Optimal Management of Patients with Phlegmonous Esophagitis: A Systematic Review and Meta-Analysis

Goals: To assess the characteristics and prognosis-influencing factors of phlegmonous esophagitis, a rare condition marked by suppurative inflammation of the esophageal submucosa and muscular layers. Background: Effective management strategies for phlegmonous esophagitis are lacking. This study aims to systematically review cases to better understand the disease’s features and prognostic determinants. Method: A systematic search was performed using PubMed/MEDLINE and Google Scholar from inception to 20 April 2023. Phlegmonous esophagitis case reports and studies with patient information were included; clinical manifestations, laboratory results, imaging findings, other diagnostic findings, and outcomes were analyzed. A pooled analysis was performed to investigate mortality-related risk factors. Results: A total of 35 cases of phlegmonous esophagitis were selected from 31 case reports and 2 case series (median age, 57.0 years; male, 54.3%). The patients presented various clinical symptoms, with neck-to-epigastric pain and dysphagia being the most common. Comorbid diabetes mellitus was a major predisposing factor; one-third of the patients had no previous medical history. Computed tomography (CT) and endoscopic examinations were predominantly used for phlegmonous esophagitis diagnosis. Radiological findings showed that the upper and middle esophagus were most frequently involved. Treatments included administration of broad-spectrum antibiotics and drainage via endoscopy or surgery. There were three cases of mortality, and non-survivors tended to have shorter hospital stays, indicating rapid disease progression. In logistic regression, thoracic surgery was a significant mortality-related risk factor (odds ratio, 19.30; 95% confidence interval, 1.33–282.00, p = 0.03). Conclusion: Advancements in CT and endoscopy have led to less-invasive diagnostic and treatment methods for phlegmonous esophagitis. Endoscopic localized abscess treatment is associated with positive outcomes.


Introduction
Phlegmonous enteritis is an infection characterized by purulent inflammation of the submucosa and muscularis of the gastrointestinal tract with an unaffected mucosa.This condition was initially reported by Cruveilhier in the early 18th century.Although many studies have reported on phlegmonous gastritis [1], phlegmonous esophagitis remains poorly understood, despite its life-threatening potential .
Patients with phlegmonous esophagitis exhibit a broad spectrum of clinical manifestations that range from fever, sore throat, and chest pain to shock [2][3][4][5][6].The reported predisposing factors include immunosuppression, alcoholism, uncontrolled diabetes mellitus, old age, malnutrition with low albumin levels, low socioeconomic status, and tumor burden [4].The diagnosis of phlegmonous esophagitis was initially mainly reliant on surgery or autopsy.However, with advancements in diagnostic imaging, computed tomography (CT) and endoscopy have emerged as effective diagnostic tools [3,7,8].Yun et al. reported the radiological characteristics of phlegmonous esophagitis and presented a flow chart for its differential diagnosis and treatment [8].Regarding treatment regimens, broad-spectrum antibiotics and surgery are typically used; however, a recently developed endoscopic approach has shown favorable outcomes.Kim et al. reported that endoscopic drainage, in addition to traditional open surgery, is a feasible treatment option for phlegmonous esophagitis [9].Several studies have described the benefits of jejunostomy or gastrostomy for early enteral feeding, resulting in better clinical outcomes [3,4,7,10,11].Without early diagnosis and proper treatment, phlegmonous esophagitis can lead to many complications, such as peritonitis, mediastinitis, empyema, perforation, or sepsis-and even mortality.
Karimata et al. conducted a review of 13 cases of phlegmonous esophagitis [3].However, the limited number of reported cases has hindered the understanding of this disease.Herein, we analyzed 35 cases from the published literature to conduct a comprehensive systematic review and identify prognostic factors related to disease outcomes.

