Key words : Coronavirus disease 2019, Novel coronavirus, Pandemic, Severe acute respiratory syndrome coronavirus 2, Transplant

Introduction

The COVID-19 pandemic caused by SARS-CoV-2, which emerged at the end of 2019, has affected the entire world for 1 year. According to the data from the World Health Organization, 83.52 million COVID-19 cases were detected by late December 2020, and 1.82 million people had died of COVID-19 disease.¹ During the COVID-19 pandemic, like all surgical procedures, solid-organ transplant processes were adversely affected in many ways.² Patients on the lung transplant wait list have had to face the risk of SARS-CoV-2 infection in addition to the morbidity and mortality of their existing diseases. Causes such as high-dose immunosuppressant therapy, prolonged hospitalization, and transmission from asymptomatic health care personnel increase the risk of SARS-CoV-2 infection for lung transplant recipients.^2,3 The fact that health care providers had to deal with this unexpected public health problem, which nearly exhausted all institutional capacity, negatively affected the donor organ procurement/preparation process, which is managed in intensive care units and requires intense attention. As a result, the number of lung transplants has decreased substantially with the decrease in donor organ presentations.

In this study, we analyzed donors and the lung transplant operations that we performed in a period of 9 months as of March 11, 2020, when the first COVID-19 case was reported in Turkey.⁴ We emphasized our donor evaluation process (Figure 1), as well as the measures taken during and after the operation.

Materials and Methods

This study was designed as a retrospective, descriptive, and cross-sectional study. The study included 15 lung donors presented by the national coordination center to the Lung Transplantation Unit of University of Health Sciences, Ankara Hospital as of March 11, 2020, when the first COVID-19 case was reported in Turkey, and 5 lung transplant cases managed in this period. Donor information was electronically obtained from the National Organ and Tissue Transplant Coordination Center, and the medical records of lung transplant recipients were reviewed.

During this period, 15 donors diagnosed with brain death and who tested negative for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR), studied on 2 nasopharyngeal and deep tracheal aspirate samples sent over at least 24-hour intervals to eliminate the infection (in line with recommendations from the Ministry of Health of the Republic of Turkey), presented to our center for donor evaluation. In the donor evaluation process, the donor’s history of contact with people with confirmed or suspected SARS-CoV-2 infection was questioned. Chest computed tomography (CT) was performed for all of the donors at admission. An additional chest CT was ordered on the day of organ presentation for the radiological elimination of COVID-19 for donors considered to meet the organ acceptance criteria of our center.

Of the 15 donors, 5 (33.3%) were evaluated to be eligible for lung transplant. All of the accepted donors were in centers that required airline transportation. Organ procurement processes were performed by the procurement team, which consisted of only 2 surgeons. In compliance with the recommendations of the Ministry of Health Science Board, during trans­portation, the procurement teams wore surgical masks. From the bronchoalveolar lavage (BAL) samples collected during the fiberoptic bronchoscopy (FOB) procedure, which is followed as a standard protocol before procurement, samples were also collected for SARS-CoV-2 RT-PCR. Organ procurement was carried out in the presence of only the essential number of personnel needed for the task.

During the COVID-19 pandemic period, all 5 candidates for lung transplant reached our center after donor organs were accepted, and after we obtained detailed anamnesis for COVID-19 from all of the candidates; rapid RT-PCR tests from nasopharyngeal swabs along with routine blood tests and chest radiographies were performed for SARS-CoV-2. The patients were not transferred to the operation site until negative PCR results were confirmed. During the recipient pneumonectomy and implantation stages, the entire operation team wore N95 filtering facepiece respirators without exhalation valves and also wore surgical masks
in addition to standard surgical clothing. The procurement team was not included in recipient surgeries, to avoid the potential increase in risk.

