Journal Pre-proof

Lung transplantation during the outbreak of Coronavirus disease 2019 (COVID-19) in

China

Wu Bo, MD, Huang Man, MD, Jiao Guohui, MD, Hu Chunxiao, MD, Yang Yi, MD,
Chen Jingyu, MD, China Lung Transplantation Alliance (CLTA) and National Lung
Transplantation Expert Group for COVID-19
PII: S0022-5223(20)33147-0
DOI: https://doi.org/10.1016/j.jtcvs.2020.10.154
Reference: YMTC 17143

To appear in: The Journal of Thoracic and Cardiovascular Surgery

Received Date: 17 June 2020

Revised Date: 30 October 2020
Accepted Date: 30 October 2020

Please cite this article as: Bo W, Man H, Guohui J, Chunxiao H, Yi Y, Jingyu C, China Lung
Transplantation Alliance (CLTA) and National Lung Transplantation Expert Group for COVID-19, Lung
transplantation during the outbreak of Coronavirus disease 2019 (COVID-19) in China, The Journal of
Thoracic and Cardiovascular Surgery (2020), doi: https://doi.org/10.1016/j.jtcvs.2020.10.154.

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Copyright © 2020 Published by Elsevier Inc. on behalf of The American Association for Thoracic Surgery
 Title Page

Lung transplantation during the outbreak of Coronavirus disease 2019 (COVID-19) in China

Wu Bo MDa,#, Huang Man MDb,#, Jiao Guohui MDa, Hu Chunxiao MDa, Yang Yi, MDc,*, Chen Jingyu,

MDa,d*, and China Lung Transplantation Alliance (CLTA) and National Lung Transplantation Expert Group

for COVID-19.

a Wuxi Lung Transplant Center, Wuxi People’s Hospital affiliated to Nanjing Medical University, Wuxi,

China.

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b General ICU, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

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c Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University,
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Nanjing, China.
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d Center for Lung Transplantation, China-Japan Friendship Hospital, Beijing, China.

# Contribute equally to the work

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*Corresponding author full contact details:

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Yang Yi, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast
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University, Nanjing, China.

Email: yiyiyang2004@163.com

Chen Jingyu, QingYang Road, No 299#, Wuxi Lung Transplant Center, Wuxi People’s Hospital affiliated to

Nanjing Medical University, Wuxi, China, 214023

Email: chenjy@wuxiph.com

Funding: Research funding for “lung transplantation as therapeutic option for COVID-19 related critical

patients” (N2020X002).

Article word count 3700

Conflict of interest: None

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 1 Title Page

2 Lung transplantation during the outbreak of Coronavirus disease 2019 (COVID-19) in China

3 Wu Bo MDa,#, Huang Man MDb,#, Jiao Guohui MDa, Hu Chunxiao MDa, Yang Yi, MDc,*, Chen

4 Jingyu, MDa,d*, and China Lung Transplantation Alliance (CLTA) and National Lung Transplantation

5 Expert Group for COVID-19.

6 a Wuxi Lung Transplant Center, Wuxi People’s Hospital affiliated to Nanjing Medical University,

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Wuxi, China.

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b General ICU, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou,
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9 China.
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10 c Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast

11 University, Nanjing, China.

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12 d Center for Lung Transplantation, China-Japan Friendship Hospital, Beijing, China.

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13 # Contribute equally to the work

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14 *Corresponding author full contact details:

15 Yang Yi, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast

16 University, Nanjing, China.

17 Email: yiyiyang2004@163.com

18 Chen Jingyu, QingYang Road, No 299#, Wuxi Lung Transplant Center, Wuxi People’s Hospital

19 affiliated to Nanjing Medical University, Wuxi, China, 214023

20 Email: chenjy@wuxiph.com

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21 Funding: Research funding for “lung transplantation as therapeutic option for COVID-19 related

22 critical patients” (N2020X002).

23 Article word count 3490

24 Conflict of interest: None

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26

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27 Abbreviations and Acronyms

28 COVID-19 coronavirus disease 2019

29 CT computed tomography

30 SARS-COV-2 severe acute respiratory syndrome coronavirus 2

31 LTx lung transplantation

32 BMI body mass index

33 ECMO extracorporeal membrane oxygenation

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34 MV mechanical ventilation

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35 IQR interquartile range

36 FiO2 fraction of inspiration O

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37 EF ejection fraction
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38 PAP pulmonary artery pressure

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39 SOFA sequential organ failure assessment

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40 LAS lung allocation score

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41

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42 Keywords COVID-19, lung transplantation, China, ECMO, outcome

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43 Central Picture

44 Overall survival of lung transplantation recipients by Kaplan-Meier plots, comparing the outcome of

45 patients who were transplanted during January 23rd - March 23rd, in 2019 (Cohort 2019) and in 2020

46 (Cohort 2020).

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48 Central Message: Lung donation and transplantation amid COVID-19 could be performed safely and

49 could be the salvaging therapy for critical post-COVID-19 patients.

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Perspective: Candidates referral and transplantation can be adopted with coordinated effort on
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52 medical resource sharing and medical staff protected according to the stratification of infection risk.
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53 Short term follow-up of transplanted critically severe COVID-19 patients with confirmed

54 positive-turned-negative virology status demonstrated a promising result.

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56 Abstract

57 Objectives: To illustrate our workflow for lung donation and transplantation during the COVID-19

58 crisis and report our preliminary experience with perioperative care.

59 Methods: We retrospectively analyzed data in the China Lung Transplantation Registration from

60 January 23rd, 2020, to March 23rd, 2020 (2020 cohort), compared to the same period in 2019 (2019

61 cohort). Pre- and post-lung transplantation (LTx) management strategies, including measures aiming

62 to prevent SARS-CoV-2 infection, were applied for all recipients, including five post-COVID-19

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transplants during the COVID-19 pandemic period in China.

