Phosphomannomutase 2 (PMM2) variants leading to hyperinsulinism-polycystic kidney disease are associated with early-onset inflammatory bowel disease and gastric antral foveolar hyperplasia.

Phosphomannomutase 2 (PMM2) deficiency causes Congenital Disorder of Glycosylation (PMM2-CDG), but does not have a recognised association with Inflammatory Bowel Disease (IBD). A distinct clinical syndrome of hyperinsulinism and autosomal recessive polycystic kidney disease (HIPKD) arises in the context of a specific variant in the PMM2 promotor, either in homozygosity, or compound heterozygous with a deleterious PMM2 variant. Here, we describe the development of IBD in three patients with PMM2-HIPKD, with onset of IBD at 0, 6, and 10 years of age. In each case, intestinal inflammation coincided with the unusual finding of gastric antral foveolar hyperplasia. IBD disease was of variable severity at onset but well controlled with conventional and first-line biologic treatment approaches. The organ-level pattern of disease manifestations in PMM2-HIPKD-IBD may reflect a loss of cis-acting regulatory control by hepatocyte nuclear factor 4 alpha (HNF4A). Analysis of published transcriptomic data suggests that IBD most likely arises due to an impact on epithelial cellular function. We identify a specific pattern of variation in PMM2 as a novel association of early-onset IBD with distinctive gastric pathology.

Safety and Efficacy of Split-Dose Thiopurine vs Low-Dose Thiopurine-Allopurinol Cotherapy in Pediatric Inflammatory Bowel Disease.

INTRODUCTION: Split-dose thiopurine and allopurinol-thiopurine cotherapy strategies have been suggested as rescue therapeutic options for children with inflammatory bowel disease (IBD) and impaired thiopurine metabolism. We compared the efficacy and safety of these regimens in patients who previously failed conventional thiopurine treatment. METHODS: Children with IBD treated with split-dose thiopurine or low-dose thiopurine-allopurinol cotherapy were retrospectively identified. Medical records were reviewed for demographics, treatment regimen, reason for thiopurine failure, side effects, and discontinuation of treatment. Laboratory findings were evaluated at different time points. RESULTS: After prior therapeutic failure, 42 patients were on split-dose regimen (group A) and 20 patients were on thiopurine-allopurinol cotherapy (group B). Twelve patients crossed from group A to group B because of treatment failure, 1 patient was lost at follow-up, and 1 patient discontinued the treatment. The final cotherapy group comprised 29 children (group C), while the split-dose group (group D) included 31 children. Intention-to-treat analysis showed significant differences between split-dose regimen and thiopurine-allopurinol cotherapy for 6-thioguanine nucleotide (6-TGN)/6-methyl mercaptopurine (6-MeMP) ratio ( P < 0.001), 6-TGN ( P < 0.05), and 6-MeMP ( P < 0.001) at 1-3 months. As per protocol analysis, there was a significant difference between group C and group D at 6 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.05) and at 12 months for 6-MeMP ( P < 0.05) and 6-TGN/6-MeMP ratio ( P < 0.001). Side effects were more frequent in allopurinol-thiopurine cotherapy ( P < 0.05). DISCUSSION: In children with IBD and impaired thiopurine metabolism, split-dose thiopurine and low-dose thiopurine-allopurinol cotherapy are both effective therapeutic strategies. The latter shows higher efficacy but a higher side effect rate, suggesting the use of split-dose regimen as the first-line approach.

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease: results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study.

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD). AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab. RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure. CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure.

Abdominal US in Pediatric Inflammatory Multisystem Syndrome Associated with SARS-CoV-2 (PIMS-TS).

Background Children with pediatric inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children, present with abdominal pain among other nonspecific symptoms. Although initial imaging features of PIMS-TS have been reported, the duration of sonographic features remains unknown. Purpose To describe the abdominal US features of PIMS-TS at initial presentation and follow-up. Materials and Methods A retrospective review of children and young adults presenting with clinical features suspicious for PIMS-TS between April 2020 and June 2021 was carried out. US features were documented and reviewed at initial presentation and follow-up. Descriptive statistics were used and interobserver variability was calculated. Results Of 140 children and young adults presenting with suspected PIMS-TS, 120 had confirmed PIMS-TS (median age, 9 years; interquartile range, 7-12 years; 65 male patients) and 102 underwent abdominal US at presentation. PIMS-TS was present as a single abnormality in 109 of the 120 patients (91%) and abdominal symptoms were present in 104 of the 109 (95%). US examinations were abnormal in 86 of 102 patients (84%), with ascites being the most common abnormality in 65 (64%; 95% CI: 54, 73). Bowel wall thickening was present at US in 14 of the 102 patients (14%; 95% CI: 7, 20) and mesenteric inflammation was present in 16 (16%; 95% CI: 9, 23); all of these patients presented with abdominal symptoms. Among the patients with bowel wall thickening, the distal and terminal ileum were most involved (eight of 14 patients, 57%). Abdominal symptoms decreased to seven of 56 patients (13%) in those followed up at 6 months. Thirty-eight patients underwent follow-up US, and the presence of bowel inflammation had decreased to three of 27 patients (11%; 95% CI: -1, 23) in those followed up for less than 2 months and 0 of 17 (0%) in those followed up for more than 2 months. Conclusion Of 102 patients with pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 who underwent US at presentation, 14 (14%) had abdominal US findings of bowel inflammation and 16 (16%) had mesenteric edema. All US abnormalities resolved after 2 months. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by van Rijn and Pajkrt in this issue.

