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.