The Effectiveness of Convalescent Plasma Infusion on the Recovery of Covid-19 Patients

Capstone Project: The Effectiveness of Convalescent Plasma Infusion on the

Recovery of Covid-19 Patients

Abstract

The capstone project explores the effectiveness of the infusion of convalescent plasma (CP) on patients with COVID-19. The data includes systematic reviews, meta-analyses, and randomized controlled trials. The use of CP has historical significance. It was first utilized during the Spanish Influenza in 1918-1920 (Ripoll et al., 2021). The outcomes for this project include mortality rates and the number of hospital days. This study shows some positive outcomes regarding patients’ mortality rates, while it did not improve the number of hospital days. However, some literature suggests that CP decreases patients’ viral loads, enhances IgM and IgG, and improves the symptoms. Further high-evidence studies are recommended to validate its effectiveness.

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The Effectiveness of Convalescent Plasma Infusion

The world was deluged with a danger that was declared a worldwide emergency in 2020. COVID-19 hit Wuhan, a city in China in the province of Hubei, in the final weeks of 2019. Month after month, the spread of the coronavirus has collapsed the healthcare systems’ ability to contain the threat.  At present, the arrival of the COVID vaccines has helped reduce the risk of illness and mortality.  However, as of this writing, there is still no known cure. Most of the treatments are aimed at symptomatic treatments such as the use of antibiotics, antivirals, off-label medications, respiratory ventilation, convalescent plasma (CP) infusion, and other non-pharmacological approaches.  According to Johns Hopkins University and Medicine (2022), there are a total of 434 243,270 cases of COVID worldwide and a mortality of 5 944, 020.

The use of CP infusion is not a novel approach. In 1890, the immunologist Emil von Behring started using a passive type of immunization by utilizing antibodies obtained from the blood of a horse to discover a treatment for tetanus and Diphtheria (Fischer et al., 2020). Behring’s work was successfully utilized in other disease outbreaks including the Spanish influenza that devastated the world in 1918, the US’ measles outbreak in 1934, MERS-CoV, and  the Ebola outbreak in the year 2015 (Fischer et al., 2020). This study will explore the use of CP infusion on COVID-19 patients and compare the recovery of COVID patients who received and did not receive the infusion. By facilitating this study, the utilization of CP infusion may be validated. If deemed effective, CP can be regulated and incorporated into the treatment guidelines for COVID-19 patients.

Background and Significance

The COVID pandemic has stirred the healthcare system significantly. Although there are new interventions, the cure for COVID-19 remains discovered. Passive immunotherapy has been utilized in the past to help curb infections that had no treatments available such as the Spanish Influenza, Ebola, MERS-CoV, and Severe Acute Respiratory Syndrome or (SARS). The implementation of passive immunotherapy is not a new concept. Convalescent plasma was first used to counteract the damaging consequences of mumps, measles, and flu in the 1890s and in the early part of the twentieth century (“Saving lives with convalescent,” 2020). The understanding of COVID-19’s pathophysiology is not well comprehended, and at present, there is no known cure (Xu et al., 2020). As a result, the researcher considers that utilizing CP therapy in tandem with other therapies would result in an improved outcome than not using it at all. Most  COVID-19 patients do not possess enough antibodies to fight SARS-CoV-2 in the first ten days of the disease(Casadevall et al., 2020). In comparison, the administration of CP would significantly boost the antiviral immunity of a person. In some current trials in India, it was demonstrated that 18 of 20 sick individuals recovered (“Saving lives with convalescent,” 2020).

The appropriateness of the use of CP was observed in outbreaks due to new pathogens. These factors include fast deployment, ease of manufacturing and utilization, accessibility, specificity, immediate action, safety, and scalability (Khaire et al., 2021).

PICOT Clinical Project Question

PICOT Title: The Effectiveness of Convalescent Plasma Infusion as opposed to the Non-administration of Convalescent Plasma on patients diagnosed with COVID-19.