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Results: Twenty-eight LTx procedures were performed, including LTx for five patients with acute
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65 respiratory distress syndrome (ARDS) due to COVID-19-related pulmonary fibrosis. Compared to
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66 the 2019 cohort, more patients with urgent conditions were transplanted in 2020, with a shorter
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67 pre-LTx admission time and early mobilization post-LTx. A large proportion (60%) of lung donations

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were transported on high-speed trains and commercial flights or commercial flights and highways.

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Grafts in the preservation containers were handed over to the receiving staff at the airport for 40%

70 (10/25) of donations, which reduced the unnecessary quarantine of transporting staff entering the city.

71 Listed candidates were urgently transferred to other qualified centers in 17.9% (5/28) of cases, which

72 reduced the risk of SARS-CoV-2 exposure in COVID-19 designated hospitals. The 90-day survival

73 rate of the recipients transplanted in 2020 was 85.7%, including 3 of 5 (60%) recipients who were

74 critically severe COVID-19 patients.

75 Conclusion: LTx and lung donation amid COVID-19 can be performed safely with coordinated

76 efforts on medical resource sharing and medical staff protection based on stratification of the

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77 infection risk. Outcomes were not compromised during the COVID-19 outbreak. LTx can be

78 regarded as salvage therapy for critical COVID-19 patients with a confirmed

79 positive-turned-negative virology status.

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 80 Introduction

81 SARS-CoV-2-induced COVID-19 is a global pandemic that is wreaking havoc worldwide1.

82 Sustained community transmission of the virus continues despite the adoption of precautionary

83 measures, such as quarantine and temporary city lockdowns. The "new normal" post-COVID-19

84 pandemic era may permanently change our previous model of medical care. The COVID-19

85 outbreak in cities saturated the healthcare system and decreased organ donation and transplantation

86 activity due to the risk of cross-infection with unrecognized viral shedding by potential donors and

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87 recipients2. For transplantation centers, the balancing of resources to ensure the safety of recipients,

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listing candidates and professionals while carrying out elective and urgent lung transplantation (LTx)
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89 surgeries remains a considerable challenge. Publications and guidelines on screening donors,
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90 assessing recipients and preventing the risk of SARS-CoV-2 infection emerged3-4. However,

91 evaluations of the LTx performed during the COVID-19 outbreak remain scarce.
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92 We collected LTx data from the time when the city of Wuhan declared a state of emergency and
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93 imposed a lockdown with containment measures on January 23rd 2020, to provide our experience of
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94 in the management and prompt resumption of LTx activity during the unprecedented outbreak of

95 COVID-19. The number of existing confirmed COVID-19 cases decreased in China after February

96 15th, and candidates listed for LTx were gradually admitted to LTx centers, and donated grafts were

97 transported based on a collaborative effort by the China Lung Transplantation Alliance (CLTA)5 (see

98 detailed information in the Supplementary text). We further documented post-LTx outcomes,

99 including data from five recipients who were critical COVID-19 patients with confirmed

100 positive-turned-negative virology status (hereafter referred to as post-COVID-19 patients), to

101 confirm the feasibility and safety of performing lung donation and transplantation in the midst of the

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102 COVID-19 pandemic.

103 Methods

104 Study population

105 We retrospectively analyzed nationwide data in the Chinese lung transplantation registry from

106 January 23rd, 2020, to March 23rd, 2020 (2020 cohort). Data collected from January 23rd 2019, to

107 March 23rd, 2019 (2019 cohort), were used as a benchmark for outcomes in 2020. As the study

108 employed a retrospective design and data were analyzed anonymously, this study was exempt from

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ethical approval and the requirement of obtained informed consents from patients. This study was

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conducted in compliance with the provisions of the Declaration of Helsinki.
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111 Ethics
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112 The Institutional Ethics Committees of all the qualified centers approved the procedures, including

113 verbal consent procedures and data collection. Written informed consent was obtained from the
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114 patients and next of kin. The transplanted organs were obtained from volunteer donations, and the
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115 next of kin voluntarily provided written informed consent. No lungs were obtained from executed
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116 prisoners5. The Institutional Ethics Committees of the Organ Procurement Organization (OPO)

117 approved the donation procedures. Donor lungs were allocated through the China Organ Transplant

118 Response System (COTRS) (https://www.cot.org.cn/) with comprehensive consideration of factors,

119 such as the recipient’s body size, blood type, and urgency status, the locations of the donors and

120 recipients, and time spent on the waiting list. The National Transplant Medical Review Board

121 (Chinese Lung Transplantation Society and Transplantation Data Management & Quality Control

122 Center) approved and registered the donors’ and recipients’ data (Supplementary Figure 1).

123 Organ donation, allocation and logistics

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124 The routine protocol for donated lung transportation and transplantation in China was based on the

125 CLTA-coordinated workflow after September, 2018 (see the supplementary material)5. Special

126 measures were applied during the COVID-19 pandemic to protect medical staff and recipients from

127 the risk of infection. Collaboration was implemented among the members of the CLTA. Lung

128 recovery teams and transplantation teams participated in the online discussion and shared the entire

129 donor’s medical information with continuous updates. Inter-city quarantine policies were considered

130 before scheduling procured lung transportation. If long-distance transportation was anticipated, staff

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from the procurement team transported the organ preservation containers to the airport in the

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receiving city. The donated grafts were handed over to receiving staff at the airport, and the
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133 transporting staff returned directly to their resident city on the next outbound flight.
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134 During the COVID-19 pandemic, some of the transplant team members, who were also proficient

135 with critical care or extracorporeal membrane oxygenation (ECMO) maintenance, were called to
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136 support designated hospitals in Wuhan and served as auxiliary medical teams in Wuhan city. Centers
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137 in other cities were designated as COVID-19 hospitals, and medical resources were reallocated per
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138 local government policies. Therefore, key personnel and medical resources from various transplant

139 centers were diverted to Wuhan and COVID-19 patients, which imposed a strain on the manpower of

140 individual centers in the capacity to offer LTx services. At the onset of the expected surge of

141 COVID-19 cases, all elective lung surgeries were temporarily cancelled in Wuxi People’s Hospital,

142 which hosts the largest LTx program in China6 but was designated for the care of COVID-19 patients.

