key: cord-0955951-5o0v978h
authors: Yan, Yan; Jiang, Xiufeng; Fu, Juanjuan; Huang, Jiehui; Qiu, Yuanwang; Ding, Difei; Ge, Lina; Zhang, Hao; Huang, Lihua; Lu, Xiaojie; Hu, Qinxue
title: Immune responses and residual SARS-CoV-2 in two critically ill COVID-19 patients before and after lung transplantation
date: 2020-11-12
journal: J Infect
DOI: 10.1016/j.jinf.2020.11.006
sha: ad95cd20e1870359453d257f228f90d9df7b7860
doc_id: 955951
cord_uid: 5o0v978h

nan

A small number of COVID-19 patients develop critical illness resulting in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Although lung transplantation (LT) can be used to rescue patients from COVID-19-related ARDS 1,2 , current information concerning the immune statues and pathogenic conditions of such transplant patients is lacking. In this study, we assessed the immune responses and the residual SARS-CoV-2 nucleic acids in patients before and after LT, including the first COVID-19 lung transplant patient in the world.

There were two critically ill COVID-19 patients in Wuxi of China, from January 25 to March 31, 2020, who eventually recovered after LT (Ethics No. 2020-014) 2 3 . For comparison purposes, we analyzed the whole blood lymphocytes, immunocyte subclasses (T, B and NK cells), blood cytokines and Ag-specific IgM and IgG of hospitalized COVID-19 patients in Wuxi (Ethics No. 2020-010-1). We focused on the analyses of the two critically ill COVID-19 patients (Patient 1: a 58-year-old male had COVID-19-associated ALI and ARDS; Patient 2: a 73-year-old male had COVID-19-associated multiple organ failure and ARDS).

In view of the limited number of critically ill patients, we merged severe and critical illness, designated as severe illness (Fig 1) . Most of the severely ill patients had low levels of blood lymphocytes during hospitalization, and in particular, the blood lymphocytes in the two critically ill patients remained below the normal value before and after LT (<1.1×10 9 /L) (Fig. 1A ). There were statistically significant lower levels of blood CD3 + CD45 + T (<60%) (Fig. 1B and 1C) , CD4 + T, CD8 + T and NK cells in individuals with critical clinical manifestations (P < 0.05), and a reduction of CD8 + T cells was the most statistically significant in the severely ill patients (P < 0.01) ( Fig.   1B and 1D ). Compared with untreated mildly ill patients, no significant increase of T and NK cells was observed in blood before and after LT, and only B cells increased slightly in the two critically ill patients, likely owing to mesenchymal stem cell infusion therapy ( Fig. 1B and 1D ). The two critically ill patients developed mildly positive SARS-CoV-2-specific IgM and IgG before LT, and such humoral immune responses became negative post LT (data not shown), likely due to blood transfusion therapy in the absence of new pathogen stimulation. It was reported that IL-6 and IL-10 play distinct roles in immune tolerance 4, 5 . In our study of the two critically ill Pathological analyses were performed by immunostaining for CD3 + T, IgA + and SARS-CoV-2 S protein + cells in the diseased lungs. In immunohistochemistry, critically ill patient' lungs (Patient 2) showed obscure mature CD3 + cells in tissues, and extensively fibrosis (Fig. 1F ), interstitial hemorrhage (Fig. 1G ) and mucous exudative necrosis in the bronchioles (Fig. 1H) , as well as alveolar epithelial atrophy, hyperplasia and shedding in the alveolar cavity (Fig. 1I ). The number of IgA + cells from alveoli epithelial cells decreased in both the right and the left pulmonary lobes ( Fig. 1J-1M) . Residual SARS-CoV-2 in the lungs has been suggested to be the main reason for viral positivity of discharged COVID-19 patients 6, 7 . We observed a direct evidence of residual SARS-CoV-2 in excised lungs (Fig. 1N-1Q) , suggesting that antiviral therapy may not completely eliminate the virus in the dysfunctional lungs. Briefly, SARS-CoV-2 RNA was detected by real-time RT-PCR. Target genes (ORF1ab + N) were set as described in the reagent instructions. A cycle threshold value (Ct value) less than 36 was defined as a positive (+), and Ct value between 36 and 37 was defined as mildly positive (±). 1, 2 and 3 on CT images mean the different axial images within the lungs. ph: post-hospitalization; plt: post LT.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.