Abstract

Objectives: To analyze the influence of pulmonary infection after radical esophagectomy on serum inflammatory markers, pulmonary function, and prognosis.

Methods: We enrolled 278 esophageal cancer patients who underwent radical esophagectomy. Patients were split into the infected (n=51) and uninfected groups (n=227). The inflammatory parameters, complications, and prognosis were compared.

Results: In the infected group, interleukin (IL)-6 was 16.19±2.63 ng/L, tumor necrosis factor-α was 19.64±3.07 µg/L, and IL-1β was 22.49±5.13 ng/L at 7 days postoperatively; white blood cell counts was 12.65±2.14 ×109/L, percentage of neutrophils (NEU%) was 67.04±10.48%, and platelet (PLT) counts was 249.82±63.26 ×109/L; the increasing ranges of the above factors after the operation were much raised compared with the uninfected group (p<0.05). Compared with the uninfected group, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC were greater declines in ranges (p<0.05), and the arrhythmia incidence and the mortality within 60 days postoperatively were greater in the infected group (p<0.05).

Conclusion: Postoperative pulmonary infection can lead to pulmonary function damage, proinflammatory factor overexpression, and an increased risk of early death.

Keywords:

Esophageal cancer (EC) has high malignancy, extensive metastasis, and poor prognosis.1 Its morbidity rank 7th and mortality rank 6th among malignant tumors worldwide.2 China is a high-risk EC nation, particularly in Central North China, which has the highest incidence rates in the world.3 Current treatment options include surgery, radiotherapy, and chemotherapy, all of which are widely applied in clinical practice.4 However, the 5-year overall survival rate of EC patients is 30-40%, and for the intermediate and advanced stages, it is less than 10%.1

Radical esophagectomy with lymph node dissection is an important and curative approach to cases of early or locally advanced EC.5 However, the consequent complications can worsen the quality of life due to complex procedures with surgical incisions in the neck, chest, and abdomen.5 Pulmonary infection occurs in 13-40% of EC cases and is the most predominantly occurring nosocomial infection in patients after curative esophagectomy.6 Patients experience various degrees of pulmonary function decline postoperatively.7 Consequently, the pulmonary infection may be associated with increased postoperative death.5,7 However, there is still no consensus on whether postoperative pulmonary infection adversely affects patients’ prognosis.8,9

Therefore, in the present study, we focused on pulmonary infection-related factors, including serum factors and pulmonary function indicators. We further analyzed the impact of pulmonary infection on the patient’s outcome after curative esophagectomy.

Methods

In this study, we recruited 278 EC patients who underwent radical resection at the Department of Cardiothoracic Surgery of The Affiliated Hospital of Putian University, Putian, China, between January 2016 and June 2020. Among them, 51 patients with postoperative pulmonary infection were assigned to the infected group, and the remaining cases were assigned to the uninfected group. Each patient provided written informed consent to participate in the trial. The ethics committee of the Affiliated Hospital of Putian University, Putian, China, approved the study plan (no.: 202305). All procedures were carried out based on the Helsinki declaration.

The inclusion criteria were as follows: I) according to the Chinese guidelines for diagnosis and treatment of esophageal carcinoma 2018, patients should undergo contrast-enhanced computed tomography (CT) of the neck, chest, and upper abdomen, abdomen ultrasound, gastroscopy, and pathological biopsy; II) tumor staging met the criteria for the International Union Against Cancer and the American Joint Committee on Cancer tumor, node, and metastasis (TNM) staging (8th edition); III) all patients were newly diagnosed and underwent radical resection at the same hospital; and IV) the case records were complete.10,11 The exclusion criteria were as follows: I) cases of coagulation defects, cardiopulmonary dysfunction, hepatorenal insufficiency, immune system disorders, and other primary malignancies; II) patients complicated with serious end-stage diseases that may affect the prognosis; III) patients having received anti-tumor therapy preoperatively; IV) patients with postoperative infections at other sites besides the lung; V) patients for whom pulmonary function tests could not be carried out postoperatively; and VI) pregnant or lactating patients. Diagnostic criteria for postoperative pulmonary infection: significant symptoms included coughing and sputum 48 hours after the operation based on the diagnostic criteria of Hospital Acquired Bronchial-Pulmonary Infection.12 Other criteria (specific pathogens and new inflammatory lesions) should rely on imaging and laboratory examinations, such as blood culture, pathogen isolation, sputum washing and quantitative culture, and chest CT.

