Hypereosinophilic Syndrome Presenting with Digestive Symptoms in Pediatric Patients: A Portuguese Tertiary Hospital Case Series Open Access

Hypereosinophilic syndrome (HES) is a rare heterogeneous condition, first described in 1968 by Hardy and Anderson [1]. According to the World Health Organization (WHO), HES is characterized by peripheral hypereosinophilia (HE) – eosinophil counts greater than 1,500 cells/μL – on two examinations separated by at least 1 month and organ/tissue damage [2] due to eosinophil infiltration and release of cytokines and humoral factors from their degranulation [3]. HES can be subclassified according to the pathogenic mechanisms in primary (or neoplastic) HES; secondary (or reactive) HES, typically associated with allergies, autoimmune disorders, parasitic and nonparasitic infections; and idiopathic HES [2].

As a multisystemic disease, it can involve any organ, including the skin, lungs, digestive system, and central and/or peripheral nervous system. Among these, gastrointestinal (GI) involvement – which corresponds only to 14% of the cases of HES [4] – is particularly challenging due to its varied presentation and the potential for significant morbidity [2, 5].

Although HES predominantly affects adults, it can also affect pediatric patients, often with diverse and complex clinical manifestations. Due to the lack of systematic registration of pediatric HES, its incidence is unknown. Data on treatment and survival outcomes are limited and have not been systematically documented [3, 6].

In pediatric patients, HES with GI manifestations can mimic other common conditions, leading to diagnostic delays [2, 4]. The pathophysiology underlying GI involvement in HES is not entirely understood, but it is thought to result from eosinophil-mediated tissue damage and inflammatory processes [4, 6].

Digestive symptoms may range from abdominal pain, diarrhea, and vomiting to more severe complications such as intestinal obstruction or perforation. In many cases, symptoms may be discordant with endoscopic or histopathologic appearance.

Lastly, treatment for patients with multisystem HES with GI manifestations is mainly focused on systemic rather than topical or dietary therapies. Understanding the natural history of this condition is essential to improve treatment decisions and prognostication [7]. Due to its rareness, there is no consensus on managing pediatric HES.

This case series aims to shed light on the clinical characteristics, diagnostic challenges, and therapeutic approaches for pediatric patients with HES presenting with digestive manifestations. Only case reports and small series of HES have been described in pediatric ages [8]. By sharing these cases, we aim to enhance awareness among clinicians and highlight the importance of considering HES in the differential diagnosis of pediatric patients with unexplained digestive involvement and HE.

A previously healthy 15-year-old female presented to the emergency department (ED) with pruritic, intermittent and refractory mucocutaneous lesions, including oral ulcers, hair lesions, and vesicles on the umbilicus and toes (Fig. 1), which began 3 months earlier. She also reported self-limited bloody diarrhea, weight loss, and secondary amenorrhea.

Blood tests showed eosinophilia (maximum 3,300/µL), and the skin biopsy revealed pustular folliculitis with eosinophilic infiltrate. The diagnosis of HES was suspected, and the patient went through an extensive investigation to rule out other causes of HE. Fecal exams were negative for ova, cysts, and parasites, and calprotectin was elevated (1,050 µg/g). Antineutrophil cytoplasmic antibodies (ANCAs) were negative.

Endoscopic exams revealed macroscopic alterations (Fig. 2): flat and pleomorphic lesions in the esophagus with a raised whitish border, measuring 3–10 mm; the mucosa of the ileum and colon was continuously and diffusely edematous, friable and showed complete loss of the vascular pattern. Microscopy confirmed ileitis, colitis, and proctitis (marked distortion of the glandular architecture and a reduction in the mucosal secretory activity), with eosinophilic infiltration – with 67, 42, 48, 75, 70, and 128 eosinophils per high-power field, respectively, in the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum.

The diagnosis of HES with GI, skin, and mucosal involvement was assumed, and she was treated with oral prednisolone (0.5 mg/kg/day) for 6 weeks and topical betamethasone. Clinical and laboratory improvement was evident.