Literature Review

A systematic review was published in the Journal of Medical Virology (Rajendran et al., 2020). There were eight experiments reviewed, and they’ve all been clinical trials. In this review comprising eight studies, five demonstrated significant results. The patients for CP therapy were given different doses ranging from 200 mls up to 4.5 liters. The review results showed that the patients’ symptoms had significantly improved (Rajendran et al., 2020). Their physical temperatures returned to normal, and their lung lesions showed varying degrees of absorption, ARDS resolution was observed, and they were removed off the ventilators between days one and 35 after CP administration (Rajendran et al., 2020)

The study’s strong points are the extensive investigation of scientific studies that are already existent and the demonstration of the included study findings with participant traits. Even though the analysis yielded encouraging findings, its flaws involve factors that increase the probability of bias. The criteria review for choosing studies for assessment were not stated; there were non-randomized samples and a lack of an appropriate methodological process in participant selection. The duration and dosage of CPT as well as the administration of other therapies such as antibiotics and antivirals also create factors that may have influenced the results.

Another study, published on August 18, 2020, in the DARU Journal of Pharmaceutical Sciences, comprised a systematic review and meta-analysis. “Is there any potential management against COVID-19?” asks the article’s title. 2020 (Talaie et al.). There are  15 cohort trials,11 case studies,  and 19 randomized controlled among the 45 studies. The approach included 26 studies with 3263 respondents in qualitative methodology out of the 45 evaluations that met the standards.   The study looked at the influence of various COVID-19 therapies or interventions (antimalarials, antibiotics with antimalarials, immunomodulatory medications, CP therapy, and antivirals) on patients’ outcomes  (clinical progress, ventilation requirement, admission in ICU, a negative conversion frequency, and death)

The research’s outcomes revealed a fewer mortality and better health outcomes (Talaie et al., 2020). However, no significant effects were detected in negative conversion, Intensive Care Unit admission, or adjustment of mechanical ventilation settings (Talaie et al., 2020). The addition of proof from cohort studies and RCTs and the non-inclusion of reports with insufficient data, descriptive reports, and case reports are among the review’s strengths (Talaie et al., 2020). The disadvantages of this study include the existence of minimal sizes of samples and the uncertainty of other drug’s efficacy. Because the benefits outweigh the flaws, this study could be considered a reasonable basis for modification in practice. A large-scale RCT focusing on CPT would be beneficial in determining the effectiveness of this therapeutic intervention.

The third literature is a meta-analysis and systematic review reported in the Archives of the Canadian Medical Association. “Safety and efficacy of convalescent plasma treatment for serious COVID-19 based on evidence from other respiratory viral infections,” according to the study’s title. Six studies out of the 1099 files met the criteria. The respondents in the six studies were not COVID patients. The study included people with severe SARS-CoV MERS-CoV, SARS-CoV, Ebola, and influenza complications (Devasenapathy et al., 2020). Time for recovery, deaths, ICU stay length, and hospital stay duration were all outcomes of the study.

Four of the six studies were randomized controlled trials on influenza (Devasenapathy et al., 2020). Patients suffering from Severe Acute Respiratory Syndrome (SARS)were included in one non-randomized, retrospective cohort, and patients with the Ebola virus were included in another prospective non-randomized experiment. Three out of the four Randomized trials blinded the clinicians and patients: a couple utilised lowered immunoglobulin (IVIG), a saline infusion was used as a control, and one used an open-label approach (Devasenapathy et al., 2020). The Severe acute respiratory group’s retrospective group did receive 200-400 mls of convalescent plasma transfusion as opposed to methylprednisolone as a control.The treatment group in the Ebola study were given a couple of CP tranfusions of 200 to 250 milliliters of CP with a gap of two days in between.

The extensive utilization data stores to explore novel and previous scientific proof, as well as the GRADE strategy to analyze evidence quality, are the study’s strong points (Devasenapathy et al., 2020).

