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| LETTER TO EDITOR |
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| Year : 2020 | Volume
: 36
| Issue : 3 | Page : 419-423 |
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Convalescent plasma therapy in COVID 19: Every dark cloud has a silver lining
Kunal Deokar, Gopal Chawla, Benhur Joel Shadrach, Naveen Dutt
Department of Pulmonary Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| Date of Submission | 26-Aug-2020 |
| Date of Acceptance | 30-Aug-2020 |
| Date of Web Publication | 16-Oct-2020 |
Correspondence Address:
Dr. Gopal Chawla
Department of Pulmonary Medicine, All India Institute of Medical Sciences, Jodhpur, Rajasthan
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/joacp.JOACP_523_20
How to cite this article:
Deokar K, Chawla G, Shadrach BJ, Dutt N. Convalescent plasma therapy in COVID 19: Every dark cloud has a silver lining. J Anaesthesiol Clin Pharmacol 2020;36:419-23 |
How to cite this URL:
Deokar K, Chawla G, Shadrach BJ, Dutt N. Convalescent plasma therapy in COVID 19: Every dark cloud has a silver lining. J Anaesthesiol Clin Pharmacol [serial online] 2020 [cited 2020 Oct 21];36:419-23. Available from: https://www.joacp.org/text.asp?2020/36/3/419/298278 |
Dear Editor,
COVID-19 has been raging havoc throughout the world. There are various treatment modalities which are in fray. Clinicians are implementing a variety of therapeutics measures including retroviral medications such as lopinavir/ritonavir, favirapivir and remdesivir, few repurposed drugs such as hydroxychloroquine, ivermectin, doxycycline and azithromycin. Consideration has also been given to the possibility of using plasma from convalescent donors to treat patients with severe COVID-19 infection where patients who have recovered from infections have variable antibody levels which can be used to treat other critically ill patients. Convalescent plasma has shown promising results in various observational studies and case reports.[1],[2],[3],[4],[5] [Table 1] Ye M, et al.[3] did not mention the dose of CP used in their patients while in other studies, dose ranged from 200 ml single dose to 2400 ml in eight divided doses. The interval between admission and CP transfusion varied widely from 6th day to 39th day. We found fever, cough resolved or decreased within 1 to 3 days of CP transfusion. Radiological improvement was observed in all the patients. Blood inflammatory markers also decreased. Viral load became negative in all the patients. Oxygenation improved and all intubated patients could be extubated. No significant adverse events were observed. Most of the patients (22 of 27) received steroids and antivirals in addition to CP transfusion. While Li and colleagues[6] have reported a first randomised controlled trial (RCT) of convalescent plasma (CP) in patients with severe to life threatening COVID-19 which was a well conducted, randomised, open label, multicentre, placebo-controlled trial. Of the 103 patients randomised, 52 received convalescent plasma and standard therapy while 51 received standard therapy alone. They used plasma units with high antibody titres to SARS-CoV-2. The primary outcome was time to clinical improvement within 28 days, defined as patient discharged alive or reduction of 2 points on a 6-point disease severity scale. There was no significant difference in the primary outcome between CP arm and standard therapy arm. However, the study was terminated prematurely (estimated sample size was 100 in each group) as the pandemic subsided in China making it underpowered. But the findings of subgroup analysis based on the severity of disease in which CP therapy seemed to be of benefit in patients with severe disease. However, because the test for interaction by disease severity was not statistically significant, the findings for the severe and life-threatening subgroups should not be interpreted as different. These analyses are needed to be interpreted with caution especially when the trial is underpowered even for its primary outcome.[7] As it was underpowered trial, if statistical significance is not seen then it means that the findings are inconclusive. Thus, no conclusion can be drawn from this trial regarding the efficacy of convalescent plasma in patients with severe and life threatening COVID-19.
