Helicobacter pylori in children: think before you kill the bug!

Abstract

Since the discovery of Helicobacter pylori (H. pylori) as the causative organism for gastric and duodenal ulcers four decades ago and subsequent recognition as class 1 gastric carcinogen, countless numbers of studies have been conducted and papers published, on the efficacy of various management strategies to eradicate the infection. In adults, a global consensus by the experts in the field concluded that H. pylori gastritis is an infectious disease and requires treatment irrespective of the presence or absence of symptoms due to the potential for serious complication like peptic ulcer disease and gastric neoplasia. However, although more than half the world’s population harbors H. pylori, these serious complications occur only in a small minority of the infected population, even less so in childhood. More importantly, there is accumulating evidence for beneficial role of H. pylori against many chronic health conditions, from several epidemiological and laboratory studies. No doubt, eradication therapy is indicated in children with H. pylori-related peptic ulcer disease. Even though the pediatric guidelines from various learned societies recommend against a “test and treat” strategy, this is not always adhered to. With the accumulating evidence of the possible beneficial role of H. pylori, it is time to pause and think, are we causing more harm than good by eradicating H. pylori in every child who has this bug?

Introduction

Helicobacter pylori (H. pylori), a gram-negative bacterium that colonizes the gastric mucosa, is one of the most common gastrointestinal infections, infecting more than half the world’s population. ¹ The prevalence varies from 24% to 73% depending on geographical region and economic development. ² The infection is mostly acquired in childhood and persists for life in the infected host unless treated. ³ Since the discovery of H. pylori by Warren and Marshall in 1983, ⁴ its causative role in peptic ulcer disease (PUD) and gastric cancers is well established. Eradication of H. pylori heals the ulcer, reduces the ulcer recurrence, ⁵ and might confer long-term protection against gastric cancer in high-risk populations. ⁶ In addition, iron deficiency anemia^7–9 and idiopathic thrombocytopenic purpura ¹⁰ are found to be strongly associated with the infection. There also appears to be growing interest in the potential role of H. pylori in other extragastric conditions including cardiovascular, respiratory, neurological, dermatological, and metabolic diseases.^11,12 An excellent recent review summarizes the extra gastric diseases associated with H. pylori. ¹² With this background, various guidelines have evolved and updated by several professional bodies, endorsing testing and treating H. pylori infection in the adult population.^13–15

However, children are not little adults, and this is true with respect to H. pylori infection too. The prevalence is lower; children have a low rate of severe disease associated with H. pylori and almost an absence of gastric malignancies. ¹⁶ Infection is generally asymptomatic in children. Several studies have shown a lack of evidence of relation between abdominal pain or other abdominal symptoms in children and H. pylori infection.^17–21 There is no evidence that eradication of H. pylori, in the absence of PUD, is beneficial in improvement of abdominal symptoms. In addition, there is increasing antibiotics resistance, particularly to Clarithromycin.^22–24

Recognizing these differences, pediatric guidelines from many learned societies including that from the European Society of Pediatric Gastroenterology Hepatology and Nutrition and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition on the management of H. pylori in Children recommend against a ‘test and treat strategy’. The primary goal of clinical investigation should be to identify the cause of abdominal symptoms rather than look for H. pylori infection. ²⁵ Unfortunately, in real life, guidelines are not always adhered to. ²⁶ It is all too common to see inappropriate tests (e.g., H. pylori serology or breath test) being used to diagnose the infection and any positive test leading to eradication treatment (authors personal experience). No doubt, eradication treatment should be done in children with PUD. What is not clear is whether treating H. pylori infection without PUD is beneficial at all. On the contrary, there is accumulating evidence that this may even be harmful, by exposing children to greater risks of various chronic conditions, as discussed in the following sections.

Method: Review of beneficial effects of H. pylori infection in children.