SARS-CoV-2 and the Gastrointestinal Tract in Children.

Coronavirus disease 2019 (COVID-19), caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is predominantly a respiratory disease. However, its significant impact on the gastrointestinal (GI) system is now well-known. SARS-CoV-2 enters cells via the angiotensin-converting enzyme-2 (ACE-2) receptor, which is abundantly expressed on lung cells, but also on enterocytes. Several etiopathogenetic mechanisms have been postulated to explain the GI involvement in COVID-19, including loss in intestinal absorption, microscopic mucosal inflammation and impaired ACE-2 function, which plays a significant role in maintaining gut homeostasis. In children the GI manifestations include anorexia, nausea, vomiting, diarrhea and abdominal pain, which may represent the earliest presenting symptoms of the disease. However, although rare, a significant GI mucosal inflammation, such as terminal ileitis mimicking an atypical appendicitis, and other GI manifestations have been reported. COVID-19 pandemic has posed a significant challenge in healthcare provision in term of ability in providing safe diagnostic procedures, face-to-face consultations, and offering comprehensive care. For instance, changes in health services have raised the risk of empirical or sub-optimal management of chronic GI disorders such as inflammatory bowel disease (IBD) due to delayed endoscopic and clinical assessment. This review will discuss the acute GI involvement in COVID-19 in children and reflect on challenges and major changes observed in clinical practice during COVID-19 pandemic by sharing both the published literature and personal experience. We also suggest potential strategies for providing optimal gastroenterology care during this unprecedented era.

Evaluation of a health service adopting proactive approach to reduce high risk of lung cancer: The Liverpool Healthy Lung Programme.

OBJECTIVES: This Liverpool Healthy Lung Programme is a response to high rates of lung cancer and respiratory diseases locally and aims to diagnose lung cancer at an earlier stage by proactive approach to those at high risk of lung cancer. The objective of this study is to evaluate the programme in terms of its likely effect on mortality from lung cancer and its delivery to deprived populations. METHODS: Persons aged 58-75 years, with a history of smoking or a diagnosis of chronic obstructive pulmonary disease (COPD)2 according to general practice records were invited for lung health check in a community health hub setting. A detailed risk assessment and spirometry were performed in eligible patients. Those with a 5% or greater five-year risk of lung cancer were referred for a low dose CT3 scan. RESULTS: A total of 4 566 subjects attended the appointment for risk assessment and 3 591 (79%) consented to data sharing. More than 80% of the patients were in the most deprived quintile of the index of multiple deprivation. Of those attending, 63% underwent spirometry and 43% were recommended for a CT scan. A total of 25 cancers were diagnosed, of which 16 (64%) were stage I. Comparison with the national stage distribution implied that the programme was reducing lung cancer mortality by 22%. CONCLUSIONS: Community based proactive approaches to early diagnosis of lung cancer in health deprived regions are likely to be effective in early detection of lung cancer.

Pilot randomised controlled trial of focused narrative intervention for moderate to severe depression in palliative care patients: DISCERN trial.

BACKGROUND: Depression is poorly detected and sub-optimally managed in palliative care patients, and few trials of psychosocial interventions have been carried out in this group of patients. AIMS: A pilot trial to determine the effect of a focused narrative intervention on depression in palliative care patients when used in addition to usual care. DESIGN: Patients scoring 10 or higher on Patient Health Questionnaire-9 randomised to focused narrative intervention in addition to usual care or usual care only and followed up at 2, 4 and 6 weeks. A reduction of five points on Patient Health Questionnaire-9 was regarded as clinically significant response to treatment. SETTING/PARTICIPANTS: Palliative care patients aged over 18 recruited from hospice day care services - exclusion criteria included an estimated prognosis of 6 weeks or less, cognitive impairment and unable to understand written or spoken English. RESULTS: Out of 57 participating patients (71% female), with mean age 65.1 years (range 36-88 years), 33 patients were randomised to the intervention and 24 to usual care only. Mean Patient Health Questionnaire-9 score at baseline was 16.4. Patients receiving intervention had greater reduction in Patient Health Questionnaire-9 score at 6-week follow-up ( p = 0.04). Median survival was 157 days for intervention and 102 days for control group patients ( p = 0.07). CONCLUSION: This pilot trial suggests a focused narrative intervention in palliative care patients with moderate to severe depression can reduce depression scores more than usual care alone. Patients receiving intervention appeared to have longer survival. These results support the need for a fully powered trial.

Nutritional status and nutritional management in children with cancer.

Malnutrition is often seen at the point of diagnosis in childhood malignancy or may develop during the course of treatment. Strategies for optimal diagnosis and management of nutritional problems in children with cancer are limited in the published literature. Identification of children who may be malnourished or at nutritional risk can be achieved through improved approaches for risk stratification and classification. Once recognised, various strategies have been demonstrated to reduce malnutrition, minimise side effects of treatment and improve survival. Novel approaches in vivo and adult oncology populations provide future avenues for investigation.