143 Candidates waiting in Wuxi center were transferred to Hangzhou center (located approximately 200

144 km away) if their conditions allowed them to tolerate transportation in an effort to protect

145 immunosuppressed and vulnerable patients from the risk of developing COVID-19. Transplant

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146 physicians and surgeons jointly cared for patients with experienced transplant critical care staff.

147 In addition, the Wuxi team prepared another transplant center called “Wuxi communicable diseases

148 hospital” with full transplant equipment and isolation facilities to receive post-COVID-19 patients

149 for LTx (Supplementary Table 1). The transfer plans were prepared according to the transplant

150 center’s capacity, candidates’ locations, the regional risk of infection and medical insurance policies.

151 Variables

152 In general, the registry collected pre-transplant baseline data, post-transplant data at hospital

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discharge, and annual follow-up data. Baseline data included the date of transplantation, age at

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transplantation, gender, body mass index (BMI), blood type and the primary diagnostic indication for
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155 LTx. Donor characteristics, including age, BMI, blood type, donation type, size match, the fraction of
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156 inspired oxygen (FiO2) and ventilation time, were collected.

157 Perioperative and postoperative factors, such as mechanical ventilator (MV) or ECMO use before
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158 and after transplantation, intensive care unit (ICU) duration and hospitalization duration, were
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159 analyzed. The registry received survival data from participating sites and collectives. Patient status
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160 (including living, dead, and lost to follow-up) was recorded. Follow-up data were collected through

161 July 31st, 2020, with censoring at the last known follow-up before this date. As we intended to

162 determine the feasibility of LTx during the COVID-19 pandemic, we collected data pertaining to

163 confirmed cases in cities in which donation occurred and key events that might impact the national

164 organ donation and transplantation workflow.

165 Statistics

166 Demographic data related to donors, recipients and transplants were presented as numbers and

167 percentages for categorical variables. Continuous variables were expressed as the mean ± SD if they

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168 were exhibited a normal distribution or the median [interquartile range, IQR] if they displayed a

169 skewed distribution. Continuous and categorical variables were compared using Student's t-test or

170 the Mann-Whitney U test, chi-square or Fisher's exact test as appropriate. Data calculations and

171 comparisons were performed using SPSS version 25 (SPSS Inc., Chicago, IL, USA) and GraphPad

172 Prism 7 software (GraphPad Software Inc., La Jolla, CA, USA). Kaplan-Meier plots with

173 calculations were used to assess survival. STATA version 16.0 (Stata Corporation, College Station,

174 TX) was used to generate Kaplan-Meier plots. A p value less than 0.05 was considered significant.

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Results

176 Lung donation and transportation -p

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177 Twenty-five donated lungs were obtained after brain death of the donors in 2020 cohort. No history
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178 of epidemiological exposure to SARS-Cov-2 was identified in any of the donors. All donors had

179 normal body temperatures over the previous 30 days and normal chest imaging results. Before a
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180 donation was accepted, the donor was required to have had at least two consecutive negative
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181 nasopharyngeal swab nucleic acid test (NAT) results (at least one day apart) for SARS-CoV-2.
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182 The donor/recipient screening and triage workflow is illustrated in Figure 1. The deceased donor

183 program was suspended in the city of Wuhan, and no donations were accepted from Wuhan city in

184 this period. Fifteen (15/25, 60%) donated organs were transported on high-speed trains and

185 commercial flights or commercial flights and highways (Table 1) compared to 33.9% (19/56) in 2019

186 cohort. Donations were handed over at the airport in 40% (10/25) of cases in 2020 cohort. No

187 donations were handed-over at the airport in 2019 cohort. Meanwhile, transferred LTx cases were

188 recorded for 17.9% (five cases, from Wuxi to Hangzhou) of patients. No transferred cases were

189 recorded in the same period of 2019. Transfers occurred between neighboring qualified LTx centers

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190 that were also CTLA members, facilitating team collaborations and reducing candidates’ waiting

191 time. All patients were transferred without complications or illness exacerbation. The principle of

192 allocating organs to the nearest recipient was still followed. To date, SARS-CoV-2 infection has not

193 been reported in any medical staff involved in the organ donation and transportation process. No

194 significant differences in other donor characteristics were observed between the two groups.

195 Recipients

196 In the 2020 cohort, twenty-eight LTx operations were performed, including LTx for five patients with

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acute respiratory distress syndrome (ARDS) due to COVID-19-related pulmonary fibrosis.

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Twenty-one (75%) males and seven (25%) females received transplants, and the average age was
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199 56.6±15.4 years (Table 2). The recipients were admitted to eight centers distributed in seven cities. In
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200 the 2019 cohort, sixty LTx surgeries were performed in eleven centers.

201 Three high-volume (>30 transplants per year) centers performed 11 LTx operations (39.3%) in 2020,
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202 reflecting a change from the 75% of LTx cases performed by those centers during the same period in
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203 2019 (Supplementary Figure 2). However, no significant differences in gender, age or BMI
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204 distributions were identified between the two years. Patients with idiopathic pulmonary fibrosis

205 accounted for the highest percentage of patients on the waiting list for LTx (33.3% in 2019 vs. 35.7%

206 in 2020).