The fourth literature was issued in the Journal of Medical Virology under the title “Convalescent plasma is a clutch at straws in COVID-19 management” (Sarkar et al.,  2020). This is, once again, a Level I type on the EBP hierarchy. This study included 5444 participants, five cohort trials, and two randomized controlled trials. The goal of this study was to see how effective CPT was on COVID-19 patients. The outcomes that were assessed were death, clinical improvement, and viral load reduction (Sarkar et al., 2020).

In all seven trials, the use of CP infusion diminished the risk of death by nearly half (Sarkar et al., 2020). Five studies evaluated patients’ clinical improvement and found that the treatment group managed to improve more than the control group. Those who received the CPT had substantially lower viral loads.

The final research is a Level IV RCT issued in The Journal of the American Medical Association titled “Effect of convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19” (Li et al., 2020). The 103 participants in this RCT were categorized depending on the intensity of their condition (Control group had 51 participants, the treatment group had 52 participants).CPT with primary therapy versus primary therapy alone was the intervention and comparison. The study’s goal was to determine the efficacy and side repercussions of CPT on COVID-19 patient groups (Li et al., 2020). The primary endpoint was a 28-day asymptomatic improvement. The fatality rate, duration of stay prior to discharge, and three-day PCR observations denoting viral polymerase chain reaction were the secondary outcomes. The trial ran from February 14 to April 1, 2020, with a follow-up on April 28, 2020. (Li et al., 2020).

Within 28 days, clinical improvement was noted in 27 respondents in the experimental group (51.9 %) and 22 respondents in the normal control group (43.1 % ). Among those who were critically ill, 91.3 percent improved in the treatment group compared to the 68.2 % in the normal control group. Those in life-threatening situations fared differently: 20.7 % managed to improve in the treatment group compared to 24.1 % improved in the control group. There were no significant findings in terms of discharge time or death rates. The PCR results of the treatment group enhanced by 87.2 %, while the control group continued to improve by 37.5 percent.

Recent Supporting Evidence

In addition to the above-discussed literature based on the year 2020, there are recent studies that were conducted in 2021 which reveal significant results about the outcomes being measured. The graphs below show the mortality rates and hospital days of patients who received and did not receive the CP infusion:

Purpose of Study

The study aims to determine the effectiveness of CP infusion on the measurable outcomes of patients with COVID-19. The outcomes include mortality and the number of hospital days. The infection caused by the coronavirus has no known cure and is being treated symptomatically. Fortunately, newly developed vaccines have helped vaccinated individuals cope with the fatal effects of COVID. Nevertheless, the quest for a suitable treatment for COVID has not yielded significant results. With this study, the author aims to contribute information regarding the validity or non-validity of CP infusion as a treatment for COVID. In addition,  the author anticipates that through this capstone project, the potential of CP as a treatment for other infectious diseases or conditions may also be realized.

Theoretical Frameworks

To understand the use of passive immunity in this study, it is relevant to understand the processes of the body’s immune responses. Some frameworks have been suggested about the body’s immune response and the formation of antibodies after pathogen exposure. The author selected two models, namely the Self versus Non-self model and the Danger Model, to set a foundation or structure in exploring the effectiveness of CP infusion.

Burnet first proposed in the 1940s that the immune system’s fundamental role is to recognize and defend the host from hazards that could harm the body (Manjili, 2014). As a result, when a pathogen infects a host organism, the immune system recognizes it as a danger. Antigen-binding receptors use this procedure to classify foreign substances or organisms as either self or non-self. Pathogen recognition receptors (PRR) are nonself or self-proteins sensors that determine the distinctive properties of pathogens known as patterns of pathogen-associated chemicals in immune system cells (Manjili, 2014). Toll-like receptors (TLR) on APC identify certain structures of microbes, allowing the difference between viruses and bacteria to be made.

The author selected to add the Danger Model proposed by Matzinger in 1994 to supplement the Self versus Non-Self Model. Adaptive immune responses are initiated by chemicals secreted in the event of tissue damage, according to the Danger Model ( Relja & Land, 2020). Damage-associated molecular patterns (DAMPs), which are regarded biomarkers and trigger inflammation and immunological response, were coined by this approach. When a pathogen, such as a bacteria or virus, is exposed, an immune response is generated due to microorganisms’ harm in tissues and organs.

