Severe Immune-Related Enteritis after In Utero Exposure to Pembrolizumab.

Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab.

Cytoplasmic RNA quality control failure engages mTORC1-mediated autoinflammatory disease.

Inborn errors of nucleic acid metabolism often cause aberrant activation of nucleic acid sensing pathways, leading to autoimmune or autoinflammatory diseases. The SKIV2L RNA exosome is cytoplasmic RNA degradation machinery that was thought to be essential for preventing the self-RNA-mediated interferon (IFN) response. Here, we demonstrate the physiological function of SKIV2L in mammals. We found that Skiv2l deficiency in mice disrupted epidermal and T cell homeostasis in a cell-intrinsic manner independently of IFN. Skiv2l-deficient mice developed skin inflammation and hair abnormality, which were also observed in a SKIV2L-deficient patient. Epidermis-specific deletion of Skiv2l caused hyperproliferation of keratinocytes and disrupted epidermal stratification, leading to impaired skin barrier with no appreciable IFN activation. Moreover, Skiv2l-deficient T cells were chronically hyperactivated and these T cells attacked lesional skin as well as hair follicles. Mechanistically, SKIV2L loss activated the mTORC1 pathway in both keratinocytes and T cells. Both systemic and topical rapamycin treatment of Skiv2l-deficient mice ameliorated epidermal hyperplasia and skin inflammation. Together, we demonstrate that mTORC1, a classical nutrient sensor, also senses cytoplasmic RNA quality control failure and drives autoinflammatory disease. We also propose SKIV2L-associated trichohepatoenteric syndrome (THES) as a new mTORopathy for which sirolimus may be a promising therapy.

Prior infection with intestinal coronaviruses moderates symptom severity and mortality in patients with COVID-19: A hypothesis and preliminary evidence.

The pandemic of acute respiratory illness caused by the novel betacoronavirus SARS-CoV-2, officially designated COVID-19, has attained the proportions of a global health crisis. Though all nations of the world have been affected by this disease, there have been marked cross-national variations in prevalence, severity and mortality rates. Various explanations, based on demographic, social and climatic factors, have been suggested to account for this variability, but these remain unverified to date. Based on recent research findings suggesting that human enterocytes may serve as a point of entry for SARS-CoV-2, leading to intestinal viral replication, this paper puts forward the hypothesis that prior intestinal infection with coronaviruses, either symptomatic or asymptomatic, may moderate this process and minimize the severity of SARS-CoV-2 infection. This hypothesis is supported by evidence on the gastrointestinal manifestations of SARS-CoV-2 and related infections, on the geographical patterns observed in the variability of COVID-19 mortality, and on the occurrence and geographical distribution of outbreaks of diarrheal disease, as well as asymptomatic infection, with human coronaviruses as verified by direct or serological testing. Preliminary supporting evidence based on national and international health statistics is presented, along with suggestions on more robust methods by which this hypothesis may be tested. If the proposal put forth in this paper can be confirmed either wholly or in part, it would have significant implications in terms of strategies aimed at minimizing the severity of COVID-19 in a clinical setting.

Secretory immunoglobulin A (sIgA) in saliva versus virulence proteins of enteropathogenic Escherichia coli (EPEC) in ill and colonized children / Inmunoglobulina A secretoria en saliva frente a proteínas de virulencia de Escherichia coli enteropatogénica en niños enfermos y colonizados

INTRODUCTION: We evaluated the presence of sIgA in saliva, versus Escherichia coli secreted proteins (Esp) related to the type III secretion system (T3SS), and its semi-quantitative concentration in children under 2 years-old (no longer breastfed) who were previously colonized or infected with enteropathogenic E. coli (EPEC). METHODS: We analyzed the presence of sIgA in 40 children, who previously had positive cultures for EPEC associated (n = 17) or not associated (n = 23) with diarrhea, using the Western Blot technique versus E. coli secreted proteins: EspABCD. A semi-quantitative measurement of the reaction for each protein was made by its density peaks (OD). RESULTS: We found sIgA versus all or some EspABCD proteins in both groups. However, the ill patients had higher concentrations of these antibodies than colonized patients. DISCUSSION: The presence of sIgA in saliva could reflect an intestinal immune response and their levels could be related to a greater exposure and/or bacterial load