207 Compared to the 2019 cohort, the 2020 cohort had a significantly shortened median time from

208 admission to LTx (5 days in 2020 vs. 10 days in 2019, p=0.012), and these patients had a higher

209 pulmonary artery pressure (p=0.014) and a lower PaO2/FiO2 (p=0.025) before LTx. Seven LTx

210 recipients (25%) in the 2020 cohort received ECMO and mechanical ventilation (MV) support prior

211 to LTx, including five post-COVID-19 patients. No differences in the number of infection events,

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212 lymphocyte counts and the levels of inflammatory markers were not observed between the two

213 groups. Short-term survival rates were comparable, as illustrated in Figure 2.

214 In addition to the five transplanted post-COVID-19 patients, another nine critical end-stage

215 COVID-19 patients were also referred to the CTLA committee and National Lung Transplantation

216 Expert Group for COVID-19 for urgent LTx evaluations. Details of the patients’ clinical

217 characteristics and preoperative CT imaging (if available) are shown in Supplementary Table 3 and

218 Figure 3. Three of the nine patients (33.3%) survived after weaning off of ECMO and MV support

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without transplantation. The other patients who were not transplanted (66.7%) had uncontrollable

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sepsis, and death could not be avoided. During the COVID-19 pandemic, we transplanted
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221 post-COVID-19 patients supported by ECMO within a shorter time (no LTx vs. LTx, median time
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222 from ECMO to LTx assessment, 57.5 vs. 10 days, p=0.00), approximately one month after a

223 confirmed diagnosis of COVID-19.

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224 Post-LTx surveillance

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225 Excluding the aforementioned post-COVID-19 LTx recipients, none of the other recipients had
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226 epidemiological exposure to COVID-19. All of these recipients had two consecutive negative

227 nasopharyngeal swab results (at least one day apart) before they were added to the recipient list. The

228 five post-COVID-19 patients were consecutively tested for SARS-CoV-2 using multiple types of

229 specimens, including nasopharyngeal swab, anal swabs and bronchoalveolar lavage fluid (BALF).

230 Among the recipients who received transplantation in the 2020 cohort, 27 patients survived after LTx,

231 and the 30-day survival rate was 89.3%, as shown in Table 3. Patient 1, who was the first LTx

232 recipient post-COVID-19, died due to uncontrolled bleeding during the procedure. The cause of

233 death for the other patient (patient 5) was severe sepsis. The characteristics of the other

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234 post-COVID-19 patients are shown in Table 4. The patients were supported by MV and ECMO (at a

235 median time of 13 days). ECMO was weaned shortly after LTx in the four surviving recipients.

236 Considering the severely impaired immune function of these recipients before LTx, two

237 immunosuppressant treatment strategies were considered at the Wuxi center and Hangzhou center.

238 Prescriptions were initiated with a lower dose than routinely required, and drug doses were adjusted

239 according to lymphocyte counts and drug plasma concentrations. One recipient treated at the

240 Hangzhou center presented with acute rejection and a higher dose of steroid was included as part of

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241 the treatment strategy7. Maintenance therapy, including tacrolimus-based and cyclosporine A-based

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regimens, were initiated at a lower dose and adjusted gradually. During the first month post-LTx, the
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243 plasma concentration of tacrolimus was maintained within 6-7 ug/L (mean lymphocyte count 0.55×
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244 109/L). In cyclosporine A-based regimen, trough levels (C0) of cyclosporine A were maintained at an

245 average of 30 ug/L, and levels at 2 hours post-dose (C2) fluctuated within 100 ug/L (mean
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246 lymphocyte count 0.30×109/L ).

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247 The post-LTx courses and events of the post-COVID-19 patients did not deviate from the general
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248 cohort. However, all of these patients had extremely low muscle strength due to prolonged intubation

249 with sedation. Therefore, progressive rehabilitation training was warranted, including active

250 mobilization (e.g., a bed bicycle), swallowing, breathing exercises, secretion clearance, and posture

251 improvement. Balancing activities, building upper and lower extremity range of motion and active

252 coughing were encouraged. Upon this writing, all the other post-COVID-19 recipients have survived

253 post-LTx for 3 months with lymphocyte count level around 0.8~1.0×109/L. The one-year survival

254 conditional upon discharge for 2019 cohort was 90.7% and three-month survival post-LTx for 2020

255 cohort was 85.7%.

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256 Discussion

257 During the COVID-19 pandemic, global recommendations regarding organ donation and

258 transplantation have been released8-10. NATs for SARS-CoV-2 in BALF were even mandated for

259 screening tissues from deceased donors to ensure the absence of SARS-CoV-2 infection11. Interim

260 precautions, including the screening of care providers and family members who accompanied

261 recipients, were also warranted (Supplementary Table 2). Personnel involved in donor maintenance,

262 transplant coordinators, personnel certified to make brain death determinations, and Red Cross staff

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263 were screened in accordance with national guidelines12. As shown in Figure 3, 80% of donation

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264 procedures were performed after February 15th, when most cities in China had a continuously
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265 decreasing trend of existing confirmed COVID-19 cases, and lung transplantation activities resumed.
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266 With prevention measures, the organ recovery teams and patients transferred to qualified centers

267 were separated from confirmed or suspected COVID-19 patients to guarantee that LTx proceeded
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268 smoothly.
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269 Especially for critical end-stage COVID-19 patients, additional screening considerations and
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270 principles were applied when they were referred for assessment, listed and received LTx. Upon the

271 decision for LTx referral, the patients had refractory respiratory failure dependent on MV/circulation

272 support for at least one month without severe hepatorenal or heart failure, and multiple samples

273 negative for SARS-CoV-2 on at least two consecutive occasions, with IgM(-), IgG(+) or IgG(-). In

274 the five transplanted post-COVID-19 patients, LTx was considered within 3 weeks of ECMO

275 initiation as guidelines recommended that 21-day ECMO support without lung recovery might be

276 futile13. However, as we learned more about COVID-19 and observed more patients weaning off of

