key: cord-0766501-8p9u8eyg
authors: Moosavi, Seyed Ali; Mashhadiagha, Amirali; Motazedian, Nasrin; Hashemazar, Alireza; Hoveidaei, Amir Human; Bolignano, Davide
title: COVID‐19 clinical manifestations and treatment strategies among solid‐organ recipients: a systematic review of cases
date: 2020-07-24
journal: Transpl Infect Dis
DOI: 10.1111/tid.13427
sha: 4ed47336b9bac6756dcf72a0e1af3ba060f879ed
doc_id: 766501
cord_uid: 8p9u8eyg

BACKGROUND: COVID‐19 has been spreading worldwide with a significant death toll. Solid‐organ transplantation (SOT) recipients are at higher risk due to their suppressed immune system. In this study, we aimed to conduct a systematic review on COVID‐19 clinical manifestations and treatment strategies in SOT recipients. METHODS: We searched three databases for relevant terms related to COVID‐19 and transplantation. 50 studies, including 337 patients, were reviewed. RESULTS: 236 patients were male, with a mean age of 49.9 years. The most prevalent group was the kidney 57.0%, followed by 17.2% heart, and 13.6% liver. Fever and Cough were the most reported clinical presentations. Infiltration (55.4%) in chest x‐ray and ground‐glass opacity (67.1%) in CT scans were the most radiological findings. It was found that 96.8% and 72.4% of patients present with CRP level and lymphocytopenia, respectively, and 70.6% of kidney recipients patients presented with high creatinine levels. The most common baseline immunosuppressants were Calcineurin inhibitors (88.9%), and antimetabolites (73.2%). Antimetabolites (84.3%) and Calcineurin inhibitors (54.3%) were discontinued/decreased 84.3% whereas glucocorticoids dosage almost have no change (77.9%) or even increased. 18.4% of cases had died, and 65.9% were discharged. CONCLUSIONS: Patients’ demographics, signs, symptoms, and radiographic findings in SOT recipients are almost similar to the general population. However, gastrointestinal symptoms appear to be more common. There are different treatment strategies, but in most of them, antimetabolite and Calcineurin inhibitors were decreased or discontinued, while corticosteroids were increased. Finally, Covid‐19 seems to be more severe and has higher mortality in SOT recipients compared to the general population.

Coronavirus disease (COVID-19) is caused by a single-stranded RNA virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first human case was reported in Wuhan, Hubei province of China in December 2019, and by a few weeks, the COVID-19 infection has the characteristics of a "pandemic 1 .

According to the world health organization (WHO), fever, fatigue, and dry cough are the most common symptoms of COVID-19. Patients may also experience shortness of breath, myalgia, sore throat, and gastrointestinal (GI) symptoms. Real-time polymerase chain reaction (RT-PCR) is the most accurate detection method by now; however, some centers have chosen chest x-ray (CXR) or computerized tomography (CT) investigations as first-line triage tools due to long RT-PCR turnaround times 2, 3 .

There are several threats for transplant recipients, but one particularly significant threat is emerging of infectious diseases. There have been several new viral diseases since 1980, including HIV, SARS-CoV, West Nile Virus, Influenza A/H1N1 , Zika, Ebola, and now COVID-19 4, 5 .

Since the outbreak, there is increasing evidence that those with existing comorbidities, older age, or a compromised immune system are at higher risk of developing severe and even fatal respiratory diseases. Solid-organ transplant (SOT) recipients are also considered to be in this risk group, especially as they get treated with immune-suppressive drugs 3, 6 . It is also assumed that transplant recipients may have a more significant viral burden and shedding, resulting in higher infectivity and potential spread to other individuals, including healthcare professionals. Moreover, they have shown atypical clinical manifestations and worse prognosis in comparison to the general population; hence, different treatment approaches may be needed [7] [8] [9] [10] .

This article is protected by copyright. All rights reserved COVID-19 has immediately and dramatically impacted the world. Considering the early nature of the pandemic, knowledge about COVID-19 and its impact on SOT patients is limited to case reports and experts' discussions 11 . In the present study, we aimed to perform a thorough systematic review aiming at collecting any clinical evidence accrued to date on the impact of COVID-19 on SOT recipients.

The present study was conducted along with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, and it has been listed in the International Prospective Register of Systematic Reviews (PROSPERO) database (ID CRD42020181465). A comprehensive literature review of PubMed, Embase, and Scopus entries between December 1, 2019, and May 22, 2020, was conducted for relevant terms related to COVID-19 and SARS-CoV2 in transplant patients and setting (Appendix 1). Inclusion criteria for studies were the description of SOT recipients who got infected with COVID-19.

Excluding criteria were pediatric transplantation, guidelines, unavailable full texts, and lack of sufficient data. Non-English publications were translated into English, using Google's translation service. If eligibility was indeterminable, the full text was considered, and disagreements were resolved by consensus. Of all articles, 50 were regarded as relevant to this review 3, 7, . PRISMA flow chart of study selection is shown in Figure 1 .

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Three authors (A.M, S.M, A.H.) then separately extracted data from all relevant manuscripts using a pre-defined data extraction sheet. Parameters such as patients' demographics including age, sex, country of residency, comorbidities, past medical history including the transplanted organ and posttransplant time, baseline immunosuppressant therapy regimen, COVID-19 clinical manifestations (Signs, Symptoms), Intensive care unit (ICU) admission and intubation, abnormal laboratory data (WBC count, C-reactive protein (CRP) serum level and serum Creatinine level (Cr), RT-PCR tests, reported radiographic findings, and patients' outcome were extracted.

