key: cord-0721210-x6nqnupa authors: Cai, Yixin; Hao, Zhipeng; Gao, Yi; Ping, Wei; Wang, Qi; Peng, Shu; Zhao, Bo; Sun, Wei; Zhu, Min; Li, Kaiyan; Han, Ying; Kuang, Dong; Chu, Qian; Fu, Xiangning; Zhang, Ni title: Coronavirus Disease 2019 in the Perioperative Period of Lung Resection: A Brief Report From a Single Thoracic Surgery Department in Wuhan, People’s Republic of China date: 2020-04-11 journal: J Thorac Oncol DOI: 10.1016/j.jtho.2020.04.003 sha: 1e7e75326e0839ddc81e3cd7c6a72dbc0fe8edec doc_id: 721210 cord_uid: x6nqnupa Abstract Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, People’s Republic of China, and has subsequently spread worldwide. Clinical information on patients who contracted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the perioperative period is limited. Here, we report seven cases with confirmed SARS-CoV-2 infection in the perioperative period of lung resection. Retrospective analysis suggested that one patient had been infected with the SARS-CoV-2 infection before the surgery and the other six patients contracted the infection after the lung resection. Fever, lymphopenia, and ground-glass opacities revealed on computed tomography are the most common clinical manifestations of the patients who contracted COVID-19 after the lung resection. Pathologic studies of the specimens of these seven patients were performed. Pathologic examination of patient 1, who was infected with the SARS-CoV-2 infection before the surgery, revealed that apart from the tumor, there was a wide range of interstitial inflammation with plasma cell and macrophage infiltration. High density of macrophages and foam cells in the alveolar cavities, but no obvious proliferation of pneumocyte, was found. Three of seven patients died from COVID-19 pneumonia, suggesting lung resection surgery might be a risk factor for death in patients with COVID-19 in the perioperative period. As of March 5, 2020, there have been 80,565 cases of coronavirus disease 2019 (COVID-19) confirmed in the People's Republic of China with 3015 deaths. 1 As the confirmed cases are increasing, studies with a large sample size have provided detailed clinical information, including the clinical characteristics, laboratory and radiographic findings, and outcomes of COVID-19. 2 Thus far, there has been one case report by Tian et al. 3 who described the clinical course and pathologic findings of two cases infected with COVID-19 before lung lobectomy surgery. Nevertheless, there is still a lack of reports focusing on the cases of hospitalized patients infected with COVID-19 in the perioperative period, especially in patients who underwent lung resection surgery. From January 1 to January 22, 2020, the period before human-to-human transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was declared by the national authority, the Thoracic Surgery Department of Tongji Hospital was on schedule to perform routine operations. A total of 139 patients underwent lung resection. Among these patients, seven cases were laboratory confirmed to be infected with SARS-CoV-2 after the lung resection. The confirmation of COVID-19 was on the basis of positive results of the patients' oropharyngeal swabs tested for SARS-CoV-2 by real-time reverse-transcriptase polymerase chain reaction assay. In this report, we present the clinical characteristics and pathologic findings of patients diagnosed with COVID-19 in the perioperative period of lung resection and evaluate the influence of surgery on the progression of COVID-19. The seven patients were initially hospitalized for surgical treatment for lung tumor. The median age of the patients was 60 years (25th-75th percentile, 57-66 y), and five were men. The comorbidities included chronic obstructive pulmonary disease (in two patients), coronary atherosclerosis (three patients), interstitial lung disease (one patient), and hyperlipidemia (one patient). Six patients were diagnosed with NSCLC, and one patient was diagnosed with pulmonary sclerosing pneumocytoma. The surgeries were successfully performed in all cases without event, which included video-assisted thoracic surgery lobectomy (in four patients), videoassisted thoracic surgery segmentectomy plus wedge resection (in one patient), thoracotomy sleeve lobectomy (in one patient), and lobectomy plus bronchus reconstruction (in one patient). None of the patients had surgery-related postoperative complications, including air leak, hemorrhage, bronchopleural fistula, and arrhythmia (Table 1) . All seven patients presented with fever after the surgery; six had body temperature greater than 39 C. The time from surgery to onset of fever ranged from 0 days to 23 days (mean, 8.6 d). Accompanying symptoms included shortness of breath (in five patients), nonproductive cough (four patients), fatigue (two patients), productive cough (one patient), myalgia (two patients), and diarrhea (one patient) ( Table 2) . On the first day after the surgery, the number of neutrophils in the peripheral blood was found to be increased in all seven patients, and four patients had lymphopenia. At the onset of COVID-19 infection, five patients had lymphopenia, and a decline in the lymphocyte count was observed in all seven cases, which was more prominent in patients 1, 3, and 7. Regarding liver function, only one patient had increased concentrations of alanine