277 ECMO support after more than 3 weeks, the best time for consideration of LTx should be further

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278 explored while following up all these recipients. Continuous renal replacement therapy was used

279 more frequently in LTx patients for non-renal indications during LTx, to remove inflammatory

280 mediators14. All of the referred patients had extremely high lung allocation scores (LASs), revealing

281 a “ceiling” effect of LASs in capturing high-risk features to stratify urgent listed patients with a high

282 mortality rate related to COVID-1915-16. Higher level of SOFA (sequential organ failure assessment)

283 scores were also observed in transplanted patients (Supplementary Table 3). SOFA scores changed

284 substantially one week post-LTx, which indicates a reduced risk of mortality17. We would

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286 immune status, and experience of the medical team. -p

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287 For post-LTx management, we recommended the use of conventional immunosuppressant drugs
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288 based on institutional protocols for non-COVID-19 patients. Meanwhile, earlier initiation of

289 post-LTx rehabilitation and a reduced ICU stay with additional psychological support considerably
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290 improved patients’ confidence in their survival. We ascribed the relatively shorter ICU stay of the
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291 urgent transplant recipients to the reduced case load in the ICU, where only non-COVID-19 patients
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292 were admitted. After weaning from ECMO and intubation, these patients were transferred to single

293 rooms for further treatment.

294 As we had taken measures to prevent SARS-CoV-2 infections in non-COVID-19 post-LTx recipients,

295 procedures, such as bronchoscopies, were performed under routine protective conditions. Close

296 cooperation with other departments (e.g., radiology) enabled us to prepare single examination units

297 for the recipients. More importantly, psychological support and consultations for all medical staff and

298 recipients were provided during the COVID-19 crisis. Most centers imposed a no-visitor policy

299 during the COVID-19 pandemic, but video communication and interactions with families were

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300 encouraged for patients admitted to isolation wards. Due to city-wide containment measures during

301 the COVID-19 pandemic, recipients were admitted to single rooms for prolonged periods after

302 discharge from the ICU. Evidence from our transplanted patients did not reveal a higher risk of

303 SARS-CoV-2 infection at five months after transplantation. Post-LTx infection control was always a

304 big challenge in the 30-day survival of Chinese recipients, and a lower nosocomial infection rate was

305 achieved in 2020 cohort, which was a significant decrease (p=0.004) compared to 2019. Considering

306 the dynamic status of SARS-CoV-2 transmission in the long term, we suggest the adoption of two

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strategies in advance to facilitate scheduled LTx procedures: the inter-center transfer of candidates

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with collaborative effort is necessary to avoid COVID-19 exposure in the designated center; and
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309 donated lungs transported over long distances are handed over at airports without staff entering cities
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310 to avoid requiring quarantine. Strategies based on multi-team collaboration are recommended to

311 guarantee the safety of recipients and post-LTx outcomes.

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312 Reports from heart transplant recipients showed that COVID-19 infections in these patients had a
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313 milder course, possibly due to the concomitant use of immunomodulatory drugs18. This finding
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314 further enhances our confidence in excluding possible subclinical cases of COVID-19 when

315 interpreting lymphopenia due to the effects of immunosuppressant therapy. During the routine

316 follow-up visits of LTx recipients at the Wuxi center, no cases of COVID-19 were reported to the

317 center or during telemedicine-based consultations. However, the dose of immunosuppressant for

318 post-COVID-19 LTx recipients should be modified on a case-by-case basis due to severe

319 lymphopenia before transplantation. Critical COVID-19 patients presented with cytokine release

320 syndrome as a signature of immune function impairment19. Although intensive life support facilities

321 were available for patients with negative NAT and positive serum SARS-CoV-2 IgG results, death

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322 was unavoidable in some patients unless urgent LTx was performed20. All of the post-COVID-19

323 patients in our study received convalescent serum before transplantation, but none showed a

324 sensitized status before transplantation. Cyclosporine A inhibited diverse coronaviruses21, and it was

325 safely administered to other transplant recipients22. Tacrolimus was also safely used in the other

326 regimen adopted at the Hangzhou center. Close monitoring of the plasma concentration and more

327 importantly, lymphocyte and CD4+ and CD8+ T cell counts is particularly important.

328 There are much more research results published on the fibrosis-promoting environment observed in

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329 patients with severe COVID-19 from single-cell analysis23 and immune disturbance involving

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330 mechanisms, such as T cell exhaustion during COVID-19 progression24. Our data also verified that
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331 the death rate for critically ill patients with severe COVID-19 may be extremely high if they did not
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332 receive a transplant. Our transplanted post-COVID-19 patients exhibited a normalized level of IL-6

333 and restored CD4+/CD8+ populations on immunosuppressants. The patient who died post-LTx at
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334 POD 71 suggested that precise monitoring of immune status and drug modification still require
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335 improvement. We need to gain more experience and knowledge from the long-term follow-up of the
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336 surviving patients.

337 The limitations of this study should be considered when interpreting the data given the retrospective

338 nature of the analysis. The baseline characteristics of the patients varied with respect to underlying

339 comorbidities, especially in critical patients suffering from COVID-19. Confounder effects should be

340 considered when determining the survival outcomes of LTx patients between cohorts, which may

341 require further investigation. We compared data from only two years because a renewed lung

342 donation, transportation and transplantation collaboration system has been established since

343 September 2018 in China. We still need more data to demonstrate whether this system can operate

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344 during health crisis events, such as COVID-19, which may have an enormous impact on health

345 systems in the entire nation. The uniqueness of the lung donation and allocation system in China, and

346 the Green Channel for lung transportation, may differ from the systems in other countries. However,

347 even if a globally decreasing trend of the COVID-19 pandemic is achieved and people face the "new

348 normal" post-COVID-19 pandemic era, a new paradigm for lung donation and transportation should

349 be considered to account for future uncertainty.

