Coronavirus disease 2019 has affected more than 4 million people throughout the world since December 2019. It seems this infection has been the most insidious virus of the coronavirus family. This virus causes severe respiratory failure and symptoms in patients and can result in death. Designing a restrict protocol to deal with infections from severe acute respiratory syndrome coronavirus type 2 is critical in cell therapy institutes. In this review, we present the important aspects related to this virus in cell therapy protocols.
Key words : Coronavirus, Pandemic, SARS-CoV-2
IntroductionThe pandemic involving the novel coronavirus, severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has resulted in serious problems throughout the world. This virus causes coronavirus disease 2019 (COVID-19). Although scholars had thought that coronaviruses were restricted to animals, in the 1960s, human coronavirus was detected.1 In 2019, the novel coronavirus was identified in Wuhan, China.2,3 The symptoms of this disease include fever, cough, and shortness of breath.4,5 The SARS-COV-2 binds to angiotensin-converting enzyme 2 and enters different kinds of cells such as lung cells.6
By mid-May 2020, COVID-19 had infected more than 4 million people in almost 210 countries. Until now, there are no vaccines and approved drugs against this global threat.7 However, not much time has passed since the outbreak of this disease, and many researchers have focused on different aspects related to COVID-19.8,9 One of the most important challenges during the COVID-19 pandemic has been cell therapy procedures.
Scientists from King’s College London have identified 6 distinct types of COVID-19, including “flu-like” with no fever, “flu-like” with fever, gastrointestinal, severe level 1 (fatigue), severe level 2 (confusion), and severe level 3 (abdominal and respiratory).10 According to these clusters, outcomes in patients vary from mild symptoms to severe disease and even to death. Moreover, it is essential to consider that a significant number of patients do not present with clinical symptoms and that there are silent carriers of novel coronavirus. Therefore, it should be emphasized that every individual related to the cell therapy process should be screened regularly with polymerase chain reaction and antibody tests.
A systematic review and meta-analysis showed that decreased albumin, high C-reactive protein, high lactate dehydrogenase, lymphopenia, and high erythrocyte sedimentation rate are the most common laboratory results. Moreover, chest radiography results have revealed that bilateral pneumonia with ground-glass opacity is the most prevalent in image findings.11 Overall, the range of accuracy of screening tests is different, and these should also be considered for asymptomatic patients. Current investigations have suggested that multiplex assays are necessary to improve SARS-CoV-2 testing capacity.12
Although there has been significant progress in transplant methods, viral infections remain critical issues. Whole organ transplant has been introduced as an efficient method mainly for the treatment of patients with end stages of diseases or with several incurable conditions. Specifically, cell therapy in the field of transplantation may actually be superior to whole organ transplant of pancreas13 and liver14 in terms of reduced cell volume for transplant, decreased inflammation and immunologic responses to the engraft, and a less invasive transplant method. On the other hand, transplant of hematopoietic stem cells, mesenchymal stem cells,15,16 epithelial stem cells,17 and adult cells, including keratinocytes18 and melanocytes,19 has been accepted as therapeutic methods for a variety of clinical conditions.
The actual impact of COVID-19 on cell-based therapies is not entirely clear. It has been reported that immunocompromised recipients probably present with different features of COVID-9 infection, including with regard to the viral incubation period and shedding duration, clinical signs and symptoms, and responses to therapeutic approaches.20 Therefore, the extensive clinical range of cell transplant applications and the conceivable vulnerability of recipients prompted us to consider preventive protocols to avoid possible infections and the subsequent complications in recipients.
The most important recommendation in pandemic conditions is limiting transplant to urgent patients and postponement of transplant in individuals who can wait.21 Although researchers have focused on the importance of SARS-CoV-2 infection in organ transplant, the consideration of separate protocols for this infection in cell therapy procedures seems beneficial. In cell therapy, there are separate challenges, including cell isolation, cell culture, and the shipment of isolated cells between centers. In this review, we summarized important issues related to SARS-CoV-2 infection in different steps of cell therapy (Figure 1).
Pan and associates22 released a letter on the protocol of Sichuan Provincial People’s Hospital for organ donation during the SARS-CoV-2 epidemic. The group explained the protocol with regard to epidemiological screening, education, management, and follow-up.22 Because COVID-19 can result in severe respiratory failure and symptoms in recipients, for now, it seems critical to screen all recipients and donors.