The study group established the quality control system and prepared the quality control protocol. The terms to be searched in the hospital information system database were carried out uniform by the study protocol. The 2 independent groups entered the data into the Statistical Package for the Social Sciences (SPSS), version 23.0 software after extracting medical data. Then the group director reviewed the data. If there were discrepancies in the data, the group director convened the 2 study teams to discuss and decide the final results. In addition, the previous related research in this manuscript was all obtained from the PubMed database.

Data on several basic characteristics, including age, gender, smoking history, underlying disease, TNM stage, surgical method, operation time, blood loss, and preoperative plasma albumin (Alb), were extracted in this investigation. Tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, peripheral white blood cell (WBC), percentage of neutrophils (NEU%), and platelet (PLT) counts were examined one day preoperatively and 7 days postoperatively. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were simultaneously measured to calculate FEV1/FVC.

Statistical analysis

The Statistical Package for the Social Sciences, version 23.0 software (IBM Corp., Armonk, NY, USA) was used for statistical analysis. Measurement data were shown as mean ± standard deviation (SD). Count variables were presented as numbers or percentages. Factors consistent with independence, normal distribution, or homogeneity of variance were assessed using the t-test between the groups. Sample rates were assessed with the Chi-square or Fisher exact probability test. A p-value of <0.05 was considered significant.

Results

Table 1 revealed that 2 groups had comparable TNM stages (stages I, II, and III) and surgical methods (open and minimally invasive) (both p>0.05). The infected patients had higher proportions of smoking history and diabetes mellitus than the uninfected counterparts (both p<0.05). However, the 2 groups had a similar rate of hypertension disease (p>0.05). The infected group had longer operation time and lower preoperative Alb levels than the uninfected group (p<0.05).

Table 1

- Clinical characteristics of the 2 groups.

Compared with the indices one day before the operation, 7 days after radical resection, the blood indicators (IL-6, TNF-α, IL-1β, WBC, NEU%, and PLT counts) of the 2 groups significantly increased and the pulmonary function parameters (FEV1, FVC, and FEV1/FVC) significantly decreased (Table 2, p<0.05). The pre-and postoperative indicators showed significant differences between the 2 groups (p<0.05). However, the 2 groups had similar inflammatory factor levels and pulmonary function indices one day before the operation (p>0.05). Conversely, the above indicators before and after the operation showed higher change ranges in the infected groups (p<0.05).

Table 2

- Comparisons of serum inflammatory markers and pulmonary function indices before and after the operation between the 2 groups.

The complications and prognosis were compared and examined within 60 days postoperatively. There were no cases of loss to follow-up in either group. As shown in Table 3, the infected patients had significantly increased arrhythmia incidences during 60 days after surgery (p<0.05). In contrast, the 2 groups did not statistically significantly differ in terms of other postoperative complications, including heart failure, atelectasis, and pulmonary embolism (p>0.05). There were 5 (9.8%) deaths during the study period in the infected group and one (0.44%) death in the uninfected group (p<0.05).

Table 3

- Comparisons of postoperative complications and short-term prognosis between the 2 groups.

Discussion

In this research, we evaluated the influence of pulmonary infection after curative EC resection on serum inflammatory markers, pulmonary function indices, and patient prognosis. Consistent with previous studies, we found the overall incidence rate of pulmonary infection to be 18%.13 Several studies reported high multidrug-resistant bacteria detection rates and found that Escherichia coli and Staphylococcus aureus were the most prevalent pathogens with severe antibiotic resistance.14,15 Therefore, preventing and treating pulmonary infection is of great clinical significance. For effective control of respiratory complications after radical esophagectomy, it is of critical importance to select effective antibiotics with evidence from bacterial culture and drug sensitivity tests. Our results further showed that the probability of developing a pulmonary infection postoperatively was associated with underlying diseases and preoperative Alb level. The situation was much worse for the elder individuals with relatively poor cardiopulmonary function and nutrition reserves.16 Considering that EC patients present with long-term difficulties with eating and the consequent malnutrition after undergoing radical surgery, they should receive standardized adjustments to cardiopulmonary function and get ample nutritional support before the operation.17 We also discovered that intraoperative bleeding was attributed to pneumonia, possibly due to the suppression of the immune system during the procedure. Similarly, Fuchita et al18 revealed that blood loss was related to pulmonary morbidities and hospital death after EC surgery.