350 Conclusion

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351

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Our preliminary data described the feasibility and safety of lung donation and transplantation during

352 -p
the COVID-19 pandemic. Our initial efforts serve as a basis for management practices among
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353 transplant teams, thus safeguarding vulnerable donors, recipients and related medical staff. In the
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354 context of the COVID-19 outbreak, the global community should work together to save lives and

355 benefit patients.

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358 Reference
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362 2 Zhang BH, Yan LN, Yang JY. Organ transplantation management in the midst of the COVID-19
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368 4 Guidance on Coronavirus Disease 2019 (COVID-19) for Transplant Clinicians. Updated 16
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376 7 Han WL, Zhu MH, Chen Jun, et al. Lung Transplantation for elderly patients with end-stage
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380 9 Ianiro G, Mullish BH, Kelly CR, et al. Screening of faecal microbiota transplant donors during the
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386 11 Ministero Della Salute. Oggetto: aggiornamento delle misure di prevenzione della trasmissione

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401 16 Tang A, Thuita L, Siddiqui HU, et al. Urgently Listed Lung Transplant Patients Have Outcomes
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403 doi.org/10.1016/j.jtcvs.2020.02.140.
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404 17 Karakike E, Kyriazopoulou E, Tsangaris I, Routsi C, Vincent JL, Giamarellos-Bourboulis EJ.

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405 The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: analysis through
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407 18 Ren ZL, HuR, Wang ZW, et al. Epidemiological and clinical characteristics of heart transplant
408 recipients during the 2019 coronavirus outbreak in Wuhan, China: A descriptive survey report. J
409 Heart Lung Transplant, 2020, https://doi.org/10.1016/ j.healun.2020.03.008.
410 19 D'Antiga L. Coronaviruses and immunosuppressed patients. The facts during the third epidemic.
411 Liver Transpl. 2020 Mar 20. doi: 10.1002/lt.25756.
412 20 Moore JB, June CH. Cytokine release syndrome in severe COVID-19. Science.
413 2020;368(6490):473 474. doi:10.1126/science.abb8925.
414 21 Chen JY, Qiao K, Liu F, et al. Lung transplantation as therapeutic option in acute respiratory
415 distress syndrome for COVID-19-related pulmonary fibrosis. Chin Med J (Engl).

22
416 2020;10.1097/CM9.0000000 000000839.
417 22 de Wilde AH, Zevenhoven-Dobbe JC, van der Meer Y, et al. Cyclosporin A inhibits the replication
418 of diverse coronaviruses. J Gen Virol. 2011;92(Pt 11):2542 2548.
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422 Progression. Cell Host Microbe. 2020;S1931-3128(20)30185-2.
423

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424 Table 1 Donor characteristics and donated lung transportation

January 23rd - January 23rd - P

March 23rd, 2019 March 23rd, 2020 value
Transportation via GCHOTa (%) 19(33.9) 15(60)
Median Transportation distance 300 [IQR 30-1350] 725[IQR 20-1200] 0.827
(km)
Donor Transportation time (h) 3.2±1.8 3.3±1.7 0.772
Donor age (years) 35.6±13.6 39.1±13.7 0.455
Donor on ventilator (days) 7.5±9.1 7.4±9.6 0.984
Donor type (%)
DBD 54(96.4) 25(100)
DBCD 2(3.6)

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425 Abbreviations: GCHOT, green channel of human organ transportation; DBD, donation after brain

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426 death; DBCD, donation after brain and cardiac death.

427
a
-p
GCHOT was activated when long-distance organ transportation was needed, included connection of
428
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high-speed train and commercial flight or, commercial flight and highway.

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 431 Tab
432 le 2
January 23rd,- January 23rd, - 433 Cha
March 23rd, 2019 March 23rd, 2020 434
P value ract
Transplant Volume 60 28 435 erist
Transplant centers 11 8 436 ics
Age (years) 56.3±13.3 56.6±15.4 0.933437 of
Median admission to LT (days) 10 [IQR:1-22] 5 [IQR:1-25] 0.012438 LTx
Male: Female (Male %) 52/8 (86.7) 21/7 (75) 0.225439 reci
BMI (kg/m2) 19.9±3.4 21.2±4.3 0.157440 pien
Main Diagnosis 441 ts in
ARDS* (%) 0 1(3.6) 442 the
COVID-19 (%) - 5(17.8) 443 sam

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IPF (%) 20(33.3) 10(35.7) 444 e
ILD-non IPF (%) 11(18.3) 2(7.2) 445 peri

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2(3.4) 2(7.2) 446 od
IPAH (%)
447 of
COPD (%)
Pneumoconiosis (%)
17(28.3)
5(8.3)
-p 6(21.4)
1(3.6)
448
449
201
9
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Cystic fibrosis (%) 0 1(3.6)
450 and
Bronchiectasis (%) 3(5) 0
451 202
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LAM (%) 1(1.7) 0

452 0
Non-IPAH (%) 1(1.7) 0
na

Pre-LTx status
Admitted in general ward (%) 46(76.7) 14(50) 0.016453 Abb
Admitted in ICU (%) 14(23.3) 14(50) 454 revi
ur

Pre-transplant MV (%) 9 (15) 8 (28.6) 0.154455 atio

ECMO+MV (%) 6(10) 7 (25) 0.104456 ns:
Jo

Mean PAP(mmHg) 23.2±9.4 39.1±18.8 0.014457 LTx,

Ejection fraction (%) 65.7±6.2 66.4±14.4 0.832458 lung
Creatinine (umol/L) 63.90±35.5 61.1±13.7 0.612459 tran
19.9±60.6 17.5±27.7 0.865460 spla
Total bilirubin (umol/L)
ALT (U/L) 34.8±53.7 30.2±27.4 0.723461 ntati
462 on;
PaO2/FiO2 before LTx 263.9±105.2 189.8±108.9 0.025
463 BMI,
(mmHg)
464 bod
465 y mass index; ARDS, acute respiratory distress syndrome; IPF, idiopathic pulmonary fibrosis; ILD,
466 interstitial lung diseases; IPAH, idiopathic pulmonary artery hypertension; COPD, chronic
467 obstructive pulmonary diseases; LAM, lymphangioleiomyomatosis; ECMO, extracorporeal
468 membrane oxygenation; MV, mechanical ventilation; PAP, pulmonary artery pressure.
469 *ARDS due to non-COVID-19 viral pneumonia
470

