Impact of Helicobacter pylori Infection on Short-Term Outcomes in Acute Non-Variceal Upper Gastrointestinal Bleeding

Abstract

Background: The clinical significance of Helicobacter pylori (H. pylori) infection in acute non-variceal upper gastrointestinal bleeding (NVUGIB) remains uncertain, particularly regarding short-term outcomes beyond rebleeding. Methods: We conducted a single-center retrospective cohort study of consecutive adults admitted with acute NVUGIB to Hatyai Hospital, Thailand, between January 2016 and December 2020. H. pylori status was determined during the index hospitalization using rapid urease testing and/or histopathologic examination of gastric biopsy specimens obtained during upper gastrointestinal endoscopy. The primary outcome was 30-day all-cause mortality. Secondary outcomes included in-hospital mortality, rebleeding, requirement of packed red blood cell transfusion, and length of hospital stay. Multivariable regression analyses were performed to adjust for potential confounders. Results: Among 933 patients, 289 (31.0%) were H. pylori-positive and 644 (69.0%) were H. pylori-negative. The H. pylori-positive group was younger, predominantly male, and had lower rates of cirrhosis and prior proton pump inhibitor use. They also more often had peptic ulcer bleeding and underwent earlier endoscopy. H. pylori positivity was independently associated with lower 30-day mortality (adjusted odds ratio 0.39, 95% confidence interval 0.18–0.84), but not with rebleeding, requirement of transfusion, or length of stay. Conclusions: H. pylori positivity was associated with lower short-term mortality in acute NVUGIB, although this finding may reflect baseline clinical differences rather than a direct effect on bleeding severity.

1. Introduction

Acute upper gastrointestinal bleeding (UGIB) remains a common medical emergency and continues to be associated with substantial morbidity, mortality, and healthcare utilization despite advances in endoscopic and pharmacologic management. Non-variceal UGIB (NVUGIB), particularly peptic ulcer bleeding, remains the predominant cause in many settings and is strongly associated with nonsteroidal anti-inflammatory drug (NSAID) use, antithrombotic therapy, and Helicobacter pylori (H. pylori) infection [1].

H. pylori infection is a well-established etiologic factor in peptic ulcer disease and ulcer recurrence. At the same time, H. pylori is a common chronic gastric colonizer worldwide, and many infected individuals remain asymptomatic, indicating that the organism may be present in the stomach of otherwise healthy people without causing overt disease. Previous observational studies and meta-analyses have shown that H. pylori infection increases the risk of peptic ulcer bleeding, while successful eradication reduces long-term ulcer recurrence and recurrent bleeding [2,3,4,5]. Accordingly, testing for and eradicating H. pylori are standard components of management in patients with ulcer-related bleeding. Community-based data have also demonstrated substantial background prevalence of H. pylori among healthy populations. For example, a study from Lebanon reported a prevalence of 42.1% among screened healthy individuals, further emphasizing that the clinical consequences of H. pylori depend on host, environmental, and disease context rather than infection alone [6].

In contrast, the relationship between H. pylori infection and short-term outcomes during the index episode of acute NVUGIB remains less clearly defined. Patients presenting with acute bleeding often have multiple competing determinants of prognosis, including older age, comorbidity burden, hemodynamic instability, NSAID or antithrombotic exposure, and high-risk endoscopic findings [7]. Some cohort studies have suggested that H. pylori-associated ulcer bleeding may be associated with more favorable short-term outcomes than NSAID-related or idiopathic ulcer bleeding, whereas ulcers unrelated to H. pylori or NSAID exposure have been linked to worse prognosis [7,8].

However, the available evidence remains heterogeneous, and most prior studies have emphasized long-term recurrence rather than early clinical outcomes. In addition, data addressing short-term prognosis in acute NVUGIB from Southeast Asian populations such as Thailand remain scarce, despite potential regional differences in H. pylori epidemiology, comorbidity burden, and clinical care pathways. Accordingly, the clinical implications of H. pylori status in acute NVUGIB remain insufficiently characterized in this setting.

Therefore, this study aimed to evaluate the association between H. pylori infection status and short-term clinical outcomes in patients presenting with acute NVUGIB. Specifically, we compared 30-day mortality and other in-hospital outcomes between H. pylori-positive and H. pylori-negative patients to determine whether infection status was associated with differences in early clinical course.

