

 

Neutralizing antibodies issues:

    --neutralizing antibodies are a subset of the antibody response that bind to the surface epitopes of viral particles and block viral entry into a cell. And these antibodies may play a part in viral destruction through activation of complement, etc (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098029/ )

    --there is less of a bump in these antibodies in patients with mild Covid-19 illness, sometimes not measurable at all

    --their level decreases over time, so measurement of level is time-dependent (which does not necessarily mean they lose effectiveness, since there might be an anamnestic response to re-exposure to SARS-CoV2).

        --The sample in the PLACID trial above involved neutralizing antibodies that were harvested 1-2 months after infection. However, there was no difference in the neutralizing antibody titers whether patients received the transfusion or not.

    --in this study, the level of neutralizing antibodies in the beginning was the same between those to be given transfusion and those in control group

        --and there was no more of a bump in those receiving the transfusion

       --so, it seems that adding more neutralizing antibody does not seem to add much in terms of their titers, or the clinical effectiveness

-- also, there can be neutralizing antibodies in vitro that actually do not protect people in vivo. 

    --In fact, neutralizing antibodies could potentially lead to an increased proinflammatory response and more lung injury (there was suggestive data for this with SARS)

-- And, as a perspective, neutralizing antibodies are one of several immunologic responses, so even low or absent neutralizing antibodies does NOT mean that there is no effective immune response

 Limitations of the study:

--this trial was not limited to major medical centers: so the plus is that their results are more generalizable, the minus is that the “best standard of care” may not reflect the optimal, cutting-edge care

--this was an open-label study, so the doctors may have been biased in their assessment of outcomes. For example, there was discordance between the subjective patient benefit (less shortness of breath or fatigue with transfusion) vs the objective responses (no difference in primary outcomes or fever or cough or the biomarkers measured). ?bias of the clinicians in ascertaining this information

--they were unable to measure the neutralizing antibody titers prior to transfusion because there was insufficient access to rapid, reliable tests at the start of the study. (though this might reflect the reality in much of the world currently)

--and they had trouble recruiting patients who had been very sick with Covid-19, more likely to have higher neutralizing antibody titers (people were unwilling to come back to the hospital to donate their plasma, after their likely horrendous hospital experience when they were sick). Not sure if this would be true in other countries, but I would not be surprised

--their baseline neutralizing antibody titers from the donors were low; some very small studies finding benefit for plasma transfusion used a minimum cutpoint of a titer >1:640 in order to harvest/transfuse their plasma(eg, see http://gmodestmedblogs.blogspot.com/2020/04/covid-convalescent-plasma-seems-to-help.html ). And, per the New York health care worker study mentioned above, that titer only occurred in 5% of infected people...

so, yet another disappointing Covid-19 therapy study about what seemed like a promising candidate treatment. this one for convalescent plasma transfusion therapy for those with severe Covid-19 infections. Unfortunately, we will likely need more effective therapies as we come into the current huge upsurge in the virus. And, as predicted by pretty much all of the non-Trumpian epidemiologists/researchers/scientists/hobbits/orcs/etc, we are likely to relive the horrible past of insufficient medical protective and therapeutic equipment, and overwhelmed hospital/ICU beds.

And this negative study further reinforces the imperative for prevention: masks/distancing/etc do work and should be reinforced... (see http://gmodestmedblogs.blogspot.com/2020/10/covid-mostly-asymptomatic-or.html )

other countries with resurgent cases but very aggressive testing and isolation mandates have been very successful (see http://gmodestmedblogs.blogspot.com/2020/09/covid-second-wave-in-china-aggressively.html )

and, David Leonhardt had a poignant editorial today suggesting that the current surge of the virus has been handled well by Canada and Germany: see https://www.nytimes.com/2020/10/29/briefing/lockdown-france-miles-taylor-early-voting.html

geoff

 

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