25
471 Table 3 Characteristics of grafts and recipients’ outcomes

January 23rd - January 23rd - P value

March 23rd, 2019 rd
March 23 , 2020
Cold Ischemic time (hours) 7.6±2.1 7.1±1.5 0.480
Duration of surgery (hours) 5.4±2.9 5.4±2.1 0.905
Transplantation type
Bilateral (%) 28(46.7) 17(60.7) 0.257
Singlea (%) 32(53.3) 11(39.3)
ICU stay (days) 11.9±14.8 7.8±2.3 0.043
(Ex.
post-COVID-19)
19 (31.7) 8 (28.6) 0.810

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PGD T72h (≥grade 2)
In-hospital infection episodes (%) 45 (75) 12 (42.8) 0.004

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30-day survival (%) 48 (80) 25(89.3)
90-day survival (%) 43(71.7)
-p 24(85.7)

472
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Abbreviations: Ex., excluded. PGD, primary graft dysfunction.
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473
a
One pair of donated lungs could be unilaterally transplanted to two recipients admitted in the same
474 center or city. In 2019 cohort, 4 donated lungs shared by 8 recipients with SLTs; in 2020 cohort, 3
475 donated lungs shared by 6 recipients with SLTs.
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477 Table 4 Post-LTx outcomes of ARDS patients due to COVID-19-related pulmonary fibrosis

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Transplantation center Shenzhena Wuxi Hangzhou Hangzhou Wuxi

From diagnosis to LTx 35 33 29 35 37

(days)

From virus clear to LTx 12 9 8 20 16

(days)
b
From ECMO to LTx 15 7 13 11 19
(days)

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ECMO weaning - 37 hours 5 days 2 days 40 hours
post-LTx

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Induction drugs - 500mg MP 500mg MP 500mg MP 500mg MP
-p ╳3 days ╳3 days
Cyclosporine Ad
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Maintenance drugs - Cyclosporine Tacrolimus Tacrolimus
Ac +Steroids 1mg q12h 1mg q12h + Steroids
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WBC (╳109/L) POD30 4.13 2.6 3.8 5.14

L (╳109/L) POD30 - 0.23 0.65 0.38 0.19

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CD4/CD8 POD30 - 3.33 2.25 0.69 1.24

ur

Rejection episode - No AR post-LT No No

40h
Jo

Survival status Death Survived Survived Survived Death POD 71

POD0
478 Abbreviations: LTx, lung transplantation; ECMO, extracorporeal membrane oxygenation; MP,
479 Methylprednisolone; WBC, white blood cells; L, lymphocyte; AR, acute rejection; POD, post
480 operation day.
481
a
LTx performed by teams from Wuxi and Guangzhou centers;
482
b
Pre-operative Veno-arterio-venous-ECMO for patient 1 and veno-venous-ECMO for patient 2-5.
483
c
Initial dose of 100mg q12h and adjusted according to plasma concentration and lymphocyte count;
484 Steroids included MP 30mg╳3 days then changed to prednisone 30 mg and tapering gradually;
485
d
Initial dose of 25mg q12h and adjusted gradually; Steroids included MP 30mg╳3 days then
486 changed to prednisone 30 mg and tapering gradually.
487

27
488 Figure legend
489
490 Figure 1 LTx donor and recipient screening and triage workflow. NAT, nucleic acid test; LTx, lung
491 transplantation.
492
493 Figure 2 Kaplan-Meier plots of the overall survival rate among recipients who were transplanted
494 during January 23rd - March 23rd in 2019 (2019 cohort) and 2020 (2020 cohort); log-rank p
495 value=0.083. The overall survival of recipients who were transplanted during the outbreak period of
496 COVID-19 was not inferior to that during the same period of 2019, up to the follow-up date of July
497 31st, 2020.
498
499 Figure 3 Time points for lung donation during the COVID-19 epidemic and mitigation measures.
500 Diagram of the COVID-19 epidemic trend in cities and the donors’ locations are shown separately.

of
501 Donation dates and order numbers are also indicated. In the lower part of the figure, policies that
502 impacted the epidemic trend are shown. The data were referenced from National Health Commission

ro
503 (http://www.nhc.gov.cn/xcs/yqtb/list_gzbd_3.shtml) and visualized from https://ncov.dxy.cn/ncovh5
504 /view/en_pneumonia. Existing confirmed case statistics are shown at the provincial level. Trends for
505
-p
existing COVID-19 case volumes are depicted by colored lines.
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Table 1 Donor characteristics and donated lung transportation

January 23rd - January 23rd - P

March 23rd, 2019 March 23rd, 2020 value
Transportation via GCHOTa (%) 19(33.9) 15(60)
Median Transportation distance 300 [IQR 30-1350] 725[IQR 20-1200] 0.827
(km)
Donor Transportation time (h) 3.2±1.8 3.3±1.7 0.772
Donor age (years) 35.6±13.6 39.1±13.7 0.455
Donor on ventilator (days) 7.5±9.1 7.4±9.6 0.984
Donor type (%)
DBD 54(96.4) 25(100)
DBCD 2(3.6)

of
Abbreviations: GCHOT, green channel of human organ transportation; DBD, donation after brain death;
DBCD, donation after brain and cardiac death.

