COVID: using convalescent serum to treat patients

An intriguing Chinese study suggested benefit by infusing convalescent plasma from a prior infected Covid-19 patient into 5 critically ill patients (see covid Rx convalescent serum jama2020 in dropbox or doi:10.1001/jama.2020.4783).

Details:

-- 5 critically ill patients with laboratory confirmed Covid-19, ARDS, severe pneumonia with rapid progression, and continuously high viral load despite antiviral treatment; PaO₂/FIO₂ <300; and on mechanical ventilation

-- all were treated with convalescent plasma transfusion from donors who recovered from Covid-19 infection, were subsequently negative for SARS-CoV-2, and had serum SARS-CoV-2 specific ELISA antibody titer >1:1000 and a neutralizing antibody titer >40

Cases:

--1: 70+ yo male admitted 2 days after symptom onset, with no coexisting chronic diseases, in critical condition with bacterial pneumonia, severe ARDS, multi-organ dysfunction syndrome. On methylprednisolone and lopinavir/ritonavir (LPV/r), interferon alfa-1b, and favipiravir (a broad-spectrum inhibitor of viral RNA).  plasma transfusion given on day 22 after admission

--2: 60+ yo male admitted 4 days after symptom onset, with hypertension and mitral insufficiency, in critical condition with bacterial pneumonia, fungal pneumonia, severe ARDS, myocardial damage. On methylprednisolone, LPV/r, arbidol (there is some evidence that adding arbidol, a broad-spectrum antiviral that blocks viral fusion, to LPV/r works better than LPV/r alone: see https://www.ncbi.nlm.nih.gov/pubmed/32171872) as well as darunavir. plasma transfusion 10 days after admission

3. 50+ yo woman, admitted 2 days after symptoms, with no coexisting medical disease, in critical condition with severe ARDS. On methylprednisolone, LPV/r and interferon alfa-1b. Plasma transfusion 20 days after admission

4. 30+ yo female admitted 2 days after symptoms, with no coexisting chronic disease,  in critical condition with severe ARDS. On methylprednisolone, interferon alfa-1b, and favipiravir. plasma transfusion 19 days after admission

5. 60+ yo male admitted 3 days after symptoms, with no coexisting symptoms, in critical condition with severe ARDS. on methylprednisolone, LPV/r and interferon alfa-1b. Given plasma transfusion 20 days after admission

-- all patients had detectable SARS-CoV-2 after their antiviral treatment (at least 10 days) and before their plasma transfusion

Results:

-- body temperature normalized within 3 days in 4 of the 5 patients

-- Sequential Organ Failure Assessment (SOFA) score decreased in the 1^st 2 cases above (the sickest two) 7 days post-transfusion, and the others had low scores to begin with

-- pulmonary CT showed improvement in the pulmonary lesions on the 3^rd day in patient one and more gradual resolution at 3 days in the others

-- PaO₂/FIO₂ increased within 12 days for the sickest 2 patients, within 7 days in the others

-- viral loads decreased and became negative within 12 days, and within 1 to 3 days in the last 3 patients

-- SARS-CoV-2-specific ELISA and neutralizing antibody titers increased following the transfusion (from 40-60 to 80-320) on day 7

-- IgG and IgM titers increased at 3 days after transfusion and maintained high levels for 7 days  

-- ARDS resolved in 4 patients at 12 days after transfusion

-- 3 patients were weaned from mechanical ventilation within 2 weeks

-- 3 patients were discharged from the hospital with lengths of stay of 53, 51, and 55 days; 2 were in stable condition at 37 days after transfusion

Commentary:

-- there has been some benefit from infusing convalescent plasmas for other infections, most recently in those with SARS, influenza A(H1N1), and Ebola. for example:

    -- in the 2009 pandemic of influenza A(H1N1), a prospective cohort study including 20 of 93 patients with severe infection requiring ICU care, were given convalescent plasma with a neutralizing antibody. there were significantly fewer deaths (20% vs 55%), p=0.01, as well as lower median lymphocyte count on ICU admission. This treatment was associated with significantly lower 3, 5, and 7 day viral loads compared with the control group, as well as lower interleukin 6, interleukin 10, and TNF-alpha levels (see https://www.ncbi.nlm.nih.gov/pubmed/21248066)

     -- 48 patients with SARS given convalescent plasma transfusion <14 days after symptom onset were more likely to be discharged within 22 days of admission (58% vs 16%, p<0.001), and a systematic review/meta-analysis found that administering convalescent plasma and hyperimmune immunoglobulin lowered case fatality rate by 75%, OR 0.25 (0.14-0.45), see covid convales plasma for other viruses JInfDz2015 in dropbox, doi: 10.1093/infdis/jiu396, or, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264590/#!po=30.5556 . Notably, there were no RCTs, only case reports and some cohort studies

-- it is likely that the virus-specific neutralizing antibodies lead to accelerated viral clearance/decreased entry into target cells, and that this was the main mechanism for the restriction and clearance of the viruses by the host; it is notable that these antibody  levels increased significantly after the transfusion

-- as noted in this and several other studies, treatment of the complications of Covid-19 requires long hospitalizations, which adds to the stress on the people working there and the hospital system, as we are bombarded with increasing numbers of new patients. In the above study,  these five patients were in the hospital at least 2 months after they received plasma transfusion, which was about 15 days after admission, and then only 3 were discharged

    -- this situation has led to talk about a potential future where we may need to limit resources for some patients (see https://www.bostonglobe.com/2020/03/30/opinion/message-public-mass-doctors-nurses-ethicists-about-coronavirus/ ). 

    -- it is extraordinarily unfortunate that our government/Trump disbanded the National Security Council pandemic unit in 2018, and also imposed budget cuts for the CDC and public health initiatives (see https://apnews.com/ce014d94b64e98b7203b873e56f80e9a ), so we had no preparation (PPEs, respirators, adequate hospital and ICU beds, etc) to deal with the long-anticipated and continuing emergence of new, aggressive, and untreatable microorganisms

Limitations of the study include: it was a small case study and it is possible that these patients might have improved without the transfusion (though it was striking that they all had long hospitalizations yet improved in a similar timeframe after having the plasma transfusion, suggesting that the transfusion was indeed effective). Also, these patients were quite ill at the time of the transfusion, so it is hard to extrapolate the conclusions to patients who were less sick or got these transfusion transfusions sooner  after their deterioration

So, an intriguing study. 

-- and, there are many, many people who do well with the infection and likely have enough neutralizing antibodies to donate. 

-- If a larger RCT found that this therapy works, there might be much more profound and rapid response if given to patients with less severe but progressing  symptoms (as apparently found in the above SARS study). until a better treatment or vaccine come along...

geoff​

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