The self versus nonself and danger models are important because they give a framework for understanding immune response and antibody manufacturing mechanisms. The project may be evaluated using these models by determining a healed person’s way to generate antibodies and the effectiveness of passive immunity through convalescent plasma infusion in the recovery of COVID-19 patients. According to certain clinical encounters, Convalescent plasma treatment could be used as an empirical therapy to reduce problems and enhance early recovery (Peng et al., 2021). These models could be enhanced by adding new studies particular to the project.

Methods/Design/Sampling

To test the hypothesis, various factors must be assessed to evaluate the efficiency of the convalescent plasma (CP) infusion on the recovery of COVID-19 patients. In addition, to accurately test whether the hypothesis is null or significant, an adequate statistical analytic approach is required. The author’s research techniques, designs, and statistical analyses for the capstone project are described in the following text.

Evaluative Criteria

The following parameters can be used to assess the efficiency of the CP infusion on the rate of recovery in COVID-19 patients:

1. The total number of days spent in the hospital.
2. Death rate over 28 days.

Patients who had the CP infusion will be compared to those who did not receive the infusion on both criteria.

Research Method

Previous studies on the influence of CP on the number of hospital days and mortality rate can be used to quantify and estimate the total number of hospital days and fatality rate. The quantitative method is the most appropriate study approach for both evaluative criteria. Quantitative approaches are useful for determining the magnitude and variance of change brought about by implementation strategies (Smith & Hasan, 2020). Because this capstone project deals with measurable variables, such as the number of hospital days and the death rate in a specific length of time among patients who receive the CP versus those who did not, a quantitative research technique is applicable.

Data Collection

Quantitative data is used in the capstone project. As a result, data collecting and statistical analysis procedures should accommodate quantitative figures adequately. The author collected secondary data from past research studies. The studies will comprise findings derived from 2020 up to the present. It will include papers with a high hierarchy of evidence generated from systematic reviews, meta-analyses, and randomized controlled trials. The author will emphasize the sections of the research that involve the number of hospital days and the death rate. 

Data Analysis

The author intends to compare the mean values of hospital days and mortality rates between patients who received the CP infusion and those who did not. To analyze the data, the author will present the differences in hospital days and mortality rates between CP-infused and non-CP-infused patients in graphs.

Proposed Interventions

The author proposes in this capstone project that once CP infusion was shown to be efficacious, it should be included in the primary treatment of COVID-19 patients in acute care or perhaps in even out-patient settings. Furthermore, it could be used as an adjunct treatment combined with other novel COVID-19 treatments.

The Extent of Evidence-Based Data

Numerous studies have been conducted to date to provide perspective into how CP impacts the recovery of COVID-19 patients. According to a systematic review by Wang et al. (2021), while the results of a limited randomized-control trial (RCT) demonstrated that CP could not substantially decrease mortality, a few case reports and non-RCTs demonstrated that CP might improve patients’ clinical outcomes. Sarkar et al. (2020) discovered that CP might be beneficial in lowering mortality, viral shedding, and improving clinical outcomes in COVID-19 patients through a systematic review and meta-analysis. Talaie et al. (2020) discovered that CP combined with immunomodulators significantly reduced death rates and managed to improve clinical outcomes while having no impact on mechanical ventilation demand or negative conversion. A randomized controlled trial (RCT) conducted by Li et al. (2020) found that CP given to individuals with symptomatic or life-threatening conditions did not lead to significant improvement. On the other hand, this trial was terminated preemptively, which may have affected the result. Briggs et al. (2021) reported that giving patients CP early (within six days) to patients with moderate to severe COVID resulted in a 50% decrease in in-patient death rates, shorter times on mechanical ventilation, and significantly larger improvement in comparison to non-exposed versus exposed cohorts

Factors and Barriers to Proposed Interventions

Several factors may affect the use of CP in COVID patients. To begin with, there is no known cure for COVID-19, trying to make CP a valuable therapy alternative. CP has also been used in previous epidemics. Jha et al. (2020) observed a reduction in mortality among individuals with symptomatic influenza and SARS when CP was given early during symptom onset. The contradiction of current studies may be one of the barriers to CP implementation. Some research shows its effectiveness, whereas others demonstrate inconsistent results.