Search Strategy and Selection Criteria
This review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P, Supplemental Table S1).Additional Synthesis Without Meta-analysis (SWiM) was also used to evaluate this study, as it represents a less common type of meta-analysis that incorporates case reports/series (Supplemental Table S2).The requirement for ethical approval by the Institutional Review Board was waived due to the study design being based on published medical literature.
Herein, the inclusion criterion for reported cases was the definitive diagnosis of phlegmonous esophagitis or phlegmonous esophagogastritis using surgical or radiological methods.Patients with obvious secondary infections resulting from direct perforations caused by foreign bodies or trauma were excluded.Data was not excluded in cases where there was a possibility of perforation due to a foreign body, but a clear causal relationship could not be established through examination.Additionally, review articles, abstracts, letters to the editor, and articles that did not contain sufficient information regarding patient characteristics or outcomes were excluded.For instance, the paper was excluded if it did not contain independent data for individual patients such as demographics, laboratory results, radiologic findings, or clinical outcome.Articles in English, Korean, and Japanese were collected.
The PubMed and Google Scholar databases were searched to identify articles published until 20 April 2023, regarding patients with phlegmonous esophagitis or esophagogastritis.Detailed search strategies/terms and results can be found in Supplemental Figure S1 and Section 3.

Data Collection
Data regarding the demographic and clinical characteristics of patients, such as age, sex, medical history, symptoms, laboratory results, radiological findings, treatment methods, and clinical outcomes, including length of hospitalization, complications, and mortality, were collected and sorted.Non-existing or ambiguous data were excluded from the analysis.D.H.J. and W.W. screened literature and collected data.Any disagreements between the reviewers regarding any study were resolved through discussion until a consensus was reached.When there was disagreement, it was supervised by S.L.

Statistical Analysis
The Statistical Package for the Social Sciences (SPSS) for Windows, version 25.0 (SPSS Inc., IBM Corp., Armonk, NY, USA), and R, version 4.0.4(R Core Team, R Foundation for Statistical Computing, Vienna, Austria; https://www.R-project.org/accessed on 6 June 2023.)were used for statistical analysis.Continuous variables are presented as medians and interquartile ranges (IQRs), and categorical variables are presented as numbers and percentages.Continuous variables were compared using the Mann-Whitney U-test, and categorical variables were compared using Fisher's exact test.Logistic regression analyses were performed to identify independent risk factors for mortality.Variables with a p-value ≤ 0.05 were considered significant.

Systematic Search and Selection of Studies
A total of 115 articles regarding keyword phlegmonous esophagitis were identified using PubMed.Additional searches using the keywords "phlegmonous esophagogastritis", OR "phlegmonous gastroesophagitis", OR "phlegmonous enteritis" showed 24 articles in advanced searching and returned one or more studies that satisfied the inclusion criterion, apart from the duplicate results already found.A total of 23 papers in PubMed that met the inclusion criteria were included.A similar search was conducted on Google Scholar ("phlegmonous esophagitis" OR "phlegmonous esophagogastritis" OR "phlegmonous gastroesophagitis," language filter: English/Korean/Japanese), which resulted in 172 studies.Among these, 10 additional studies were identified that were not duplicates of the results obtained in the PubMed search.The abstracts and full texts of the articles were reviewed, and all 33 studies (31 case reports and 2 case series) met our inclusion criteria.The included studies and their abstracts are listed in Supplemental Table S3.
Logistic regression analysis to identify risk factors for in-hospital mortality revealed that pus drainage through thoracic surgery was a significant risk factor for mortality (odds ratio, 19.30; 95% confidence interval, 1.33-282.00;p = 0.03), as shown in Table 3.

