Association between Proton Pump Inhibitors Use and Spontaneous Bacterial Peritonitis Development in Egyptian Cirrhotic Patients with Ascites

their indication. Results: Out of 209 cirrhotic patients with ascites, SBP was detected in 34.9% of patients whether they were on PPIs or not. SBP patients had a significant higher use of PPIs therapy (72.6%) than the non-SBP patients (26.5%) ( P< 0.001). However, there was no statistical significant difference regarding type of PPIs or indications of use ( P> 0.05). Conclusion: The rate of PPIs use was higher in SBP patients than in patients without SBP. There were no differences regarding PPIs types or indications of use between both groups. Thus, PPIs therapy should be judiciously used and only when indicated in patients with liver cirrhosis and ascites.


INTRODUCTION
Spontaneous bacterial peritonitis (SBP) is a frequent complication in cirrhotic patients with ascites, which is associated with significant morbidity and increased mortality [1,2]. SBP is defined as infection of the ascitic fluid in the absence of any obvious source of infection and/or an intra-abdominal inflammatory focus. Around 50% of SBP episodes are diagnosed at the time of hospital admission while the remainder 50% is acquired during the hospitalization period. The significant morbidity and mortality rates associated with SBP make it critical to prompt early diagnosis and identify the predisposing factors [3,4,5].
Small intestinal bacterial overgrowth (SIBO) appears to be a predisposing factor to ascitic fluid infection in patients with advanced liver disease. It has been shown that patients with SBP had higher prevalence of SIBO than ascitic patients who had no evidence of ascitic fluid infection [6]. Patients with advanced liver disease are more liable to SIBO due to weakened GIT immunity, disturbed GIT motility as well as prolonged acid suppression [7].
In patients with liver disease there are so many indications for acid suppressive therapy such as, gastro-esophageal reflux disease (GERD), peptic ulcer disease, Barrett's esophagus, after endoscopic management of esophageal varices to prevent recurrent bleeding and/or scelerosant and postbanding ulcer [8]. Proton pump inhibitors (PPIs) are the most frequently used drugs for acid suppression. However, suppression of gastric acid by these medications has been associated with several potential adverse enteric infections (Clostridium difficile, Klebsiella spp., Salmonella spp.) and community-acquired pneumonia [6,9]. Acid-suppressive therapy is also known to predispose to bacterial overgrowth within the gastrointestinal tract and translocation across the epithelial barrier of the intestine [6]. Studies have shown the appearance of SIBO after PPIs use, to which cirrhotic patients are predisposed to given the abnormal intestinal motility and neuro-hormonal imbalance in the gut environment [10, 11,12]. There is also evidence that PPIs have depressive effects on neutrophil action and innate immunity, adding a direct anti-inflammatory component to this predisposition [13]. The aim of the study is to explore whether PPIs use in Egyptian cirrhotics patients with ascites is associated with spontaneous bacterial peritonitis development.

Patients
The study was conducted in Tropical Medicine and Medical Microbiology and Immunology Departments, Zagazig University Hospitals, Egypt.
Over one year period, the study included total number of 209 patients (112 males and 97 females) who have liver cirrhosis and ascites, their ages ranged from 38 to 65 years.

Inclusion criteria:
Adult patients of both genders who have liver cirrhosis and ascites were offered to be enrolled in the study. The patients who gave an informed written consent were divided into 2 groups according to their ascitic fluid polymorphonuclear leucocyte (PMN) cell count:

Exclusion Criteria
At least 2 weeks prior to hospital admission, all patients who received antibiotics or who had GIT bleeding; GIT endoscopy or any invasive abdominal procedures as (catheterization, cannulation, paracentesis) were excluded from the study. Furthermore, patients with secondary peritonitis, non-cirrhotic ascites as well as patients with previous history of SBP and HCC were excluded from the study.
All patients were subjected to the following: (a) full medical history taking including history of PPIs use (patients were considered PPI users if they are using a PPI daily for at least 2 weeks before hospital admission), and its therapeutic indication; (b) complete physical examination: the stigmata of liver disease, the clinical manifestations suggestive of ascitic fluid infection; (c) Laboratory tests including complete blood count, Liver function tests, kidney function tests, coagulation profile and ascitic fluid analysis (cytologically, biochemically and bacteriologically), Alpha-feto protein; (d) Modified Child-Turcotte-Pugh (CTP) score [14]; (e) Pelvi-abdominal ultrasonography with stress on liver cirrhosis & its complications; (f) Chest X-ray and (g) Complete urine analysis.