aminotransferase and aspartate aminotransferase, and three patients had lower albumin level than the reference range (35-52 g/liter). Elevated high-sensitivity C-reactive protein and procalcitonin, the biomarkers for inflammation, were observed in all seven patients at the onset of the symptoms. The levels of fibrinogen and D-dimers were increased in five and seven patients, respectively ( Table 2 ). All the patients had computed tomography (CT) scans. After the onset of the symptoms, all seven patients presented with emerging multifocal ground-glass opacities (GGOs) with (four cases) or without (three cases) superimposed reticulation (Fig. 1A-G) . Bilateral involvement and progression on CT images were observed in three patients (patients 1, 3, and 7) (Fig. 1A , C, and G). Pathologic examination of the specimens from all these patients was performed. The findings of patient 1 have been reported in a previous study. 4 Among all the seven patients, typical malignant pathologic features of the primary tumors were identified. Hematoxylin and eosin-stained sections of the lung tissues distant from the tumors were reviewed. For patient 1, there was a wide range of lung interstitial inflammation with numerous infiltrating immune cells seen under the microscope. The infiltrating cells were mainly composed of plasma cells and macrophages, but lymphocytes were rare. Thickened alveolar septum and fibrous connective tissue proliferation were noted. Besides that, there were a large number of macrophages and foam cells in the alveolar cavities, but no evident pneumocyte hyperplasia was observed. Moreover, no obvious viral inclusion bodies and hyaline membrane were found ( Fig. 2A and B) . The other six patients had no evident inflammation in their lung tissues distant from the tumors (Fig. 2C-H) . Oseltamivir was initially administered when the seven patients presented with the virus infectionassociated symptoms. As the symptoms were progressing, other antivirus regimens were also used, including umifenovir in two patients and lopinavir and ritonavir in one patient. Four patients received systemic corticosteroid therapy. Patients 1, 3, and 7 received mechanical ventilation and eventually died of respiratory failure on , and 25 d after the symptom onset), respectively. Two patients have been cured and discharged from the hospital, and the remaining two patients were still hospitalized in stable condition at the time of manuscript submission with normal body temperature for more than 3 days and objective relief from symptoms (Table 2 ). The incubation period of COVID-19 has been reported to be 5.2 days (95% confidence interval: 4.1-7.0), and for some cases, it could be as long as 14 days. 5 To properly identify and screen patients with atypical symptoms during the incubation period is a big challenge. Although the laboratory confirmation of COVID-19 infection was obtained on postoperative day 5, the clinical course of patient 1 revealed that the patient had been infected with SARS-CoV-2 before the surgery. By retrospectively examining his clinical manifestations, we found that the patient immediately developed a fever (38.5 C) just 3 hours after the surgery and had recurrent pyrexia (>39 C) in the whole postoperative period. Chest CT scan on postoperative day 4 revealed diffused GGOs in bilateral lungs. As the pneumonia rapidly worsened, the patient died on day 5 after the surgery. We also reviewed the CT scan image of the patient performed 2 weeks before the surgery and noticed a subpleural ground-glass attenuation in the right lower lobe in addition to the diffusely infiltrative opacifications in the subpleural regions of both lungs, which were previously associated with interstitial lung disease. At that time, there was lack of awareness of the significance of the ground-glass findings. In the report of Tian et al., 3 pathologic examination of the two cases infected with the novel coronavirus before the lobectomies revealed evident alveolar damage with alveolar edema and proteinaceous exudates. These lung injury findings were also generally observed in patients infected with SARS by autopsy. 6 In patient 1, we did not observe typical alveolar damages and pneumocyte hyperplasia; instead, we found extensive interstitial inflammation with numerous plasma cells and macrophages infiltrating the lung tissues. The pathologic pattern of COVID-19 pneumonia in patient 1 differs from that of the two cases reported by Tian et al. 3 Given that patient 1 had interstitial lung disease, the pathologic changes may be affected by this pulmonary comorbidity. Taken together, the lesson from patient 1 indicates that it is vitally important to perform careful preoperative examination and screening for those patients who plan to undergo an operation during the COVID-19 epidemic. All seven patients were found to have postresection changes on radiographic images in the early period after the surgery, including infiltration, atelectasis, and pleural effusion. After the onset of the symptoms, all seven patients presented with emerging multifocal GGOs, which were reported as the most common CT findings of COVID-19 7 and SARS, as well. 8 Although the postresection radiographic abnormalities increased the difficulty in early detection of the viral infection, the typical radiologic features and distribution pattern can