Resources Needed

Patients in the convalescent stage of the disease should be encouraged to donate blood for the convalescent plasma infusion to be implemented. Furthermore, certain health institutions should be encouraged to support CP therapy early in the disease. Resources for this project’s completion should include high-evidence studies.

Implementation Steps and Strategies

For CP administration to be included in COVID treatment guidelines, credible, definitive, and high-quality studies must be conducted. According to Sarkar et al. (2020), more RCTs are needed to verify the initiation, safety factor, duration, maximum dosage, and CP therapy titer. After studies have concluded that CPT is effective, government agencies such as the Department of Health and Human Services (HHS) would verify and endorse its use. The Food and Drug Administration (FDA), an HHS agency, regulates medical products such as CP. This agency is in charge of overseeing and tracking the progress of CP therapy. CP is presently only authorized for emergency use in the United States by the FDA.

As of now, there is no timetable for this project because it is ongoing. This capstone is set to be submitted at the end of February 2022.   The author’s secondary data, on the other hand, will cover studies conducted between 2020 and 2022. Conducting further high-evidence research, gathering plasma from donors with high levels of COVID antibodies, and administering CP within the first six days of admission are all methods that can expedite the application or alteration of the proposed action.

Expected Outcomes

Currently, there are contradicting and inconclusive results regarding the efficiency of CP infusion. In addition, it has been shown in some studies to be beneficial early in the disease process. One of the project’s expected outcomes is to ascertain whether CP therapy lessens death rates and enhances recovery in COVID-19 patients. With the completion of new studies, it is hoped that the time of initiation, dosage, frequency and therapeutic index of CP will be decided.

Anticipated Conclusion

The pandemic only began in 2020, and studies to conclude the effectiveness of CP infusion should be further conducted, particularly high-evidence studies. For this project, the conclusion would be that CP’s effectiveness is partially proven due to other factors that may contribute to the recovery or worsening of patients. Most studies included in this project demonstrate a significant difference between the mortality rate of CP-treated vs. non-CP-treated patients.

Possible Limitations

At present, the use of CP is still under emergency use authorization. In addition, it is still regarded as an investigational new drug by the FDA. The length of time of studies on COVID is limited due to the fact that COVID just recently occurred in the last two years. In addition, some newly discovered medications and therapies for COVID may be preferred by some clinicians. Because it is still considered a EUA/IND product, the number of willing donors and patients may also be limited.

Potential Implications to Practice

The approval of CP infusion for emergency use has opened the way for this intervention to be evaluated on a wider scale. As there is a lesser viral burden in the early stages of the disease, CP may be more effective if used earlier in the disease process (Khaire et al., 2021). Furthermore, it can be used in conjunction with other COVID-19 therapies. Because CP has been used throughout history, it can be used in the future. CP could be used in future disease outbreaks where no pharmacological treatment is available. Immunocompromised patients may benefit from CP because these units already contain antibodies that patients with immune problems may struggle to produce.

References

Casadevall, A., Joyner, M. J., & Pirofski, L. A. (2020). SARS-CoV-2 viral load and antibody responses: The case for convalescent plasma therapy. The Journal of Clinical Investigation.

