Critical patients of coronavirus disease (COVID-19) have worse outcomes and higher mortality. Recent reports have shown pathologic findings of COVID-19, whereas these tissues were taken from postmortem evaluation.1 Information on histologic findings of COVID outside of the autopsy setting is limited. As far as we know, this is the first case about pathologic findings of critical COVID-19 underwent lung transplantation, which was predescribed on February 27, 2020.2
The 66-y-old patient presented with high fever and cough when he reached Shenzhen city from the Wuhan epidemic on January 4, 2020. On admission, the viral infection was verified by nasal swab and bronchial alveolar lavage fluids through qRT-PCR (GeneoDX Co., Ltd., Shanghai). The brightness of the lungs was increased and multiple shadows were observed by chest computed tomography. This patient had no preexisting interstitial lung disease. He had progressive deterioration from mild to critical condition during the 45-d duration, which was accompanied by increased plasma levels of IL-6 (range, 9.6–5000.0 pg/mL), CD4+T (range, 241–495 cells/µL), and CD8+T (range, 48–276 cells/µL) cells by laboratory results. Eventually, the patient developed severe respiratory failure and then was treated with bilateral lung transplantation on February 15, 2020. However, he still died of COVID-19–related disease deterioration. Informed consent was obtained.
The surface of the lungs was diffusely congested with superimposed punctate hemorrhagic foci and areas suggesting frank parenchymal necrosis (Figure 1A). Microscopically, the bronchioles and alveoli exhibited significant mural edema and intraluminal mucin and hemorrhage (Figure 1B,C). There was evidence of pneumocyte injury and might contribute to the severe hypoxemia in patients. Recently, Wang FS group took needle autopsy examinations from 1 COVID-19 case.1 Hyaline membrane formation was found indicating early-phase acute respiratory distress syndrome. However, hyaline membrane formation was not detected in our study, suggestive of severe-phase acute respiratory distress syndrome. In this case, one of the main pathologic changes of critical COVID-19 was diffuse pulmonary interstitial fibrosis (Figure 1B,D). Additionally, vascular wall thickening, lumen stenosis, and occlusion occurred frequently under the microscopy. These major changes might explain why critical patients develop severe respiratory failure, whereas some patients with late-stage have pulmonary hypertension due to vascular changes. Venous thromboembolism and microvascular injury in the management of COVID-19 are concerning.3 It is noteworthy that microthrombosis formation was also detected (Figure 1B), which might lead to lung hemorrhagic necrosis. Indeed, there was frank parenchymal necrosis accentuated in the right lower lung. These hemorrhagic changes indicate that pulmonary lesions of COVID-19 might originate from here.
Cytokine storm links to an excessively exaggerated immune response, and uncontrolled proinflammatory responses might cause severe lung damages.5 During the critical condition of this patient, the plasma levels of cytokine storm factors including IL-6, CD4, and CD8 T cells were strongly displayed by laboratory results. Microscopically, there was permeation of the interalveolar septa by lymphocytes, macrophages, and plasma cells. The lymphocytes represented a mixture of CD4 and CD8 T cells (Figure 1E), whereas the macrophages were highlighted by CD68. It is possible that cytokines released by the intrapulmonary inflammatory cells contribute to the terminal lung parenchymal injury.
In summary, the multiple sections of the lung disclosed intra-alveolar septal capillary thrombosis with attendant intra-alveolar hemorrhage. Diffuse reparative interstitial fibrosis was observed. The dominant parenchymal changes were concentrated involved in the terminal lung, larger vessels exhibited lumen stenosis and thrombosis. Therefore, we here show histopathologic findings in the whole lungs of a patient with critical COVID-19 treated with bilateral lung transplantation, which displays diffuse alveolar damages including chronic proliferative and fibrotic inflammation besides acute phase. Our findings might provide a deep understanding of the severity of this disease, and help clinicians to take effective treatment measures timely.
We thank Shenzhen Institute of Hepatology for collaboration and providing the P3 laboratory. We thank Marge limited company for providing ultrasonic rapid tissue dehydrator and the clinically pathologic report was finished on February 18, 2020. We thank 3DHISTECH, and we launched the digital pathology of COVID-19 for reading online globally on February 24, 2020 (http://3dhistech.cn/xg.html).
1. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020; 8:420–422. doi:10.1016/S2213-2600(20)30076-X
2. Luo W, Yu H, Guo J, et al. Clinical pathology of critical patient with novel coronavirus pneumonia (COVID-19). Preprints. 20202020020407
3. Magro C, Mulvey JJ, Berlin D, et al. Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res. 2020; 220:1–13. doi:10.1016/j.trsl.2020.04.007
4. Yan R, Zhang Y, Li Y, et al. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science. 2020; 367:1444–1448. doi:10.1126/science.abb2762
5. Mehta P, McAuley DF, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395:1033–1034. doi:10.1016/S0140-6736(20)30628-0