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Address for reprints: Filippos-Paschalis Rorris, MD, Department of Thoracic and Cardiovascular Surgery, Evangelismos General Hospital, Ypsilantou 45-47, Athens, 106 76, Greece.
A remarkable increase in the number of patients presenting with tracheal complications after prolonged endotracheal intubation and mechanical ventilation for the management of the severe COVID-19–associated respiratory failure has been observed. In this study, we assessed the postoperative outcomes of tracheal resection in patients with COVID-19.
Methods
We conducted a retrospective study in which all patients with a history of prolonged invasive mechanical ventilation due to COVID-19 infection, who were treated with tracheal resection and reconstruction, were included. The primary objective was in-hospital mortality and postoperative reintervention rate. The secondary objective was the time to tracheal restenosis.
Results
During the 16-month study period, 11 patients with COVID-19 with tracheal complications underwent tracheal resection with end-to-end anastomosis. Mean patient age was 51.5 ± 9 years, and the majority were male (9 patients). Eight patients were referred for management of postintubation tracheal stenosis, and 3 patients were referred for tracheoesophageal fistula. Eight patients had a history of tracheostomy during the COVID-19 infection hospitalization. There was 1 in-hospital death (9.1%) due to septicemia in the intensive care unit approximately 2 months after the operation. Postoperatively, 32 reinterventions were required for tracheal restenosis due to granulation tissue formation. The risk for reintervention was higher during the first 3 months after the index operation. Four patients developed tracheal restenosis (36.4%), and 2 of them required endotracheal stent placement during the follow-up period.
Conclusions
Tracheal resection and reconstruction after COVID-19 infection are associated with a high reintervention rate postoperatively. Such patients require close follow-up in expert interventional pulmonology units, and physicians should be on high alert for the early diagnosis and optimal management of tracheal restenosis.
Postintubation tracheal complications in patients post–COVID-19 may be a different entity of a known disease that requires special attention in the postoperative period. Such patients must be followed up in dedicated tracheal centers qualified for the management of potential tracheal restenosis.
The COVID-19 pandemic has resulted in an increased number of critically ill patients requiring endotracheal intubation with mechanical ventilation for the management of the severe respiratory failure resulting from the infection. A previously reported consensus statement from the European Laryngological Society suggested an increase in postintubation tracheal complications, namely, airway granulomas, postintubation tracheal stenosis (PITS), tracheomalacia, and tracheoesophageal fistulae (TEF).
Long-term intubation and high rate of tracheostomy in COVID-19 patients might determine an unprecedented increase of airway stenoses: a call to action from the European Laryngological Society.
Such complications are directly related to the often long intubation periods. In addition, recent reports have observed tracheal epithelial changes by the SARS-CoV-2 virus as well as tracheal stenosis in a patient with COVID-19 with no history of intubation.
Such reports may suggest a multifactorial causality of PITS in patients with COVID-19 and may be related to the severity of the disease in this particular group of patients. Close monitoring and follow-up of COVID-19 survivors with prolonged mechanical ventilation have been proposed in expert societal publications, targeting the early diagnosis and optimal management of such patients.
Long-term intubation and high rate of tracheostomy in COVID-19 patients might determine an unprecedented increase of airway stenoses: a call to action from the European Laryngological Society.
The aim of this study was to report our experience with the management and postoperative follow-up of patients with COVID-19 with postintubation tracheal complications who underwent tracheal resection with end-to-end anastomosis.
Material and Methods
Between April 2021 and August 2022, we retrospectively included all adult patients with a history of prolonged endotracheal intubation due to COVID-19 infection who were treated with surgical management of tracheal complications in our Thoracic Surgery Department. Patients were followed up prospectively. Patients who underwent tracheal surgery for reasons other than post–COVID-19 infection were excluded. The primary objectives were in-hospital mortality and reintervention rate. The secondary objective was time to tracheal restenosis. A Video Abstract presentation of our study is available online.
STrengthening the Reporting of OBservational studies in Epidemiology guidelines were followed in this retrospective, observational study, and a complete STrengthening the Reporting of OBservational studies in Epidemiology item checklist is shown in Online Data Supplement (Supplementary Methods).
Preoperative Evaluation and Follow-up
Patients who had been discharged from the intensive care unit (ICU) after prolonged ventilation for COVID-19 infection were typically followed up in a respiratory medicine outpatient department. The diagnosis of PITS was suspected due to respiratory stridor and was often discovered by simple chest x-ray or computed tomography scan and confirmed by bronchoscopy. Likewise, tracheostomy closure failure in the inpatient setting was a main indication of referral to the interventional pulmonology unit.
