FPIES after umbilical cord blood transplantation: a case series.All authors disclose any potential conflict of interest. They received no specific funding for this work.Keywords: Food Protein–Induced Enterocolitis Syndrome I FPIES I umbilical cord blood transplantation I recurrent vomitingTo the Editor,Acute Food Protein–Induced Enterocolitis Syndrome (FPIES) is a potentially severe non-IgE-mediated food allergy.1FPIES is a clinical diagnosis defined by repeated vomiting 1 to 4 hours after food ingestion, often accompanied with pallor, lethargy and (bloody) diarrhea, which in severe cases can lead to hypotension and shock. Unlike IgE-mediated anaphylaxis, FPIES does not involve respiratory or cutaneous symptoms and has a delayed onset.2 To diagnose FPIES, a patient must meet the major criterion and at least three minor criteria as described in table 1. An oral food challenge (OFC) can help confirm the diagnosis, see table 2, in case of unclear history in combination with a favorable risk/benefit ratio. Common triggers include cow’s milk, soy, and grains, with geographical variation in prevalence. FPIES typically presents in infancy (solid food-induced FPIES between 5-7 months), and children usually outgrow it by 35-42 months.We observed two patients in our pediatric transplantation ward (combined University Medical Center Utrecht and Princess Máxima Center, the Netherlands) with documented FPIES after an umbilical cord blood transplantation (UCBT). There is institutional biobank approval for the use of data within retrospective studies, for which both patients gave informed consent.UCBT is an important treatment option for patients in need of an allogeneic hematopoietic stem cell transplantation where there is no fully matched donor available.3 While IgE-mediated hypersensitivity can sometimes be transferred after allogeneic bone marrow transplantation, FPIES following UCBT is a newly identified phenomenon.4, 5, 6 A recently published case report detailed an 8-month-old girl diagnosed with FPIES six months following UCBT.7 The onset of FPIES typically coincides with dietary expansion during infancy; however, it remains uncertain whether the condition would have developed in the absence of UCBT. In contrast, our cases involve two patients who were not diagnosed with FPIES prior to transplantation but exhibited atypical onset of the syndrome during adolescence following UCBT.Our best documented case is a 15-year-old girl with late juvenile metachromatic leukodystrophy for which she had a 6/6 UCBT without complications or graft versus host disease (GvHD). She first presented four months post-transplant with repeated vomiting, bloody diarrhea, reduced alertness and eventually hypovolemic shock. Treatment included IV fluid resuscitation, blood transfusions, broad-spectrum antibiotics, and increased hydrocortisone to address potential adrenal insufficiency. There were no signs of classical IgE-mediated symptoms. Blood culture, viral and bacterial feces test were all negative. Her symptoms improved within hours.In total she had five episodes of repeated vomiting, (bloody) diarrhea and in several cases hypotension. The initial presentation was the most critical, the clinical presentation was less severe in subsequent episodes. The suspicion rose that these episodes were correlated with eating fish, shellfish or crustaceans for which she was referred to a pediatric allergist. Table 1 shows the clinical symptoms in our patient during five episodes consistent with a diagnosis of FPIES. In addition to FPIES, she developed a symptomatic IgE-mediated allergy for cow’s milk and macadamia nuts with elevated serum IgE levels. Before the UCBT, she had no history of allergic reactions or FPIES-like symptoms. Clinical OFCs with whitefish and crustaceans both resulted in repeated vomiting and diarrhea, for which she needed ondansetron and IV resuscitation, in combination with a more than 1.5x109/L increase in neutrophil count. In table 2 can be seen that the OFC also confirms the diagnosis of FPIES. Whitefish, shellfish and crustaceans were eliminated from her diet and the patient had no further episodes of repeated vomiting.Our second case is a 16-year-old girl with myelodysplastic syndrome, subtype refractory cytopenia in childhood (MDS-RCC), who underwent a 5/6 UCBT. Her post-UCBT course was complicated with intestinal GvHD. She presented in our center eight months after the UCBT with symptoms of repeated vomiting, bloody diarrhea (six times), pallor and hypotension. There were no signs of IgE-mediated symptoms. She was started on IV rehydration and anti-emetics. After six hours, the symptoms of vomiting and diarrhea disappeared. The symptoms started several hours after eating hazelnut, in hindsight she had two earlier mild reactions of vomiting and diarrhea without need for a visit to the emergency department after eating hazelnut. Feces PCR was since three months after the UCBT still positive for