2. Materials and Methods

2.1. Study Design and Setting

This was a single-center retrospective cohort study conducted at Hatyai Hospital, a tertiary referral hospital in southern Thailand. Consecutive adult patients admitted with acute non-variceal upper gastrointestinal bleeding between January 2016 and December 2020 were screened for eligibility. The study period was intentionally restricted to the pre-pandemic era to preserve a cohort with more consistent clinical workflows and outcome ascertainment. The study protocol was approved by the Institutional Review Board of Hatyai Hospital (HYH EC 02-69-01), and the requirement for informed consent was waived because of the retrospective design. The study was conducted in accordance with the Declaration of Helsinki.

2.2. Study Population

Eligible patients were aged 18 years or older and presented with clinical features of acute NVUGIB, including hematemesis, coffee-ground emesis, and/or melena, and underwent upper gastrointestinal endoscopy during the index hospitalization. Patients were excluded if they had undergone upper endoscopy at another hospital before transfer, had a documented episode of upper gastrointestinal bleeding within the preceding 3 months, had no identifiable bleeding source on index endoscopy, or had incomplete medical records precluding determination of Helicobacter pylori status or study outcomes.

2.3. Assessment of H. pylori Infection

H. pylori status was determined from diagnostic testing performed during the index hospitalization as part of routine clinical care rather than a study-mandated protocol. All included patients underwent upper gastrointestinal endoscopy with gastric biopsy during the index hospitalization. Biopsy specimens were obtained during upper gastrointestinal endoscopy and were assessed using rapid urease testing and/or histopathologic examination of gastric biopsy specimens. Patients were classified as H. pylori-positive if at least one documented test performed during the index hospitalization was positive, and as H. pylori-negative if all available tests performed during the index hospitalization were negative. Accordingly, the analytic cohort already represented a biopsy-tested population. Because testing was non-protocolized, not all patients underwent the same diagnostic modality. In addition, biopsy-based testing during acute bleeding and prior proton pump inhibitor exposure may reduce diagnostic sensitivity. Accordingly, H. pylori status in this study should be interpreted as an observational exposure variable that may be subject to non-differential misclassification.

2.4. Data Collection and Covariates

Clinical data were retrospectively extracted from electronic medical records using a standardized data collection form. Variables included demographic characteristics, comorbidities, medication history, presenting clinical features, laboratory values at admission, and endoscopic findings. Medication history included nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, and proton pump inhibitors.

Baseline covariates were defined a priori as values obtained at initial hospital presentation before endoscopic evaluation. Vital signs were recorded from the initial triage assessment or first physician evaluation, and laboratory values were obtained from the first blood sample collected on arrival. Repeat measurements obtained after initiation of treatment were not used for baseline adjustment in order to minimize bias related to evolving disease severity and early therapeutic interventions.

A recorded history of prior gastrointestinal bleeding in the baseline characteristics referred to any remote episode occurring more than 3 months before the index admission and, therefore, did not conflict with the exclusion criterion for recent bleeding.

Endoscopic diagnoses were categorized according to the primary bleeding source identified during index endoscopy. For prespecified subgroup analyses, patients with peptic ulcer bleeding, including gastric and duodenal ulcers, were analyzed separately to reduce etiologic heterogeneity.

2.5. Clinical Management

Patients were managed according to routine guideline-based clinical practice rather than a formal institutional protocol. Initial management focused on hemodynamic stabilization, including intravenous fluid resuscitation, blood transfusion when indicated, and airway protection when clinically necessary. Proton pump inhibitors were routinely administered in patients with suspected non-variceal bleeding.

Upper gastrointestinal endoscopy was generally performed within 24 h of presentation when feasible. Endoscopic hemostasis included standard modalities such as thermal coagulation, mechanical clipping, injection therapy, or combination therapy, at the discretion of the endoscopist. Adrenaline injection monotherapy was not used at our center. Escalation to radiologic intervention or surgery was reserved for patients with ongoing or recurrent bleeding despite endoscopic management, failure to achieve durable endoscopic hemostasis, or when endoscopic therapy was considered technically infeasible or clinically inadequate after multidisciplinary discussion.

2.6. Outcome Measures

The primary outcome was 30-day all-cause mortality, defined as death from any cause within 30 days of hospital presentation. Mortality data were obtained from hospital records and the Thai civil registration system.

