Effectiveness of various treatment strategies in COVID-19 patients having Solid Organ Transplant: A Systematic Review

Introduction: This narrative review provides an evidence-based summary of the various interventions in the management of Post Solid organ transplant patients who reported positive for COVID-19. Materials and Methods: For this systematic review, observational and experimental studies; conducted on PostOrgan transplant patients, either symptomatic or asymptomatic, who tested positive for COVID-19 were included. Only solid organ transplant patient studies were considered standard for this review type. The English version, both published and unpublished articles, from Dec 2019 to Aug 2020, were evaluated using Pubmed, Google Scholar, Science direct, Medrixv search engines. The articles with incomplete details about a transplant or covid management were excluded. Results: We selected 43 articles out of which 9 were retrospective studies, 2 were cohort studies, one was an experimental study, and 31 were case studies. According to the literature review, effective management therapy includes the withdrawal of immunosuppressive drugs, increase/ constant steroid dose, and regimen containing HCQ, interleukin inhibitor, and one antiviral drug especially remdesivir proved to be the most effective among all. In others, administration of IV immunoglobulins/convalescent plasma therapy proved effective in various trials but related data is currently limited. While Lop/Rit, Interferons alpha, and oseltamivir trials are also given; these therapies didn’t prove to be much effective individually. Conclusion: More trials are required to find the effectiveness of Convalescent plasma therapy. It can be proved as an effective treatment in critical patients. IV immunoglobulins effectiveness should also be tested in critical patients and for this more experimental trials are needed.


Introduction
In early December 2019, coronavirus disease rapidly swept across Wuhan, China. Due to its widespread transmission, it was declared a pandemic by WHO in January 2020. 1 As this pandemic maintains to spread, statistics on the scientific characteristics and consequences of COVID-19 are emerging throughout continents. 2 The novel coronavirus has been found strikingly similar to the virus which causes severe acute respiratory syndrome (SARS) in its morphology. 3,4 The symptoms of COVID-19 vary but commonly fever, dry cough, fatigue and, generalized weakness have been observed. 5 Our study is based on how COVID-19 manifests in patients with solid organ transplants. By analyzing data from 2008 for 104 countries, every year 100800 solid organ transplants are performed worldwide: 69400 are kidney transplants, 20200 are liver transplants, 3400 are lung transplants, 2400 are pancreas transplants and 5400 are heart transplants. The clinical findings, therapeutic approach, and consequences of COVID-19 in patients with solid organ transplants remain unknown. 6 We collected data from different databases to conclude how COVID-19 manifests in patients with solid organ transplants and how we can manage its progression and immunosuppression via effective treatment options.

Materials and Methods
The eligibility criterion of our study was researches related to COVID-19 management in solid organ transplant patients. We searched four databases PubMed, Google scholar, science direct, and medrixv for our systematic review from December 2019 till August, 2020. Original articles, retrospective studies, and case studies in English were selected. Search terms used were: COVID-19 treatment in organ transplant patients, management of COVID-19 in solid organ transplant patients, and effectiveness of various treatments in COVID-19 patients with organ transplants. Four reviewers reviewed the database separately. In the first step, articles were excluded based on the title. Those studies were excluded which were not related to the management of COVID 19 in organ transplant patients. In the second step, duplicate articles and articles based on abstract were removed. All the articles other than original, retrospective and case studies were excluded. In the third step, full-text articles were assessed and articles based on quality and incomplete data were removed. Articles with ambiguous information were reviewed by more than one author and then excluded after the final discussion. All studies based on experiments on animals, artificial intelligence, editorials, comments of authors were excluded. Articles in a language other than English were also excluded. Data were extracted by four authors individually and finally reviewed by one author. Data were extracted based on variables which include study type, number of patients, time since organ transplant, COVID-19 symptoms, and management of covid19 patients in organ transplant patients.

Results
For this systematic review, we searched four research engines. Out of 2454 articles initially acquired, only 43 were selected in the final review based on the inclusion and exclusion criteria. Among these 43 articles: 9 were retrospective studies, 2 were cohort studies, and 31 were the case series. We extracted the respiratory complications and management of Covid-19 from these articles in the form of a table. We made a column for "Covid-19 respiratory complications" in which we mentioned all the changes that were observed in the lungs of the patient during the progression of covid-19. "Covid-19 specific treatment column" represented the treatment strategies used by health care professionals specifically against covid-19. The next column was "management of immunosuppression in Covid-19 patients", which represented the changes made in patient organ transplant immunosuppression regime while treating a patient for Covid-19. In the end, "outcome "represented the final result whether the patient survived or not. Either the patient is discharged or still hospitalized was also mentioned in this column. The results of COVID-19 treatment and immunosuppressive management have been summarized in the following sections: Covid-19 in Renal Transplant patients: Data retrieved from case reports and retrospective studies suggest that kidney transplant patients with an average age of 50, normally presented with fever, cough, and malaise and later on developed respiratory complications. Almost all of them had comorbidities but no association was found between them and the progression of COVID-19. Patients recovered with symptomatic treatment along with temporary amendments in the immunosuppressive regimen. COVID-19 specific and immunosuppression management in renal transplant patients is discussed in Table 1.   Table 3.   Table 4. Hepatitis B, Jaundice, splenomegaly, diabetes, and hypertension are reported as common comorbidities and are effectively treated. Covid-19 specific and immunosuppression management in liver transplant patients is discussed in Table 5. specific and immunosuppression management in variable transplant patients is discussed in Table 6. There is solid evidence that management of immunosuppressive therapy in SOT patients stays the focal point of COVID-19 treatment. In all of the SOT patients who presented with COVID-19 complications, immunosuppressive therapy was transiently modified, usually halted or reduced. Many times this alone proved effective. HCQ proved to be the mainstay of COVID-specific treatment. Azythromycin was synergistically used along HCQ in lowering a viral load. Among antivirals, remdesivir was most competently used and it proved productive whereas lopinavir/ritonavir didn't prove to be effective. Interleuikin inhibitor, Tociluzumab was frequently used however nothing at this point can be predicted about its efficacy. Scarce evidence is available on the use of convalescent plasma therapy, however, in some critical cases, it proved to be the life-saving option. The most effective management therapy in severe cases includes the withdrawal of immunosuppressive drugs, increase/ constant steroid dose and regimen containing HCQ, interleukin inhibitor, and one antiviral drug especially remdesivir..