The statistical analysis was performed using SPSS version 21.0 (SPSS Inc. Chicago, IL). Continuous variables were displayed as mean ± standard deviation, and categorical variables were reported as counts and percentages.

We found 1047 references by applying the search strategy in the databases. We then discarded 499 duplicate citations. 426 articles were also excluded due to apparent irrelevancy of their topics in primary screening (Figure 1 ). In the secondary screening of 122 full-texts, we excluded 72 papers. Table   1 has summarized the studies and patients' characteristics.

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A total of 337 patients who met the criteria were included in the current systematic review. More than two-thirds (236 patients) were male, and 101 were female. Regarding the available clear data, the mean ± SD age of patients was 49.9, with a range of 24 to 80 years in different studies. The most prevalent patient group was the kidney transplant recipients with a population of 192 (57.0%), followed by 58 (17.2%) with heart, 46(13.6%) with liver, 25 (7.4%) with lung, eight (2.4%) with heartkidney, three (0.9%) with pancreas-kidney, one (0.3%) with heart-kidney, and one (0.3%) with lungkidney, with an average of 10.6 (0.2 -31) years transplant history among the clearly reported data.

Forty-six cases were defined with their donor status; fourteen (30.4%) cases were mentioned that had a living donor, and 32 (69.6%) got their transplanted organ from deceased donors.

164 patients were mentioned to have hypertension, 114 Diabetes Mellitus, and 10 malignancies. The patients were under medication for these underlying diseases, such as antihypertensive, or antihyperglycemic treatments. All patients were under immunosuppressive treatment due to history of transplantation; Calcineurin inhibitors were used by 88.9% of patients; it was followed by glucocorticoids for 62.8% of patients. The baseline immunosuppressive treatment of patients is summarized in Table 2 .

The most reported clinical presentation was fever (228 cases) followed by cough (181 cases). The frequency of reported sign/symptoms is shown in Figure 2 .

It was stated that 209 RT-PCR tests were done for the studied patients; all had a positive PCR test except one with a negative test who was diagnosed via CT-scan. 189 cases were evaluated through CXR, and there were 21 cases of normal CXR, while 168 (88.9%) were not; among these abnormal cases, 74 cases were reported with details of findings that included 41 (55.4%) cases of infiltrations, Accepted Article (6.8%) cases with other findings.

Chest CT scan is mentioned to be performed for 76 cases, and 68 were reported with details. Sixtyseven (98.5%) patients were reported to have abnormal findings; 45 (67.1%) cases were reported with ground-glass opacity (GGO), 8 (11.9%) with mixed patterns, 3 (4.5%) with viral infection presentation, 2 (3.0%) with patchy consolidation, and one (1.5%) with regular patterns. eight cases Immunoglobulin-based therapies with 41 cases. In 4.1% of the patients who were using glucocorticoids, it was stopped using or the dosage was decreased, and in 77.9%, the dosage was not changed. The baseline and final immunosuppressant therapies with their changes for patients are summarized in Table 2 

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According to Global observatory on donation and transplantation, kidney, liver, heart, and lung are the most frequently transplanted organs in the world 63 , however, the published cases from heart recipients seems to be more than liver recipients. Therefore, SOT patients may suffer from GI symptoms more often than the general population.

Since SOT patients are on medications that modulate the inflammatory response, symptoms associated with community-acquired respiratory viruses are typically less severe and less frequent than in regular healthy hosts, especially in patients with severe lymphocytopenia 68 Calcineurin inhibitors, antimetabolites, and corticosteroids are the most frequently used as baseline immunosuppressants; however, in COVID-19 confirmed cases, antimetabolites were mostly ceased whereas prescription of corticosteroids was kept in treatment or even increased in dosage. It was considered essential to use appropriate doses of corticosteroids throughout the process, as it could suppress inflammatory storms and promote the recovery from pneumonia without severe side effects as described in Zhong, Z et al 55 may still be in hospitals, some even in the ICU, and the outcome is still not predictable. These findings

show that SOT patients are at a higher risk of mortality than the general population but lower in comparison with normal hospitalized patients as mentioned in Richardson, S et al 61 .

To best of our knowledge, this is the only systematic review on SOT recipients with COVID-19 that has evaluated the different aspects of the disease from diagnosis, to treatment modifications. The emergence of the outbreak and lack of high-level evidence in the reviewed literature makes this study much more critical, which may shed light on the better management of transplant patients, who should be considered as a vulnerable group during this pandemic.

This article is protected by copyright. All rights reserved interactions and reasons for changing some drugs were available. Besides, given the fact that a significant number of individuals may not present with symptoms until the disease progresses to advanced stages, the overall generalizability of results and conclusions may somewhat be hampered by publication bias. Another limitation was that performing pooled data analyses was impossible due to the lack of information from the studies retrieved and their design, which are mostly case study and series. At the time of writing this study, many cases were still at the hospital, some even intubated, and the reported mortality can be higher since the outcome of these patients is not

completely reported yet. In addition, it is too soon for evaluation of the long-term effects of immunosuppressant discontinuation or dose reduction in SOT patients on graft rejection, and there is an essential need for more comprehensive clinical studies including short and long-term follow up cohort assessments. Also, more concentration is needed on prolonged viral shedding since there is a potential of putting the lives of other patients and health workers at risk. 

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This article is protected by copyright. All rights reserved 

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