3.10 Adverse effects
Most of the patients experienced very few adverse effects. The incidence of adverse effects and mortality rate were < 1 % and 0.3%, respectively, as stated by Joyner et al. Transfusion-associated circulatory overload (TACO) (n = 7), transfusion-related lung injury (TRALI) (n = 11) , and severe allergic reactions (n = 3) were reported.24 This is the largest study done and was focused especially on the safety of CP therapy. Besides, a study done by Pei et al. showed anaphylaxis as a severe side effect of CP therapy, but the number of study subjects was small.26 Some abnormal skin reactions like red spots or morbilliform rash have been explained in only one patient each in the study done by Duan and Salazar et al.14,23 Fever was seen in a study done by Tan et al following CP therapy.25
Table 1:Studies on CP therapy for COVID-19 treatment
Currently, 75 clinical trials are being done all around the world28(Supplementary data 3 – Clinical trials/ Table 2 ). With most of the 30 trials in the US, followed by other trials in Colombia-5 trials, Mexico-5 trials, Italy- 4 trials, and Egypt-3 trials. Switzerland, Chile, France, Canada, Sweden, Spain, and India are conducting 2 trials each. While countries like North Macedonia, Russian Federation, Saudi Arabia, Pakistan, Netherlands, Bahrain, China, Hungary, Indonesia, Argentina, Iran, and Denmark are also conducting 1 trial each. No location is being provided in the case of 2 trials. A total of 40 trials are recruiting participants while 24 trials have not yet begun recruiting. There are 2 active and not recruiting trials, 3 trials are enrolled by invitation, and 6 trials are in available status. A total of 2 trials are observational and 6 available trials are of expanded excess type, while the rest of the trials are RCTs. The smallest trial enrollment is 10 while the largest trial enrollment is 2000.28
DISCUSSION
The review was primarily done to focus on the therapeutic efficacy and safety of CP therapy among COVID 19 patients. For this purpose, we included 12 different studies ranging from case series, case reports, case trials, observational cohort study, retrospective study, and single-arm intervention study.
Only one CT has been done so far, which has primarily focused on the early safety of CP therapy.24 Based on the trial, there has been preliminary evidence of CP therapy being a safe treatment with < 1 % mortality. Due to the lack of studies focusing on the therapeutic efficacy of CP therapy alone, a query remains to comprehend whether the results of the studies were due to natural disease progression, CP therapy, or other concomitant treatments. Major outcomes are discussed below:
Mortality following CP therapy
There were a total of 622 mortalities out of 5079 patients across the 12 studies. The majority of mortalities were found in the clinical trials with a total of 602 mortalities in Joyner’s study, but this trial is in the early phase and more reporting is still to be done as only 5000/8932 trial reports are mentioned in this study.24 Zeng’s study has 19 mortalities out of 21 patients which can be considered high, but CP therapy was given at a median of 21.5 days after infection, and there is theoretical evidence that such therapy is only most effective when given early in the disease course.22Salazar’s study had just 1 mortality out of 25 patients as CP therapy was given early with a median of 10 days from the onset of symptoms.23 Therefore, early initiation of CP therapy might have a positive impact on mortality. However, in 10 studies except for Joyner’s and Pie’s study, the patients received concomitant drug therapy, which puts a query in the determination of the exact effect of CP therapy even though the CP therapy was initiated earlier.
Improvement of clinical symptoms
Clinical improvements were seen in 9 studies following CP therapy, though most of the patients required respiratory support at baseline. Finally, most patients were weaned from ventilator support and other forms of oxygen therapy.
ICU Admission and discharge
The range for the discharge of patients was from 4 - 35 days following CP therapy across 9 studies. The total number of patients discharged was 49 out of 79 across 11 studies except for the study conducted by Joyner et al. Among the studies reviewed, a total of 3391 patients were admitted to ICU. Most of the patients did not need ICU at the end and some got discharged in 10 studies. The studies conducted by Joyner et al and Pei et al did not mention the patients’ status at the end.24,26
Viral load and antibody titer
Viral loads were negative following CP therapy in 8 studies and antibody titers following such therapy were measured only in 2 studies.14,19. It is important to conduct trials on known antibody titers following CP therapy as it is important to determine the protective titer that is necessary for safeguarding against COVID-19. US-FDA has recommended the titer of 1:160 for the donation of blood for plasma.13 The protective titer of the antibody for Middle East respiratory syndrome was found to be 1:80 in a study conducted by Ko et al.29 Two of the reviewed studies found the antibody titer following CP therapy to be 1:80-1:480 and 1:640.14,19 In Zhang’s study, the IgG antibody titer after 29-46 days of 6 patients who recovered from COVID-19 without the use of CP therapy was found to be more than 1:320 among 5 of the 6 donors.30 It is not clear whether the antibody titers mentioned in the 2 studies were due to CP therapy alone or as an innate immune response to the infection like in Zhang’s study.
Adverse effects
Because of the large clinical trials done in the US where the results of 5000 people are out, it is remarkable that CP therapy is a safe treatment option for COVID-19 as only < 1% adverse events have been observed with 0.3% mortality.24 However, the trial was not randomized and early reporting of 5000 cases may have led to selection bias in the studies. Based on multiple studies, the adverse events found were severe allergic reactions including anaphylaxis, TACO, TRALI, transient red macular spots, morbilliform rash, and fever.14,23-26
LIMITATIONS OF THE STUDY
Most of the included studies were case reports and case series. Only one clinical trial was included which focused solely on side effects and was non-randomized and had early reporting. Because of incomplete clinical trials focusing on the therapeutic efficacy of CP therapy so far, we could not include these in our study. Most of our studies lacked a control group except for the one conducted by Zeng et al. There was a moderate to high risk of biases in our studies.
CONCLUSION
Based on data from the reviewed studies; CP therapy, in addition to concomitant drug therapy and other supportive therapies, has shown superior evidence in clinical improvement, viral clearance, safety, and survival rate. The perplexities remain for getting a conclusion about the possible favorable outcome is due to CP therapy alone based on given evidence and not due to natural disease progression or additional therapies. This question can only be answered after the ongoing RCTs focusing on therapeutic efficacy in terms of mortality rates, requirements of respiratory support, changes in viral load, and antibody titers following therapy are completed. In the end, it is noteworthy to tackle the global pandemic by CP therapy as a last resort along with additional therapies accompanied by risk-benefit judgment until the availability of therapeutic and/or prophylactic agent(s) for use.