Secondary outcomes included in-hospital mortality, in-hospital rebleeding, requirement of packed red blood cell transfusion, and length of hospital stay. In-hospital rebleeding was defined as recurrent clinical evidence of upper gastrointestinal bleeding after initial stabilization, accompanied by a decrease in hemoglobin of more than 2 g/dL or the need for additional blood transfusion.

2.7. Statistical Analysis

Baseline characteristics were summarized using descriptive statistics. Continuous variables were expressed as mean ± standard deviation or median (interquartile range), as appropriate, and categorical variables as counts and percentages. Comparisons between H. pylori-positive and H. pylori-negative groups were performed using Student’s t test or the Wilcoxon rank-sum test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables.

Multivariable regression analyses were performed to assess the association between H. pylori status and clinical outcomes. Logistic regression was used for binary outcomes, and linear regression was used for continuous outcomes. Specifically, linear regression models were applied for continuous outcomes including length of hospital stay and total packed red blood cell units transfused. Covariates for adjusted models were prespecified on clinical grounds based on established predictors of adverse outcomes in UGIB and potential confounders of the relationship between H. pylori status and short-term prognosis. These included age, sex, cirrhosis, shock at presentation, use of nonsteroidal anti-inflammatory drugs or antiplatelet agents, presence of fresh blood on nasogastric tube aspiration, international normalized ratio, serum albumin, creatinine, and timing of endoscopy. As a supplementary analysis, we fitted an expanded multivariable model that additionally incorporated available comorbidity-related variables from the retrospective dataset to assess the robustness of the main findings to broader adjustment for baseline disease burden.

Missing data were infrequent (<5% for all baseline variables); therefore, analyses were conducted using a complete-case approach. All statistical analyses were performed using Stata version 15.1 (StataCorp LLC, College Station, TX, USA). A two-sided p value < 0.05 was considered statistically significant.

3. Results

3.1. Study Population and Baseline Characteristics

A total of 933 patients admitted with acute non-variceal upper gastrointestinal bleeding (NVUGIB) were included in the analysis. Of these, 289 (31.0%) were classified as Helicobacter pylori-positive and 644 (69.0%) as H. pylori-negative.

Baseline characteristics are summarized in

Table 1. Baseline characteristics of patients with acute non-variceal upper gastrointestinal bleeding stratified by Helicobacter pylori status.

