Outcomes of Thoracoscopic Lobectomy after Recent COVID-19 Infection

Background: The COVID-19 outbreak had a massive impact on lung cancer patients with the rise in the incidence and mortality of lung cancer. Methods: We evaluated whether a recent COVID-19 infection affected the outcome of patients undergoing thoracoscopic lobectomy for lung cancer using a retrospective observational mono-centric study conducted between January 2020 and August 2022. Postoperative complications and 90-day mortality were reported. We compared lung cancer patients with a recent history of COVID-19 infection prior to thoracoscopic lobectomy to those without recent COVID-19 infection. Univariable and multivariable analyses were performed. Results: One hundred and fifty-three consecutive lung cancer patients were enrolled. Of these 30 (19%), had a history of recent COVID-19 infection prior to surgery. COVID-19 was not associated with a higher complication rate or 90-day mortality. Patients with recent COVID-19 infection had more frequent pleural adhesions (p = 0.006). There were no differences between groups regarding postoperative complications, conversion, drain removal time, total drainage output, and length of hospital stay. Conclusions: COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population.


Introduction
The COVID-19 outbreak had a massive impact on healthcare worldwide. COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first detected in December 2019 in Wuhan, (China) and declared a pandemic in March 2020 [1,2].
The aim of this study was to evaluate the outcomes of thoracoscopic lobectomy for lung cancer in patients with recent COVID-19 infection, and whether previous COVID-19 infection was associated with a higher rate of complications and mortality compared to the control group.

Study Design
This was a retrospective mono-centric study including all consecutive patients undergoing VATS lobectomy for lung cancer between January 2020 and August 2022.
The clinical data of (i) patients undergoing VATS lobectomy for lung cancer and (ii) patients with complete data and a follow-up for at least 9 months were included in the analysis. We excluded the data of (i) patients undergoing lung resection different from lobectomy (i.e., wedge resection and segmentectomy); (ii) patients undergoing lobectomy via upfront thoracotomy; and (iii) patients with incomplete data and follow-up.
The endpoint of the study was to evaluate whether recent COVID-19 infection prior to surgery negatively affected the outcome of VATS lobectomy. The patients were divided into two groups based on whether they had a history of COVID-19 infection in the 3 months prior to surgery (the COVID group) or not (the no-COVID group).
Diagnosis of COVID-19 infection was documented in all patients of the COVID group with positive RT-PCR molecular swab test for SARS-CoV-2. Postoperative complications, mortality, and general surgical outcomes were evaluated and compared between the two groups. Furthermore, univariable, and multivariable analyses were performed to evaluate whether COVID-19 infection was an independent predictive risk factor for complications.
All procedures performed were in accordance with the international guidelines, with the Helsinki Declaration of 1975, revised in 1983, and the rules of the Italian laws of privacy. Each patient signed an anonymous informed consent letter for the use of their data for anonymous clinical investigations and scientific publications. The local research ethics committee approved the study design. Due to the retrospective nature of the study, no specific approval code was required because there was no modification in the standard of patient care.

Study Population
For each patient, the following data were recorded: •  (grade I and II, requiring no therapy or pharmacologic intervention only) and major  complications (grade IIIa, IIIb, IVa, and IVb, requiring surgical, endoscopic, or radiological intervention without general anesthesia, with general anesthesia, admission to  the intensive care unit (ICU), and multiorgan failure, respectively).