Preoperative tracheal endoscopic intervention was carried out according to the interventional pulmonologist's protocols and included balloon dilatation, electroknife treatment, cryopexy of granulomatous tissue, and endotracheal stent placement. Postoperatively, patients typically underwent bronchoscopy during the first month after the tracheal resection and thereby were followed up according to the interventional pulmonologist's discretion.
Reintervention Procedures
Reintervention procedures that took place in the postoperative period were defined as any tracheal procedure necessary and included both endoscopic and surgical interventions. The following interventions were observed: (1) cryopexy of granulation tissue; (2) electroknife treatment; (3) balloon dilatation; (4) tracheal stent placement; and (5) tracheostomy. Each intervention was counted as a unique number of reintervention event. Postoperative diagnostic bronchoscopy in which no therapeutic intervention took place was not counted as a reintervention event.
Statistical Analysis
All baseline characteristics were presented as raw values and (%) percentages for categorical variables and means ± standard deviations for continuous variables. We fitted a Cox proportional hazards model using multiple failure per-subject data. Kaplan–Meier curve was used to present reintervention-free estimates for patients with COVID-19 with tracheal resection and end-to-end anastomosis. Subgroup analysis was performed using the Kaplan–Meier curve for reintervention-free estimates for patients with or without tracheostomy. Furthermore, the smoothed hazard estimate was used to evaluate the course of reintervention during the overall time frame. Statistical analyses were performed with Stata version 17.0 (StataCorp).
Results
During the study period, 11 patients with a history of COVID-19 infection underwent tracheal surgery in our department. Patient baseline characteristics are shown in Table 1. Mean patient age was 51.5 ± 9 years, and the majority of patients were male (9 patients [82%]). Eight patients (73%) were referred for management of PITS and 3 patients for management of TEF. Most patients had a history of tracheostomy (8 patients [72%]) during the initial hospitalization for COVID-19 or had a tracheostomy tube at the time of referral. All patients underwent tracheal resection with end-to-end anastomosis via transverse cervical incision. The patients with TEF required more extensive repair; one of the subjects required a right thoracotomy before the transverse cervical incision for esophagectomy and repair of the thoracic part of the trachea. Additionally, 2 patients with TEF required tracheal resection, esophageal repair, and interposition of sternocleidomastoid muscle flap between the esophagus and trachea followed by end-to-end anastomosis. The mean number of tracheal cartilaginous rings removed was 3.6 (range, 2-5). All patients with PITS had grade III tracheal stenosis.
One patient died during the postoperative period in the ICU. This patient had been transferred from an ICU of a different hospital after 3 months of mechanical ventilation because of a persistent large TEF (Figure 1). She died 2 months after the operation in the ICU due to septicemia. The rest of the patients were discharged to their homes, and all remain alive at a mean follow-up of 6.6 ± 4.8 months (range, 1-12.1 months).
Figure 1TEF. A, Bronchoscopy image showing a large deficit in the membranous (posterior) part of the trachea in direct communication with the esophageal lumen. B, Preoperative computed tomography scan showing extraluminal spread of gastrographin contrast agent around the tracheostomy, when given through a gastrostomy tube.
Necessity for early and multiple reinterventions was observed (Figure 2). Postoperatively, 32 reinterventions were required in 5 patients. The crude rate of patients with any reintervention at the end of follow-up was 45.5%. The most common reintervention was cryopexy of granulation tissue (21 events). One patient required a tracheostomy postoperatively. Combination of different intervention methods was also observed. Kaplan–Meier reintervention-free analysis is plotted in Figure 3, A. A steep decline in freedom from reintervention was observed from the beginning of follow-up. At 2 months, 25% freedom from reintervention is seen, which decreases to less than 5% after the first 6 months. In addition, the risk for reintervention was observed to be highest during the first 3 months in postoperatively, with a decline thereafter (Figure 3, B). Patients without previous tracheostomy had a longer reintervention-free period, but this trend failed to reach statistical significance (P = .17, Figure E1, Online Data Supplement).
Figure 3A, Kaplan–Meier reintervention-free curve. B, Smooth hazard curve for postoperative reintervention rate. The hazard for reintervention peaks at approximately 2.5 months after tracheal resection. CI, Confidence interval.