Two weeks after stopping the prednisolone, the oral mucosal lesions reappeared, and she experienced bloody diarrhea again. Her eosinophil count was normal. At this time, prednisolone was restarted at 0.5 mg/kg/day, resulting in rapid clinical improvement. Treatment with prednisolone was kept for 2 years at a low dose (2.5 mg on alternate days), and after this period, it was stopped, and she remained symptom free.

A 16-year-old teenage girl with a previous medical history of asthma presented to the ED with complaints of asthenia, abdominal pain (including nocturnal pain), diarrhea (5 times/day, without blood or mucus), nausea, vomiting, and anorexia. These symptoms began 3 weeks prior to hospitalization. She denied fever, weight loss, or any epidemiological context suggestive of infectious diseases.

On physical examination, she had abdominal distension with no signs of an acute abdomen. Blood tests revealed eosinophilia (maximum 15,480/µL). The diagnosis of HES was suspected, and other exams were performed to clarify the organ involvement:

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  abdominal ultrasound: large-volume ascites and exuberant diffuse parietal thickening of the small bowel loops, mainly of the duodenum;

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  abdominopelvic CT: large-volume ascites in all abdominal quadrants and small bilateral pleural effusion;

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  diagnostic abdominal paracentesis: drainage of 660 mL of ascitic fluid, with 1,882 leucocytes/µL, 86% of which were eosinophils, and fluid laboratory characteristics were compatible with an exudate;

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  upper digestive endoscopy (Fig. 3) revealed mucosal edema of the bulb, the second portion of the duodenum (D2), and the papilla of Vater. No macroscopic lesions were seen in the esophagus. Histopathological examination revealed an inflammatory infiltrate consisting of lymphocytes and eosinophils in the esophageal mucosa that was also present in the stomach and duodenum.

Inflammatory, infectious, and tumoral causes were ruled out. The autoimmune and rheumatologic panel, serum immunoglobulin levels, stool examination of ova, cysts, and parasites, and tests for other infections like HIV and tuberculosis were all negative. The diagnosis of HES, with GI and serosal involvement, was assumed, and prednisolone 1 mg/kg/day was started, maintained for 4 weeks, and then gradually reduced over a total treatment period of 8 weeks. Two weeks after discontinuing therapy, her eosinophil count increased, and symptoms of abdominal pain and diarrhea recurred, leading to a restart of prednisolone, which led to rapid clinical and hematological improvement. During 2 years of follow-up, there was noncompliance with medication on a low dose (5 mg/day), and frequent clinical and hematological flares occurred; in all of them, a rapid response to low doses of prednisolone was observed. After 6 months of good compliance with prednisolone at 5 mg/day, the medication was stopped, and she had no recurrence of symptoms.

A 16-year-old female with a medical history of unilateral hypoacusis presented at the ED with persistent biliary vomiting and epigastric pain without fever or diarrhea, since the previous week. Ascites was noted on the physical exam. Laboratory workup showed eosinophilia (maximum 6,210/µL) and IgE elevation (3,756 kU/L). An abdominal ultrasound revealed moderate intra-abdominal ascitic fluid and thickening of the colon, particularly prominent in the transverse and descending segments, with the ileocecal region and the small bowel loops relatively spared.

An upper endoscopy was performed to assess organ involvement, which showed no macroscopic abnormalities. In the histopathologic exam, there was eosinophilic exocytosis and mucosal infiltration in the stomach (56 eos/high-power field in the antrum). A bilateral pleural effusion was detected on the echocardiogram.

Investigation into the etiology of eosinophilia revealed a positive PCR for EBV, along with positive IgM and IgG antibodies. Other infectious causes were excluded. Bone marrow tests were normal, and the autoimmunity tests were negative.

Treatment with intravenous methylprednisolone (1 mg/kg/day) was administered for 3 days, followed by a transition to oral prednisolone (0.6 mg/kg/day). Clinical improvement and a decrease in the eosinophil count were observed. The abdominal ultrasound performed 1 month later showed no bowel thickening. After 12 months of follow-up, she remains on a low dose of prednisolone (2.5 mg on alternate days).