Characteristic	Overall (N = 933)	Helicobacter pylori-Negative (N = 644)	Helicobacter pylori-Positive (N = 289)	p Value
Demographics
Age, years	60 (17)	61 (17)	58 (17)	0.028
Male sex	713 (76%)	475 (74%)	238 (82%)	0.005
Body mass index, kg/m2 †	23.0 (4.7)	23.0 (4.7)	22.9 (4.5)	0.679
Comorbidities
History of gastrointestinal bleeding	128 (14%)	103 (16%)	25 (8.7%)	0.004
Hypertension †	338 (36%)	234 (36%)	104 (36%)	>0.999
Diabetes mellitus †	107 (12%)	75 (13%)	32 (12%)	0.801
Cirrhosis †	83 (8.9%)	71 (11%)	12 (4.2%)	<0.001
Chronic kidney disease	94 (10%)	72 (11%)	22 (7.6%)	0.120
Ischemic heart disease	36 (3.9%)	30 (4.7%)	6 (2.1%)	0.087
Congestive heart failure †	13 (1.4%)	12 (1.9%)	1 (0.3%)	0.126
Dyslipidemia	134 (14%)	103 (16%)	31 (11%)	0.043
Cerebrovascular disease	45 (4.8%)	34 (5.3%)	11 (3.8%)	0.420
Chronic obstructive pulmonary disease	29 (3.1%)	20 (3.1%)	9 (3.1%)	>0.999
Medication exposure
Aspirin	90 (9.6%)	64 (9.9%)	26 (9.0%)	0.741
Clopidogrel	30 (3.2%)	23 (3.6%)	7 (2.4%)	0.472
Any antiplatelet agent	75 (8.0%)	55 (8.5%)	20 (6.9%)	0.477
Warfarin †	26 (2.8%)	21 (3.3%)	5 (1.7%)	0.271
Nonsteroidal anti-inflammatory drugs	205 (22%)	139 (22%)	66 (23%)	0.732
Herbal supplements	53 (5.7%)	33 (5.1%)	20 (6.9%)	0.346
Prior proton pump inhibitor use	88 (9.4%)	73 (11%)	15 (5.2%)	0.004
Clinical presentation
Fresh blood on nasogastric tube	154 (17%)	116 (18%)	38 (13%)	0.079
Shock at presentation	69 (7.4%)	48 (7.5%)	21 (7.3%)	>0.999
Endoscopic diagnosis
Gastric ulcer	390 (42%)	236 (37%)	154 (53%)	<0.001
Duodenal ulcer	270 (29%)	153 (24%)	117 (40%)	<0.001
Mallory–Weiss tear	58 (6.2%)	53 (8.2%)	5 (1.7%)	<0.001
Gastritis	185 (20%)	135 (21%)	50 (17%)	0.227
Duodenitis	32 (3.4%)	16 (2.5%)	16 (5.5%)	0.030
Esophagitis †	102 (11%)	79 (12%)	23 (8.0%)	0.065
Esophageal ulcer	52 (5.6%)	44 (6.8%)	8 (2.8%)	0.019
Tumor	32 (3.4%)	28 (4.3%)	4 (1.4%)	0.035
Laboratory values at presentation
Hemoglobin, g/dL *	9.0 (3.5)	9.1 (3.5)	9.0 (3.4)	0.822
Platelet count, ×103/µL *	237 (121)	231 (129)	249 (101)	0.018
Blood urea nitrogen, mg/dL **	32 (18–49)	29 (17–46)	35 (23–51)	<0.001
Creatinine, mg/dL **	1.01 (0.79–1.40)	1.01 (0.78–1.40)	1.02 (0.84–1.40)	0.429
Albumin, g/dL †,*	3.33 (0.73)	3.31 (0.77)	3.39 (0.63)	0.091
Total bilirubin, mg/dL †,**	0.50 (0.30–1.00)	0.60 (0.30–1.10)	0.50 (0.30–0.80)	<0.001
Sodium, mEq/L *	138.6 (7.6)	138.6 (7.9)	138.7 (7.1)	0.799
International normalized ratio **	1.11 (1.04–1.24)	1.13 (1.04–1.26)	1.10 (1.04–1.18)	<0.001
Risk assessment and timing
Glasgow–Blatchford score **	10.0 (6.0–12.0)	10.0 (5.0–12.5)	10.0 (6.0–12.0)	0.361
Time to endoscopy, hours **	20 (13–39)	21 (13–41)	19 (12–34)	0.008
Endoscopy within 24 h	590 (63%)	392 (61%)	198 (69%)	0.030

Notes: Data are presented as n (%) unless otherwise specified; * mean (SD); ** median (IQR, interquartile range). Between-group comparisons for continuous variables were performed using Student’s t test for normally distributed variables and the Wilcoxon rank-sum test for non-normally distributed variables. ^† Variables with missing data (percentages calculated from available data).

. Patients in the H. pylori-positive group were younger than those in the H. pylori-negative group (mean age, 58 vs. 61 years; p = 0.028) and were more frequently male (82.0% vs. 74.0%; p = 0.005). A history of prior gastrointestinal bleeding was less common in the H. pylori-positive group (8.7% vs. 16.0%; p = 0.004), as was cirrhosis (4.2% vs. 11.0%; p < 0.001). Prior proton pump inhibitor use was also less frequent among H. pylori-positive patients (5.2% vs. 11.0%; p = 0.004). Most other individual comorbidities were comparable between groups.

Clinical presentation at admission was broadly similar, with no significant between-group differences in shock at presentation or fresh blood on nasogastric tube aspiration. However, the endoscopic bleeding source differed according to H. pylori status. Gastric ulcer bleeding (53.0% vs. 37.0%; p < 0.001) and duodenal ulcer bleeding (40.0% vs. 24.0%; p < 0.001) were more common in H. pylori-positive patients, whereas Mallory–Weiss tear, esophageal ulcer, and tumor-related bleeding were more frequent in H. pylori-negative patients. At presentation, H. pylori-positive patients had higher platelet counts and lower international normalized ratio and total bilirubin levels. They also underwent endoscopy earlier (median, 19 vs. 21 h; p = 0.008), and more frequently within 24 h of presentation (69.0% vs. 61.0%; p = 0.030).

3.2. Clinical Outcomes

Clinical outcomes are shown in

Table 2. Clinical outcomes of patients with acute non-variceal upper gastrointestinal bleeding stratified by Helicobacter pylori status.

