Allergic Colitis and Enterocolitis

GI food allergies are quite common in infants and children²¹ and include allergic colitis (AC), allergic enterocolitis, and food protein enteropathies (Fact Sheet 7.2). The term ‘food allergy’ refers to an immune reaction (immunoglobulin [Ig] E-mediated, cell-mediated, or both²¹) that develops in response to the ingestion of a specific type of food. In IgE-mediated disorders, symptoms in other target organs are common. In cell-mediated disorders, the symptoms are usually localised to the gut. These disorders are usually transient and may have variable repercussions on the nutritional state of the patient.

Allergic colitis and enterocolitis typically affect infants and adolescents, and most infantile cases are probably the result of an allergy to cow’s milk protein. However, many foods have been associated with the development of AC.^{22, 23} The patients usually present with rectal bleeding (with or without diarrhoea) and generally recover promptly after elimination of the allergen from their diet.^{24, 25} Interestingly, eosinophilic colitis may occur more often in infants that are exclusively breast fed (probably because of the maternal diet). Although cow’s milk–induced allergy is relatively common, with an estimated prevalence between 2% and 7.5% in otherwise normal infants, the exact prevalence of AC overall is unknown.^{23, 26}

The clinical diagnosis of AC can be difficult. Although a careful history detailing the relationship of symptom onset to feeding (as well as a personal or family history of allergies) may be helpful, the presence or absence of these features has no proven predictive value in identifying infants with AC.²⁷ Symptoms may include abdominal pain, anorexia, and weight loss, but bleeding is the most common sign. Peripheral blood eosinophilia and stool eosinophils may be present. Most affected infants lack constitutional symptoms and are otherwise healthy. Sigmoidoscopy, in conjunction with the evaluation of multiple mucosal biopsy specimens, may be helpful in confirming the diagnosis, particularly in patients with severe disease and in patients whose condition does not improve after the introduction of an elimination diet.

Lesions in AC may involve any segment of the colon. They most often affect the rectum and sigmoid and the changes are usually most severe in this region. Typically, the abnormal areas are separated by intervening zones of mucosa that look entirely normal or show focal erythema. The abnormal mucosa may appear friable with increased nodularity suggestive of lymphoid hyperplasia. More severe cases may show decreased mucosal vascularity, multiple superficial erosions (aphthous type with erythematous margins), or, rarely, frank ulceration with surface exudate mimicking the endoscopic features of infectious colitis.^{24, 28}

Microscopically, the most remarkable and characteristic histological feature is the presence of infiltrates of eosinophils in all mucosal compartments, but particularly in the lamina propria (≥60 eosinophils per 10 high-power fields [hpfs]), as well as numerous intact or degranulated eosinophils located at the base of the mucosa and interspersed among muscle fibres of the muscularis mucosae²⁶ (Figure 7.2). Crypt abscesses also occur, but in AC are typically composed of both neutrophils and eosinophils. Crypt architecture is normal, without the features of chronicity typical of IBD (i.e. distorted, branched, or atrophic crypts, Paneth cell metaplasia, basally located lymphoid aggregates, and/or basal plasmacytosis). However, the features are not specific and AC is, in effect, a diagnosis of exclusion.

(A) Inflammatory infiltrate in the lamina propria, including numerous eosinophils (intact or degranulated).

(B) Crypt abscesses can also be present, typically including both neutrophils and eosinophils.

Figure 7.2 Allergic colitis in a neonate.

There are no consensus criteria on how many eosinophils are necessary to make a diagnosis of AC. Machida et al proposed a threshold of>20 eosinophils per hpf.²⁹ Odze et al., on the basis of the findings in more than one study, proposed different histologic criteria: (1) an increase in the number of eosinophils in the lamina propria (≥60 per 10 hpfs), often seen in close association with lymphoid aggregates; (2) epithelial (crypt or surface) or muscularis mucosae eosinophil infiltration (≥1 eosinophil per hpf); (3) a mixture of eosinophils and neutrophils in crypt abscesses; and (4) the absence of other specific histological features (parasites, ova, crypt architectural abnormalities) that would suggest an alternative diagnosis.^{26, 30} According to the authors, the presence of all four histological criteria in a specimen strongly supports the diagnosis of AC if encountered in the appropriate clinical setting.

Involvement by eosinophilic infiltrates of other deeper layers of the GI wall in the absence of an identified cause should suggest a diagnosis of primary eosinophilic gastroenteritis, a different entity that is rarer in paediatric age groups.

Eosinophilic Gastroenteritis

Eosinophilic gastroenteritis (EGE) is an infrequent disease of unknown aetiology, is both IgE- and cell-mediated, and is characterised by focal or diffuse eosinophilic infiltration of the GI tract (Fact Sheet 7.3). The disease occurs over a wide age range – from infancy to the seventh decade – but usually presents between the second and fifth decades.^31–33 The frequency of its diagnosis in children is increasing. There are no significant differences between childhood and adult forms. When the disease manifests in infancy, and if specific food sensitivities are identified, the likelihood of remission by late childhood is high. GI obstruction is the most common complication.

