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Atrophic gastritis and chronic diarrhea due to Helicobacter pylori infection in early infancy

Abstract Rationale: Helicobacter pylori infection causes atrophic gastritis in childhood, but atrophic gastritis due to H pylori infection is extremely rare in infancy. The relationship between H pylori infection and chronic diarrhea without protein leakage remains controversial. Patient concerns: An 8-month-old male infant presented to our hospital with severe watery diarrhea, erythema, and failure to thrive from approximately 1 month after birth. Blood, stool, esophagogastroduodenoscopy, total colonoscopy, and H pylori urease analysis results were positive, thereby suggesting atrophic gastritis. Diagnoses: Atrophic gastritis and chronic diarrhea due to H pylori infection. Interventions: We performed H pylori eradication therapy using triple therapy with vonoprazan (6 mg/kg), amoxicillin (300 mg/d), and clarithromycin (120 mg/kg) for 7 days. Outcomes: From approximately 1 week after the H pylori eradication therapy, the frequency of defecation had decreased, stool shape had improved, and body weight had gradually increased. Lessons: H pylori infection can cause atrophic gastritis and chronic diarrhea even in infancy. Early eradication therapy for H pylori infection may be useful for prevention of gastric cancer and improvement in growth disorders.


Introduction
Helicobacter pylori (H. pylori) infection is generally established in the family at 5 years of age in Japanese children [1] and is known to cause atrophic gastritis in childhood. [2][3][4][5] Atrophic gastritis due to H pylori infection is extremely rare in infants; therefore, only few studies have reported this condition in infancy to early childhood. [5] H pylori infection is also known to be one of the causes of Ménétrier disease [6,7] and protein-losing gastroenteropathy, [8] which leads to protein leakage and diarrhea.
There are a few studies that have reported the correlation between Ménétrier disease and H pylori infection, chronic diarrhea, and malnutrition. [9] Conversely, H pylori infection has not been shown to cause diarrhea without protein leakage. [10] Here we report a case of an infant with atrophic gastritis and chronic diarrhea due to H pylori infection who was successfully treated with eradication therapy, with recovered growth.

Case presentation
An 8-month-old male infant presented to our hospital with severe watery diarrhea and erythema of the face, neck, and trunk ( Fig. 1A and B). From approximately 1 month after birth, the patient had severe watery diarrhea and poor body weight gain. At 3 months of age, he was suspected of having a milk allergy and was hydrolyzed milk; however, his diarrhea did not improve and erythema gradually appeared. The results of the milk-specific immunoglobulin E, allergen-specific lymphocyte stimulation tests for casein, lactoferrin, and lactalbumin as well as the stool eosinophil test performed by the previous doctor were normal, but symptoms worsened and the patient was referred to our hospital for closer examination of his digestive tract.
On admission, the patient had more than 8 episodes of diarrhea per day. His height was 63.0 cm (À3.1 standard deviation [SD]) and body weight was 5.6 kg (À3.0 SD), demonstrating a failure to thrive (Fig. 2). His vital signs were normal: body temperature was 37.4°C, heart rate was 115 beats/min, and blood pressure was 92/44 mm Hg. Physical examination revealed erythema and crust Editor: N/A. Informed written consent was obtained from the patient's parents for publishing this manuscript.
The authors have no conflicts of interest to disclose.
To observe the presence of digestive tract diseases, we performed esophagogastroduodenoscopy (EGD) and total colonoscopy (TCS). Figure 3 presents the findings of EGD. No abnormal findings were found in the esophagus, but the stomach showed atrophic mucosa localized from the antrum to the upper corner. The degree of atrophy according to the Kimura-Takemoto classification system for atrophic gastritis was grade C-2. [11] No obvious abnormal findings were observed from the duodenal bulb to the second portion. The only pathological findings of the duodenal mucosa were mild edema and infiltration of inflammatory cells in the lamina propria ( Fig. 4A and B). Electronic microscopic images showed no abnormal villi ( Fig. 4C and D). The rapid urease test using gastric mucosa was positive. TCS revealed no obvious localized lesions from the terminal ileum to the rectum (Fig. 5). The only pathological findings of the terminal ileum and rectum mucosa were mild edema and infiltration of inflammatory cells in the lamina propria ( Fig. 6A and B). Electronic microscopic images showed no abnormal villi, similar to that for the duodenum (Fig. 6C and D).
There were no obvious abnormal findings for the causative agent of diarrhea and poor weight gain other than the positive H pylori urease test. Therefore, we performed H pylori eradication triple therapy using vonoprazan (6 mg/kg), amoxicillin (300 mg/ d), and clarithromycin (120 mg/kg) for 7 days. There were no side effects during or after this eradication treatment. From approximately 1 week after H pylori eradication therapy, the frequency of defecation was decreased, stool shape was improved, and body weight was gradually increased. The only other treatment in addition to H pylori eradication therapy was that including coping treatments such as nutrition administration, hydration, vitamin supplementation, and probiotics. After treatment, the diarrhea had completely disappeared and the body weight had steadily increased, reaching the mean value for transverse standard height and weight curve in Japanese boys 1 year later. Skin erythema was rapidly improved by biotin administration because it was thought to be due to the long-term consumption of allergy milk containing no biotin ( Fig. 1C and D).
At 3 years and 3 months of age, EGD was performed for the purpose of follow-up (Fig. 7). Atrophic gastric mucous spreading from the entire vestibular area to the side of the comet was observed; it was rated as grade C-2 according to the Kimura-Takemoto classification system, which was the same as the previous test. Figure 8 presents the pathological findings. Atrophy of the crypt epithelium and infiltration of the chronic inflammatory cells into the stroma were noted in both the antrum (Fig. 8A-C) and stomach body (Fig. 8D-F). The pathological findings were suggestive of atrophic gastritis. The rapid urease test for H pylori was negative, serum pepsinogen I was 34.1 ng/ mL, and pepsinogen I/II ratio was 4.2. At present, no diarrhea symptoms are observed, and height and body weight has remained within the normal range for Japanese boys