Outcome	Overall (N = 933)	Helicobacter pylori-Negative (N = 644)	Helicobacter pylori-Positive (N = 289)	p Value
Clinical outcomes
In-hospital mortality	35 (3.8%)	31 (4.8%)	4 (1.4%)	0.009
30-day mortality	59 (6.3%)	51 (7.9%)	8 (2.8%)	0.002
In-hospital rebleeding	128 (14%)	93 (14%)	35 (12%)	0.459
Length of hospital stay, days	4.0 (3.0–6.0)	4.0 (3.0–6.0)	4.0 (3.0–6.0)	0.213
Resource utilization and interventions
Patients requiring PRBC transfusion	704 (75%)	487 (76%)	217 (75%)	0.844
Total PRBC units transfused	2.0 (0.0–3.0)	2.0 (0.0–3.0)	1.0 (0.0–3.0)	0.781
Radiologic intervention	17 (1.8%)	14 (2.2%)	3 (1.0%)	0.343
Surgical intervention	9 (1.0%)	9 (1.4%)	0 (0%)	0.058

Notes: Categorical variables are presented as n (%); continuous variables as median (IQR). Between-group comparisons for continuous variables were performed using the Wilcoxon rank-sum test. Total PRBC units represent units transfused during the index hospitalization. Abbreviations: PRBC, packed red blood cells.

. In-hospital mortality was lower in the H. pylori-positive group than in the H. pylori-negative group (1.4% vs. 4.8%; p = 0.009). Similarly, 30-day all-cause mortality was lower among H. pylori-positive patients (2.8% vs. 7.9%; p = 0.002).

In contrast, in-hospital rebleeding rates were similar between groups (12.0% vs. 14.0%; p = 0.459). Length of hospital stay and transfusion-related outcomes were also comparable, including the proportion of patients requiring packed red blood cell transfusion (75.0% vs. 76.0%; p = 0.844) and the total number of transfused units during the index hospitalization. Radiologic and surgical interventions were infrequent in both groups, with no statistically significant between-group differences.

3.3. Multivariable Analysis

Multivariable associations between H. pylori status and clinical outcomes are presented in

Table 3. Multivariable association between Helicobacter pylori infection and post-bleeding clinical outcomes.

Outcome	Adjusted Odds Ratio (95% CI)	p Value
In-hospital mortality	0.34 (0.11–1.01)	0.051
30-day mortality	0.39 (0.18–0.84)	0.019
In-hospital rebleeding	0.85 (0.54–1.35)	0.493
Pulmonary edema	0.60 (0.32–1.13)	0.113
Radiologic intervention	Not estimable †	—
Surgical intervention	0.00 (0.00–0.00)	—

Notes: Multivariable logistic regression models were adjusted for age, sex, cirrhosis, shock at presentation, use of nonsteroidal anti-inflammatory drugs or antiplatelet agents, presence of fresh blood on nasogastric tube, international normalized ratio, albumin, creatinine, and timing of endoscopy. Reference group: H. pylori-negative patients. ^† Radiologic intervention models did not converge because of low event counts. Abbreviations: CI, confidence interval.

. After adjustment for age, sex, cirrhosis, shock at presentation, use of nonsteroidal anti-inflammatory drugs or antiplatelet agents, presence of fresh blood on nasogastric tube aspiration, international normalized ratio, serum albumin, creatinine, and timing of endoscopy, H. pylori positivity remained independently associated with lower 30-day mortality (adjusted odds ratio [aOR], 0.39; 95% confidence interval [CI], 0.18–0.84; p = 0.019).

The association with in-hospital mortality was directionally similar but did not reach conventional statistical significance (aOR, 0.34; 95% CI, 0.11–1.01; p = 0.051). No significant association was observed between H. pylori status and in-hospital rebleeding (aOR, 0.85; 95% CI, 0.54–1.35; p = 0.493) or pulmonary edema (aOR, 0.60; 95% CI, 0.32–1.13; p = 0.113). Because radiologic and surgical interventions were rare, adjusted analyses for these outcomes were not considered reliable.

In a supplementary analysis using an expanded multivariable model with additional adjustment for available comorbidity-related variables, the main findings were materially unchanged. H. pylori positivity remained independently associated with lower in-hospital mortality and lower 30-day mortality, whereas no significant associations were observed for in-hospital rebleeding, pulmonary edema, or surgical intervention (Supplementary Table S4).

3.4. Prespecified Subgroup Analysis

In the prespecified subgroup restricted to patients with peptic ulcer-related UGIB (n = 586), baseline patterns were broadly similar to those observed in the overall cohort. H. pylori-positive patients were younger, more frequently male, and had lower rates of cirrhosis and chronic kidney disease. Endoscopy was also performed earlier in this subgroup.

