key: cord-1056570-5yo46u75 authors: Wein, Alexander N.; Liu, Jing; Lin, Chieh‐Yu title: Evolution of pathological findings in surveillance biopsies of lung transplant recipients infected with SARS‐CoV‐2 date: 2022-03-21 journal: Transpl Infect Dis DOI: 10.1111/tid.13823 sha: 3b4706a6dad789239d2e9a61d6f35ad1444c5b0b doc_id: 1056570 cord_uid: 5yo46u75 BACKGROUND: Previous reports of coronavirus disease 2019 (COVID‐19) following lung transplantation generally described a grim prognosis, but these were anecdotal case series of symptomatic patients. A systematic study of the outcomes and pathology of SARS‐CoV‐2 infection in a large cohort of lung transplant patients is lacking. METHODS: To determine the histopathologic evolution of COVID‐19 in lung transplant recipients, we identified all patients who underwent surveillance transbronchial biopsies at our institution, tested positive for SARS‐CoV‐2, and had multiple pathology specimens available for evaluation. Histology was reviewed and immunofluorescence for SARS‐CoV‐2 nucleocapsid protein was performed. RESULTS: Ten patients met inclusion criteria. Half (5/10) had incidental diagnosis on routine respiratory pathogen testing at the time of transbronchial biopsy. Six patients were hospitalized, with three requiring intensive care unit (ICU) admission. One patient died. Two specimens showed new onset International Society for Heart and Lung Transplantation (ISHLT) Grade A2 rejection at or following diagnosis. One patient developed bronchiolitis obliterans 111 days following diagnosis and 1 year post transplant. Two patients had organizing pneumonia at diagnosis and three patients showed evolving lung injury following diagnosis. The SARS‐CoV‐2 nucleocapsid protein was detected in a subset of samples at diagnosis and up to 111 days following diagnosis. CONCLUSIONS: Overall, the pathology of SARS‐CoV‐2 infection in lung transplant patients is varied, ranging from no pathologic alterations to organizing pneumonia and lung injury. The pathology findings did not necessarily correlate with clinical acuity, as one patient admitted to the ICU had normal pathology. These findings may be generalizable to non‐transplant patients and require more follow‐up regarding long‐term outcomes. Lung transplant recipients are a unique patient population in the coronavirus disease 2019 (COVID-19) pandemic due to pre-existing conditions and immune modulation. The majority of previously published case series on COVID-19 in patients following lung transplantation have been anecdotal case series and reported poor outcomes and high mortality. [1] [2] [3] [4] [5] However, these studies are biased toward clinically symptomatic patients. An unbiased analysis to examine clinicopathological characteristics of SARS-CoV-2 infection in a large cohort of lung transplant patients or the general population is lacking. Here, we report our single-institute experience of SARS-CoV-2 infection in lung transplant recipients, and examine the clinicopathologic evolution in routine surveillance transbronchial biopsies (TBBx). The histological features of TBBx of these 10 patients are summarized in Table 1 and representative images are shown in Figure 1 . There is no meaningful increase of acute cellular rejection, antibody- To identify persistent viral antigens, immunofluorescence staining for the SARS-CoV-2 nucleocapsid protein was performed on biopsy tissue from diagnosis (n = 5) and post-diagnosis (n = 8) specimens. Immunofluorescence microscopy highlighted viral nucleocapsid protein in one of five (20%) of the diagnosis samples and five of eight (63%) of post-diagnosis samples (Table 1 and Figure 1 ). Of the five patients with detectable SARS-CoV-2 nucleocapsid protein, two (40%) also had SARS-CoV-2 RNA detected by PCR of the concurrent BAL. Three (60%) of the patients with detectable SARS-CoV-2 nucleocapsid protein had negative PCR results of BAL and three (60%) patients with positive PCR results were negative for nucleocapsid protein by immunofluorescence. In this study, we report the heterogeneity of pathologic findings in 16 While none of the patients who remained outpatient during their illness showed any histopathologic abnormalities on TBBx, those who were admitted displayed a spectrum of findings ranging from normal lung histology to subacute lung injury pattern. Immunofluorescence microscopy of diagnosis and post-diagnosis TBBx specimens showed only one diagnosis specimen with detectable SARS-CoV-2 nucleocapsid protein despite positive PCR testing on all five concurrent BAL specimens; however, the majority of postdiagnosis biopsies showed SARS-CoV-2 nucleocapsid protein by immunofluorescence. In fact, all post-diagnosis samples were positive for SARS-CoV-2 by immunofluorescence and/or PCR. This is in keeping with prior reports of extended SARS-CoV-2 viral replication in transplant recipients, which is believed to play a role in the evolution of multimutational variants. 17 The extended infection in these patients also complicates the evaluation of post-diagnosis biopsy specimens for acute cellular rejection, and recent COVID-19 should be considered when attempting to distinguish between the immune infiltrates of acute cellular rejection, AMR, and viral infection. While our current work is limited to a small sample of lung transplant patients with short-term follow-up, it highlights disease heterogeneity that is likely generalizable to COVID-19 patients as a whole and warrants further studies with larger series and longer follow-up. This project is supported by intradepartmental funding from Department of Pathology and Immunology, Washington University in St. Louis. 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Alexander N. Wein and Chieh-Yu Lin designed the study, analyzed the data, and wrote the manuscript. Jing Liu performed the immunofluorescence staining. Alexander N. Wein https://orcid.org/0000-0002-8813-3523Chieh-Yu Lin https://orcid.org/0000-0002-4269-3234