The present study found significantly reduced lung function and inflammatory response in infected cases than in uninfected cases. Nevertheless, it is noteworthy that patients without pulmonary infection have reportedly shown reduced pulmonary function after the operation.19 Therefore, the deterioration of postoperative pulmonary function could not be entirely attributed to the pulmonary infection. The pulmonary function status of patients was decided by multiple factors. First, minimally invasive esophagectomy with a shorter operative time and lesser surgical trauma could better preserve pulmonary function than traditional open esophagectomy; this finding could be attributed to the suppressed level of inflammatory stress and the reduced degree of immune damage after surgery.20 Second, resection of the pulmonary vagal branch had little effect on lung function during the surgical procedure, particularly in patients with airway hyperresponsiveness, which may facilitate improvement and recovery of postoperative pulmonary function.21,22 Third, the drug used for intraoperative anesthesia could have affected the pulmonary function. The anesthetic regimen of propofol + dexmedetomidine showed less damage than sevoflurane.23 Fourth, preoperative pulmonary function was correlated with the risk of postoperative infection and pulmonary function indicators.24 Furthermore, the postoperative decline in patients’ pulmonary infection can also be attributed to the invasion of pathogenic microorganisms like bacteria and viruses; this change can result in the chemotaxis of phagocytes and immune cells to lung tissues. The inflammatory mediators released by the immune cells induce vascular endothelial cell damage, inflammatory reactions, hemorrhage, and edema in the lung tissue, thus further compromising postoperative lung function.25

The findings confirmed that patients with postoperative pulmonary infection had a poor clinical prognosis. Our follow-up was primarily aimed at the short-term outcome at 60 days postoperatively. The main factor contributing to patient mortality within this period was postoperative complication; this might be related to organ dysfunction without including long-term prognostic factors like recurrence and distant metastasis. The reasons may comprise the following aspects. First, the pulmonary infection can result in a postoperative hyperinflammatory reaction. Elevated systemic inflammation can cause multiple organ damage and poor prognosis.26 Second, the pulmonary infection can slow down the process of pulmonary rehabilitation and negatively impact postoperative pulmonary function. The postoperative lung function impairment can reportedly exacerbate tissue oxygen supply disorders, increase multiple organ dysfunction risks, and ultimately affect the patient’s prognosis.8 Third, pathogenic microorganism invasion and proliferation can intensify the body’s stress response and impair immune function.27 Finally, the decreased immune function can exacerbate the immunosuppressive state during postoperative chemoradiotherapy, thus leading to treatment-related adverse effects, such as superinfection.28

Study limitations

First, we did not investigate the medium- and long-term outcomes for postoperative patients because long-term follow-up of discharged cases is relatively complex in clinical practice. Second, the relatively small samples in this study were obtained from a single center, thus affecting the generalizability of our findings. Finally, we could not incorporate other potential risk factors into this research, such as education level, chronic obstructive pulmonary disease, and anesthesia method.29,30 Further studies are required to explore the factors associated with pulmonary infection after curative resection for EC.

In conclusion, the present study identified smoking history, diabetes mellitus, and preoperative Alb level as predictors of the risk of postoperative pulmonary infection. The pulmonary infection could result in pulmonary function decline, inflammatory factor overexpression, and increased short-term mortality. Clinicians should adopt targeted interventions preoperatively to reduce the incidence of postoperative infection. Future evaluations should be carried out with large samples and multi-center institutions.

Acknowledgment

The authors gratefully acknowledge Medjaden Inc. (www.medjaden.com) for English language editing.

Footnotes

Disclosure. This study was supported by the Science and Technology Plan Project of Putian, Fujian Province, China (Grant no.: 2018S3F019).

Received September 28, 2023.Accepted November 29, 2023.Copyright: © Saudi Medical Journal

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