Tracheal restenosis greater than 50% was observed in 4 patients at a mean time of 30.5 (range, 10-57) days. Such stenoses were initially treated with cryopexy or electroknife therapy of granulomatous tissue and in severe, persistent cases with stent placement. Two of the patients ultimately required stent placement, one of whom developed restenosis distally to the initial stent (Figure 4), and a different, longer stent was required to cover the lesion. The DUMON (Novatech) silicone tube stent was used in all cases.
Figure 4Distal restenosis after endotracheal stent placement.
The present study reports on the postoperative complications and treatment after tracheal resection with end-to-end anastomosis in patients with prolonged mechanical ventilation for COVID-19 infection. At a mean follow-up of 6.6 ± 4.8 months, we observed a total of 32 postoperative interventions to treat signs of early restenosis after tracheal resection. Four patients (36.4%) developed tracheal restenosis in more than 50% of the tracheal lumen. In addition, we observed an early and steep decline in the freedom from reintervention curve that led us in further analysis, showing the highest reintervention hazard to be approximately 2 months after the operation. However, due to multiple reintervention events per patient, the approximately 50% crude rate of patients with reinterventions might underestimate the severity of COVID-19 infection upon the risk for tracheal reintervention. For that reason, the multiple-failure event analysis was undertaken, which fully incorporated all 32 reintervention events captured to the entire cohort of patients. Kaplan–Meier analysis on multiple failure events (Figure 3, A) showed that after 6 months, the freedom from reintervention decreases to less than 5%, a figure that is important when estimating the impact of COVID-19 infection on these patients. This is also supported by the estimated hazard analysis (Figure 3, B) that showed the highest risk for reintervention was observed during the first 3 months after the initial operation, with a decline thereafter.
Furthermore, during the study period, we treated 3 patients with TEF, a rare complication of prolonged intubation. Over the last decade, a few sporadic cases of TEF were referred to us for surgical management. The occurrence of such number of TEF cases within the short period of our study is highly unusual and is derived from COVID ICU stay. To the best of our knowledge, this is the first study to report on more than 1 year of follow-up of patients with COVID-19 who underwent tracheal resection for tracheal complications, including TEF.
reported low rates (<2%) of granulation tissue formation in a large series of patients with tracheal resection and reconstruction. This was the case as well in our experience before the occurrence of tracheal stenosis in patients with COVID-19.
However, in a previous large series, before the COVID-19 era, restenosis occurred in 16% of the patients, and clinical comorbidities, previous tracheal resection, and the extent of tracheal resection had been proven statistically significant factors for complications.
underlines that caution should be repeated against operating prematurely on a massively inflamed trachea.
In our cohort, alteration of the medical status of the patients due to COVID-19 infection potentially contributes to the high restenosis rate, but the patients did not only show granulation tissue formation in the anastomotic site but also throughout the remaining trachea, requiring the high number of tracheal reinterventions mentioned earlier. Evidently, a patient who required stent placement postoperatively to treat substantial lumen stenosis required additional stenting to treat newly formed downstream stenosis.
Given that apart from the prolonged intubation period, no additional risk factors have been identified for the recurrence of tracheal stenosis postoperatively,
the COVID-19 infection might have been the new determining factor. Although the prolonged intubation periods necessary to treat SARS-CoV-2–related respiratory insufficiency are undoubtedly a reality, additional factors may be implicated. Most of our patients (72%) had a tracheostomy performed during their COVID hospitalization; those patients fared worse in terms of a reintervention-free period when compared with patients without a history of tracheostomy. A trend toward statistical significance was observed but not reached, presumably due to the small number of patients.
Direct tracheal epithelial invasion by viral particles resulting in viral tracheitis has been observed and implicated in the pathophysiological mechanism of tracheal stenosis in patients with COVID-19.
Such observation is yet to be confirmed in large pathology series. In a recently published report of our group, we have examined the possible effects of COVID-19 in pathology specimens of resected tracheas. Although severe inflammatory epithelial response was observed, there were no microscopically visible differences in the tracheas of patients post–COVID-19 when compared with resected tracheas of patients without COVID-19.
Among other factors, several infections are implicated in the pathophysiology of tracheal stenosis through a mechanism of tracheitis and inflammatory changes.
Amid viruses, parainfluenza types 1 to 3, influenza A and B viruses, adenoviruses, coronavirus NL63, H1N1 influenza virus, human papilloma virus, and respiratory syncytial virus have been associated with upper airway obstruction.
characterized by fibrosis and chronic inflammation. The combination of both entities (virus infection with coronavirus that triggers an immunological reaction with cytokine storm) is the mechanism of COVID-19 severe disease.