adeno- and norovirus, a recent endoscopy showed no signs of active GvHD. The patient was referred to a pediatric allergist who diagnosed FPIES based on a clear clinical history (1 major and 6 minor criteria). There was therefore no indication for an OFC to confirm the diagnosis. After a year, another more minor reaction to hazelnut ingestion occurred.The exact pathophysiology of FPIES remains unclear which makes it difficult to explain why some patients develop FPIES after a stem cell transplant and if the phenomenon is specific to UCBT. The hypothesis is that naïve T cells are exposed to the trigger food proteins and mistakenly recognize these food proteins as dangerous which leads to the activation and differentiation of naïve T cells into antigen specific T cells. Antigen-specific T-cells produce proinflammatory cytokines (TNF-α and IL-6) which lead to inflammation of the intestinal lining increasing permeability and fluid secretion, causing symptoms like vomiting and diarrhea.8After an UCBT, naive T cell counts are higher than after bone marrow or peripheral blood stem cell transplantation.9Furthermore, the neonatal naïve T cell compartment differs from that of adults, which may explain why FPIES has only been observed in UCBT patients and not in those receiving stem cells from other sources.10 The time of onset post-UCBT mirrors that in infants, hinting at a common mechanism involving the developing immune system. With one of our two patients also diagnosed with gastro-intestinal GVHD it is unclear if this correlates with FPIES, but the activation of T cells seen in GVHD might increase the risk.Of note, last decade we have observed four additional cases of potential FPIES in post-UCBT patients, though the data were insufficient for a definitive diagnosis. These two cases identify FPIES as a crucial consideration in the differential diagnosis alongside gastrointestinal GvHD for patients experiencing recurrent vomiting and diarrhea post-UCBT, even at an age older than infancy. Food as a culprit and the rapid recovery without treatment besides IV rehydration are the main clinical discriminators. Therefore, (pediatric) oncologists and transplant specialists should be familiar with FPIES diagnostic criteria and a thorough (food intake) history in patients with acute self-limiting vomiting and diarrhea is essential.Further research is imperative to comprehend FPIES pathophysiology, enabling the identification of at-risk individuals and GvHD as a possible risk factor. More follow-up is needed to determine whether these patients develop natural tolerance just as infants do, and after how long this tolerance evolves.Ludo Cuppen, MD, Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands.Annemieke Schuurhof, MD, PhD Pediatric Allergology, Wilhelmina Children’s Hospital, UMC Utrecht, UU, Utrecht, The NetherlandsBirgitta Versluijs, MD, PhD, Princess Máxima Center for pediatric oncology, Utrecht, The NetherlandsDorine Bresters, MD, PhD, Princess Máxima Center for pediatric oncology, Utrecht, The NetherlandsMarike Staderman MD, PhD, Pediatric Allergology, Wilhelmina Children’s Hospital, UMC Utrecht, UU, Utrecht, The Netherlands & Allergy center Diakonessenhuis, Utrecht, The NetherlandsCaroline Lindemans, MD, PhD, Dept of Pediatrics, UMC Utrecht, & Princess Máxima Center for pediatric oncology, Utrecht, The Netherlands, Utrecht, The Netherlands

Background Childhood cancer survivors face late health problems; despite advances in research, details on risk remain unclear. We describe the methodological aspects of the Dutch Childhood Cancer Survivor Study (DCCSS) cross-sectional clinical study (LATER 2 study). Procedure From the multi-center DCCSS LATER cohort of 6,165 five-year survivors diagnosed 1963-2001, we invited 4,735 eligible in 2016, as well as siblings and parents of survivors. Gaps in evidence identified during development of surveillance guidelines were translated into clinical research questions for 16 outcome-specific sub-projects. The regular care visit to the LATER outpatient clinic forms the backbone of outcome assessment complemented with research-defined measurements (physical examination, diagnostic tests, questionnaires). Furthermore, blood/saliva samples were taken for DNA extraction. Results In total, 2519 (53.2%) survivors participated in the LATER 2 study. Of those participating survivors, 49.3% was female. Median time since childhood cancer diagnosis was 26.9 years (range 14.8 to 54.7 years) and median attained age was 34.4 years (range 15.4 to 66.6 years). Conclusions The high-quality data generated in the LATER 2 study will provide valuable insights into risks of and risk factors for clinical and (psychosocial) health outcomes and factors for early recognition of (psychosocial) health outcomes in long-term childhood cancer survivors. This will contribute to fill in important gaps in knowledge and improve the quality of life and care for childhood cancer survivors.