To date, COVID-19 influenza is still rapidly spreading worldwide. Clinical data from China have shown that the severe COVID-19 rate can be as high as 41.1%~48.3% in the early stage of the epidemic [15, 16]. Due to the rapid progression with high mortality in severe COVID-19 patients, effective treatment is urgently needed to control the deterioration of the disease. However, there are no current proven antiviral drugs that could effectively treat the novel virus [17, 18]. A multicenter trial showed that plasma therapy could accelerate the rate of viral negative conversion and clinical recovery in COVID-19 patients, shorten the length of hospital stay, and reduce the risk of death by 35% . Ibrahim et al. reported that early application of plasma therapy was helpful to accelerate clinical recovery and reduce mortality . In a large retrospective case-control study, Xia et al. also showed that CP therapy improved clinical symptoms, reduced ICU admission risk, and reduced mortality (the death risk was reduced by 50%) . Previous studies have also shown that early application of plasma to severe patients was more effective, while the overall benefit of CP in extremely critical patients, such as tracheal intubation or life-threatening conditions, was not significant [7, 12, 19, 20]. The three cases in our study were severely elderly patients with basic diseases such as diabetes and high blood pressure but without endotracheal intubation. After admission, the condition of these patients progressed rapidly, and there was a high risk of developing critical illness. Then, CP was administered based on conventional treatment. After the combined therapy, the symptoms were alleviated rapidly, the lung lesions were significantly absorpted, the inflammatory indexes were decreased, and the oxygenation function and cellular immune function were improved. The remarkable improvement of these patients suggests that plasma treatment is an effective remedy for severe COVID-19 patients. Hegerova et al. reported that patients who received CP within one week after admission had a significantly reduced risk of death within 14 days (mortality was 0) . The CP treatment time of all patients in our study was within one week after admission (within 10 days after onset), which was significantly earlier than the time reported by Xia et al. (the median time from onset to CP was 45 days) . Significant improvement was achieved within 72 hours of CP treatment in our research, suggesting that early active CP therapy in severe COVID-19 patients becomes even more effective.
Notably, although the three patients improved significantly after CP, one of them (Case 3) remained positive for SARS-CoV-2 RNA for more than one month (33 days). At the beginning of the disease, the lymphocyte counts in the three patients all decreased, and the number of lymphocytes gradually increased after CP, which was consistent with a previous report . However, the lymphocyte counts in one patient (Case 3) were still lower than the normal standards 30 days after CP, whereas the other two patients (Case 1, Case 2) all returned to normal. The prolonged viral removal in Case 3 was considered to be associated with a prolonged period of immunodeficiency. Additionally, the donor plasma antibody titer results showed that the titer in Case 1 was the highest (≥ 1:160), and the titers in the other two patients (Case 2, Case 3) were ≥ 1:80, but the antibody titer in Case 3 was only weakly positive at 1:80. This suggested that this patient (Case 3) received the lowest antibody level of CP in these three patients, which may reduce the plasma efficacy .
Additionally, only one patient (Case 2) had a mild allergic reaction with erythema and pruritus at the early period of transfusion, but no other serious adverse reactions were found in the follow-up. As previously described in our paper, the blood type of this patient (Case 2) was type A and negative RhD, which is a rare Rh blood type. She later received CP with blood type A and positive RhD, suggesting that the allergic reaction in this patient might be related to treatment with incomplete Rh-compatible plasma, but other serious adverse reactions, such as acutehemolytic transfusion reaction and shock response, were not found. Generally, plasma treatment in our study was safe and reliable, consistent with the literature reports [19, 21].
Notably, there are some limitations in our research. First, this study was only performed with 3 patients without solid controls (directly compared to patients with CP and without CP treatment). Second, the patients were also given other medications (including antiviral drugs, antibiotics, anti-inflammatory agents, immunostimulants and Chinese herbal medicine)/treatment. Hence, this does serve as one of the confounding factors. It could be that these factors might play an important role in recovery as well in synergy with CP treatment. However, there were no proven effective antiviral drugs or other traditional therapies in our study for controlling the novel virus. Combined CP therapy was initiated after the condition worsened with conventional treatment. Additionally, as mentioned previously, patients who received CP earlier can have more favorable clinical outcomes . The CP remedy in our study was utilized in the early disease course. Moreover, the first curative effect evaluation was assessed in a short time after CP transfusion (within 48 to 72 hours), and the findings that showed obvious improvement with clinical symptoms, radiological images and laboratory tests were encouraging. As a result, we think the marked efficiency should be mainly attributed to additional CP treatment.
In summary, the early application of CP for severe COVID-19 patients can improve the condition rapidly, and the therapy is generally effective and safe. This therapy can reduce the COVID-19 progression risk from severe to critical, lower the mortality rate , and is helpful to raise the rescue success rate of severe patients. Due to the absence of effective anti-SARS-CoV-2 drugs, CP therapy is an alternative adjuvant method to treat severe COVID-19 patients .