Surgical Procedure
In all cases, the tumor was staged with a whole-body PET/CT scan. Preoperative histological diagnosis was obtained in the majority of patients with CT-guided lung biopsy, or alternatively with a trans-bronchial needle aspiration biopsy or broncho-alveolar lavage during bronchoscopy. Neoadjuvant chemotherapy was administered when indicated following oncological consultation.
When the preoperative diagnosis was not possible or in case of undetermined results, the diagnosis was made through intra-operative pathological examination. Patients with lung function impairment (predicted postoperative FEV1 or DLCO < 30%) were evaluated with cardiopulmonary exercise testing (CPET) and if not functionally fit for surgery, redirected to alternative treatments through a multidisciplinary discussion.
For this reason, 10 patients were excluded from surgical treatment due to respiratory impairment: 2 patients for post-COVID-19 respiratory impairment and 8 for severe chronic obstructive pulmonary disease.
Twenty-four hours before admission, all patients routinely performed an RT-PCR molecular swab test for SARS-CoV-2, mandatory for hospital admission during the study period to exclude asymptomatic infections.
All the patients underwent pulmonary lobectomy with systematic ilo-mediastinal lymphadenectomy using an anterior thoracoscopic triportal approach. The procedure was performed under general anesthesia with selective intubation. At the end of the procedure, a single 28Fr drainage tube was placed in the pleural cavity through the camera incision and connected to an underwater seal chest drain system. The chest drainage was removed when re-expansion of the lung was achieved, when the amount of fluid drained was less than 250 mL in 24 h, and in absence of air leaks. After the surgery, the patients were directed either to follow-up or oncological treatment based on the pathological stage and histology.
The patients in the COVID group were scheduled for surgery after at least four weeks from reverse transcription polymerase chain reaction (RT-PCR) negativity, and in all cases performed an additional high-resolution CT scan of the thorax after COVID-19 infection. Patients with severe symptoms or that required hospitalization were carefully evaluated by the thoracic surgeon and anesthesiologist to schedule the surgery.

Statistical Analysis
Data were expressed as mean ± standard deviation (SD) for continuous variables and as absolute numbers and percentages for categorical variables. Intergroup differences were compared using chi-square for categorical variables and with a t-test for continuous variables. Univariable and multivariable logistic regression was performed to identify predictive risk factors for postoperative complications (dependent variables).
A p-value less than 0.05 was considered statistically significant. MedCalc statistical software (Version 12.3, Broekstraat 52; Mariakerke, Belgium) was used for this analysis.

Results
In the study period, 182 patients underwent lung resections for cancer. The data of 29 patients were excluded from the analysis due to resections different from lobectomy (n = 21); upfront thoracotomy (n = 6); and incomplete data (n = 2).
There was no difference in the rate of vaccination against COVID-19 between groups (p = 0.36).

Perioperative Outcomes and Complications
The data regarding perioperative outcomes and complications were summarized in Table 3. No significant differences were found regarding operative time (p = 0.57), blood loss (p = 0.41), conversion (p = 0.82), and transfusion rate (p = 0.65) between the two groups. The chest drainage output (p = 0.16), length of chest drainage (p = 0.23), LHOS (p = 0.23), and ICU stay (p = 0.13) were also similar between groups.
The distribution of complications and postoperative outcomes were analyzed in the COVID group since during the study period different SARS-CoV-2 variants with different The COVID group patients had a higher incidence of pleural adhesions compared with the no-COVID group (46% vs. 21%, p = 0.006). The adhesions were more frequently firm and vascular and localized in the portion of the pleural cavity in both groups.
No significant difference was found regarding the incidence of postoperative complications between groups (p = 0.51). Mortality at 90 days was 2%, without significant differences between groups (p = 0.38).
The most common non-respiratory complication was postoperative anemia (16%). No patient needed reoperation, while two patients needed re-drainage due to persistent air leaks and atelectasis.
On univariable analysis (Table 4) capturing as a dependent variable the presence of complications, we found that significant risk factors were COPD (p = 0.015), coronary artery (p = 0.007), and FEV1 < 70% (p = 0.03). However, in multivariable analysis, COPD (p = 0.006) and coronary artery disease (p = 0.016) were the only two independent significant prognostic factors for complications.