Asthma and allergies

The prevalence of allergic diseases and asthma had been increasing in many countries in recent decades,^27,28 which coincided with increased hygiene and socioeconomic conditions along with decrease in many infectious diseases. ²⁹ The prevalence of H. pylori infection, both in children and adults, is decreasing in the western world as well as in some developing countries, as H. pylori-associated disease has led to aggressive diagnostic and eradication strategies. This contrasts with increase in childhood asthma and allergic diseases.^2,30–32 Though opposite prevalence trends of H. pylori infection and allergies have been reported, accumulating evidence supports an inverse relationship between H. pylori and the risk of asthma. After the first report by Chen and Blaser who found an inverse association between H. pylori seropositivity and asthma in children, ³³ several studies and meta-analyses have confirmed this negative association. A recent meta-analysis of 18 observational studies reported the exact same conclusion that H. pylori infection, particularly CagA +ve infection, is inversely associated with the risk of childhood asthma. All 18 studies included in this analysis were of moderate to high quality and included a total of 17,196 children. ³⁴ In a hospital-based case-control study, Elias et al. concluded that H. pylori infection and related gastric inflammation may have a protective role against pediatric asthma. ³⁵ This inverse relationship with pediatric asthma is seen even in a high H. pylori prevalence population. ³⁶ A recent cross-sectional study again demonstrated a significant inverse association between H. pylori infection and pediatric asthma. ³⁷ There is also report that H. pylori not only protects against childhood asthma but also inversely correlates to its clinical and functional severity. ³⁸ Chen et al. in their meta-analysis of 24 studies, which included both pediatric and adult subjects, concluded that the accumulated evidence supports that H. pylori infection (especially Cag A positive H. pylori) is inversely associated with the risk of asthma. ³⁹

Similar to asthma, systematic reviews and meta-analyses have reported an inverse correlation of H. pylori infection with atopy.^40–43 Children, in particular, appear to benefit from their H. pylori infection in that the inverse correlation with allergy is strongest in pediatric cohorts. ⁴⁰ Though causality is not proven in humans, animal studies have shown a direct protective effect of H. pylori via regulatory T cells (Tregs).^44–46

However, not all studies have demonstrated this inverse relationship with asthma. In their review of relevant surveys, cohort studies, meta-analyses, and studies testing the protective hypothesis of H. pylori against atopy, allergy, and asthma, Miftahussurur et al. reported that the meta-analyses showed a significant but weak inverse correlation, but studies directly testing the protection hypothesis in relation to asthma failed to confirm a protective effect ⁴⁷

Eosinophilic esophagitis (EoE), a chronic immune-mediated inflammatory disease of the esophagus, is increasing in frequency. ⁴⁸ Interestingly, large cross-sectional analyses of several populations have identified an inverse relationship with EoE and the presence of H. pylori.^49–51 In their comprehensive meta-analysis of 11 observational studies comprising data on 377,795 individuals worldwide, Shah et al. reported that exposure to H. pylori was associated with a 37% reduction in odds of EoE, irrespective of study location, prevalence of H. pylori in the population, time period, or whether studies were performed in pediatric or adult population. ⁵²

There are several proposed mechanisms as to how H. pylori infection in children could reduce the risk of asthma and allergies. It has been shown that the Tregs induced by H. pylori were able to skew adaptive immune response toward immune tolerance. ⁵³ Other mechanisms include regulating Th1/Th2 and Th17/Tregs balance, inhibition of dendritic cells and Heat shock protein 70, activation of Toll-like receptors, reduction of gastroesophageal reflux, hygiene hypothesis, and gut–lung axis theory. ⁵⁴ However, others have concluded that H. pylori is inversely related to good hygiene and its presence just serves as a biomarker rather than any specific prevention role for H. pylori or H. pylori antigens. ⁴⁷ Also, research on molecular mechanisms of the “hygiene hypothesis” and genetic analysis have highlighted that the allergies and asthma are not due to a single mechanism but multifactorial diseases with complex interplay between the organism and environment. ⁵⁵

Inflammatory bowel disease

The incidence and prevalence of inflammatory bowel disease (IBD) is increasing worldwide, both in pediatric and adult populations.^56,57 A steady rise in the incidence of IBD is observed in H. pylori endemic regions, which corresponds to the beginning of anti-H. pylori therapy for PUD. ⁵⁸ Although a small number of studies reported no association between H. pylori and IBD, the overwhelming majority of the studies to date, both epidemiological and basic experimental, strongly suggest a protective role of H. pylori infection against IBD. Luther et al. reported a protective effect of H. pylori against IBD in their meta-analysis and systematic review. ⁵⁹ Sonnenberg and Genta compared the presence of H. pylori in more than 1000 IBD subjects with 65,000 control subjects and found that control subjects harbored H. pylori twice as frequently as IBD patients, confirming an inverse association between H. pylori and IBD. ⁶⁰ Several meta-analyses and systematic reviews subsequently have confirmed this significant negative association between H. pylori and IBD, both in the pediatric and adult populations.^61–67 Kayali et al. reported a striking inverse association between H. pylori and IBD prevalence, independent of IBD subtypes and geographical regions. ⁶³ Others reported evidence of H. pylori conferring more protection against Crohn’s compared to UC and also more protective effect in East Asian population compared to Mediterranean regions, ⁶⁷ nonetheless protective against any type of IBD. Roka et al. observed that the occurrence of H. pylori gastritis is less frequent in children with IBD compared to controls. ⁶⁸ It has also been shown that H. pylori is associated with less fistulizing and less active colitis in patients with Crohn’s disease. ⁶⁹ A study from Taiwan, where H. pylori infection rate approaches 80% in the general population, reported that the treatment of H. pylori infection was associated with a significant increase in the risk of autoimmune diseases including IBD. ⁷⁰ As opposed to this, a recent study, utilizing a large electronic medical records database from 26 major integrated health-care systems in the United States, showed that H. pylori eradication therapy is not associated with the development of IBD in the first 5 years after therapy, but it did confirm lower prevalence of IBD in the presence of H. pylori. ⁷¹ Studies indicate that H. pylori colonization reduces the risk of IBD by 38–52%!^61,62