All 5 recipients of bilateral lung transplant were transferred to the intensive care unit with mechanical ventilation as the only support. All of the lung transplant recipients at our center are followed up in isolated intensive care units reserved exclusively for organ transplant patients. Fiberoptic bronchoscopy was performed on the recipients who were transferred to the isolated intensive care unit at the first opportunity, and RT-PCR tests were ordered from BAL samples for SARS-CoV-2. During the intensive care follow-up, the patients received FOB daily, the RT-PCR test was performed from BAL samples each time for SARS-CoV-2, and the RT-PCR test was carried out from nasopharyngeal, conjunctival, and rectal swab samples collected from the recipients. After the patients were hemodynamically stabilized, they were evaluated with thorax CT scans performed between postoperative days 10 and 15. In all recipients, immunosuppressive drug administration, antibiotic prophylaxis, and conservative approaches were managed as in the pre-COVID-19 period.

Statistical analyses were performed with SPSS software (version 22.0). Descriptive statistics are presented as mean values ± SD, number, and percentage of total. A P value of <.05 was considered statistically significant.

This study was approved by both the local ethics committee and the Ministry of Health of the Republic of Turkey.

Results

In 2020, 15 donor organs were presented to our center for lung transplant evaluation as of March 11, 2020. The number of donor presentations for lung transplant between the same dates in the previous year was 78 (Figure 2). In 2020, there were 5 lung transplants performed in our center as of March 11, 2020. The comparison of the data of donors presented to our center for both periods is presented in Table 1.

Of the total potential donors, 6 were female (40%) and 9 were male (60%) (Table 1), with a mean age of 37.9 ± 14.0 years (range, 9-53 years). Of the accepted donors, 4 were male and 1 was female. The brain death causes for the donors were blunt head trauöma (n = 8; 53.3%), cerebrovascular accident (n = 4; 26.7%), firearm injury (n = 2; 13.3%), and drug intoxication (n = 1; 6.7%). The brain death causes of 4 and 1 of the accepted donors were head trauma and cerebro­vascular accident, respectively (Figure 3). The des­criptive data of the donors are presented in Table 2.

The ratio of Pao₂ to fraction of inspired oxygen (Pao₂/Fo₂) was over 300 mm Hg in all of the accepted donors. The Pao₂/Fo₂ ratio was below 300 mm Hg in 7 of the rejected donors. One of the other 3 donors had Acinetobacter growth in the blood culture. Another patient with a history of multiple trauma had bilateral diffuse contusion areas on thorax CT and a smoking history of more than 20 pack-years. Although the SARS-CoV-2 RT-PCR test of the other patient with a brain death cause of gunshot injury was negative, the organ was rejected because bilateral pneumonic infiltration was noted in the thorax CT performed on the day of presentation.³

There were no statistically significant differences between the accepted donors and the rejected donors in terms of Pao2/Fo2 ratio, age, duration of endotracheal intubation, and smoking (pack-years) (Table 3).

None of the donors had a history of contact with a COVID-19-positive individual in the last 14 days. The mean endotracheal intubation duration of the donors was 3.9 ± 2.5 days (range, 2-10 days). For all donors, the SARS-CoV-2 RT-PCR tests ordered from the tracheal aspirate and nasopharyngeal swabs (at least 24-hour intervals from the date of endotracheal intubation to the date of presentation) were negative. The results of the SARS-CoV-2 RT-PCR tests ordered from the BAL samples collected by FOB before organ procurement were also negative.

The mean total follow-up time of our recipients was 33.6 ± 3.7 days (range, 30-39 days). The mean intensive care follow-up time was 13.8 ± 2.7 days (range, 10-17 days), and the mean follow-up time after intensive care until discharge was 19.8 ± 1.4 days (range, 19-22 days). All of the SARS-CoV-2
RT-PCR results of the nasopharyngeal, conjunctival, and rectal swabs and BAL samples obtained posto­peratively from the recipients were negative. No pathological finding suggestive of COVID-19 was noted on follow-up CTs and posteroanterior chest radiographs.

In our center, the SARS-CoV-2 RT-PCR tests are regularly performed for all physicians and auxiliary staff within the scope of health screening.