Discussion
The management of oncological patients during the COVID-19 pandemic has been challenging, and while it is suspected that COVID-19 infection during the perioperative period is a risk factor for morbidity and mortality [56][57][58], the majority of the studies in the literature are not specific to thoracic surgery or pulmonary lobectomy for lung cancer, or do not discriminate between preoperative and postoperative COVID-19 infection [59]. At present, only Gabryel et al. [60] evaluated the outcomes of anatomical lung resections in patients with COVID-19 history, reporting no difference in the incidence of postoperative complications and 90-day mortality between patients with and without COVID-19 history before surgery, except for a higher reoperation and re-drainage rate in the COVID group.
First, there was no difference in the incidence of complications and 90-day mortality between patients with a history of recent COVID-19 infection and patients without a history of recent COVID-19 infection, and we found that COVID-19 infection was not an independent predictive risk factor for complications. In our study population, we found that the patients with recent COVID-19 infection had more frequent pleural adhesions compared with the control group. Since pleural adhesions are often a result of previous inflammatory processes [61], this difference between groups is interesting and may be related to recent COVID-19 infection, but the studies that reported pleural adhesions at CT or thoracoscopy in patients with a history of COVID-19 are few, and are more often in patients with severe infection [62][63][64][65]. Despite the increased incidence of pleural adhesions in the COVID patients, there was no difference in the conversion rate between groups.
We reported two cases of extensive pleural adhesions in patients with a history of COVID-19 in Figures 1 and 2; in both cases, the surgery was carried out using a thoracoscopy.
the COVID group.
First, there was no difference in the incidence of complications and 90-day mortality between patients with a history of recent COVID-19 infection and patients without a history of recent COVID-19 infection, and we found that COVID-19 infection was not an independent predictive risk factor for complications. In our study population, we found that the patients with recent COVID-19 infection had more frequent pleural adhesions compared with the control group. Since pleural adhesions are often a result of previous inflammatory processes [61], this difference between groups is interesting and may be related to recent COVID-19 infection, but the studies that reported pleural adhesions at CT or thoracoscopy in patients with a history of COVID-19 are few, and are more often in patients with severe infection [62][63][64][65]. Despite the increased incidence of pleural adhesions in the COVID patients, there was no difference in the conversion rate between groups.
We reported two cases of extensive pleural adhesions in patients with a history of COVID-19 in Figures 1 and 2; in both cases, the surgery was carried out using a thoracoscopy.  We also found that the patients with a history of COVID-19 had a higher rate of preoperative thoracic pain, which has been described as part of post-COVID pain syndromes [66] and should be investigated to exclude cardiac sequelae related to COVID.
Second, our results highlighted that coronary artery disease and COPD were risk factors for complications.
In the literature, COPD has been already associated with an increased risk for pulmonary complications [67,68], while coronary artery disease is not a recognized risk factor for complications after VATS lobectomy, reported only by some authors [69]. In our population, the patients with coronary artery disease mostly had cardiac complications, mainly arrhythmias that were managed in the immediate postoperative period with medical therapy.
Third, we observed that many patients were referred to our department exhibiting post-COVID chest X-ray or CT scans recommended by general practitioners as a followup after the infection. In these cases, COVID-19 infection has incidentally influenced the course of the patient's treatment since small nodules could have otherwise gone unnoticed until a more advanced stage.
Post-COVID-19 HRCT often showed pulmonary changes, even in asymptomatic or mildly symptomatic patients, such as generally newly found GGO opacities, subpleural interstitial involvement, bronchial dilation, and subpleural bands. We performed a thorough examination of preoperative CT, and when needed we used 3D reconstruction of the lung to predict possible difficulties in the resection and to assist the nodule localization in case of lung tissue alterations.