It could be argued that this protective effect may just be apparent rather than real, just an epidemiological association, reflecting the “hygiene hypothesis,” H. pylori being a surrogate marker for other phenomena such as reduced infections and improved socioeconomic conditions. But then, a systematic review and meta-analysis found that the closely related bacteria including enterohepatic Helicobacter species and campylobacter species increase the risk of IBD, suggesting an immunomodulatory effect specific to H. pylori. ⁷² Similarly, another systematic review of gastrointestinal infections and incident IBD found that Salmonella species, Campylobacter species, and Clostridioides difficile demonstrated consistent positive association with the risk of incident IBD, whereas H. pylori and helminth infections were associated with a reduced risk of IBD. ⁷³ This protective role of H. pylori is replicated in several animal studies and in vitro experimental studies too. Mice that were colonized with H. pylori prior to the induction of Salmonella typhimurium experimental colitis experienced markedly less severe inflammation compared to mice that were not colonized with H. pylori. ⁷⁴ It has also been shown that prior oral administration of 20–50 μg H. pylori DNA ameliorated the severity of dextran sulfate-sodium-induced acute or chronic colitis in mice, in terms of both pathology and symptoms such as bleeding and weight loss. ⁷⁵ This protective effect could be attributed to H. pylori-induced systemic immune tolerance and suppression of inflammatory response. Tolerogenic phenotype dendritic cells and immunosuppressive Tregs are thought to be involved in this protective mechanism.^76–78 Taking all these into consideration, it could be argued strongly that H. pylori is a potent modulator of the immune system and prevents IBD.

Gastroesophageal reflux disease, Barrett’s esophagus, and esophageal adenocarcinoma

Several epidemiological studies have demonstrated a negative association between H. pylori and gastroesophageal reflux disease (GERD) and related complications like Barrett’s esophagus and esophageal adenocarcinoma in the adult population. Just about two decades after the discovery of H. pylori, a systematic review found that the prevalence of H. pylori infection was significantly lower in those with gastroesophageal reflux than those without. ⁷⁹ This inverse relationship between GERD and H. pylori has been reported in several subsequent studies. ⁸⁰ This is also true for Barrett’s esophagus and esophageal adenocarcinoma.^81–83 The relationship between H. pylori and GERD is not as clear cut in the pediatric population however. Some studies reported higher prevalence of reflux esophagitis in H. pylori-infected children^84,85 and others reported the contrary.^86,87 The reason for this disparity may lie in that the determinants affecting GERD in H. pylori are the location of gastric inflammation and CagA positivity in both children and adults. ⁸⁸ It is well established that gastric acid secretion is a key factor in the pathophysiology of reflux esophagitis. Depending on the type of gastritis related to H. pylori, acid secretion may either increase or decrease. Gastritis in corpus leads to hypoacidity, while antrum gastritis leads to hyperacidity. In adults, HP infection is often associated with atrophic gastritis in the corpus, whereas in children, it is often associated with antral predominant gastritis. Depending on the type of gastritis, the H. pylori eradication may either aggravate or alleviate GERD.