INTRODUCCIÓN: Evaluamos la presencia de inmunoglobulina secretoria A (sIgA) frente a proteínas secretadas por E. coli (Esp) relacionadas con el sistema de secreción tipo III (T3SS) en saliva, y su concentración semicuantitativa en niños menores de 2 años (no lactantes) colonizados o infectados previamente con E. coli enteropatógena (EPEC). MÉTODOS: Analizamos la presencia de sIgA en 40 niños con cultivos positivos previos para EPEC asociados (n=17) o no (n=23) con diarrea, mediante la técnica de Western-blot frente a las proteínas secretadas por E. coli (EspABCD), realizando mediciones semicuantitativas de la reacción de cada proteína mediante sus picos de densidad (OD). RESULTADOS: Ambos grupos presentaron sIgA frente a las proteínas EspABCD, aunque los pacientes enfermos presentaron mayores concentraciones de estos anticuerpos que los colonizados. DISCUSIÓN: La presencia de sIgA en la saliva podría reflejar una respuesta inmune intestinal y sus niveles podrían estar relacionados con una mayor exposición y/o carga bacteriana

Combined Immunodeficiency in Patients With Trichohepatoenteric Syndrome.

The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.

Campylobacter jejuni and associated immune mechanisms: short-term effects and long-term implications for infants in low-income countries.

PURPOSE OF REVIEW: Campylobacter jejuni is recognized as one of the most common causes of food-borne gastrointestinal illness worldwide, resulting in a self-limiting dysentery in developed countries. However, it is increasingly gaining attention due to its association with postinfectious complications such as Guillain-Barré Syndrome and recently recognized importance in early childhood diarrhea in developing countries. We hypothesize that the inflammation mediated by C. jejuni infection causes environmental enteric dysfunction, and with contribution from diet and the host, microbiome may be responsible for growth faltering in children and developmental disability. RECENT FINDINGS: Diet plays a major role in the impact of C. jejuni infection, both by availability of micronutrients for the bacteria and host as well as shaping the microbiome that affords resistance. Early childhood repeated exposure to the bacterium results in inflammation that affords long-term immunity but, in the short term, can lead to malabsorption, oral vaccine failure, cognitive delay and increased under-5 mortality. SUMMARY: As interest in C. jejuni increases, our understanding of its virulence mechanisms has improved. However, much work remains to be done to fully understand the implications of immune-mediated inflammation and its potential role in diseases such as environmental enteric dysfunction.

Natural History of Cryptosporidiosis in a Birth Cohort in Southern India.

BACKGROUND: Cryptosporidium is a leading cause of moderate to severe childhood diarrhea in resource-poor settings. Understanding the natural history of cryptosporidiosis and the correlates of protection are essential to develop effective and sustainable approaches to disease control and prevention. METHODS: Children (N = 497) were recruited at birth in semiurban slums in Vellore, India, and followed for 3 years with twice-weekly home visits. Stool samples were collected every 2 weeks and during diarrheal episodes were tested for Cryptosporidium species by polymerase chain reaction (PCR). Serum samples obtained every 6 months were evaluated for seroconversion, defined as a 4-fold increase in immunoglobulin G directed against Cryptosporidium gp15 and/or Cp23 antigens between consecutive sera. RESULTS: Of 410 children completing follow-up, 397 (97%) acquired cryptosporidiosis by 3 years of age. PCR identified 1053 episodes of cryptosporidiosis, with an overall incidence of 0.86 infections per child-year by stool and serology. The median age for the first infection was 9 (interquartile range, 4-17) months, indicating early exposure. Although infections were mainly asymptomatic (693 [66%]), Cryptosporidium was identified in 9.4% of diarrheal episodes. The proportion of reinfected children was high (81%) and there was clustering of asymptomatic and symptomatic infections (P < .0001 for both). Protection against infection increased with the order of infection but was only 69% after 4 infections. Cryptosporidium hominis (73.3%) was the predominant Cryptosporidium species, and there was no species-specific protection. CONCLUSIONS: There is a high burden of endemic cryptosporidiosis in southern India. Clustering of infection is suggestive of host susceptibility. Multiple reinfections conferred some protection against subsequent infection.