It is known that an antibody therapy works best when given early in the course of the disease as it works as neutralizing agent against coronavirus.[8] Most of the patients in the trial received CP fourteen days after symptom onset and were already in cytokine storm as suggested by elevated IL-6 levels in most of the patients. As a result, though CP therapy was associated with a significantly higher rate of negative SARS-CoV-2 viral PCR, it did not have any effect on time to clinical improvement. This suggests that though CP was successful in neutralizing the virus, the cascade of cytokine storm which had already started was probably responsible for poor clinical outcome. Earlier administration in severe disease could probably have given better results. This is also suggested from the fact that patient with severe disease responded better than those with life threatening disease. Also, the role of combined therapy with convalescent plasma and tocilizumab which will target both viral replication and cytokine storm need to be explored. In resource limited settings, where IL-6 levels are not available, incorporation of clinical parameters like fever, hypotension, decreased capillary filling time along with bedside lung ultrasound to identify non-cardiogenic pulmonary edema (light beam sign, multiple focal or diffuse B-lines, irregular or fragmented pleura, vertical subpleural pattern on M-mode) may be helpful to identify patients in cytokine storm.[9],[10] It is recommended that neutralising antibody (NAbs) titres should be greater than 1:320, but lower thresholds could also be effective. Plasma is usually released for transfusion without testing titres in emergency situations and most centres. Ones with high levels of antibody can donate plasma every two weeks as long as the titres remain adequate. ABO compatibility plasma between donors and recipients is of paramount. Transfusion of plasma from at least two donors may be more favourable to achieve more effective immune protection from delivery of diverse antibodies. Usually initial transfusion of 200 mL, followed by one or two additional transfusions of 200 mL according to disease severity and tolerance to the infusions. Although CP is likely to have potential benefits and low risks, the complications of CP like allergic transfusion reactions, transfusion-associated circulatory overload (TACO), and transfusion-related acute lung injury (TRALI) are not likely to be different from standard transfusions. While the risk of TRALI is minimal, it is very relevant in severe COVID-19 infections where there is already potential priming of the pulmonary endothelium. Risk factors for TACO like cardiorespiratory disease, advanced age, renal impairment is shared by those at risk of severe COVID-19, highlighting the need of diligent fluid volume management.[11] Thus, though the results of the various studies were variable, but it has raised a signal that convalescent therapy helps in reducing viral load and may be of benefit if administered early in patients with severe disease. Till we do not have any better drugs or a vaccine for novel coronavirus the option of convalescent plasma is good one which seems to boost the immune system of infected patients immediately and help in tiding over acute crisis. Initial published literature has shown a favourable effect of CP therapy in patients with COVID-19 and till the results of other well performed clinical trials are available it can be considered as a valuable option in spectrum of therapeutics of COVID 19.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | |  |
| 1. | Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020;117:9490-6.  |
| 2. | |
| 3. | Shen C, Wang Z, Zhao F, Yang Y, Li J, Yuan J, et al. Treatment of 5 critically ill patients with COVID-19 with convalescent plasma. JAMA 2020;323:1582-9. |
| 4. | Duan K, Liu B, Li C, Zhang H, Yu T, Qu J, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A 2020;117:9490-6. |
| 5. | Ye M, Fu D, Ren Y, Wang F, Wang D, Zhang F, et al. Treatment with convalescent plasma for COVID-19 patients in Wuhan, China. J Med Virol 2020; 10.1002/jmv. 25882. doi: 10.1002/jmv.25882. Online ahead of print. |
| 6. | Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. JAMA 2020;324:1-11. |
| 7. | Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis) uses of baseline data in clinical trials. Lancet 2000;355:1064-9. |
| 8. | Casadevall A, Dadachova E, Pirofski L. Passive antibody therapy for infectious diseases. Nat Rev Microbiol 2004;2:695-703. |
| 9. | Volpicelli G, Gargani L. Sonographic signs and patterns of COVID-19 pneumonia. Ultrasound J 2020;12:22. |
| 10. | Volpicelli G, Lamorte A, Villén T. What's new in lung ultrasound during the COVID-19 pandemic. Intensive Care Med 2020;46:1445-8. |
| 11. | Casadevall A, Pirofski LA. The convalescent sera option for containing COVID-19. J Clin Invest 2020;130:1545-8. |
[Table 1]
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