Discussion
The clinical course of the patient's disease provided 2 important clinical suggestions. First, H pylori infection can cause atrophic gastritis even in early infancy. Several studies have suggested that H pylori eradication in young children before gastric mucosa atrophy can effectively prevent new gastric cancers. [12,13] This work lead to clinical trials for screening and treatment of H pylori infection among junior high school students as a prevention strategy against gastric cancer in Japan. [14,15] However, H pylori eradication therapy for children at <15 years of age is not covered by insurance in Japan. Severe gastric mucosal atrophy and submucosal inflammation are rarely observed in children [16][17][18] ; moreover, H pylori eradication therapy is not recommended in junior high school students because children have a low risk of differentiated gastric cancer. [16,17] In our study, atrophic gastritis was recognized in early childhood and gastric mucosal atrophy persisted for >2 years after eradication. Because gastric mucosal atrophy is a cause of gastric cancer, [19] we believe that H pylori eradication must be performed as soon as possible.
Second, H pylori infection can cause chronic diarrhea without protein leakage as well as growth failure. The patient in our study presented with chronic diarrhea with no apparent protein leakage in the stool. No abnormal findings were observed except the positive H pylori urease test; therefore, H pylori eradication therapy drastically improved the diarrhea. Although the relationship between H pylori infection and chronic diarrhea without protein leakage remains controversial, chronic diarrhea positive for H pylori infection should be considered an indication for eradication treatment. Although H pylori infection may play a protective role against bacterial diarrhea in children, [20] it is known to affect the gastric and intestinal microbiota [21][22][23] and may cause chronic diarrhea due to any cause other than infection. In our study, we found that long exposure to H pylori infection possibly decreased the growth rate, which adversely affected the patient's height and body weight. Regardless of the improvement in diarrhea, H pylori eradication itself may contribute to improvement in growth disorders. We believe that H pylori infection must be considered as a cause of chronic diarrhea and growth disorders even in early childhood.
In conclusion, H pylori infection can cause atrophic gastritis and chronic diarrhea without protein leakage as well as growth failure even in early infancy. We believe that early H pylori eradication therapy must be promoted for prevention of gastric cancer and improvement in growth disorders.