TY - JOUR
T1 - Premortem Skin Biopsy Assessing Microthrombi, Interferon Type I Antiviral and Regulatory Proteins, and Complement Deposition Correlates with Coronavirus Disease 2019 Clinical Stage
AU - Laurence, Jeffrey
AU - Nuovo, Gerard
AU - Racine-Brzostek, Sabrina E.
AU - Seshadri, Madhav
AU - Elhadad, Sonia
AU - Crowson, A. Neil
AU - Mulvey, J. Justin
AU - Harp, Joanna
AU - Ahamed, Jasimuddin
AU - Magro, Cynthia
N1 - Funding Information:
Supported by grants from Omeros, Inc., Jazz Pharmaceuticals, and the Angelo Donghia Foundation (J.L.), and partly supported by National Heart, Lung, and Blood Institute grant HL148123 (J.A.). This work was made possible through data provided by the Cornell COVID-19 Registry, led by Drs. Parag Goyal, Justin Choi, Laura Pinheiro, and Monika Safford of Weill Cornell Medicine. Disclosures: J.L. has received grants and honoraria from Alexion, Inc. and Omeros, Inc., manufacturers of anticomplement drugs, and Jazz Pharmaceuticals, manufacturer of defibrotide.
Funding Information:
Supported by grants from Omeros, Inc. , Jazz Pharmaceuticals , and the Angelo Donghia Foundation (J.L.), and partly supported by National Heart, Lung, and Blood Institute grant HL148123 (J.A.). This work was made possible through data provided by the Cornell COVID-19 Registry, led by Drs. Parag Goyal, Justin Choi, Laura Pinheiro, and Monika Safford of Weill Cornell Medicine.
Publisher Copyright:
© 2022 American Society for Investigative Pathology
PY - 2022/9
Y1 - 2022/9
N2 - Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I–driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I–based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre–COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre–COVID-19 ARDS/AKI (P < 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre–COVID-19 ARDS/AKI (P < 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P < 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions.
AB - Apart from autopsy, tissue correlates of coronavirus disease 2019 (COVID-19) clinical stage are lacking. In the current study, cutaneous punch biopsy specimens of 15 individuals with severe/critical COVID-19 and six with mild/moderate COVID-19 were examined. Evidence for arterial and venous microthrombi, deposition of C5b-9 and MASP2 (representative of alternative and lectin complement pathways, respectively), and differential expression of interferon type I–driven antiviral protein MxA (myxovirus resistance A) versus SIN3A, a promoter of interferon type I–based proinflammatory signaling, were assessed. Control subjects included nine patients with sepsis-related acute respiratory distress syndrome (ARDS) and/or acute kidney injury (AKI) pre–COVID-19. Microthrombi were detected in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre–COVID-19 ARDS/AKI (P < 0.001). Cells lining the microvasculature staining for spike protein of severe acute respiratory syndrome coronavirus 2, the etiologic agent of COVID-19, also expressed tissue factor. C5b-9 deposition occurred in 13 (87%) of 15 patients with severe/critical COVID-19 versus zero of six patients with mild/moderate COVID-19 (P < 0.001) and none of the nine patients with pre–COVID-19 ARDS/AKI (P < 0.001). MASP2 deposition was also restricted to severe/critical COVID-19 cases. MxA expression occurred in all six mild/moderate versus two (15%) of 13 severe/critical cases (P < 0.001) of COVID-19. In contrast, SIN3A was restricted to severe/critical COVID-19 cases co-localizing with severe acute respiratory syndrome coronavirus 2 spike protein. SIN3A was also elevated in plasma of patients with severe/critical COVID-19 versus control subjects (P ≤ 0.02). In conclusion, the study identified premortem tissue correlates of COVID-19 clinical stage using skin. If validated in a longitudinal cohort, this approach could identify individuals at risk for disease progression and enable targeted interventions.
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U2 - 10.1016/j.ajpath.2022.05.006
DO - 10.1016/j.ajpath.2022.05.006
M3 - Article
C2 - 35640675
AN - SCOPUS:85135229801
SN - 0002-9440
VL - 192
SP - 1282
EP - 1294
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 9
ER -