Discussion
Acute phlegmonous esophagitis and esophagogastritis are rare, life-threatening diseases.During their clinical course, rapid deterioration is often observed, emphasizing the need for prompt diagnosis and appropriate treatment.In this systematic review, we collated information from 35 cases of phlegmonous esophagitis to understand the clinical manifestations, diagnostic methods, treatment options, and possible complications associated with this rare disease.Furthermore, we aimed to identify the risk factors associated with mortality.
Contrary to concerns regarding the high mortality rate of phlegmonous esophagitis reported in many previous studies, our review revealed a low occurrence of mortality (3/35, 8.6%).This was not considered significantly higher compared with that of phlegmonous gastritis, a common type of phlegmonous enteritis that has a mortality rate of approximately 40% following late diagnosis [34].There are several possible explanations for this.First, advancements in diagnostic technologies, especially CT, have led to early identification, before clinical deterioration can occur.Previously, the diagnosis of phlegmonous esophagitis was challenging as no pathognomonic signs or clear diagnostic test results could be obtained.Simple radiography or ultrasonography could provide assistive information, such as mediastinal widening, empyema, pleural effusion, or localized abscess, but often failed to provide sufficient anatomical information required for concrete diagnosis and intervention.With recent advancements in CT, rapid diagnosis and proper strategies for pus drainage have become achievable.Additionally, knowledge regarding conservative treatments, including antibiotic use [34], nutritional support [7,22], and cardiorespiratory support, has improved over time.Moreover, the development of endoscopic treatments has allowed the use of less invasive procedures than traditional surgery, which requires general anesthesia; accordingly, the prevalence of cases with postoperative complications has also declined.
In the present study, thoracic surgery was found to be a risk factor for mortality.Considering the predisposing factors for patients with phlegmonous esophagitis, such as old age, diabetes mellitus, alcoholism, and immune suppression, thoracic surgery may be an invasive option, and the surgery itself can lead to serious complications.Furthermore, even though precise localization of lesions can be obtained with CT scans, it may be difficult to distinguish normal tissues for optimal incision and anastomosis sites during esophageal reconstruction surgery.Diffuse, purulent inflammation of phlegmonous esophagitis can spread from the esophagus to the mediastinum or stomach.Although these problems render surgery an inappropriate option, it remains too early to conclude whether endoscopic treatment is superior to surgery.Patients that undergo thoracic surgery may have a more aggravated clinical condition, and the degree of inflammation could differ from that in other patients.There are also some patients for whom endoscopic drainage is unsuitable.Further evaluation and interpretation based on the patient's context is needed to have an objective view regarding surgical treatment.
With recent advancements in technologies that facilitate rapid diagnosis, an increasing number of patients are being diagnosed with relatively stable conditions.In such cases, appropriate conservative treatment rather than immediate intervention may be worth considering.If a patient does not respond to conservative treatment, endoscopic or surgical intervention should be considered.Additionally, because rapid clinical deterioration is often observed in cases of mortality, close observation is essential.
This systematic review has several limitations.First, the small number of cases limits the ability to generalize the present findings and draw general conclusions regarding this disease.Although we attempted to include articles in several languages, the number of available studies was limited.This led to difficulty in statistical analysis and multivariate risk factor analysis was not possible.Second, many case reports lacked important information, especially regarding continuous variables, such as laboratory data, possibly limiting the strength of the statistical analysis.Finally, as this was a systematic review of case reports, it was based on data reported from various centers, which may have introduced bias and heterogeneity owing to various backgrounds and study periods.However, because of the low incidence of the disease, it is difficult to obtain much larger amounts of data from major institutions.
In conclusion, owing to advancements in CT and endoscopy, phlegmonous esophagitis can now be diagnosed more rapidly and treated using less invasive approaches.This has led to an increasing trend of conservative treatment for patients with early diagnosis and endoscopic treatment for localized abscesses, resulting in favorable in-hospital outcomes.However, the management of diffuse and advanced lesions remains uncertain, and despite aggressive surgical interventions, some cases still show a poor prognosis.Herein, nonsurvivors demonstrated rapid clinical deterioration, often leading to death within a few days, suggesting a need for intensive treatment.Furthermore, although thoracic surgery was observed to be a significant risk factor for mortality, the study's limitations prevent us from definitively asserting that endoscopic treatment is superior.Therefore, additional studies are required to establish effective treatment strategies and identify the predictors of patient outcomes.

Table 1 .
Characteristics and clinical findings of phlegmonous esophagitis patients.
Data are presented as n, n/N(%), or median [interquartile range].

Table 2 .
Treatment and clinical outcome of patients with phlegmonous esophagitis.

Table 3 .
Risk factors univariate analysis for mortality according to clinical presentation and outcome.