In this case series, we present 3 patients diagnosed with HES, all exhibiting digestive symptoms. In all cases, there was eosinophilic infiltration in the GI tract mucosa. HES should be considered in patients with persistent HE (>1,500/μL) accompanied by evidence of organ damage caused by eosinophils [4, 9].

HES is rare in children, and its incidence remains unclear [8]. Globally, parasitic infections are the most common cause of eosinophilia, whereas allergic conditions are more frequently seen in developed countries. The differential diagnosis of eosinophilic gastroenteritis is also relevant. These two entities have similarities, but HES is characterized by persistently elevated eosinophil count in peripheral blood, which is usually absent or mild in eosinophilic GI disorders. These values can result in certain complications, such as cardiac morbidity, which is not the case in primary eosinophilic gastroenteritis [10]. Diagnosing idiopathic HES requires a comprehensive evaluation to exclude other possible causes of eosinophilia [7, 9], as was conducted in our patients.

HES includes multiple subtypes, and its diagnosis involves a systematic and organized approach. In our cases, we focused on digestive manifestations. However, involvement of the cardiovascular system – such as restrictive cardiomyopathy, valvular dysfunction, and heart failure – remains the leading cause of morbidity, along with neurological complications [8]. Other clinical features may include pulmonary manifestations (chronic cough, lung infiltrates, fibrosis), digestive symptoms (hepatitis, cholangitis, pancreatitis, colitis), ocular symptoms, skin manifestations (pruritic papules, nodules, mucocutaneous ulcers), and rheumatologic symptoms (joint pain, muscle aches, joint effusions, Raynaud’s phenomenon) [8, 9].

The diagnostic investigation aims to confirm peripheral HE, exclude alternative causes, and identify any organ involvement (Table 1). If secondary causes of eosinophilia are excluded, the workup should proceed with the evaluation of a primary bone marrow disorder. This involves examining the blood smear and blood tests (e.g., circulating blasts, cellular dysplasia, monocytosis), bone marrow morphologic assessment, cytogenetic analysis, immunophenotyping, and molecular studies [8, 9].

To assess for end-organ involvement, the initial recommended tests are [9] blood chemistries – complete blood count and morphology, liver enzymes, creatine kinase, renal function, and troponin – electrocardiogram, echocardiogram (which is mandatory even if the patient is asymptomatic [8, 9] to detect early cardiac involvement, observed in 50–75% of cases [5], assess heart function, and prevent life-threatening complications), pulmonary function tests, chest radiograph and CT, abdominal CT, and tissue biopsies as clinically indicated. All patients should undergo hematologic evaluation to identify possible HES subtypes or underlying causes not previously identified: T-lymphocyte phenotyping on peripheral blood (flow cytometry), including concomitant staining and analyses for CD3, CD4, and CD8 [8]. Several biomarkers are under study for their predictive value regarding HES subtypes and should be measured: serum tryptase, serum vitamin B12 (both elevated in myeloproliferative variant, M-HES), and serum immunoglobulins (particularly IgE), often elevated in lymphocytic variant (L-HES). Serial eosinophil counts are performed to assess the duration and severity of eosinophilia and the treatment response.

One patient in this series had concomitant EBV infection. Although EBV infection can induce reactive eosinophilia and, in certain instances, act as a trigger or exacerbating factor for HES, it is not considered a direct cause of primary HES. A case of L-HES was reported in a patient with chronic active EBV infection, along with an EBV-infected T-cell clone producing eosinophilopoietic cytokines [2]. A previously published case described a 3-year-old patient with HES and hepatic involvement – in which liver biopsy demonstrated mild fibrosis with lymphocytic and eosinophilic infiltration – and pericardial and pleural effusions. Etiologic investigations revealed the presence of EBV DNA in blood, liver tissue, and bone marrow, along with positive EBV serologies. During follow-up, the patient also developed fasciitis in an upper limp. A deep cutaneous biopsy showed fibrosis and lymphocytic infiltration extending into the skeletal muscle, although eosinophilic infiltration was not evident, likely due to prior initiation of corticosteroid therapy. The patient was treated with prednisolone and methotrexate, leading to progressive clinical and laboratory improvement [11].