Unadjusted outcomes again favored the H. pylori-positive group, including lower in-hospital mortality, lower 30-day mortality, and lower transfusion requirements. However, after multivariable adjustment, the effect estimates were attenuated, and several associations no longer reached statistical significance, although the overall direction of effect remained consistent with the primary analysis (Supplementary Tables S1–S3).

4. Discussion

In this single-center retrospective cohort study of patients hospitalized with acute NVUGIB, H. pylori positivity was independently associated with lower short-term mortality, particularly 30-day all-cause mortality. After adjustment for major clinical and laboratory confounders, H. pylori-positive patients had a significantly lower risk of 30-day mortality, whereas the association with in-hospital mortality showed a similar direction but did not reach statistical significance. In contrast, rebleeding, length of hospital stay, packed red blood cell transfusion requirements, and other indicators of acute resource utilization were broadly comparable between H. pylori-positive and H. pylori-negative patients. Collectively, these findings suggest that H. pylori status was not clearly associated with early bleeding-related instability or acute hemostatic failure in this cohort. Rather, H. pylori positivity may have functioned primarily as a surrogate marker of a more favorable clinical phenotype, characterized by younger age, lower cirrhosis burden, and a more ulcer-predominant bleeding pattern. Accordingly, the observed mortality difference is more likely to reflect variation in baseline patient vulnerability and competing mortality risk than a direct effect of infection on bleeding severity.

This dissociation—where mortality differed but rebleeding did not—supports the interpretation that H. pylori status is more closely associated with patient-level vulnerability and baseline clinical phenotype than with lesion-level hemostatic failure. This is consistent with the current understanding that short-term outcomes in UGIB are influenced by both lesion-level and patient-level factors [9,10]. Early rebleeding is driven predominantly by endoscopic stigmata, adequacy of hemostasis, and post-endoscopic pharmacotherapy [11], whereas short-term mortality in NVUGIB is often more strongly influenced by age, frailty, cirrhosis, renal dysfunction, malignancy, cardiopulmonary decompensation, and other non-bleeding complications [12,13]. In our cohort, H. pylori-negative patients were older, had more cirrhosis and biochemical features of hepatic dysfunction, and more often presented with non-ulcer bleeding etiologies such as tumor-related bleeding, esophageal ulcer, and Mallory–Weiss tear. Accordingly, the lower mortality observed in the H. pylori-positive group may be better understood as a reflection of case-mix differences rather than a direct protective effect of infection itself [8,14,15].

This interpretation is also supported by previous studies showing poorer outcomes among patients with non-H. pylori, non-NSAID ulcer bleeding and other comorbidity-heavy phenotypes [8]. In contrast, H. pylori-associated ulcer bleeding may represent a more etiologically defined and therapeutically tractable condition in which the principal driver of ulcer disease is identifiable [16]. Therefore, the less favorable short-term outcomes in the H. pylori-negative group may reflect broader etiologic heterogeneity and greater systemic illness burden, rather than the absence of infection per se [17,18].

In our dataset, H. pylori-positive patients underwent endoscopy earlier than H. pylori-negative patients. Earlier endoscopy may contribute to improved outcomes through more rapid diagnosis and hemostatic intervention, but it may also reflect differences in triage, clinical stability, or care pathways rather than a direct causal mechanism [19,20,21,22]. Notably, the association between H. pylori status and mortality persisted after adjustment for endoscopy timing, suggesting that this factor alone did not explain the observed difference. This observation is compatible with prior observational and meta-analytic evidence indicating that, once appropriate resuscitation has been achieved, the relationship between endoscopy timing and mortality is complex and may be strongly influenced by underlying illness severity [23,24,25].

In the prespecified peptic ulcer bleeding subgroup, H. pylori-positive patients again showed lower crude mortality and lower transfusion requirements, although several adjusted associations were attenuated and no longer statistically significant. This attenuation within a more etiologically homogeneous subgroup suggests that part of the mortality signal observed in the overall cohort may have been driven by the concentration of non-ulcer and clinically complex causes of bleeding in the H. pylori-negative group [7,8,10]. This subgroup finding further supports the interpretation that H. pylori status may operate primarily as a marker of clinical phenotype rather than as an independent determinant of short-term bleeding severity.