Obesity

Obesity has become a major public health problem of global significance. The incidence of obesity in the general population has skyrocketed during the past 20 years, and more than doubled in children and quadrupled in adolescents in the past 30 years. Clearly, the most important risk factors are related to changes in the diet and lifestyle. Interestingly, an inverse relation with H. pylori infection has been reported by many studies, both in the adult and pediatric populations.^89–91 It has been postulated that H. pylori-induced gastritis modulates the levels of gastric hormones, ghrelin and leptin, that influence eating behavior. Ghrelin secreted by the stomach is an appetite-stimulating hormone. H. pylori is found to decrease ghrelin secretion by reducing the number of gastric ghrelin-producing cells. ⁹² Leptin, on the other hand, is an anorexigenic hormone. Though mainly produced by adipose tissue, it is also synthesized in the stomach. H. pylori infection upregulates gastric leptin secretion. ⁸⁹ It has been shown that long-term eradication of H. pylori infection is associated with a significant increase in body mass index, lean, and fat mass along with a significant decrease in circulating ghrelin levels and an increase in leptin levels in prepubertal children. ⁹³

Discussion

There is increasing evidence suggesting beneficial role of H. pylori with several studies, systematic reviews, and meta-analyses showing an inverse association between H. pylori and various chronic health conditions, as discussed above. It could be argued, quite rightly, that these inverse associations could just reflect the significant socioeconomic improvements and the lifestyle changes seen in recent decades with improved sanitation, reduced infections, dietary habits, etc., H. pylori being just a surrogate marker of this. But then, several experimental studies directly showing potential benefits of H. pylori cannot be ignored. On the one hand, H. pylori is clearly demonstrated to cause PUD and gastric cancers, albeit, in a minority of the infected population. On the other hand, several epidemiological and experimental studies demonstrate beneficial aspects of this bacterium against various human health conditions. It is important to remember that H. pylori has coevolved with humans for several thousands of years. Though more than half of world’s population is infected, clinical disease occurs only in a small proportion of the infected subjects. The majority of the infected individuals show histologic chronic gastritis even though asymptomatic, ⁹⁴ but only a small fraction of infected individuals develop H. pylori-associated diseases such as PUD and more rarely gastric carcinomas. ⁹⁵ It has been estimated that the H. pylori infection is linked to gastric and duodenal ulcers in 1–10% of infected patients, gastric carcinoma in 0.1–0.3%, and gastric MALT lymphoma in less than 0.01%. ⁹⁶ Therefore, there is an alternative point of view that H. pylori may be considered as a commensal symbiont, part of normal human stomach microbiome.^97–100 Unlike other pathogenic bacteria, H. pylori colonization in infancy leads to the development of immune tolerance. ⁹⁸ Just as we do not attempt to eradicate the gut microbiome, so should be H. pylori, to be treated only if it causes problem, which, we know, happens only in a small minority of infected subjects.

In contrast to the pediatric guidelines, adult guidelines to date have recommended eradication of H. pylori in all patients with infection, regardless of the presence of PUD or background risk of gastric cancer. Interestingly however, in recent years, there has been increasing recognition of the beneficial role of H. pylori. Many experts have now questioned the unconditional recommendation to eradicate H. pylori in every case. Instead, they call for a more individualized treatment approach in the context of additional risk factors.^{97,98,101,102}

From a practical point of view, what does this mean for pediatricians and pediatric gastroenterologists? On the face of it, it is simple enough, just follow the guidelines – do not “test and treat.” What do we do, if during investigation of child’s symptom, H. pylori is detected? Available evidence would suggest not to eradicate unless ulcer disease is present. Of course, this would need to be discussed with the family, explaining the rationale for the decision not to treat (or treat). What is not clear at present is, how long and how often the children in whom decision is made not to treat, should be followed up. ¹⁶ In part, this would be dependent on the background risk of gastric cancer in the population, but further longitudinal studies are needed to address this. For now, however, when you next encounter a child with H. pylori infection/gastritis but no PUD, let it not trigger an automatic eradication treatment prescription but rather consider leaving H. pylori alone, taking into account the probable beneficial effects of H. pylori as discussed above and the low-frequency complications in children.

Conclusion

The decision to treat H. pylori infection in children should be based on providing true benefit and do no harm. No doubt, eradication treatment needs to be undertaken in children with PUD but not in every child in whom H. pylori is detected. The aim of this review is not to dispute the fact that H. pylori is a class 1 human carcinogen and is etiologically related to gastric and duodenal ulcers, gastric cancer, and mucosa-associated lymphoid tissue lymphoma but to draw reader’s attention to possible beneficial effects H. pylori may confer against asthma, allergies, EoE, and IBD especially in childhood. There appears to be increasing evidence base for these beneficial effects of H. pylori. Various molecular mechanisms have been elucidated to explain these beneficial effects; detailed description of these is beyond the scope of this review.