Given the rarity and the diversity of presentation of HES in pediatric patients, there is no universally accepted treatment protocol for this age group. The primary goal in managing HES is to control the eosinophil count to minimize damage to the affected organs. Corticosteroids are the first-line treatment. Immunosuppressive therapies and biologic agents are second-line options. Dietary therapies are more focused on supportive care, particularly for GI involvement and managing malnutrition. They can be considered in patients with overlapping eosinophilic GI diseases, but the main problem with this option is compliance when a prolonged period of treatment is necessary. After achieving initial control, the steroid dosage is gradually tapered [7, 12]. The objective is to manage symptoms using the lowest effective dose [4, 8, 12]. Some patients may require prolonged treatment or long-term, low-dose maintenance therapy. An initial positive response to prednisolone (1 mg/kg/day) is generally considered a good prognostic indicator for a more favorable disease course. Budesonide has also been proposed as an alternative therapeutic option [6, 12].

Other treatment options for patients who do not respond to corticosteroid therapy or have more severe multiorgan involvement are cytotoxic agents such as hydroxyurea, methotrexate, and immunomodulatory drugs like interferon-alpha or cyclosporine. Hydroxyurea is an effective first-line agent for HES, which may be used with corticosteroids. It has a favorable toxicity profile, low cost, and good efficacy. The initial dose is 500–1,000 mg daily, and it is increased to 2,000 mg/day as tolerated [2, 9]. It helps to control leukocytosis and eosinophilia by suppressing erythropoiesis [9], but it has no proven role in modifying the natural history of HES [2].

Recently, biological therapies like mepolizumab, a monoclonal antibody targeting interleukin-5 (IL-5), have been approved for treatment [3, 4, 6, 13]. Additional therapies, including JAK2 and FGFR1 inhibitors, as well as benralizumab, are currently under investigation for their potential effectiveness [2, 12]. All these options are off-label for use in pediatric patients, and their safety profiles should be considered when compared with the use of low-dose corticosteroids. Bone marrow transplantation is a feasible option, but because of its high morbidity and mortality, it is considered only for patients with uncontrolled disease [7]. In conclusion, this case series underscores the diagnostic challenges of HES in pediatric patients. The nonspecific nature of digestive manifestations may contribute to a delay in diagnosis in children [2, 9]. Comprehensive clinical evaluation, supported by laboratory and imaging studies, was essential for identifying HES and guiding effective treatment. Early recognition and intervention remain critical to prevent long-term complications [7], but the rarity and variable presentation of HES in pediatric populations highlight the need for increased awareness and further research to improve diagnostic accuracy and management strategies in these cases.

We would like to thank Beatriz de Sousa (Unidade Local de Saúde do Alto Ave, Hospital de Guimarães) for providing the images for case 1.

All rules of the local Ethics Committee (“Comissão de Ética para a Saúde da Unidade Local de Saúde de São João/Faculdade de Medicina da Universidade do Porto, Portugal”) were followed, preserving the patients’ identities and confidentiality. Written informed consent was obtained from the patients’ legal guardians for publication of this case series and any accompanying images. This retrospective review of patient data did not require ethical approval in accordance with local guidelines. The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545921).

The authors have no conflicts of interest to declare.

This case report was not supported by any sponsor or funder.

Maria Sousa wrote the manuscript; Sara Catarino wrote the manuscript; Eunice Trindade and Céu Espinheira provided the endoscopic images and wrote and reviewed the manuscript; Mariana Rodrigues wrote and reviewed the manuscript, and Fátima Ferreira reviewed the manuscript.

This article and its online supplementary material include all data generated or analyzed during this study. Further inquiries can be directed to the corresponding author.