Several limitations should be considered when interpreting these findings. First, this was a single-center study conducted at a tertiary referral hospital, which may limit the generalizability of the findings to other institutions, healthcare systems, and patient populations. Second, misclassification of H. pylori status is an important concern in acute UGIB because active bleeding and proton pump inhibitor exposure may reduce the sensitivity of biopsy-based testing and rapid urease testing [26]. Because H. pylori status in this study was determined during the index hospitalization as part of routine clinical care, false-negative classification was possible. Such misclassification may have biased the observed associations, likely toward the null, although its true magnitude and direction cannot be determined with certainty in a retrospective design [27,28]. Third, H. pylori testing was not protocolized, introducing the possibility of ascertainment-related confounding. Clinicians may have been more likely to test patients with ulcer-appearing lesions than those with tumor bleeding, esophageal ulcer, Mallory–Weiss tear, or marked clinical instability, thereby potentially enriching the tested population for patients with a more favorable baseline profile [8]. In particular, if patients with greater illness severity were less likely to undergo equally complete H. pylori assessment, the H. pylori-positive group may have appeared artificially healthier, which could have biased the mortality association away from the null. Fourth, cause-specific mortality data were not consistently available, especially for deaths identified through post-discharge civil registration linkage. As a result, we could not determine whether the mortality difference was directly related to bleeding complications or to underlying comorbid illness. Fifth, data on eradication therapy, treatment completion, and post-treatment confirmation of eradication were not systematically available; therefore, the potential influence of subsequent H. pylori management on short-term outcomes could not be assessed. Sixth, clinician-level thresholds for escalation to radiologic or surgical intervention were not available in sufficient detail, limiting evaluation of differences in escalation practices between groups. Seventh, a validated summary measure of comorbidity burden, such as the Charlson Comorbidity Index, could not be reliably reconstructed from the retrospective dataset. Residual confounding related to overall disease burden may therefore remain despite adjustment for individual comorbidities. However, in a supplementary analysis using broader adjustment for available comorbidity-related variables, the main mortality findings remained directionally and statistically consistent, providing some support for the robustness of the primary results. In addition, the study period was also restricted to the pre-pandemic era. Patients from 2021 onward were not included because the COVID-19 pandemic substantially altered hospital operations, referral patterns, endoscopy timing, and case mix at our center, which may have affected short-term outcomes independently of H. pylori status. In addition, post-pandemic data were not yet sufficiently complete and harmonized for reliable analysis. Finally, although the multivariable models adjusted for several key predictors, residual confounding cannot be excluded because data on ulcer stigmata, frailty, malignancy stage, antithrombotic intensity, and hemostatic modalities were not uniformly available.

These limitations are important because they constrain causal interpretation. The present findings should not be interpreted as evidence that H. pylori infection protects against adverse outcomes, nor that a negative test result aggravates bleeding severity. Rather, they suggest that H. pylori status during the acute hospitalization may capture differences in underlying etiology, comorbidity burden, and competing mortality risk.

From a clinical perspective, H. pylori status should not be used as an isolated predictor of acute rebleeding risk in NVUGIB, as no such association was observed in this cohort. At the same time, H. pylori-negative NVUGIB may warrant careful consideration of alternative bleeding etiologies, broader systemic vulnerability, and the possibility of false-negative testing during acute bleeding [10,12]. Thus, the principal value of H. pylori assessment in this context may lie in etiologic characterization and follow-up management rather than in short-term prognostic stratification during the index hospitalization. Future prospective studies using protocolized diagnostic strategies, standardized measures of comorbidity burden and bleeding severity, and cause-specific mortality assessment are needed to determine whether the observed association reflects true biologic differences, residual confounding, or exposure misclassification [29].

5. Conclusions

In this retrospective cohort of patients hospitalized with acute NVUGIB, H. pylori positivity was associated with lower short-term mortality but was not associated with rebleeding, length of hospital stay, or other markers of acute bleeding severity. These findings should be interpreted cautiously in light of the retrospective design, non-protocolized H. pylori testing during the index hospitalization, and the potential for residual confounding and false-negative exposure classification. Overall, the observed pattern suggests that H. pylori status may function more as a marker of underlying clinical phenotype and competing mortality risk than as a direct determinant of short-term bleeding outcomes. Therefore, in the acute setting, H. pylori assessment may be more informative for etiologic interpretation and longitudinal management planning than for immediate prognostic stratification of bleeding severity.