Statistical analysis:
Data were checked, entered and analyzed using SPSS (Statistical Package for the Social Sciences) version 19. Data were expressed as mean ± SD for quantitative variable, number and percentage for qualitative one. Chi-squared (X 2 ), t test were used when appropriate. P-value <0.05 was considered significant.

Patient characteristics
Out of all included cirrhotic patients with ascites (209 patients), SBP was detected in 73 (34.9%) patients whether they were on PPIs or not. Table  1 shows the comparison of the demographic and baseline characteristics of both groups. There were no statistical significant differences between the studied groups as regards age and gender distribution (P =0.29 and 0.79 respectively). All of the patients in both groups were Child-Pugh class (B) or (C) with no statistical significant difference (P =0. 1). No cases were classified as Child-Pugh class (A).

Ascitic fluid parameters
As regard laboratory parameters (Table 1), total leucocytic count (TLC), in both blood and ascitic fluid, and PMN leucocyte cell count in the ascitic fluid were statistically significant higher in SBP patients (P <0.001). Among SBP patients, ascitic fluid culture revealed positive results in 60.2% (44 out of 73 patients) of cases (Figure 1). Table 2 shows PPIs use among both studied groups which revealed that SBP patients had a significant higher use for PPIs (72.6%) than the non-SBP patients (26.5%) (P <0.001). In the current study PPIs were used for judicious specific indications for more than 2 weeks, and different generations of PPIs were used. As expected the most common indication of use was related to endoscopic management of varices (as shown in Figure 2 and Table 2). However, there was no statistical significant difference as regards type of PPIs or indications of PPIs use (P >0.05) between patients with and without SBP.

DISCUSSION
The present study revealed that the frequency of SBP in cirrhotic ascitic patients was 34.9% whether they were on PPIs or not, with most of the SBP patients were classified as CTP-class C (89.0%). These results agree with previous studies which reported that frequency of SBP is ranged from 10 . Furthermore, in 2021, Alhumaid and his colleagues conducted a large meta-analysis which aimed at re-assessing the association between PPIs use and SBP development with larger and better-quality data. Twenty three observational (7 case control and 16 cohort) studies were reviewed and 10,386 cirrhotic patients with or without ascites were included in the meta-analysis. The overall results showed a statistically significant association between SBP and PPIs use (OR= 1.8). However, the magnitude of the possible association diminished when analysis focused on higher quality data that were more robust.

CONCLUSION
Among patients with liver cirrhosis and ascites, the rate of PPIs use was higher in SBP patients than in patients without SBP. There were no differences regarding PPIs types or indications of use between both groups. Thus, PPIs therapy should be judiciously used and only when indicated in patients with liver cirrhosis and ascites.

Conflicts of interest:
None.

Ethical considerations
All adult cirrhotic patients who participated in this study gave a written informed consent before being enrolled in the study after explanation for the concept, steps, benefits and risks of the study. The study conforms to declaration of Helsinki. The study was approved by the Institutional Review Board (IRB) of the Faculty of Medicine, Zagazig University.

HIGHLIGHTS
 Spontaneous bacterial peritonitis is a dreading complication in cirrhotic patients with ascites  The use of Proton pump inhibitors is associated with development of spontaneous bacterial peritonitis in cirrhotic patients  Neither the type of the proton pump inhibitor used nor the indication of its use were associated with the risk of spontaneous bacterial peritonitis development