Discussion

According to the National Organ Coordination data, the annual average number of lung transplants performed in our country in the past 5 years was 34 (range, 22-43), whereas only 11 lung transplants could be performed in 2020, and 5 of which were before March 11, 2020, when the first COVID-19 case was seen in Turkey. As a result of the COVID-19 pandemic, it is emphasized that patients on the wait list are affected by organ scarcity and high mortality rates because of the striking decrease in the number of solid-organ transplants.⁵ Compared with the prepandemic period, the number of donors presented to our center and the number of lung transplants performed in our center have significantly decreased. In the 9-month period, our center had only 15 lung presentations, with 5 of these donor organs being accepted (33.3%). During the same time period in the previous year, 78 lung donors were presented to our center, and 16 of these were accepted (20.5%). Although it is not possible to make an accurate comparison for this situation, in which many factors may be in play, we speculate that the number of donor presentations decreased significantly, at least in the COVID-19 pandemic period, whereas the organ availability rates did not decrease.

To ensure the continuity of organ transplants, recommendations for process management are provided by authorized centers.^6-8 It is highly recommended that donor history be thoroughly questioned for COVID-19, and the rapid SARS-CoV-2 RT-PCR test should be a routine part of donor and recipient evaluation.^5,6 A negative test result is recommended to be confirmed twice.^6,9,10 The false-negative rates for the SARS-CoV-2 test from nasopharyngeal samples have been reported to range from as low as 2% to as high as 30% to 40%.^5,7,8 Sampling from BAL is the most effective method for viral detection with very low false-negative rates, especially in cases of high clinical suspicion and in settings in which SARS-CoV-2 exposure is suspected, due to such variable rates.^5,9,10 However, BAL cannot be performed on every patient because of the risk associated with the potentially high rate of aerosol formation and the requirement for competent personnel. In addition, the SARS-CoV-2 RT-PCR sampling from BAL samples has a higher sensitivity in the later stages of infection, whereas the nasopharyngeal swab test has the highest sensitivity in the early period.^9,10

Some researchers argue that the sputum test for SARS-CoV-2 is more reliable and sensitive in both the early and late stages of the disease.¹¹ During our study period, at least 2 SARS-CoV-2 RT-PCR tests were performed from both nasopharyngeal swab and tracheal aspirate samples in the evaluation of the donor lung, and donor history was questioned in detail in terms of COVID-19 contact. Second RT-PCR samples were collected 24 hours later instead of 48 hours later, to lower the risk to donor hemo­dynamics. Donors with negative PCR results were presented for transplant. Furthermore, for the 5 lung donations that we accepted, the SARS-CoV-2 RT-PCR was ordered from BAL samples during the bronchoscopic evaluation before procurement. An additional RT-PCR test was performed for SARS-CoV-2 from nasopharyngeal swabs of the recipients on the day of transplant. In the postoperative period, immediately after the recipients were transferred to the intensive care unit, SARS-CoV-2 RT-PCR tests were conducted again from BAL samples in the first bronchoscopic evaluations. The SARS-CoV-2 RT-PCR was performed from the BAL samples collected during the bronchoscopies performed daily for all the recipients during the intensive care period and during the inpatient ward follow-up when necessary. The SARS-CoV-2 RT-PCR was studied from nasopharyngeal, conjunctival, and rectal swab samples at regular intervals during the follow-up period. None of the transplant patients was found to have a positive test result.

In the diagnosis of COVID-19, the SARS-CoV-2 RT-PCR test and radiological imaging are used in combination. The most significant involvement site of COVID-19 disease is the lungs, and the disease is characterized by pneumonia.^12-14 In radiological evaluation, the first approach is direct radiograph, and in positive cases, pneumonia foci with low opacity (viral pneumonia), which mostly involve the bilateral middle-lower zones, are visualized. However, the sensitivity of direct radiographs is low (30%-60%).¹² In general, nonspecific findings such as ground-glass opacities located peripherally in the lung, consoli­dation areas, and air bronchograms are visualized on thorax CT. A multicenter study reported the most common thorax CT findings of COVID-19 as ground-glass opacity and crazy-paving pattern (86%), the coexistence of ground glass opacity consolidation (64.4%), vascular dilatation and bronchial thickening within the lesion (71.3%), and traction bronchiectasis (52.5%).¹³ In the diagnosis of COVID-19, the sensitivity of thorax CT is quite high, and the SARS-CoV-2 RT-PCR test provides a chance to detect 93% of negative patients earlier.¹⁴ In our study, all donors evaluated during the pandemic period underwent at least 1 thorax CT examination until the time of presentation. Since lung donors are often hospi­talized in intensive care units for a certain period of time, those who met the acceptance criteria were evaluated with thorax CT on the day of presentation. The recipients were followed up with direct radiographs throughout the intensive care period. Although there was no finding in favor of COVID-19, thorax CT was performed between postoperative days 10 and 15 for both routine evaluations and to rule out SARS-CoV-2 infection in the recipients who were highly immunosuppressed. Radiological findings in favor of COVID-19 were not observed in the lungs of any of the recipients.