An important challenge in cell therapy is susceptibility of recipients to infections, including COVID-19. Susceptibility is mainly because of the consumption of immunosuppression drugs, which leads to increased rates of infection. Therefore, establishment of an appropriate protocol to deal with SARS-CoV-2 is essential in cell therapy centers. In the first step, all those involved in these centers, donors and recipients, and their families should be trained on COVID-19 protocols. In the next step, attention to clinical symptoms and confirmed laboratory tests is important to determine infection in donors, recipients, and related medical staff. Finally, followup after transplant can help to detect possible infection. Based on the variety of symptoms and the presence of asymptomatic carriers, attention to screening methods and the application of multiplex assays are necessary for detection in patients.Donor and Organ Donation
The first stage in cell therapy protocols is organ donation. In this stage, potential donors and related medical staff members in organ transplant units are involved. In this regard, history of traveling in infected areas and patient relationships with others in the 14 days before cell therapy must be ascertained. According to history and clinical symptoms of donors and their families, laboratory tests, including nucleic acid tests, serum tests, and chest radiography examinations, should be considered to exclude COVID-19-infected donors. These investigations are also essential for medical staff members in the organ transplant unit.
Another issue in this stage is the application of sterile surgery instruments during organ or tissue removal from the donor to avoid possible transmission of SARS-CoV-2 infection. Therefore, instruments must be disinfected according to the guidelines.
In terms of organ shipment to the cell isolation unit, safe packaging of the organ and wrapping in a sealed double-bag is mandatory. The person respon - sible for the transfer of organ must be trained about protecting the package from any damage.Cell isolation and Culture
The next concern is associated with steps involving cell isolation and culture. SARS-CoV-2 has a high rate of transmission, and the virus can shed from the respiratory system, the digestive system, and serum. Therefore, screening and training of personnel involved in cell isolation and culture need to be considered. All personnel should follow proper regulations in wearing gowns, face masks, eye protection, and gloves at all steps. Environmental control is a necessity for cell isolation and culture laboratory tests to stop or restrict the contamination or cross contamination of products. Overall, the consideration of principles and guidelines of good manufacturing practice is necessary at all steps of cell isolation and culture.
It is also important to avoid contamination of previously banked cells. In this regard, attention should be paid to the processes of cell melting and culture.
Deficiencies in appropriate shipping measures of isolated cells to the transplant unit can be another source of infection in cells. Accordingly, following the mentioned points on organ shipment is strongly recommended.Recipients, Transplantation, and Follow-Up
In recipients under immunosuppressive therapy, SARS-CoV-2 can especially cause serious problems. Therefore, in cell transplant, recipients should undergo extensive laboratory tests even when there are no problems with clinical symptoms and history. Finally, all recipients need posttransplant follow-up to prevent the occurrence of SARS-CoV-2 infection and its life-threatening complications. In this regard, efforts should be employed to block nosocomial transmission.23 According to the Centers for Disease Control and Prevention and the World Health Organization, strict adherence to the standards and regulations, including social distancing, eye protection, and wearing appropriate masks, can decrease the risk of nosocomial transmission.24 In addition, recipients and their families should be trained on ways to prevent COVID-19 and to be aware of suspicious symptoms. Individuals should avoid visiting potentially infected individuals. Moreover, social distancing and sanitization can help recipients to maintain their healthy condition.25 If the patient is exposed to someone with COVID-19 or develops symptoms, hospital admission, the use of screening with accurate tests, and close monitoring are critical.Conclusions
COVID-19 can result in severe respiratory failure and death, especially in susceptible transplant patients. Therefore, designing a strict protocol to screen people before transplant and to address SARS-COV-2 infections by protecting and managing these vulnerable patients is critical in cell therapy units.
DOI : 10.6002/ect.2020.0239
From the Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
Acknowledgements: The authors have not received any funding or grants in support of the
presented research or for the preparation of this work and have no declarations of potential
conflicts of interest.
Corresponding author: Negar Azarpira, Transplant Research Center, Mohammad Rasoulallah Research Tower, Khalili street, Shiraz, Iran, 7193711351
Phone: +98 7136281529
Figure 1. Summary of Important Issues Related to Severe Acute Respiratory Syndrome Coronavirus Type 2 Infection in Different Phases of Cell Therapy