The clinical presentation is variable and includes abdominal pain, weight loss, vomiting, and diarrhoea. The traditional classification of EGE identifies three forms, depending on the depth of inflammation in the wall: mucosal, muscular, or serosal. This, together with the digestive tract segments involved, determines the clinical presentation. The stomach is the most common site, followed by small intestine and colon.³⁴ Fatalities are rare.

There is limited understanding of the aetiology and pathogenesis. Peripheral eosinophilia, abundant eosinophils in the GI tract, and a dramatic response to steroids may constitute evidence that the disease is mediated by a hypersensitivity reaction.³⁵ The damage to the GI tract wall seems to be a result of eosinophilic infiltration and degranulation.³⁶ In EGE, food allergens may cross the intestinal mucosa and trigger an inflammatory response, with cytokines, interleukin (IL)-3, IL-5, and granulocyte macrophage colony stimulating factor facilitating the recruitment and activation of eosinophils.³⁷ In fact, many patients have a history of food allergy and other atopic conditions such as eczema or asthma.³⁸

Four criteria are required for the diagnosis of eosinophilic gastroenteritis: the presence of GI symptoms, eosinophilic infiltration of GI tract, exclusion of parasitic disease, and absence of other systemic involvement. The presence of peripheral eosinophilia is not a universal phenomenon.

The endoscopic appearance is not specific and includes erythematous, friable, nodular, and occasionally ulcerative changes. Patients with serosal disease present with ascites, and abdominal paracentesis demonstrates a sterile fluid with a high eosinophil count. Pleural effusion also may be present.³³

The correct diagnosis depends mainly on the histological findings. Microscopy demonstrates increased numbers of eosinophils (often>50 per hpf) in the lamina propria,³⁹ with large numbers in the muscularis and serosa in many cases (Figure 7.3). Localised eosinophilic infiltrates may cause crypt hyperplasia, epithelial cell necrosis, and small intestinal villous atrophy. There may be a diffuse enteritis with complete loss of villi, submucosal oedema, infiltration of the GI wall, and fibrosis. Mast cell infiltrates and hyperplastic mesenteric lymph nodes infiltrated with eosinophils may be present.^{40, 41} In superficial colonic biopsies, this condition can be very difficult to distinguish from allergic colitis. Moreover, it may be difficult to detect or completely absent because infiltration is often patchy. Laparoscopic full thickness biopsy may be necessary for histological diagnosis if there is no mucosal involvement.⁴⁰

Figure 7.3 Eosinophilic gastroenteritis: an increase in numbers of eosinophils (often>50 per hpf) in the lamina propria but also in deeper layers (submucosa).

When eosinophilic gastroenteritis coexists with eosinophilic infiltration of other systems, the diagnosis of idiopathic hypereosinophilic syndrome is worth considering.³⁹

Paediatric Ulcerative Colitis

Classically, UC is a continuous inflammatory process, beginning in the rectum and extending proximally.⁵⁴ Atypical patterns of inflammation in UC such as rectal sparing, patchiness, periappendiceal inflammation, and upper GI inflammation (that are usually more strongly associated with Crohn’s disease) are probably more common in children than in adults (Fact Sheet 7.5 and Table 7.1). Although most patients with UC have convincing histological features of chronic colitis on mucosal biopsy of the rectum, several studies have shown that paediatric patients with new-onset untreated UC may sometimes show relative or complete rectal sparing or patchy colitis.^55–58 In one report, initial rectal biopsies from 5 of 12 children with UC showed only mild patchy inflammation or normal mucosa.⁵⁹ Another study of UC in children showed patchiness of microscopic features of chronicity (21% of patients) and relative (23%) or absolute (3%) rectal sparing,⁵⁶ and in another series only 66% of rectal biopsies from paediatric patients with new-onset UC had architectural features of chronic colitis.⁵⁵

The extent and severity of the disease is also apparently different among children and adults, a higher proportion of children with UC presenting initially with subtotal colitis or pancolitis,⁶⁰ e.g., 42% of children compared to 11% adults in one report.⁵⁶ In another study, there was left-sided colitis (involvement extending no further proximally than the splenic flexure) at presentation in 10% and pancolitis in 90%.⁶⁰ The EUROKIDS Registry reported extensive colitis or pancolitis in 77% of children.⁶⁰

Upper GI inflammation (see also Chapter 16) may occur in children with UC but is not common. Nevertheless, UC remains a possible cause of upper GI inflammation in the setting of known IBD. In the upper GI tract, few features discriminate reliably between UC and Crohn’s disease except for non-cryptolytic granulomas, which strongly favour Crohn’s disease. Recommended investigations in paediatric IBD include both upper GI endoscopy and ileocolonoscopy with multiple biopsies, while upper GI endoscopy is not routine in adults. Indeed, upper GI endoscopy with biopsy is standard practice in all children irrespective of the presence or absence of upper GI symptoms.⁶¹ Non-specific inflammation in the upper GI tract may be present in up to 75% of children with UC, although the mechanism(s) underlying these abnormalities are unclear and the true prevalence of upper GI involvement by UC is very difficult to determine. For example, oesophagitis, minimal to mild non-specific gastritis or focally enhanced gastritis (FEG) can be present.⁶²

FEG is an inflammatory gastric lesion defined as the presence of one or more foci of pit or glandular inflammation containing lymphocytes, histiocytes, and granulocytes, with a relatively normal background mucosa⁶³ (Figure 7.5). The inflammatory cells may infiltrate the epithelium. FEG in adults seems to be a non-specific finding, but in paediatric patients is associated with a higher likelihood of a future diagnosis of IBD. The number of FEG foci in a review of 119 gastric biopsies from paediatric IBD patients ranged from 1 to 5 (mean 2.2) in each biopsy specimen, while each FEG lesion involved from 1 to 12 pits/glands, and mostly up to 3 pits/glands (87%). The total number of glands involved as part of a focus of FEG was higher in patients with UC than in Crohn’s disease (6.4 ± 5.1) but the lesion was also present in patients with Crohn’s disease (4.0 ± 3.0).⁶⁴

Figure 7.5 Focally enhanced gastritis (FEG) is characterised by one or more foci of inflammation including lymphocytes and histiocytes, with or without neutrophils, around pits or glands with a relatively normal background mucosa. Inflammatory cells may also extend into the epithelium.

Unlike FEG, granulomas in the upper GI tract are a specific feature of Crohn’s disease in all series^{65, 66} and upper GI granulomas in Crohn’s disease are more common in children than in adults (see Chapter 16). Histological abnormalities of the upper GI tract include other lesions besides FEG and granulomas. Some may be more common in children than in adults. For example, gastroduodenal ulceration, villous atrophy, increased intraepithelial lymphocytes, and cryptitis may be more common in UC paediatric patients.^66–68

Backwash ileitis occurs in approximately 25% of adults with pancolonic UC, but in children the prevalence is unknown. In one report, 39% of children presenting with new UC (39%) showed terminal ileal erythema with associated nonspecific inflammation and no erosions or ulcers.⁶⁹ A caecal patch occurred in 2% of patients in the EUROKIDS Registry, in contrast to the frequency of 12%–25% or higher described in adults, although frequencies vary widely.^{52, 70–72}

Paediatric Crohn’s disease

Extensive inflammatory involvement is often already present during infancy or early childhood present in children and adolescents with Crohn’s disease at disease onset (CEDATA-GPGE registry data).⁷³ Children with Crohn’s disease have a greater tendency than adults to present with isolated colonic disease (L2 Paris classification), whereas adolescents and adults are more likely to have ileal disease (L1).^{72, 73} Isolated ileocaecal involvement, which is typical in adulthood, is rare in children and adolescents, occurring in only 13.3%.⁷³ Terminal ileal disease and stricturing disease are more common in children diagnosed after 10 years of age than in younger patients, approaching the frequency seen in adults.⁷⁴

The frequency of upper GI tract involvement in Crohn’s disease (see also Chapter 16) seems also to be higher in children. Though difficult to determine precisely, the prevalence in adult Crohn’s disease is low in most reports (0.3%–16%) while oesophageal, gastric, or duodenal pathology may be identified in up to 30% of paediatric Crohn’s disease patients.⁷⁵ Histology of the upper GI tract (showing specific lesions such as granulomas) may confirm a diagnosis of Crohn’s disease in 11%–29% of cases that was otherwise not obvious^{76, 77} (Figure 7.6). Focal cryptitis of the duodenum and focally enhanced gastritis occurred significantly more frequently in children with Crohn’s disease than in children with UC and non-IBD.⁷⁸

Figure 7.6 Upper GI tract in Crohn’s disease with granuloma in duodenal mucosa.

The frequency of granulomas in Crohn’s colitis is higher in children than in adults, and this is not entirely attributable to the higher number of colonoscopic biopsies (Table 7.2).⁷⁹ Compared with adults, the incidence of granulomas may be twice as high in children (Figure 7.7).^{79, 80} The difference could be a result of evolution and regression of granulomas at different time intervals during the course of the disease. This could in turn reflect an immunological reaction by immature tissue, i.e. in children, when challenged by the (currently elusive) aetiological agent(s) responsible for Crohn’s disease. In the EUROKIDS registry, there were granulomas in 43% of paediatric patients.⁷⁴

Table 7.2 Histological findings in children with Crohn’s disease versus adults with Crohn’s disease

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Related posts:

Chapter 4 – Transplantation, Immunodeficiency, and Immunosuppression Chapter 5 – Drug-Induced Gastrointestinal Disease Chapter 11 – Infections of the Oesophagus and Rare Forms of Oesophagitis Chapter 25 – Ileal Pouch Anal Anastomosis Chapter 20 – Microscopic Colitis Chapter 21 – Inflammatory Bowel Disease Diagnosis

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