Effects of zinc supplementation in the prevention of respiratory tract infections and diarrheal disease in Colombian children: A 12-month randomised controlled trial

BACKGROUND: Among the preventive strategies for lowering the incidence of upper respiratory tract infections (URTI) and acute diarrhoea episodes, two of the most common diseases in children, zinc supplementation has received special interest. However, there is a need for additional studies that determine the preventive effects of different doses of zinc on URTI and diarrhoeal disease episodes in children. METHODS: In a randomised, triple-blind clinical trial, we evaluated the efficacy of 12 months of daily zinc supplementation in the incidence of URTI and acute diarrhoea in a population of healthy children aged between 6 and 12 months living in Bogota, Colombia. The outcomes analysed were incidence of URTI, acute diarrhoeal disease episodes, and side effects of the interventions. RESULTS: Between 2010 and 2013, a total of 355 children underwent randomisation, with 174 assigned to the zinc supplementation group and 181 to the control group. In the multivariate analyses, having been randomised to the non-supplemented control group (IRR 1.73, 95% CI 1.52-1.97, p < 0.001), and nursery attendance (IRR 1.41, 95% CI 1.07-1.87, p = 0.016) were independently linked to the number of URTI. Likewise, having been randomised to the non-supplemented group (IRR 1.43, 95% CI 1.20-1.71, p < 0.001), and lower socioeconomic status (IRR 1.86, 95% CI 1.11-3.13, p = 0.018) were independently associated to the number of diarrhoeal disease episodes. CONCLUSIONS: Daily supplementation of 5mg of zinc during 12 months significantly decreased the incidence of URTI and diarrhoeal disease episodes in a healthy population of children aged between 6 and 12 months

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Multilabel immunofluorescence and antigen reprobing on formalin-fixed paraffin-embedded sections: novel applications for precision pathology diagnosis.

We report new methods for multilabel immunofluorescence (MIF) and reprobing of antigen epitopes on the same formalin-fixed paraffin-embedded (FFPE) sections. The MIF method includes an antigen-retrieval step followed by multilabel immunostaining and examination by confocal microscopy. As examples, we illustrate epitopes localized to the apical and basolateral membranes, and the cytoplasm of enterocytes of normal small intestine and in cases of congenital enteropathies (microvillous inclusion disease and congenital tufting enteropathy). We also demonstrate localization of the bile salt excretion pump protein (BSEP) in bile canalicular membrane of normal hepatocytes and in cases of primary sclerosing cholangitis. To demonstrate colocalization of cytoplasmic and nuclear epitopes we analyzed normal control and hyperplastic pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEBs), presumed airway sensors in the lungs of infants with bronchopulmonary dysplasia (BPD). As cytoplasmic markers we used anti-bombesin or anti-synaptic vesicle protein 2 (SV2) antibody, respectively, and for nuclear localization, antibodies against neurogenic genes mammalian achaete-scute homolog (Mash1) and prospero homeobox 1 (Prox1), essential for NEB cells differentiation and maturation, hypoxia-inducible factor 1α (HIF1α) a downstream modulator of hypoxia response and a proliferation marker Ki67. The reprobing method consisted of removal of the previously immunolabeled target and immunostaining with different antibodies, facilitating colocalization of enterocyte brush border epitopes as well as HIF1α, Mash1 and Prox1 in PNEC/NEB PNEC and NEBs. As these methods are suitable for routine FFPE pathology samples from various tissues, allowing visualization of multiple epitopes in the same cells/sections with superior contrast and resolution, they are suitable for a wide range of applications in diagnostic pathology and may be particularly well suited for precision medicine diagnostics.

The role of enterocyte defects in the pathogenesis of congenital diarrheal disorders.

Congenital diarrheal disorders are rare, often fatal, diseases that are difficult to diagnose (often requiring biopsies) and that manifest in the first few weeks of life as chronic diarrhea and the malabsorption of nutrients. The etiology of congenital diarrheal disorders is diverse, but several are associated with defects in the predominant intestinal epithelial cell type, enterocytes. These particular congenital diarrheal disorders (CDD(ENT)) include microvillus inclusion disease and congenital tufting enteropathy, and can feature in other diseases, such as hemophagocytic lymphohistiocytosis type 5 and trichohepatoenteric syndrome. Treatment options for most of these disorders are limited and an improved understanding of their molecular bases could help to drive the development of better therapies. Recently, mutations in genes that are involved in normal intestinal epithelial physiology have been associated with different CDD(ENT). Here, we review recent progress in understanding the cellular mechanisms of CDD(ENT). We highlight the potential of animal models and patient-specific stem-cell-based organoid cultures, as well as patient registries, to integrate basic and clinical research, with the aim of clarifying the pathogenesis of CDD(ENT) and expediting the discovery of novel therapeutic strategies.