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a
GCHOT was activated when long-distance organ transportation was needed, included connection of
-p
high-speed train and commercial flight or, commercial flight and highway.
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 Table 2
Characteri
January 23rd,- January 23rd, - stics of
March 23rd, 2019 March 23rd, 2020 P value LTx
Transplant Volume 60 28 recipients
Transplant centers 11 8 in the same
Age (years) 56.3±13.3 56.6±15.4 0.933 period of
Median admission to LT (days) 10 [IQR:1-22] 5 [IQR:1-25] 0.012 2019 and
Male: Female (Male %) 52/8 (86.7) 21/7 (75) 0.225 2020
BMI (kg/m2) 19.9±3.4 21.2±4.3 0.157
Main Diagnosis Abbreviatio
ARDS* (%) 0 1(3.6) ns: LTx,
COVID-19 (%) - 5(17.8) lung
IPF (%) 20(33.3) 10(35.7) transplantat
ILD-non IPF (%) 11(18.3) 2(7.2) ion; BMI,

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IPAH (%) 2(3.4) 2(7.2) body mass
COPD (%) 17(28.3) 6(21.4) index;

ro
Pneumoconiosis (%) 5(8.3) 1(3.6) ARDS,
Cystic fibrosis (%) 0 1(3.6) acute
Bronchiectasis (%) 3(5)
-p 0 respiratory
LAM (%) 1(1.7) 0 distress
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Non-IPAH (%) 1(1.7) 0 syndrome;
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Pre-LTx status IPF,

Admitted in general ward (%) 46(76.7) 14(50) 0.016 idiopathic
Admitted in ICU (%) 14(23.3) 14(50) pulmonary
na

Pre-transplant MV (%) 9 (15) 8 (28.6) 0.154 fibrosis;

ECMO+MV (%) 6(10) 7 (25) 0.104 ILD,
ur

Mean PAP(mmHg) 23.2±9.4 39.1±18.8 0.014 interstitial

Ejection fraction (%) 65.7±6.2 66.4±14.4 0.832 lung
Jo

Creatinine (umol/L) 63.90±35.5 61.1±13.7 0.612 diseases;

Total bilirubin (umol/L) 19.9±60.6 17.5±27.7 0.865 IPAH,
ALT (U/L) 34.8±53.7 30.2±27.4 0.723 idiopathic
263.9±105.2 189.8±108.9 pulmonary
PaO2/FiO2 before LTx 0.025
artery
(mmHg)
hypertensio
n; COPD, chronic obstructive pulmonary diseases; LAM, lymphangioleiomyomatosis; ECMO,
extracorporeal membrane oxygenation; MV, mechanical ventilation; PAP, pulmonary artery pressure.
*ARDS due to non-COVID-19 viral pneumonia
Table 3 Characteristics of grafts and recipients’ outcomes

January 23rd - January 23rd - P value

March 23rd, 2019 rd
March 23 , 2020
Cold Ischemic time (hours) 7.6±2.1 7.1±1.5 0.480
Duration of surgery (hours) 5.4±2.9 5.4±2.1 0.905
Transplantation type
Bilateral (%) 28(46.7) 17(60.7) 0.257
Singlea (%) 32(53.3) 11(39.3)
ICU stay (days) 11.9±14.8 7.8±2.3 0.043
(Ex.
post-COVID-19)
19 (31.7) 8 (28.6) 0.810
PGD T72h (≥grade 2)
In-hospital infection episodes (%) 45 (75) 12 (42.8) 0.004

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30-day survival (%) 48 (80) 25(89.3)
90-day survival (%) 43(71.7) 24(85.7)

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Abbreviations: Ex., excluded. PGD, primary graft dysfunction.

a
-p
One pair of donated lungs could be unilaterally transplanted to two recipients admitted in the same center
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or city. In 2019 cohort, 4 donated lungs shared by 8 recipients with SLTs; in 2020 cohort, 3 donated lungs
shared by 6 recipients with SLTs.
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Table 4 Post-LTx outcomes of ARDS patients due to COVID-19-related pulmonary fibrosis

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5

Transplantation center Shenzhena Wuxi Hangzhou Hangzhou Wuxi

From diagnosis to LTx 35 33 29 35 37

(days)

From virus clear to LTx 12 9 8 20 16

(days)
b
From ECMO to LTx 15 7 13 11 19
(days)
ECMO weaning - 37 hours 5 days 2 days 40 hours
post-LTx

of
Induction drugs - 500mg MP 500mg MP 500mg MP 500mg MP
╳3 days ╳3 days

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Maintenance drugs - Cyclosporine Tacrolimus Tacrolimus Cyclosporine Ad
-p
Ac +Steroids 1mg q12h 1mg q12h + Steroids
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WBC (╳109/L) POD30 4.13 2.6 3.8 5.14

L (╳109/L) POD30 - 0.23 0.65 0.38 0.19

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CD4/CD8 POD30 - 3.33 2.25 0.69 1.24

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Rejection episode - No AR post-LT No No

40h
ur

Survival status Death Survived Survived Survived Death POD 71

POD0
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Abbreviations: LTx, lung transplantation; ECMO, extracorporeal membrane oxygenation; MP,

Methylprednisolone; WBC, white blood cells; L, lymphocyte; AR, acute rejection; POD, post operation day.
a
LTx performed by teams from Wuxi and Guangzhou centers;
b
Pre-operative Veno-arterio-venous-ECMO for patient 1 and veno-venous-ECMO for patient 2-5.
c
Initial dose of 100mg q12h and adjusted according to plasma concentration and lymphocyte count; Steroids
included MP 30mg╳3 days then changed to prednisone 30 mg and tapering gradually;
d
Initial dose of 25mg q12h and adjusted gradually; Steroids included MP 30mg╳3 days then changed to
prednisone 30 mg and tapering gradually.
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