In the COVID-19 pandemic, it has become critical for transplant centers to manage a successful transplant process under safe conditions.⁶ A study evaluating 778 solid-organ recipients with COVID-19 infection emphasized that the mortality in lung transplant increased 2.5-fold compared with other solid-organ transplants.¹⁵ In the study by Shigemura and colleagues, it was reported that 2 of 17 lung transplant recipients (11%) during the pandemic period developed serious complications and died from SARS-CoV-2 infection.¹⁶ Organ procurement for lung transplants is also one of the factors that can increase the risk of SARS-CoV-2 infection. During the procurement processes of deceased donor organs, surgical teams, mostly from recipient centers, must reach donor centers and perform procurement procedures by traveling significant distances.⁵ For this reason, the existing epidemic brought about both great risks and responsibilities in terms of contamination and contagion to procurement teams.

The statement of the American Society of Transplantation published in April 2020 recommended that transplant centers should temporarily suspend elective living donor transplant or nonurgent deceased donor transplant procedures and that centers should base these decisions on issues such as the level of circulating COVID-19 infection in their areas and/or operational issues (such as testing availability, bed capacity, and availability of basic supplies and equip­ment, including personal protective equipment).¹⁷ It was strongly recommended that transport processes that continue during the pan­demic period be managed with adequate protective equipment.^6,7

We are confident that we have so far managed every stage of the transport processes in this challenging period without any problems with personal protective equipment and diagnostic tests, in compliance with the recommendations of the Ministry of Health.¹⁸ Unlike other solid-organ transplants, we can predict the serious consequences of COVID-19 infections that may develop under the effects of high-dose immunosuppression in recipient lungs, which are in direct contact with the external environment. For this reason, during the pandemic period, we based our primary strategy for a successful lung transplant process on the protection of the recipient lungs, which are almost unprotected under the surgical stress caused by the complex lung transplant procedure and the intense use of immunosuppressives, from this highly contagious infection (Table 4). First, we implemented a detailed set of questions and an examination to increase the potential discovery of risk factors and mitigating circumstances during the donor evaluation process. During the procurement process, we followed the recommendations of the Ministry of Health Science Board.¹⁸ Procurement teams were not included in recipient surgeries, in an effort to avoid higher risk, and personal protective equipment was used by all personnel during intraoperative periods. In the postoperative period, all care and treatment were provided in isolated environments by the least number of health care professionals, all equipped with personal protective equipment. All physicians and auxiliary staff in our center were regularly tested for COVID-19 within the scope of health screening.

Conclusions

Lung transplant, which is the most complex procedure among solid-organ transplants, can be successfully managed by meticulous attention to the necessary measures at every stage of the procedure, despite the high risk of infection to the lungs in the COVID-19 pandemic period. It appears that the major obstacle to the continuity of lung transplant in this period is the limited number of donors. To ensure the continuity of lung transplant, which is the most effective treatment for terminal lung diseases, and to give hope to more patients, new policies should be developed to overcome the organ donor shortage during the pandemic period.