High density of IgG4-secreting plasma cells in the fibrotic tissue from a surgically resected tracheal ring impaired by complex subglottic stenosis post-tracheostomy as immune expression of a Th2 response due to severe COVID-19.
Less severe strictures can be initially managed by endoscopic interventions. Evidently, approximately one-third of our patients had undergone treatment by one of the mentioned endoscopic modalities before eventually being referred for definitive surgical management. Endoscopic management plays an important role in managing tracheal stenosis preoperatively, but even such treatment has been proven cumbersome in patients with COVID. Evidently, complex stenoses rather than “simpler” web-like stenoses are dominating among the stenotic lesions of patients with COVID when compared with non-COVID cohorts. Such lesions require multiple interventions with a variety of endoscopic modalities, which are fruitful in some cases and can delay or even defer surgery.
Hyperbaric oxygen therapy has been used successfully as an anti-inflammatory measure in the postoperative period for management of anastomotic complications.
Some authors have proposed aggressive management by bronchoscopy in patients with COVID-19 before being referred for tracheal resection to postpone surgery for multi-morbid patients.
Our Thoracic Surgery department's close cooperation with the expert interventional pulmonology unit within our hospital and with a large reference center
for the management of tracheal lesions has achieved the optimal management and timely referral of patients with complex tracheal stenoses who would benefit from tracheal resection.
Numerous case reports and a few case series have reported on the surgical management of patients with COVID-19 with PITS.
Our unprecedented findings focusing on the postoperative necessary reinterventions after tracheal resections in patients with COVID are not found in the published literature. Piazza and colleagues,
who have published the largest case series of patients with post-COVID tracheal resection to date, have reported only 1 patient with restenosis at their follow-up period. However, the postoperative mean follow-up time is not mentioned, and their study was not focused on the long-term postoperative treatment of such patients. Likewise, the Massachusetts General Hospital group observed early ischemic epithelial changes in 1 patient (25% of the cohort) who was treated with hyperbaric oxygen therapy.
The authors stated their concern regarding the epithelial changes in that patient, and although typical mucosal changes were observed, an unusual finding of vascular microthrombi in the affected area was mentioned. It is our belief that the discrepancy between those studies and the reintervention and restenosis rates reported here are the result of our relatively longer follow-up and the fact that our study was oriented in reporting such postoperative outcomes. Certainly, larger series and longer follow-up of patients with post-COVID tracheal resection are required.
Because of the high number of reinterventions observed in the postoperative period, we are highlighting the necessity for close follow-up after the operation. Physicians implicated in the managements of such patients must be vigilant for signs and symptoms of early tracheal restenosis. It is our belief that PITS in patients with COVID-19 may be a different entity of a known complication, and our study's goal was to delineate the severity of such disease in this group of patients. Although all our patients who developed tracheal restenosis have been endoscopically treated successfully thus far, we are yet to see the long-term results of such management.
As it has been mentioned in recent articles, the number of patients with PITS is likely to be significantly higher over the next few years as we emerge from a global pandemic. It is imperative for these patients to be treated in centers of excellence with access to all necessary adjunctive therapies.
Our study is limited by the small number of patients, the limited follow-up, and the lack of a comparative group to draw definite conclusions. Moreover, the tail of the Kaplan–Meier curve should be read with caution, because there is a limited number of patients at risk at the end of the follow-up period.
Conclusions
The increased incidence of substantial tracheal complications that arose by the COVID-19 pandemic has provided a different perspective into a known condition. The high rate of postoperative interventions required to manage restenosis must prompt physicians to be cautious for signs of newly formed strictures. Close cooperation between interventional pulmonologists and thoracic surgeons is a key element and can provide an individualized approach for the optimal management of patients with COVID-19 with postintubation airway complications.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
Long-term intubation and high rate of tracheostomy in COVID-19 patients might determine an unprecedented increase of airway stenoses: a call to action from the European Laryngological Society.
High density of IgG4-secreting plasma cells in the fibrotic tissue from a surgically resected tracheal ring impaired by complex subglottic stenosis post-tracheostomy as immune expression of a Th2 response due to severe COVID-19.
Institutional Review Board approval was obtained for this study (Approval Number 390/9-11-2022). Informed written patient consent was obtained from each individual patient or next of kin.
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