The appropriate timing of surgery after COVID-19 is still debated; some authors suggest waiting 4-6 weeks to schedule elective surgery after COVID-19 infection [70], while others recommend waiting at least 7 weeks [71]. For patients with lung cancer, the timing of surgery is crucial and delays in surgical treatment can lead to pathological upstaging, which is associated with worse outcomes [72]. One of the predictors of upstaging is a delay in resection greater than 8 weeks [73], and between the duration of COVID-19 infection and the 4-7 weeks recommended to schedule elective surgery, these patients'surgery delays easily add up to 8 weeks. We also found that the patients with a history of COVID-19 had a higher rate of preoperative thoracic pain, which has been described as part of post-COVID pain syndromes [66] and should be investigated to exclude cardiac sequelae related to COVID.
Second, our results highlighted that coronary artery disease and COPD were risk factors for complications.
In the literature, COPD has been already associated with an increased risk for pulmonary complications [67,68], while coronary artery disease is not a recognized risk factor for complications after VATS lobectomy, reported only by some authors [69]. In our population, the patients with coronary artery disease mostly had cardiac complications, mainly arrhythmias that were managed in the immediate postoperative period with medical therapy.
Third, we observed that many patients were referred to our department exhibiting post-COVID chest X-ray or CT scans recommended by general practitioners as a follow-up after the infection. In these cases, COVID-19 infection has incidentally influenced the course of the patient's treatment since small nodules could have otherwise gone unnoticed until a more advanced stage.
Post-COVID-19 HRCT often showed pulmonary changes, even in asymptomatic or mildly symptomatic patients, such as generally newly found GGO opacities, subpleural interstitial involvement, bronchial dilation, and subpleural bands. We performed a thorough examination of preoperative CT, and when needed we used 3D reconstruction of the lung to predict possible difficulties in the resection and to assist the nodule localization in case of lung tissue alterations.
The appropriate timing of surgery after COVID-19 is still debated; some authors suggest waiting 4-6 weeks to schedule elective surgery after COVID-19 infection [70], while others recommend waiting at least 7 weeks [71]. For patients with lung cancer, the timing of surgery is crucial and delays in surgical treatment can lead to pathological upstaging, which is associated with worse outcomes [72]. One of the predictors of upstaging is a delay in resection greater than 8 weeks [73], and between the duration of COVID-19 infection and the 4-7 weeks recommended to schedule elective surgery, these patients'surgery delays easily add up to 8 weeks.
The main limitations of our study is its retrospective nature and the relatively small sample size. Additionally, it is possible that some cases of COVID-19 were undetected, asymptomatic patients, but we accounted that this number would not be significant in our analysis since the patients were strictly monitored in the period before admission during the preoperative examination performed at our institution. Furthermore, the patients undergoing lung resection were highly selected and it could affect the surgical results. In the COVID group, we did not compare the complication rate between asymptomatic and symptomatic patients due to the small sample size and since the complication rate did not differ from that of the no-COVID group.
Our results point toward the safety of performing thoracoscopic lobectomy in patients with recent COVID-19 infection without lung function impairment and after at least four weeks from the infection. The treatment of patients with recent infection of COVID-19 should not be delayed, but it is mandatory to carefully evaluate the patient's respiratory and cardiac conditions, in case of ICU admission for COVID-19 or severe respiratory/cardiac comorbidities. Performing a preoperative HRCT is useful to plan the surgery and predict difficulties in nodule localization and the dissection in case of lung tissue post-COVID alterations.

Conclusions
COVID-19 infection did not affect the outcomes of thoracoscopic lobectomy for lung cancer in patients without lung function impairment, including post-COVID consequences, and was scheduled after at least four weeks from the infection. The treatment of these patients should not be delayed in case of recent COVID-19 infection and should not differ from that of the general population. An appropriate cardiorespiratory and radiological post-COVID evaluation is mandatory to prevent complications.  Institutional Review Board Statement: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee of "Universita' Degli Studi Della Campania "Luigi Vanvitelli"-Azienda Ospedaliera Universitaria "Luigi Vanvitelli". Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. All procedures performed were in accordance with the international 285 guidelines, according to Helsinki Declaration of 1975, revised in 1983, and the rules of the Italian laws of privacy. Each patient signed an anonymous informed consent letter for the use of their data for anonymous clinical investigations and scientific publications. The local research ethics committee approved the study design. Due to the retrospective nature of the study, no specific approval code was required because there was no modification in the standard of patient care.