facilitate the differential diagnosis because postresection infiltration and effusion mostly developed in the lung on the surgery side. Thus, the presence of typical GGOs, especially in the lobe contralateral to the surgery side, could be an early radiologic sign of the viral infection. Serial CT scans revealed bilateral lung involvement with evident progression in patients 1, 3, and 7. Despite comprehensive treatment, including antivirals, antibiotics, oxygenation therapy, and other supportive care, these three patients eventually developed respiratory failure and died. In contrast, the other four patients with infection predominantly involving the lung contralateral to the surgery side had less severe symptoms and better prognosis (two were cured and two were in the convalescent stage). This is consistent with the current results among the general infected population, 9 which revealed that the bilateral involvement is correlated with high severity and poor prognosis. Lymphopenia is a common feature for SARS and SARS-CoV-2 infection. 10, 11 It is worth noting that lymphopenia often occurs immediately after lung surgery. 12 The results indicated that early appearing lymphopenia after lung resection was because of lack of specificity. At the onset of the symptoms, five cases presented with lymphopenia, and a prominent decline in the lymphocyte count was observed in patients 1, 3, and 7, suggesting the degree of reduction in the number of circulating lymphocytes was closely correlated with the progression of COVID-19. Thus, compared with the absolute cell count, the dynamic reduction of lymphocytes should be considered to be of more significance in the postoperative patients with COVID-19. Patients with cancer are more susceptible to infection than individuals without cancer because of the immunosuppressive state caused by the malignancy. 13, 14 A recent nationwide analysis of patients with COVID-19, which included a cohort of 18 patients with various cancers and 1572 patients without cancer history, revealed that patients with cancer are at a high risk of severe COVID-19. 15 Among the 18 patients with cancer enrolled in this study, five patients had lung cancer. These five patients with lung cancer had lower probability of severe COVID-19 than those with other types of cancer (20% versus 62%, respectively). Nevertheless, the lower incidence of severe COVID-19 in patients with lung cancer should be interpreted with caution because of the small sampling. In our report, six patients had lung cancer, and two of them died. Some considerations also need to be taken into account in interpreting the findings from the current report. First, the effects of different surgery patterns, including operation approach and lymphadenectomy on COVID-19, remain to be evaluated. Second, whether the characteristics of the cancer, such as histologic type and stage, could influence the development and prognosis of COVID-19 in patients with lung cancer needs to be further investigated. For now, two patients are still hospitalized, and further follow-up is needed to clarify the long-term outcomes of such specific patients infected with SARS-CoV-2. Before the outbreak was declared by the national authority, our understanding of the transmission of SARS-CoV-2 was very limited. The lack of awareness of this emerging infectious disease led to the failure of implementing appropriate protective measures in place to prevent health care-associated infection. A comprehensive analysis of nosocomial infection of Middle East respiratory syndrome in a tertiary hospital in South Korea revealed that the virus transmissions mainly occurred before the infected patient had been recognized. 16 In our department, nosocomial transmission could be definitively proven on the basis of timing and pattern of exposure to infected patients and subsequent development of infection among the medical staff. On the basis of the investigation, patient 1 was presumed to be the source of transmission in our department because he was the first confirmed case in the ward and three health care workers who had close contact with him were found to be infected. Subsequently, six patients and another five health care workers were confirmed infected with COVID-19. The cross-infection highlighted the high risk of SARS-CoV-2 transmission within a thoracic surgery department. As there are more aerosolgenerating procedures performed, such as lung suctioning, intubation, and bronchoscopy, in the thoracic surgery department, the medical staff has a high risk of exposure to droplets around the patients. The outbreak of COVID-19 imposes a major challenge in deciding and managing surgical operation on patients with lung cancer and other lung disorders. We believe that it is imperative to report these cases to provide direct evidence for choosing proper strategies in the thoracic department. The preliminary results from the limited cases indicate that lung resection surgery might be a risk factor for death in patients with COVID-19 in the perioperative period. Thus, during the epidemic, any surgery-related managements should be manipulated with extra caution. At the epidemic area, any negligence is unaffordable. 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This study was approved by the ethics committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.