Oral zinc and common childhood infections--An update.

Zinc is an essential micronutrient important for growth and for normal function of the immune system. Many children in developing countries have inadequate zinc nutrition. Routine zinc supplementation reduces the risk of respiratory infections and diarrhea, the two leading causes of morbidity and mortality in young children worldwide. In childhood diarrhea oral zinc also reduces illness duration and risk of persistent episodes. Oral zinc is therefore recommended for the treatment of acute diarrhea in young children. The results from the studies that have measured the therapeutic effect of zinc on acute respiratory infections, however, are conflicting. Moreover, the results of therapeutic zinc for childhood malaria also are so far not promising.This paper gives a brief outline of the current evidence from clinical trials on therapeutic effect of oral zinc on childhood respiratory infections, pneumonia and malaria and also of new evidence of the effect on serious bacterial illness in young infants.

[Anti-rotavirus vaccination: what impedes its wide prescription]. / Quels sont les freins à la vaccination contre le rotavirus ? Enquête auprès des médecins généralistes et pédiatres de la communauté urbaine de Bordeaux.

UNLABELLED: The aim of this study was to analyze why anti-rotavirus vaccination is rarely used in France, although this infection is frequent and associated with a large number of hospitalizations. METHOD: A questionnaire was sent to 732 general practitioners and pediatricians in the Bordeaux area. RESULTS: The response rate was 57% (381 GPs and 38 pediatricians). Most of them (71.8%) declared that they received information on the vaccination and more than 80% of them feel that gastroenteritis is a severe disease. However, anti-rotavirus is never prescribed by the majority of them (59.6%) and only 2.6% prescribe it systematically. The reasons are that the patient is not refunded (64.2%), the vaccination timetable is overloaded (53.6%), and there are no recommendations for this vaccination (35.1%). Physicians believe that parents feel gastroenteritis as a benign disease (52.6%) and say that they refuse the vaccination because it is not refunded (77.7%), not mandatory (45.5%), or may have side effects (44.1%). Physicians' prescription of vaccination is correlated to their information on the vaccination and their feeling about the disease's severity. They would modify their practice if the vaccination was recommended and/or refunded. CONCLUSION: The main obstacles against anti-rotavirus vaccination are the absence of recommendations and refunding. The recent recommendation for the vaccination and a lower price should lead to its generalization in France.

The SKIV2L RNA exosome limits activation of the RIG-I-like receptors.

Sensors of the innate immune system that detect intracellular nucleic acids must be regulated to prevent inappropriate activation by endogenous DNA and RNA. The exonuclease Trex1 regulates the DNA-sensing pathway by metabolizing potential DNA ligands that trigger it. However, an analogous mechanism for regulating the RIG-I-like receptors (RLRs) that detect RNA remains unknown. We found here that the SKIV2L RNA exosome potently limited the activation of RLRs. The unfolded protein response (UPR), which generated endogenous RLR ligands through the cleavage of cellular RNA by the endonuclease IRE-1, triggered the production of type I interferons in cells depleted of SKIV2L. Humans with deficiency in SKIV2L had a type I interferon signature in their peripheral blood. Our findings reveal a mechanism for the intracellular metabolism of immunostimulatory RNA, with implications for specific autoimmune disorders.

Syndromic (phenotypic) diarrhoea of infancy/tricho-hepato-enteric syndrome.

OBJECTIVES: Syndromic diarrhoea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital syndrome. The main features are intractable diarrhoea of infancy, hair abnormalities, facial dysmorphism, intrauterine growth restriction and immune system abnormalities. It has been linked to abnormalities in two components of the putative human ski complex: SKIV2L and TTC37. The long-term outcome of this syndrome is still unknown. We aim to describe the long-term outcome, in the French cohort of patients born since 1992. DESIGN: Review of the clinical and biological features of the 15 patients with SD/THE, followed in France and born between 1992 and 2010. RESULTS: All patients presented typical SD/THE syndrome features, of intractable diarrhoea in infancy requiring parenteral nutrition, a facial dysmorphism with hair abnormalities, and immunological disorders. Half of them also had liver and skin abnormalities. Five children died, among which 3 died due to infections. