Food Protein-Induced Proctitis/Proctocolitis and Gastrointestinal Food Allergy in Childhood
Gastrointestinal food allergies are a spectrum of disorders that result from adverse immune responses to dietary antigens. The named disorders include immediate gastrointestinal hypersensitivity (anaphylaxis), oral allergy syndrome, allergic eosinophilic esophagitis, gastritis, and gastroenterocolitis, Food Protein Enterocolitis Induces Proctitis (FPIP) and enteropathy; and celiac disease. Additional disorders sometimes attributed to food allergy include colic, gastroesophageal reflux, and constipation. The pediatrician faces several challenges in dealing with these disorders because diagnosis requires differentiating allergic disorders from many other causes of similar symptoms, and therapy requires identification of causal foods, application of therapeutic diets and/or medications, and monitoring for resolution of these disorders.
A number of gastrointestinal disorders in children have been attributed to immunologic reactions to dietary proteins. The entire gastrointestinal tract can be affected, from the mouth to the rectum. Most of these disorders affect a specific region of the gastrointestinal tract, such as eosinophilic esophagitis, eosinophilic gastritis, food protein-induced enteropathy, enterocolitis, or proctitis. In 2000, a consensus conference clarified the clinical distinctions and pathophysiologic processes implicated in each of these disorders, and established the classification and terminology used in this topic review. Previously used terms (eg, milk protein intolerance, cow’s milk sensitivity, and soy intolerance) are no longer recommended.
Enterocolitis syndrome induced by food proteins usually develops in the frst six months of life. The condition generally manifests with diarrhoea as the most common problem, ranging from soft and abundant stools to liquid and explosive diarrhoea. Some patients may experience very intense vomiting and diarrhoea 2-3 hours after ingestion, and in the most severe cases the situation leads to dehydration, arterial hypotension, lethargy (15-20 %) or even shock. Colon participation would give rise to blood in stools. The infants can also present irritability and abdominal bloating of a nonspecifc nature, or a ﬂattened ponderal curve. There may be signs of malabsorption and arrested growth
Food protein-induced enterocolitis syndrome (FPIES) is a potentially severe non-IgE-mediated food hypersensitivity usually to milk and soy that has been recognized for decades but has received relatively little attention. FPIES is an uncommon but important cause of acute illness in infants. This clinical entity describes a complex of severe, repetitive emesis, diarrhea and systemic inflammatory response, with progression to dehydration and even shock in 15–20% of patients. In view of its potentially serious clinical course and the possible increase in prevalence, it is critical to consider this diagnosis in young children presenting with acute onset of gastrointestinal symptoms or shock. After exclusion of sepsis, metabolic diseases or anatomical abnormalities, the diagnosis is made on the basis of clinical criteria and/or a standardized oral food challenge.
Although FPIES is recognized as a distinct clinical entity, FPIES pathophysiology has not been clearly defined and requires further characterization. Several immunologic alterations have been reported in association with FPIES. Particularly, there is evidence to suggest the involvement of antigen-specific T cells and their production of proinflammatory cytokines that regulate the permeability of the intestinal barrier. Humoral antibody-specific responses may also play a role in the pathophysiology of FPIES. The aim of this article is to delineate the immunological characteristics of this disorder based on the existing reports and to review the possible pathophysiologic basis of this disease.
Immunologic reactions to dietary proteins may be classified as IgE mediated, non-IgE mediated, or mixed. Classically, the “allergic” mechanism involves IgE anti-food antibodies and mast cell activation, and is termed hypersensitivity. The finding of eosinophils in a gastrointestinal biopsy is suggestive of a hypersensitivity reaction but does not establish a diagnosis of an allergic reaction, because eosinophils can be a histologic finding in a number of conditions for which there is no evidence of an IgE-mediated mechanism. The literature is largely composed of retrospective case series without uniform and well-validated tests to objectively confirm or refute the presence of food allergies.
- The symptoms seen in nursing infants with protein-in-duced enterocolitis are similar to, but more severe than, those of protein-induced enteropathy. Since both bowels (large and small) are usually affected, the term “enterocolitis” is used. Other possible causes of non-allergic enterocolitis (infectious, neonatal enterocolitis) must be ruled out in all case
- The most frequently implicated food is cow’s milk. In these cases, the symptoms appear in the frst months of life, and generally in a gradual manner. Breastfeeding appears to be a protective factor against food protein enterocolitis. To date there have been no reports of the condition manifesting in infants who are exclusively breastfed; indeed, the acute disorder manifests when cow’s milk is introduced in the infant diet. However, when artifcial formulas are used from the frst days of life, the symptoms appear in a more insidious manner — affecting the progression of body weight and height, and inducing hypoalbuminaemia, together with the characteristic vomiting and diarrhoea
- Cases of infants with rectal bleeding in the first few months of life have been reported since the 1950s. However, in most cases no direct cause for rectal bleeding was able to be identified. In 1982, Lake et al. first suggested cow’s milk protein passed through breast milk as a possible cause of rectal bleeding, which they experienced in a series of 6 infants who developed bloody diarrhea in the first month of life while being exclusively breast fed. All 6 patients improved after being switched to hydrolyzed milk or soy-based formula, and the bloody diarrhea relapsed in all after being switched back to breast milk. In addition, elimination of cow’s milk protein from the maternal diet led to tolerance of breast milk in 2 of 5 patients. Therefore, Lake et al. named those cases “dietary protein-induced colitis,” meaning “food antigen-specific”. Sampson subsequently termed it “food protein-induced proctocolitis” (FPIP)
- Infants with dietary protein-induced proctitis/proctocolitis seem generally healthy but have visible specks or streaks of blood mixed with mucus in the stool. Blood loss is usually minimal, and anemia is rare. The disorder manifests in the first several months of life, with a mean age at diagnosis of 2 months. The differential diagnosis includes causes such as infection and anal fissures. The lack of systemic symptoms, vomiting, diarrhea, and growth failure help to differentiate this disorder from other gastrointestinal food allergies that may also include colitis. Cow milk proteins and, less commonly, soy protein are the common triggers. Most infants present while being breastfed and are symptomatic as a result of maternally ingested proteins excreted in breast milk. The disorder has also been noted in infants who take casein hydrolysates. Endoscopic examination is often deferred but may show focal to diffuse colitis with edema and erosions. Biopsy reveals an eosinophilic infiltration and occasionally lymphonodular hyperplasia
- The mechanism underlying the disorder is unknown, but it is not associated with immunoglobulin E (IgE) antibody (prick skin tests/radioallergosorbent tests [RASTs] are characteristically negative). Presumptive evidence to secure the diagnosis is obtained through a response to dietary elimination of the causal food protein. For breastfed infants, maternal restriction of cow milk (and more rarely other foods such as soy or egg) is required. If maternal dietary manipulations fail to resolve the bleeding and alternative diagnoses are excluded (by culture, biopsy, etc), then the physician may consider a trial of a hypoallergenic formula (eg, casein hydrolysate). However, there are currently no data to address the outcome of continued breastfeeding despite mild bleeding in an otherwise healthy-seeming infant. For cow milk- or soy formula-fed infants, substitution with a protein hydrolysate formula generally leads to cessation of bleeding. An amino acid-based formula may be needed in those who have prolonged bleeding while taking an extensive hydrolysate. Bleeding is expected to resolve within 72 hours of dietary exclusion of the causal protein. Continued bleeding may be an indication for referral for more invasive testing (ie, biopsy) and monitoring for anemia. The disorder should resolve by age 1 or 2 years, and the causal food protein can be gradually added back to the diet at that time with monitoring for visible blood. The disorder is not IgE antibody mediated, so unless additional atopic disease develops in the patient, testing for IgE antibodies to the causal protein is not needed.
- A number of gastrointestinal disorders in children have been attributed to immunologic reactions to dietary proteins. However, most reactions are presumed to be immunologic in nature, rather than proven to be so. The entire gastrointestinal tract can be affected, from mouth to rectum. Although it is difficult to classify food protein-induced gastrointestinal disorders under a single unifying concept, a consensus conference in 2000 clarified the clinical distinctions and pathophysiologic process implicated in each of these disorders.Immunologic reactions to dietary proteins were classified as IgE mediated, mixed or non-IgE mediated.
- In recent years, the recognition of non-IgE-mediated food hypersensitivity has increased. The spectrum of non-IgE-mediated gastrointestinal disorders ranges from benign proctitis to debilitating enteropathy. These disorders are almost always of a transient nature, concerning mostly infants, and with gastrointestinal symptoms that may have variable repercussions upon the nutritional state of the patient. However, these disorders can be considered self-limiting as avoidance of the incriminated allergen(s) lead to resolution of symptoms. summarizes the most important features of the non-IgE-mediated disorders, including FPIES, food protein-induced proctocolitis and enterophathy. Eosinophilic gastroenteropathies, which are classified as mixed IgE- and non-IgE-mediated disorders, have also been included in. These disorders may all present with similar overlapping features and the degree to which these conditions can be considered immunopathogenic entities remains unclear. However, they can be distinguished based on gastrointestinal symptoms as they generally differ in severity, and natural history.
- FPIES represents the severe end of the spectrum of food protein-induced gastrointestinal disorders in infants. It shares clinical features with food protein-induced enteropathy, except that the colon is also usually involved (hence the term ‘enterocolitis’). Lake hypothesized that food protein-induced proctocolitis may be a milder form of FPIES, based on the fact that in FPIES, an intense inflammatory response usually occurs in the rectum. As proctocolitis has been described in exclusively breastfed infants, Lake suggested that the protective effects of breast milk such as the presence of IgA antibodies and partially processed food proteins, would prevent the expression of the full, more severe clinical phenotype in breastfed infants. From another point of view, the threshold dose of allergen may not be reached in breast milk to trigger a reaction. The threshold dose has been investigated in a recent study including 44 patients with FPIES to milk. The authors found that the majority of patients (54%) could tolerate a large dose of milk (121 ml or more) before developing symptoms during a supervised oral milk challenge. Although it has yet to be confirmed, this concept is particularly interesting in view of the fact that in large published series of FPIES patients, there are no reports of classic FPIES in exclusively breastfed infants. Only one recently published case report described an infant with acute FPIES during exclusive breastfeeding. This is in contrast to IgE-mediated food allergies where acute reactions have been attributed to food proteins passage through breast milk.
- Although IgE antibody to the causal food is typically not detected in FPIES, there are reports of children with FPIES with detectable IgE to the causal protein either at presentation or during follow-up. These children had a more prolonged course of FPIES and some of them progressed to typical IgE-mediated sensitivity. Case series of FPIES patients also indicated a high rate (40–60%) of atopic disease. Until more specific differentiation is possible, it has been suggested that FPIES in association with IgE to the specific allergen should be considered ‘an atypical FPIES’. Although a role for IgE in the pathophysiology of the disorder has not been established, it has not been completely excluded.
- Food protein-induced enterocolitis is considered a part of a spectrum of allergic diseases that affect only the gut. Because diagnosis of FPIES can be made clinically and endoscopy examination is not performed routinely, there are no series in which biopsies are performed solely in patients with this diagnosis. However, several case series include patients who fulfil criteria for a diagnosis of FPIES and describe varied and nonspecific histological features. Endoscopic evaluation reveals diffuse colitis with variable ileal involvement. Colonic mucosa may demonstrate mild friability to severe spontaneous hemorrhage and minute ulcers similar to those seen in ulcerative colitis. Therefore, bloody diarrhea may be present, and infants generally appear sicker. Crypt abscess have been identified in some patients. Jejunal biopsies reveal flattened villi, edema and increased numbers of lymphocytes, IgM- and IgA-containing plasma cells, eosinophils and mast cells. Villous atrophy ranges from mild to severe. FPIES shows rectal ulceration and bleeding with friability of the mucosa. In some cases, focal erosive gastritis and esophagitis is found with prominent eosinophilia and villus atrophy.
- Based on the endoscopic and pathological findings, activation of eosinophils and lymphocytes associated with LNH is thought to play an important role in the pathogenesis of FPIP. In support of this notion, Ohtsuka et al. recently showed that CCL11 (eotaxin-1) mRNA and CXCL13 mRNA were highly expressed in the large-intestine mucosa of infants with FPIP compared with control subjects. However, the pathogenic mechanisms underlying induction of eosinophilic inflammation in the colon remain unclear.
- Several investigator groups have reported an interesting finding that delayed maturation of the intestinal flora possibly causes rectal bleeding in infants. In normal newborn babies, there is transient intestinal colonization by facultative anaerobes immediately after birth. Thereafter, obligate anaerobes such as Bifidobacterium, Bacteroides, Clostridium and Lactobacillus species increase and establish colonization, with reduction of facultative anaerobe counts. However, the counts of obligate anaerobes, especially Bifidobacterium, Lactobacillus, Clostridium leptum group (C. leptum) and Clostridium coccoides group (C. coccoides), were significantly lower in the feces of patients with FPIP than in healthy breast-fed infants. These findings suggest that there is delayed maturation of the intestinal flora in patients with FPIP.
- In addition, Atarashi et al. revealed that a mixture of 46 strains of Clostridium spp., including C. leptum and C. coccoides, promote regulatory T cell (Treg cells) accumulation and also affect their function in the colon of mice. The fact that there are lower counts of C. leptum and C. coccoides in the feces of patients with FPIP suggests that impaired induction of Treg cells in the colon may be involved in the pathogenesis of FPIP. In support of this, Cseh et al. found that the ratio of Treg cells in PBMC was lower in patients with FPIP than in control subjects. Moreover, C. leptum and C. coccoides also promote accumulation of IgA-positive cells in the colon and induce IgA production through induction of Treg cells that produce TGF-β.In support of this, secretory IgA concentrations in the feces tend to be lower in patients with FPIP than in control subjects. These findings suggest that impaired induction of Treg cells and IgA (which contribute to homeostasis in the intestine) due to delayed maturation of the intestinal flora may be a cause of FPIP. In fact, children who outgrew their GI allergy had higher frequencies of circulating Treg cells after OFC compared with children with persistent GI allergy.
- However, it remains totally unknown how antigen-specific immune responses link to delayed maturation of the intestinal microbiota. Further investigation is needed to elucidate whether the underlying mechanisms are the same between patients with DPIP who really respond to food antigens specifically and those who do not.
- Humoral Responses in FPIES Little is known about the humoral response in patients with FPIES. In healthy children, after birth the numbers of B cells and plasma cells increase rapidly and IgG, and more slowly IgA- and IgM-producing cells, begin to appear over the first weeks of life. Gradually, secretory IgA becomes the dominant immunoglobulin at the mucosal surface. In FPIES, jejunal biopsies revealed increased numbers of IgM- and IgA-containing plasma cells. Elevated serum IgA and IgG antibodies to food proteins have been described in FPIES patients compared with a control group. A recent study showed similar results with a trend for higher specific IgA antibody levels in children with milk FPIES. However, they did not find an increase in IgG1 and IgG4 antibodies in patients with FPIES compared with non-allergic controls. In fact, they found almost no allergen-specific IgG4 in FPIES patients. IgG4 antibodies fix complement poorly, and could have a protective role in competing with other subclasses that could activate complement. The relative lack of IgG4 in FPIES patients may be involved in the pathogenesis of the disease.
- Specific IgE antibody responses are generally not detected in FPIES. However, if skin tests are positive to the causal food, case series suggest that these patients have a decreased probability of developing tolerance. It is tempting to speculate that specific IgE antibody produced in the intestinal mucosa may play a role in the antigen uptake and local inflammation.
- FPIES may result from defects in both barrier and immunological function of the digestive tract. It is hypothesized that in FPIES, local inflammation induced upon food allergen ingestion leads to increased intestinal permeability and fluid shift. However, baseline antigen absorption is normal and does not predispose to FPIES. The inflammatory responses induced by the food allergen in FPIES patients involve different cell types that will be reviewed in this section.
Summary of Our Current Understanding of the Immune Mechanisms of Food Protein-induced Enterocolitis Syndrome. TGF-βRI: TGF-β receptor type I; TGF-βRll: TGF-β receptor type II.
- T Cells Although FPIES is often considered to be a T-cell-mediated disorder, the role of T cells remains unclear. Indeed, few studies have investigated the role of these cells in FPIES. Van Sickle et al. observed that in children with confirmed FPIES, peripheral blood mononuclear cell (PBMC) stimulation by the causal antigen induced greater cell proliferation than in children with negative oral food challenge. Examined retrospectively, these data point to the presence of an immunologically mediated response rather than intolerance. However, although Hoffman et al. also reported a higher lymphocyte proliferative response in affected children, the stimulation index was not significantly different compared with the control group. He concluded that the test could not reliably distinguish affected patients. Heyman et al. postulated a T-cell-mediated response, in which proinflammatory cytokine (TNF-α) release would alter intestinal permeability. Their results indicate that the high level of TNF-α released by antigen-specific T cells acts synergistically with IFN-γ to increase intestinal permeability. This may contribute to the influx of antigens into the submucosa with further activation of antigen-specific T cells. A critical role of TNF-α was further supported by the findings of increased amounts of fecal TNF-α in patients with cow’s milk-induced gastrointestinal reactions. IFN-γ is known to enhance the action of TNF-α on intestinal epithelial cells. Benlounes et al. later reported that intact rather than intestinally processed proteins stimulate PBMC to release TNF-α. They also showed that the threshold for PBMC reactivity to milk antigens decreases considerably during active cow’s milk allergy with intestinal symptoms compared with patients whose sensitivity resolved or with those with skin rather than intestinal manifestation of cow’s milk hypersensitivity. In addition, in vitro kinetic studies differed in these groups, with those having active disease showing two peaks in TNF-α elaboration. The second peak occurred after 5 days of culture. Chung et al. examined the presence of TNF-α in duodenal biopsy specimens by using immunostaining. They recorded a higher staining for TNF-α in infants with FPIES and with villous atrophy compared with those without villous atrophy, and with the control group. Taken together, these data support a major role of TNF-α in the acute and chronic symptoms of FPIES. The regulatory cytokine TGF-β1 is known to induce T-cell suppression and acts to protect the epithelial barrier of the gut from the penetration of foreign antigen. Indeed, in addition to its growth inhibitory effect, TGF-β is known to stimulate the synthesis of extracellular matrix proteins, collagen and fibronectin, and enhance the binding between cells and matrix proteins by altering the expression of integrins. For the intestinal epithelial cells, these events have important implications for the function of intercellular tight junctions and, ultimately, for the intestinal barrier function. A decreased expression of TGF-β1 has been described at the level of the intestinal mucosa in infants younger than 3 months of age. This may be due to the young age of the patients, as expression of TGF-β1 increased with age and increased significantly after midweaning. This result suggests that the decreased countering activity of TGF-β1 against the barrier-disrupting effect of T-cell cytokines in young infants may play a role in the pathogenesis of FPIES. A study in children with celiac disease also showed decreased expression of TGF-β in mucosa epithelium compared with that in the normal control subjects, but prominent staining was observed in the lamina propria, mostly in the subepithelial region. It was hypothesized that the destructive effect of T-cell cytokines could be counter-balanced by local TGF-β production. However, overexpression of TGF-β in the lamina propria was not detected in the FPIES patients. In their study, Chung et al. demonstrated that the type 1, but not the type 2 receptor for TGF-β was decreased in duodenal biopsy specimens in FPIES patients compared with controls. These results suggest that the impaired function of epithelial barrier function caused by the decreased TGF-β receptor 1 activity might contribute to the pathogenesis of FPIES. Recently, Mori et al. reported a case of FPIES to rice and described an increase in IL-4 and decrease in IFN-γ expression in T cells after a positive oral challenge with rice. They concluded that acute FPIES reaction may be associated with a Th2 skewing of the T cells cytokine profile. After the patient had acquired tolerance, there was an increase in IL-10 expression in CD3+ cells, as well as an increase in IFN-γ before and after the challenge. These data suggest that T-cell-derived IL-10 may play a role in the acquisition of immunotolerance by regulating the Th1 and Th2 response. These results need to be confirmed by further studies with a larger number of patients.Positive patch tests with the specific allergen in FPIES patients support a role for T cells. Only one study has evaluated the value of atopy patch test in the diagnosis of FPIES. Fogg et al. found a negative predictive value of 100% in their study, whereas the positive predictive value was 75%. Atopy patch tests appear to be useful in food allergic disorders mediated by T cells, such as atopic dermatitis, thus providing a rationale for investigating patch test for FPIES. However, there are dramatic differences between skin T cells that express cutaneous leukocyte antigen and gastrointestinal T cells that are primarily γδ T cells with a higher proportion of CD45RO+ cells. In addition, gastrointestinal T cells express a different homing adhesion molecule. These phenotypic differences between cutaneous and gastrointestinal T lymphocytes make the detection of gastrointestinal T lymphocytes in the skin unlikely.
- Regulatory T Cells Clinical findings generally suggest that most infants with FPIES become tolerant to the offending food over time. In one series, sensitivity to milk was lost in 60% and to soy in 25% of patients 2 years following the initial occurrence. We must then ask how tolerance is induced in these infants. The study by Karlsson et al. identified a role of antigen-specific CD4+CD25+ Treg cells in tolerance induction in children with non-IgE-mediated hypersensitivity to cow’s milk protein. In this study, they evaluated children outgrowing non-IgE-mediated hypersensitivity to cow’s milk following a period of dairy-free diet in comparison with children with active non-IgE-mediated hypersensitivity to cow’s milk protein. The results revealed a higher frequency of circulating CD4+CD25+ Treg cells specific for cow’s milk protein in children outgrowing non-IgE-mediated hypersensitivity to cow’s milk protein. Their results also suggested that the suppressive action of cow’s milk-specific Treg cells was exerted partly by direct cell–cell contact and partly by production of TGF-β. Similarly, IL-10 production by PBMCs tends to be increased in tolerant children. Further investigations of the role of regulatory T cells with focus on the subset of patients suffering from FPIES are needed to confirm these results.
- Eosinophils Eosinophils are a normal constituent throughout the GI tract, except in the squamous mucosa of the esophagus. Eosinophils accumulation in the gastrointestinal tract is a common feature of numerous gastrointestinal disorders, including classic IgE-mediated food hypersensitivity, eosinophilic gastroenteropathies, food-induced proctocolitis, as well as inflammatory bowel diseases and gastroesophageal reflux. Mature eosinophils originate from hematopoietic stem cells in the bone marrow; recruitment is regulated by IL-5, IL-3 and granulocyte-macrophage colony-stimulating factor to induce migration to the gut. Eosinophils are effector cells, which release secretory granules and have an immunoregulatory function by way of cytokine release and presentation of antigens. Clusters of eosinophils have been found in intestinal biopsies from infants with FPIES. Moreover, in FPIES patients with chronic diarrhea, stool samples have revealed the presence of eosinophils and Charcot-Leyden crystals with Hansel’s stain. The blood tests of FPIES patients may also exhibit eosinophilia without other characteristic alterations. However, these findings are not specific for FPIES. The differential diagnostic includes particularly eosinophilic gastroenteropathies. It can be hypothesized that eosinophilic gastroenteritis and the food protein-induced syndromes (enterocolitis, enteropathy and proctocolitis) might represent a continuum of eosinophilic gastrointestinal disorders with similar underlying immunopathogenic mechanisms. However, more work needs to be done to determine whether disorders with similar symptoms are pathophysiologically distinct from FPIES or represent a spectrum with a similar etiology whose clinical expression is modified by environmental factors.
- Neutrophils & Thrombocytes Leukocytosis and thrombocytosis have been reported in acute FPIES reactions.Leukocytosis with a left shift has long been recognized as a common finding for patients presenting with acute FPIES. This characteristic has been included in the diagnostic criteria proposed by Powell. In the Powell study, peripheral blood neutrophil counts were elevated in all positive challenges, peaking at 6 h with a mean increase of 9900 cells/µl. These results were confirmed by further studies. Neutrophils have also been found in stool mucous of FPIES patients. This increase in peripheral neutrophils most likely occurs as a result of the secretion of different cytokines and chemokines during the inflammatory reaction, in which TNF-α may play a role. Thrombocytosis was recorded in 63% of episodes in a recent series. Reactive thrombocytosis in response to stimuli such as infections is not uncommon in young children and is considered a response to cytokines such as IL-6 and other hematopoietic growth factors. In acute FPIES, thrombocytosis seems to be too rapid to result from increased megakaryocytosis. As no change in hematocrit levels was observed, hemoconcentration is also not a likely culprit in thrombocytosis. The more likely explanation is a response to epinephrine induced by stress, which can shift platelets from the spleen into the circulation.
- Association of symptoms to food protein antigens currently requires demonstration of objective improvement following withdrawal of the suspected food antigen, and in some cases, recurrence following a subsequent oral challenge. Another source of confusion is the recognition that gastrointestinal symptoms can be caused by food intolerances that do not involve immunologic mechanisms (eg, lactose intolerance). Certain common gastrointestinal disorders (eg, colic and reflux) also have symptoms that have common features with food allergy, further complicating efforts to draw clear distinctions.
- Several categories of food protein-induced gastrointestinal diseases have been recognized, based on the primary site of mucosal abnormalities, and the evidence for involvement of IgE-mediated inflammation
- The clinical features and natural course of this disorder have been elucidated through many reports, usually single cases or small case series. The presentation of FPIES varies from mild (e.g., mild emesis and/or diarrhea) to severe and potentially life-threatening symptoms.
- FPIES manifestations differ in the chronic and acute forms. Chronic FPIES occurs while the antigen is being ingested on a regular basis and has been reported in young infants fed cow milk or soy-based formulas. Symptoms typically begin in the first month of life with chronic diarrhea and intermittent vomiting, in association with failure to thrive and may progress to acidemia and shock. The onset of symptoms may occur at an older age (up to 9 months) when introduction of milk or soy protein is delayed, such as in breastfed infants, or when solid foods are introduced into an infant while being exclusively breastfed, even if the mother is ingesting the causal foods in her diet. A recent study showed a mean age of 5.5 months at initial presentation. There are also increasing reports of FPIES onset after early infancy. Removal of the offending allergen should lead to rapid and complete resolution of symptoms within a few days. This chronic initial phase can be followed by an acute phase if the antigen is removed from the diet for at least 2–3 days and subsequently reintroduced, with pathognomic symptoms starting approximately 1.5–2 h after ingestion. Severe, repetitive vomiting generally occurs 1–3 h and diarrhea occurs 5–8 h after feeding. Associated features may include pallor, lethargy and cyanosis. In a recent study including a large number of patients, vomiting was the most common clinical feature (100%), followed by lethargy (85%), pallor (67%) and diarrhea (24%). A temperature of 36°C at presentation was recorded for 24% of episodes, mostly in the more severe cases. Diminution of temperature is most likely due to significant circulatory volume loss. Rapid recovery mostly occurs within a few hours, although in the early reports, up to 15–20% of children presented in a hypovolemic shock necessitating fluid resuscitation. However, in a recent birth cohort study, no case of significant hypotension was reported and all infants were treated successfully with oral rehydration. This discrepancy might be explained by under-representation of mild FPIES due to selection bias in previous studies, mostly performed in allergy or gastroenterology clinics. In FPIES caused by solid foods such as rice or oat cereals, the initial presentation is usually that of acute FPIES.
- Overall, 75% of infants with FPIES appear acutely ill, including 15–20% with hypotension who require hospitalization and extensive evaluation before diagnosis of FPIES is established. In infants with severe reactions and acidemia, methemoglobinemia has been reported; some infants required treatment with methylene blue and bicarbonate. These patients appear ashen-gray and listless. Murray and Christie reported that 35% of their 17 cases had transient methemoglobinemia at the time of hospital admission for FPIES.Associated methemoglobinemia is attributed to increased heme oxidation caused by an elevation of nitrates in the intestine because of reduced catalase activity during inflammation.
- The genetics of FPIES and the role of heredity are unknown. Case series of patients with FPIES indicate a high rate of atopic disease (40–70% of patients), but only rarely is family history positive for food allergy or FPIES. Approximately 30% of infants develop atopic diseases such as atopic dermatitis, rhinitis, or drug hypersensitivity later in life. No reports of FPIES in siblings or relatives have been published. More studies are required to investigate genetic characteristics of FPIES.
- The diagnosis of FPIES is based on clinical criteria established by Powell in 1978, and/or a standardized oral food challenge. Oral food challenge in FPIES is considered a high-risk procedure because approximately 50% of the reactive challenges require intravenous fluid replacement. In our practice, FPIES is usually diagnosed based on the clinical manifestations. Thus oral food challenges are performed within 12–18 months following the most recent FPIES reaction, to assess whether tolerance to the offending food has developed. However, a recent study showed that 50% of patients with FPIES to milk recovered by the age of 12 months, 75% by 18 months, 89% by 24 months and 94% by 30 months. Based on these results, oral food challenge to milk could be performed at a younger age. However, further studies are required to confirm these data, particularly in patients with FPIES to solid foods. There are no laboratory diagnostic tests available, largely owing to the limited understanding of the FPIES pathophysiology. As a result of the absence of cutaneous or respiratory stigmata, the time delay from food ingestion to reaction, and the moribund appearance of many children at presentation, FPIES cases often are misdiagnosed as sepsis, a metabolic disorder, anaphylaxis, or a surgical abdominal emergency (ileus). Misdiagnosis and delays in diagnosis are very common, leading to a number of children undergoing additional, often painful investigations, and prolonged hospital admissions. There are two reports of children with FPIES being mistakenly diagnosed as having intussusception, which led to nondiagnostic laparotomies. These data highlight the importance of drawing the attention of the pediatric community to this condition.
- Incriminated Foods in FPIES In FPIES patients, the initial reaction usually occurs on first or second exposure to the food. FPIES is typically caused by milk or soy in formula-fed infants, with over half reacting to both foods in the patient populations recruited from the allergy clinics. By contrast, in a birth cohort from Israel, there was no single case of FPIES to milk or soy. However, FPIES may also be caused by ingestion of solid foods such as rice, oat, barley, chicken, turkey, green peas, sweet potatoes, lentils and peanuts. In our cohort of patients, we identified one patient with FPIES to egg as confirmed by a positive oral food challenge [Caubet J-C, Nowak-Wegrzyn A. Food protein-induced enterocolitis to hen’s egg. Manuscript Submitted]. It is likely that any food could induce FPIES. Among infants with solid food FPIES, 65% were previously diagnosed with FPIES to milk, soy, or both and fed with casein hydrolysate or amino acid-based formula; 35% were breastfed.
- Rice is the single most common solid food that induces FPIES. It is an unresolved question as to whether children with FPIES to rice are at an increased risk of FPIES to other grains. There has only been one case in the literature of a child having FPIES caused by both rice and wheat. However, further studies did not find such association. The low rate of concurrent rice and wheat may be due to the delayed wheat introduction; this practice may avoid sensitization or reactions in children with FPIES during a possible period of susceptibility in early life. An association between FPIES to rice and to oat had also been reported. However, these results could not be confirmed in another series of patients, possibly due to different dietary practices of early solid food introductions. The coexistence of FPIES to rice and oat might also be explained by the taxonomic relationship between rice and other grains. All cereals are genetically related and come from the same subfamily Festucoidae. However, wheat, rye and barely are closely related and are more genetically distant from rice and oat. Children with FPIES to rice or oat may therefore be less likely to have cross-reactions with more distantly related cereals, such as wheat, rye and barely. In adults, crustacean shellfish (molluscs, shrimp, crab and lobster) and fish hypersensitivity may provoke a similar syndrome with severe nausea, abdominal cramps, protracted vomiting and diarrhea.
- The mean age at onset of solid food FPIES tends to be higher than the mean age of onset of milk and soy FPIES,probably owing to later introduction of these foods. Infants with solid food FPIES often have a delayed diagnosis that may be explained by the common perception that grains, for example, rice, oats and vegetables, have low allergenic potential and are not considered as a cause of severe food allergic reactions, as well as lack of definitive diagnostic tests and the unusual nature of symptoms.
- Patients with FPIP typically develop grossly blood-streaked stool with mucus in the first few months of life.
- In contrast to FPIES, almost all patients with FPIP develop no systemic symptoms and seem to be well except for the bloody stool. They have no growth delay or poor weight gain.
- Mild anemia is seen in rare cases. Many patients with FPIP are breast-fed, and the cause is thought to be mainly cow’s milk protein passed through the breast milk
- Cow’s milk and soy-based formulas are the major causative foods in the remaining cases. Recently, FPIP have also been seen to manifest in childhood. However, it remains unclear whether FPIP in childhood has the same pathogenesis as that in infants.
- The diagnosis of food protein enterocolitis is based on the case history and on the patient response to withdrawal of the causal allergen. The endoscopy fndings and intestinal biopsy results obtained in some patient series have reported only nonspecifc alterations. Cryptic abscesses appear in the colon, along with a diffuse inﬂammatory infltrate with the presence of plasma cells. The small bowel in turn shows wall oedema, acute inﬂammation, and mild villous atrophy. Some cases may present focal erosive gastritis and oesophagitis, with important eosinophilia and more accentuated villous atrophy
- The blood tests may exhibit eosinophilia without other characteristic alterations. This fnding and the concomitant worsened patient general condition and lethargy may lead us to suspect the start of sepsis. The more severe cases exhibit hyponatremia, acidosis and even metahaemoglobinaemia. The latter is related to increased haem group oxidation due to an increase in intestinal nitrite levels secondary to lesser catalase activity during the inﬂ ammatory process. The stools may contain blood or prove reducer-positive. The skin tests and specifc IgE antibodies are typically negative, and in those cases which prove positive (a small proportion), the probability of developing tolerance may be lower.
- Diagnostic confrmation is based on resolution of the clinical picture after withdrawing the causal food, and on reappearance of the manifestations on repeating oral exposure. Such testing must always be performed under medical supervision in the hospital setting, and in severe cases, an intravenous catheter must be placed frs
- In 1982, Lake et al. observed a series of six infants who developed bloody diarrhea caused by cow’s milk protein passed through breast milk and confirmed the antigen-specificity using both the antigen elimination test and OFC. Subsequently, there were many reports of infants who developed bloody stool in the first few months of life and showed resolution of the symptoms after being switched to a hydrolyzed milk or soy-based formula. Based on those reports, subsequent papers have assigned a clinical diagnosis of FPIP without OFC to apparently healthy infants with bloody stool and whose symptoms disappear on an elimination diet.
- However, recent studies have questioned the accuracy of the elimination diet in diagnosis of the antigen-specificity of FPIP. To elucidate the effect of a cow’s milk elimination diet on the duration and severity of rectal bleeding in infants, Arvola et al. randomly assigned infants with bloody stool to start a cow’s milk elimination diet or to continue their current diet. As a result, the cow’s milk elimination diet did not affect the duration or severity of rectal bleeding between the two groups. In addition, only 2 of 19 patients who started the cow’s milk elimination diet experienced recurrence of gastrointestinal symptoms after reintroduction of cow’s milk protein. Jang et al. reported that 10 of 16 patients with a chief complaint of rectal bleeding showed resolution of symptoms without any dietary change, while the remaining 6 cases responded to a cow’s milk elimination diet. However, only 2 of those 6 responders developed symptoms after OFC.
- These findings indicate that infants with bloody stool might include a small percentage of patients with DPIP that is actually caused in an antigen-specific manner. In support of this notion, Ohtsuka et al. reported 2 infants who had bloody stool on the first day of life, before initial feeding, but subsequently never developed bloody stool even with breast milk without maternal diet modification. These facts suggest that there are some special enteral environments in early infancy that may result in antigen-nonspecific hemorrhage in the colon.
- In that sense, patients with bloody stool whose antigen specificity was confirmed by both an elimination diet and OFC should be referred to as “true” FPIP. However, in this review we are going to treat patients with bloody stool as having FPIP even if they were diagnosed only by an elimination diet, without OFC. Thus, a certain proportion of FPIP patients may have antigen-nonspecific bloody stool, but in order to discuss FPIP, we must include these patients because only little studies other than Lake et al.’s confirmed antigen specificity in their subjects by OFC.
- The diagnosis of FPIP is based upon a favorable response to an elimination diet and a response to a challenge with the suspected food. The condition is treated by eliminating the allergenic food from diet for as long as 9-12 months in case of cow’s milk allergy. While exclusive breast-feeding for the initial four months or more reduces the chances of development of food allergy, the role of diet restrictions in the mother in reducing the incidence of food allergy in the infant is controversial. Data on food allergy from developing countries are limited. This may be due to lack of diagnosis or less attention given to the condition relative to other diseases including infectious diarrheas and acute respiratory infections. The role of cow’s milk allergy in the pathogenesis of persistent diarrhoea, a major problem in the developing world, remains speculative. Frequent intestinal infections and reduced secretory IgA, which are associated with malnutrition, alter intestinal permeability and result in an increased uptake of food antigens. The increased antigenic load combined with factors such as an atopic predisposition may initiate an abnormal mucosal immune response resulting in chronic enteropathy.
- Clinical diagnosis FPIP requires the exclusion of nonimmunologic diseases that have similar gastrointestinal symptoms. In food allergy, the immune reactions involved can be immunoglobulin (Ig)E-mediated, cell-mediated or both. Symptoms in other target organs are common in cases of IgE-mediated disorders, but not in the cell-mediated disorders in which symptoms are usually localized to the gut. Diagnosis utilizes detailed medical history, clinical evaluation, skin testing, food-specific IgE antibodies, responses to elimination diet and oral food challenges. Endoscopic biopsies are essential in cell-mediated disorders and allergic eosinophilic gastropathies. Treatment includes avoidance of the offending food by a restriction diet in children and the use of hydrolyzed or amino acid-based formulas in young infants. Topical and/or systemic corticosteroids can also be used in eosinophilic esophagitis.
- The pediatrician faces several challenges in dealing with these disorders because diagnosis requires differentiating allergic disorders from many other causes of similar symptoms, and therapy requires identification of causal foods, application of therapeutic diets and/or medications, and monitoring for resolution of these disorders.
- Skin testing has become an integral part in the evaluation settings of GI food allergic disorders. It should be performed by a specialist for allergy testing and in a hospital equipped for emergency interventions. The intradermal skin testing has been abandoned in infants and children owing to the high false-positive rate and the increased risk of systemic reactions.
- This test is considered a safe and rapid (within 15 min) means to assess IgE-mediated food allergy. It can be performed at any age, including in young infants, with useful results. SPT has a high sensitivity (up to 90%) but low specificity (50%). The interpretation of SPT results should be coupled with clinical history suggestive of allergy to the tested protein. Therefore, it should not be used to screen patients for allergy by testing with a broad panel of food allergens without considerate clinical history, as it is likely to produce false-positive results. In addition, young infants may be less reactive to SPT yielding false-negative results in some cases. There is debate regarding the usefulness of commercial extract versus fresh foods (prick-by-prick), and the optimal cut-off values of SPT to predict a positive OFC are still undetermined.
Atopy Patch Test:
- This is a relatively recent diagnostic tool in cell-mediated food allergies, but is still under research trials and needs standardization in terms of the reagents used in the test, application methods and guidelines for interpretation. Reports concerning research works on atopy patch test (APT) have demonstrated that the test is helpful in the diagnosis of GI food allergic disorders.Moreover, the diagnostic accuracy of APT with fresh food is much better than that of commercial APT assay with freeze-dried purified food. In EE, the combined use of SPT and ATP gives high sensitivity and positive-predictive value, which indicates that false-negative results are very unlikely when both tests are negative. This was clear in the study of Spergel and associates who found that the combination of SPT and APT had excellent negative predictive value (88-100%) for all tested foods except milk, which was very low at 41%. The positive predictive value was greater than 74% for most common foods (milk, egg and soy) but dropped off as the food became a less common cause of EE (such as oat: 50% and apple: 57%). They concluded that the combination of SPT and APT in designing a diet plan has high success rate for food elimination or food reintroduction in EE.
In vitro IgE Tests:
- Food-specific IgE antibodies in the serum can be measured by two methods, the radioallergosorbent test (RAST) and the fluorescent enzyme immunoassay (FEIA) test, to identify food-specific IgE antibodies in vitro. The in vitro test is considered less sensitive than SPT. However, serum testing is useful when skin testing cannot be performed, for example in conditions when antihistamines or corticosteroids cannot be discontinued, in children with a history of severe reactions and in those with associated atopic dermatitis. In addition, in young children with very high levels of specific IgE who usually have a major risk of adverse reactions to foods, food challenges should not be tried.
- Several GI procedures are currently used in the diagnostic work-up and follow-up of children with food allergy, especially those with non-IgE-mediated and mixed IgE and non-IgE-mediated disorders. These include endoscopic procedures, histologic evaluation and esophageal pH monitoring.
- Endoscopic biopsy is considered the cornerstone in the investigation for allergic eosinophilic gastroenteropathies. In EE, biopsy should be performed after a period of acid reduction in order to decrease inflammation and make a clear interpretation of biopsy. Usually, eosinophils are absent from the esophagus and the presence of large number of eosinophils (15 or more per high-power field) is considered diagnostic. Any eosinophil in the stomach, greater than 20 in the duodenum, and greater than 30 in the terminal ileum or cecum is suggestive of EG. It is also important to look for the normal distribution of eosinophils in the colon, decreasing from cecum to the rectum, to be no more than five eosinophils/high-power field (HPF) in the rectum. Of note, peripheral blood eosinophilia may be found in only 50% of cases. Recently, it has been demonstrated that the presence of major basic protein on biopsies can be considered a useful confirmatory marker for the diagnosis.
- The recommendations for the diagnosis and treatment of EE indicated that for histological assessment of EE, endoscopic appearances should be documented and photographed, mucosal pinch biopsy specimen should be obtained from all patients in whom EE is in the differential diagnosis, and biopsy specimens should be obtained from different locations along the length of the esophagus. Biopsy specimens should also be obtained from stomach and duodenum to rule out other diseases such as EG and inflammatory bowel disease. In a retrospective analysis of 341 biopsy specimens from 66 adults with EE, Consalves and colleagues found that with a threshold of 15 eosinophils/HPF, the outcome of one biopsy specimen had a sensitivity of 55% in contrast to a sensitivity of 100% with five biopsy specimens, which indicates that more than one biopsy specimen from different parts of the esophagus are needed to confirm the diagnosis.
- An elimination diet is employed during the diagnostic settings to confirm whether the suspected food(s) is the cause of allergic symptoms or not, and is also indicated for the treatment of food allergy. Recently, guidelines for the diagnosis and management of cow’s milk allergy in infants were proposed in an attempt to aid physicians and general pediatricians while dealing with infants with food allergy. These guidelines highlighted the importance of maintaining breastfeeding in allergic infants with mild-to-moderate manifestations and that elimination diet for the mothers should be constructed according to the causal food. The duration of elimination diet depends on the response of elimination and reintroduction of food, in general, not less than 2 weeks and up to 4 weeks in atopic eczema or allergic colitis. The mothers are advised to receive calcium supplement during the period of elimination diet. Infants with severe symptoms that interfere with normal growth or those not responding to elimination diet of mothers should be referred to a specialist for reassessment. When solid foods are introduced (preferably not before 9-12 months of age), care should be taken to ensure solids are free from the food protein that the infant is allergic to. When considering weaning, infants with cow’s milk protein allergy should receive extensive hydrolyzed formulas (eHF) as a source of milk. In formula-fed infants with cow’s milk allergy, eHF is the first choice. Amino acid-based formula (AAF) should be reserved for infants refusing eHF because of its bitter taste, or if the symptoms do not improve as some infants may react to the residual allergens in eHF. In some situations, the infant may be initially switched to an AAF, especially if they experience multiple food allergies, specific GI manifestations, or both. In these conditions, the potential benefits of AAF overweigh its higher cost. However, the risk of failure of eHF is no more than 10% in children with cow’s milk allergy.
- In 97% of young children with EE, elemental diet (AAF) proved to cause resolution of symptoms and to normalize the eosinophil count in the esophagus. However, owing to the unpleasant taste of elemental formulas and their higher cost, Spergel and colleagues demonstrated that an elimination diet, guided by results of combined SPT and APT, led to clinical and histological improvement in 77% of EE patients. Kagalwalla et al. tried another dietary approach. They examined two different diet plans, elemental versus a six-food elimination diet (cow’s milk, eggs, soy, wheat, peanuts and seafood), and found that improvement of clinical and histological findings were achieved in 74% of patients on a six-food elimination compared with 88% of patients on an elemental diet.
Oral Food Challenge
- The oral challenge is an integral part of the work up for the diagnosis of food allergy. The test can either confirm or rule out the diagnosis of allergy to the tested food. In addition, during follow-up settings, the test is repeated (rechallenge), to assess the timing at which the child might have outgrown allergy to the tested food.
- The OFC begins with small amounts of the allergen and the dose is increased as tolerated; the test procedures are best described in other review articles. In cases of previous anaphylaxis, a challenge is contraindicated unless SPTs and/or specific IgE measurements show improvement. In such cases, the challenge test should be done in hospital under the supervision of an allergist. The foods selected for testing must be based upon history and results of skin and/or in vitro testing. The suspected food should be eliminated for 7 to 17 days before the challenge for IgE-mediated disorders and up to 12 weeks in some GI disorders. The open challenge means the patients knows that the tested food is the one that has caused the symptoms in the past, and this can lead to a bias in interpretation of the response to that food because the patient will be afraid or feel anxious to experience the same symptoms developed in the past. However, this is unlikely to be the case in young infants and open food challenge is considered reliable and practical. The double-blind, placebo-controlled, food challenge (DBPCFC) is considered the gold standard for the diagnosis of food allergies. It is not liable for bias like open challenge because both the patient and the physician do not know which doses contain the challenge food.
- Several research studies have been published recently on the topic of food challenge aiming to standardize the procedure. The main problems with food challenge tests are related to the wide range of symptoms, possibly related to food allergy, that lead to difficulties in the interpretation of the test results and to the optimal timing and dosage of this procedure. The choice of optimal timing should be oriented by the type of symptoms from 2 weeks for GERD and up to 8 weeks in the case of EE. The choice of open challenge or DBPCFC, or both, is another point of difference. It has been suggested that when multiple foods are suspected, open challenge may help to identify the specific food to be further tested by DBPCFC. Furthermore, open challenge may be suitable for the diagnosis of immediate symptoms (mostly objective) whereas a DBPCFC may be indicated for the diagnosis of delayed symptoms (mostly subjective), or in research settings. The false-negative rate of DBPCFC is approximately 3%, therefore, negative challenges should always be followed by supervised open feeding of normal portion of the tested food in its commonly prepared state.
- The endoscopic findings for FPIP are lymphonodular hyperplasia (LNH), with an oozing and edematous mucosal surface. The common histological features are LNH and numerous eosinophils in the lamina propria.Accordingly, apparently healthy infants with bloody stool and LNH and/or numerous eosinophils in the lamina propria were histologically diagnosed as DPIP and also called “allergic colitis”.
- LNH in the colon has been reported to be associated with food allergy. LNH can also be observed in other diseases, not just in FPIP. In addition, Xanthakos reported several patients with LNH who had spontaneous resolution of rectal bleeding without any dietary change. These findings suggest that LNH may be a self-limiting, age-related change, regardless of the antigen specificity.
- A histological finding of eosinophil infiltration (6 cells/high power field (HPF)) in the lamina propria was thought to be a useful threshold for diagnosis of FPIP. However, DeBrosse et al. recently described that eosinophils (mean 16-20 cells/HPF) were normally observed in the gastrointestinal tract of control children, especially in the colon. In addition, Jang et al. reported that only 2 of 10 patients who exhibited marked eosinophil infiltration of the lamina propria (more than 6 cells/HPF) developed symptoms after OFC
- Therefore, diagnosis of FPIP based on elimination tests, the endoscopic findings and the histological findings presents a risk of over-diagnosis. In this context, for accurate diagnosis of FPIP, OFC after an elimination diet should be recommended for apparently healthy patients with bloody stool.
- As in the case of other food allergies, elimination of causal food antigens is the gold-standard treatment for FPIP. Many patients with FPIP are breast-fed infants. Therefore, elimination of cow’s milk from the maternal diet would be the first choice and an effective method. However, some patients still react to breast milk even after the mother has strictly eliminated cow’s milk from her diet. For such patients, the infant’s nutrition should be changed to a hydrolyzed milk or soy-based formula. However, some patients respond even to hydrolyzed milk. For them, an amino acid formula is needed.
- Recommended treatment consists of hydrolysed proteins, which offer a favourable course in practically all cases. It should be remembered that 50 % of the children who react to CMPs will also react to soy proteins — as a result of which hydrolysed proteins should be indicated directly as first choice. In those infants which fail to respond favourably to such measures, and also react to hydrolysed proteins, an elemental amino acid-based formula should be provided.
- Treatment of the acute process involves the administration of intravenous ﬂuids. Corticosteroids may help arrest the cellular immune response that appears to be implicated in the process, and are considered useful in patients with a history of very severe reactions. Exceptionally, adrenalin or antihistamine dosing may be necessary due to the possibility of concomitant IgE-mediated allergy or serious cardiovascular reactions.
- An important consideration is patient and family education regarding the preventive measures needed to avoid the causal foods, and as refers to the actions to be taken in the event of accidental ingestion.
- If the disease is produced by CMPs, resolution tends to occur at about one year of age, while in the case of other causal foods such as fsh, chicken or rice, the disorder may persist throughout infancy.
- The children typically acquire tolerance of the causal food with increasing age (mostly towards 2-3 years of age), though a small proportion of subjects may maintain hypersensitivity throughout infancy.40 Reintroduction of the causal food must be done in the hospital setting, with the preparation of a venous access and ﬂuid therapy, in order to ensure prompt treatment in the event of clinical reactivity
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