References:

1. World Health Organization. WHO Coronavirus (COVID-19) Dashboard. Accessed December 20, 2020. https://covid19.who.int
   CrossRef - PubMed
   
2. Angelico R, Trapani S, Manzia TM, Lombardini L, Tisone G, Cardillo M. The COVID-19 outbreak in Italy: initial implications for organ transplantation programs. Am J Transplant. 2020;20(7):1780-1784. doi:10.1111/ajt.15904
   CrossRef - PubMed
   
3. Kumar D, Manuel O, Natori Y, et al. COVID-19: a global transplant perspective on successfully navigating a pandemic. Am J Transplant. 2020;20(7):1773-1779. doi:10.1111/ajt.15876
   CrossRef - PubMed
   
4. The Republic of Turkey Ministry of Health. COVID19 Science Committee Guideline; 2020. Accessed March 11, 2020. https://covid19.saglik.gov.tr/
   CrossRef - PubMed
   
5. Merola J, Schilsky ML, Mulligan DC. The impact of COVID-19 on organ donation, procurement and liver transplantation in the United States. Hepatol Commun. 2020. 29;5(1):5-11.doi:10.1002/hep4.1620
   CrossRef - PubMed
   
6. Loupy A, Aubert O, Reese PP, Bastien O, Bayer F, Jacquelinet C. Organ procurement and transplantation during the COVID-19 pandemic. Lancet. 2020;395(10237):e95-e96. doi:10.1016/S0140-6736(20)31040-0
   CrossRef - PubMed
   
7. United Network for Organ Sharing. Current state of donation and transplantation. Accessed September 13, 2020. https://unos.org/covid/
   CrossRef - PubMed
   
8. American Society of Transplant Surgeons. Organ retrieval for transplantation in the COVID-19 era; 2020. Accessed September 13, 2020. https://asts.org/advocacy/covid-19-resources/asts-covid-19-strike-force/asts-covid-19-strike-force-organ-retrieval-guidance#.XrG7wS2ZOt8
   CrossRef - PubMed
   
9. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA. 2020;323(18):1843-1844. doi:10.1001/jama.2020.3786
   CrossRef - PubMed
   
10. Iwasaki S, Fujisawa S, Nakakubo S, et al. Comparison of SARS-CoV-2 detection in nasopharyngeal swab and saliva. J Infect. 2020;81(2):e145-e147. doi:10.1016/j.jinf.2020.05.071
    CrossRef - PubMed
    
11. Wyllie AL, Fournier J, Casanovas-Massana A, et al. Saliva or nasopharyngeal swab specimens for detection of SARS-CoV-2. N Engl J Med. 2020;383(13):1283-1286. doi:10.1056/NEJMc2016359
    CrossRef - PubMed
    
12. Yoon SH, Lee KH, Kim JY, et al. Chest radiographic and CT findings of the 2019 novel coronavirus disease (COVID-19): analysis of nine patients treated in Korea. Korean J Radiol. 2020;21(4):494-500. doi:10.3348/kjr.2020.0132
    CrossRef - PubMed
    
13. Zhao W, Zhong Z, Xie X, Yu Q, Liu J. Relation between chest CT findings and clinical conditions of coronavirus disease (COVID-19) pneumonia: a multicenter study. AJR Am J Roentgenol. 2020;214(5):1072-1077. doi:10.2214/AJR.20.22976
    CrossRef - PubMed
    
14. Ai T, Yang Z, Hou H, et al. Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32-E40. doi:10.1148/radiol.2020200642
    CrossRef - PubMed
    
15. Coll E, Fernandez-Ruiz M, Sanchez-Alvarez JE, et al. COVID-19 in transplant recipients: the Spanish experience. Am J Transplant. 2020. doi:10.1111/ajt.16369
    CrossRef - PubMed
    
16. Shigemura N, Cordova F, Criner G, Toyoda Y. Current precautions and future directions in lung transplantation during the COVID-19 pandemic: a single center cohort study. Transpl Int. 2020;33(11):1453-1457. doi:10.1111/tri.13694
    CrossRef - PubMed
    
17. American Society of Transplantation. COVID-19 information; 2020. Accessed April 28, 2020. https://www.myast.org/covid-19-information
    CrossRef - PubMed
    
18. The Republic of Turkey Ministry of Health, General Directorate of Public Health. COVID19 Guideline (SARSCoV2 Infection), Science Committee Work. Accessed April 24, 2020. https://covid19.saglik.gov.tr/
    CrossRef - PubMed