COVID: convalescent plasma seems to help again

Another study came out suggesting the benefit of convalescent plasma therapy for those with severe COVID-19 (see covid convales plasma helps PNAS2020 in dropbox, or doi.org/10.1073/pnas.2004168117). This one has twice the number of patients as in the last blog on this therapy, having 10 patients from Wuhan China vs 5 from another area of China, though was still not an RCT

Details:

-- 10 severely infected Covid-19 patients in China were enrolled into a trial of convalescent plasma (CP) transfusion

-- patients all had severe clinical Covid infection, almost all had fever, cough, shortness of breath, and 5 had sputum production

    -- median age 53, none exposed to the Huanan Seafood Wholesale Market, median time from onset of symptoms to hospital admission was 6 days

    -- 4 patients had underlying chronic conditions (cardiovascular and/or cerebrovascular diseases, and hypertension)

    -- 9 patients received arbidol monotherapy or in combination with remdesivir, or ribavirin, or peramivir (see the prior blog noted below about these medications). 6 patients received methylprednisolone. Their Table 2 has the specific therapies given per patient (clicking the doi URL above should bring you to the whole article)

-- CT scan for all patients showed bilateral groundglass opacity and/or pulmonary parenchymal consolidation. 7 patients had multiple lobe involvement and 4 had interlobular septal thickening

-- each received one 200 ml dose of convalescent plasma derived from recently recovered donors who had a neutralizing antibody titer>1:640, in addition to routine care

-- primary endpoint was the safety of the transfusion

-- secondary endpoints: improvement in clinical symptoms and laboratory parameters within 3 days after the transfusion

-- median time from onset of illness to transfusion was 16.5 days

Results:

-- prior to transfusion, 7 of the 10 patients had positive SARS-CoV-2 viral loads by PCR, and all had serum neutralizing antibody titers between 1:160 and 1:640. 

-- post transfusion:

    -- the recipients had serum neutralizing antibody titers that were consistently 1:640, and none had PCR evidence of the virus

    -- clinical symptoms (fever, cough, shortness of breath, and chest pain) disappeared or were largely improved within 1 to 3 days, and oxygen saturation increased from 93 to 96%

    -- prior to CP therapy, 3 patients had been on mechanical ventilation, 3 on high-flow oxygen by nasal cannula, and 2 on conventional low-flow oxygen by nasal cannula; after treatment 2 patients were weaned from mechanical ventilation to high-flow oxygen by nasal cannula and one patient discontinued the high-flow oxygen completely. Another patient treated with low-flow oxygen by nasal cannula  shifted to intermittent use

    -- chest CT: all patients had benefit, showing different degrees of absorption of pulmonary lesions after transfusion, within 7 days

    -- lymphocyte counts increased from 0.65X10⁹/L to 0.76X10⁹/L

    -- CRP decreased from 56 to 18 mg/L

-- no severe adverse effects were observed

-- as one specific example, a 46-year-old male admitted 8 days after the onset of an illness had received arbidol and ribavirin, and high-flow oxygen by nasal cannula on admission, mechanical ventilation was initiated 2 days later, then CP transfusion was given the next day; a day after that his SARS-CoV-2 test turned negative, and he had a sharp decrease in the CRP from 65 to 24, and his O₂ sats increased from 86 to 90%. Mechanical ventilation was successfully weaned off 2 days after the transfusion

-- and, comparing these 10 transfused patients to a similar 10 historical non-transfused cases matched by age, gender, and severity of disease:

    -- those with transfusion: 3 cases were discharged, 7 had much improved clinical status and were ready for discharge

    -- historical controls: 3 died, 6 cases stabilized, and one case improved

Commentary:

-- CP therapy has been used for more than a century, more recently in the treatment of SARS, MERS, and the 2009 influenza A H1N1 pandemic, all showing efficacy and safety. There was no improvement with Ebola virus, although it was not clear that there were adequate neutralizing antibodies in the plasma transfused

-- use of CP therapy in MERS found that the neutralizing antibody titer needed to exceed 1:80 for efficacy; of those who recovered from a Covid-19 infection and tested for potential plasma donation, 39  of 40 showed a sufficient neutralizing antibody titer of at least 1:160. so, it seems that those who recover do often do get high enough titers (assuming that the translation from MERS to SARS-CoV-2 is appropriate, which seems to be the case given the improvement in clinical course)

-- the previous study was from a different area of China, with 5 patients having very severe Covid infection, given convalescent plasma transfusion, also with dramatic benefits often within a few days: see http://gmodestmedblogs.blogspot.com/2020/03/covid-using-convalescent-serum-to-treat.html ). Benefit was greatest in those who were less sick at the time of CP therapy

-- in this current Wuhan study, the 3 patients who received CP therapy before 14 days post onset of illness had a rapid increase in lymphocyte counts and decrease in CRP, and more impressive absorption of lung lesions on CT

--adverse effects were minimal, though this was a small study; in other cases with other viruses, there can be transfusion-related acute lung injury, or antibody-dependent infection enhancement that could suppress innate antiviral systems and increase viral growth (esp if sub-neutralizing antibody concentrations, though in this study they required higher neutralizing antibody concentrations for plasma donation)

-- limitations of study: not an RCT, small numbers of patients, combinations of different baseline treatments with the CP therapy (and were there synergies by using the additional specific therapies? hard to determine in this small observational study)

--overall, pretty impressive trial. normally severe pneumonia from Covid-19 is associated with rapid viral replication, massive inflammatory cell infiltration, elevated cytokines, and ARDS. in this study, all patients became SARS-CoV-2 negative, had better oxygenation, and increased lymphocyte counts and decreased inflammation. and clinically improved within a few days

so, adds to the data suggesting possible benefit of convalescent plasma therapy. there are ongoing clinical trials that should really help determine the clinical role of CP therapy. though one small benefit of there being so many Covid-19 cases now, with the considerable majority recovering, is that the pool of convalescent plasma should be plentiful. and it does seem in these small studies that the benefits are more impressive if given earlier than end-stage.

geoff​

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