Devasenapathy, N., Ye, Z., Loeb, M., Fang, F., Najafabadi, B. T., Xiao, Y.,  Couban, R.,Bégin, P., & Guyatt, G. (2020). Convalescent plasma’s efficacy and safety for severe COVID-19 based on evidence in other severe respiratory viral infections: A systematic review and meta-analysis. Canadian Medical Association Journal. DOI: 10.1503/cmaj.200642

Fischer, J. C., Zänker, K., Martijn, v. G., Schneider, M., Kindgen-Milles, D., Wolfram, T. K., . . . Bojar, H. (2020). The role of passive immunization in the age of SARS-CoV-2: An update. European Journal of Medical Research, 25, 1-6. doi:http://dx.doi.org/10.1186/s40001-020-00414-5

Johns Hopkins University and Medicine. (2022). COVID-19 dashboard. https://coronavirus.jhu.edu/map.html

Khaire, N. S., Jindal, N., Yaddanapudi, L. N., Sachdev, S., Hans, R., Sachdeva, N., Singh, M. P., Agarwal, A., Mukherjee, A., Kumar, G., Sharma, R. R., Suri, V., Puri, G. D., & Malhotra, P. (2021). Use of convalescent plasma for COVID-19 in India: A review & practical guidelines. The Indian Journal of Medical Research, 153(1 & 2), 64–85. https://doi.org/10.4103/ijmr.IJMR_3092_20

Li, L., Zhang, W., Hu, Y., Tong, X., Zheng, S., Yang, J., Kong, Y., Ren, L., Wei, Q., Mei, H., Hu, C., Tao, C., Yang, R., Wang, J., Yu, Y., Guo, Y., Wu, X., Xu, Z., Zeng, L.,…Liu, Z. (2020). Convalescent plasma therapy on time to clinical improvement in patients with severe and life-threatening COVID-19: A randomized clinical trial. Journal of the American Medical Association, 324(5). 1-11. doi:10.1001/jama.2020.10044

Manjili M. H. (2014). The adaptation model of immunity. Immunotherapy, 6(1), 59–70. https://doi.org/10.2217/imt.13.157

Peng, H. T., Rhind, S. G., & Beckett, A. (2021). Convalescent plasma for the prevention and treatment of COVID-19: A systematic review and quantitative analysis. JMIR Public Health and Surveillance, 7(4). http://dx.doi.org/10.2196/25500

Rajendran, K., Krishnasamy, N., Rangarajan, J., Rathinam, J., Natarajan, M., & Ramachandran, A. (2020). Convalescent plasma transfusion for the treatment of COVID-19: Systematic review. Journal of Medical Virology. https://doi.org/10.1002/jmv.25961

Relja, B., & Land, W. G. (2020). Damage-associated molecular patterns in trauma. European Journal of Trauma and Emergency Surgery, 46(4), 751–775. https://doi.org/10.1007/s00068-019-01235-w

Ripoll, J. G., van Helmond, N., Senefeld, J. W., Wiggins, C. C., Klassen, S. A., Baker, S. E., Larson, K. F., Murphy, B. M., Andersen, K. J., Ford, S. K., Casadevall, A., & Joyner, M. J. (2021). Convalescent Plasma for Infectious Diseases: Historical Framework and Use in COVID-19. Clinical Microbiology Newsletter, 43(4), 23–32. https://doi.org/10.1016/j.clinmicnews.2021.02.001

Sarkar S., Soni K.D., & Khanna, P. (2020). Convalescent plasma is a clutch at straws in COVID-19 management: A systematic review and meta-analysis. Journal of Medical Virology. doi:10.1002/jmv.26408

Saving lives with convalescent plasma. (2020, Jul. 11). Manila Bulletin. Retrieved from https://search.proquest.com/docview/2422411578?accountid=100141

Talaie, H., Hosseini, S.M., Nazari, M., Fakhri, Y., Mousavizadeh, A., Vatanpour, H., & Firoozfar, A. (2020). Is there any potential management against COVID-19? : A systematic review and meta-analysis. DARU Journal of Pharmaceutical Sciences. https://doi.org/10.1007/s40199-020-00367-4

Wang, Y., Huo, P., Dai, R., Lv, X., Yuan, S., Zhang, Y., Guo, Y., Li, R., Yu, Q., & Zhu, K. (2021). Convalescent plasma may be a possible treatment for COVID-19: A systematic review. International immunopharmacology, 91, 107262. https://doi.org/10.1016/j.intimp.2020.107262

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