Additional Recommendations
COVID-19 has been considered lethal for patients who have gone through a solid organ transplant. However, our retrieved data suggests that decreasing the immunosuppression regimen and increasing the steroids along with an appropriate dose of COVID-19 specific medicines can result in 70 to 80 percent efficacy. Antivirals like remdesivir have shown positive results which may be due to their relatively non-toxic effects and less drug-drug interaction. The use of lop/rit for treating COVID-19 has been discouraged by recent studies. In a case report by Jiao-Feng et al. lop/rit treatment of a patient with a liver transplant resulted in multiple organ failure and mortality. 49 Hydroxychloroquine combined with lop/rit must be keenly tracked due to their known hepatotoxic effects. 50 Data from different studies reveal that hydroxychloroquine can be looked after as a potential treatment option for COVID-19. However, according to a recent study, Hydroxychloroquine along with azithromycin can adversely affect the cardiac conduction pathways leading to arrhythmias so it is advisable to closely monitor the ECGs of patients especially if they have cardiac comorbidities. 51 The use of interleukin blockers like tocilizumab as a treatment option for COVID-19 is based on the belief that interleukins, especially interleukin-6, are the inflammatory substance resulting in lung damage. However, in a case series by Marcus R et al. the mortality rate of organ transplant patients who received tocilizumab was significantly higher than the patients who were treated without tocilizumab. 52 Therefore, building a shred of strong evidence about interleukin blockers as a possible treatment option for Covid-19 demands more studies. The emergence of COVID-19 has also reevaluated the effectiveness of historic convalescent plasma transfusion (CPT) which may reduce the mortality rate in critically ill patients. There is only a shred of the limited evidence available on it till now and multiple clinical trials are still ongoing. The convalescent plasma (CP) strategy is currently being used for prophylaxis as well as for the treatment of contagious diseases since the early 20th century. 53 Apheresis is the procedural methodology to obtain blood plasma, based on continuous centrifugation of blood from donors (who are potentially recovered from the disease). 54 A study by Shen et al showed 5 critically ill SARS CoV 2 infected patients recusant to antivirals, received Convalescent plasma therapy. After transfusion the fever settled down within 3 days, PaO2/FiO2 raised and PCR became negative within 12 days. 55 Another study conducted by Duan et al. showed the results from 10 severe cases who received one dose of CP leading to the disappearance of viremia in 7 days and clinical symptoms readily improved within 3 days. 56 Thus, the administration of convalescent plasma is a potentially effective strategy with promising evidence on the improvement of clinical symptoms and with no side effects reported till now.
IVIg; a pooled normal IgG having both immunemodulation and immune substitution effects, is obtained from the blood of healthy donors. 57 It can elicit passive immunity and is an ideal option for the management of COVID patients. IVIG is considered to target cytokine storms in severe COVID-19 patients. In a study, Mohtadi et al reported five critically ill SARS-CoV 2 infected patients for whom IVIG was administrated, which prevented the further downturn of symptoms. A high-dose IVIG (0.3-0.5 g/kg) was given to all patients for consecutive five days. Overall the patients' response was satisfactory and they were discharged from the hospital after complete recovery. 58 Another study by Cao et al reported 3 patients with critical Covid-19 conditions. They were given highdose intravenous immunoglobulin (IVIg). They also recovered promptly and were discharged. 59 Keeping in mind its potency in modulating immune inflammation high-dose IVIg could be considered an encouraging alternative at the initial stage of the clinical downturn of patients with COVID-19. Further experiments should be conducted to infer the effectiveness of this approach. Limitations of this study include that up till now a finite number of studies have been conducted on the management of SARS-CoV 2 disease in organ transplant patients. We excluded articles of all languages except English. We considered only the Solid-organ type of transplant, other types of transplant articles are not considered. Limited data of patients were available as most of the case report studies were found. Thus, more experiments are still required to assess the potency of different management strategies in Solid organ transplant patients with CoV disease.

Conclusion
To sum up, in organ transplant patients with covid-19, withdrawal of immunosuppressive drugs revealed considerably good results. Hydroxychloroquine manifested results up to the mark. But Lopinavir and Ritonavir were found to be non-productive. Intravenous Immunoglobulin and Convalescent plasma therapy were also used. Amidst all medicinal techniques, convalescent plasma transfusion is found to be a potentially effective strategy. But multiple clinical trials are still required to infer the efficacy of this treatment.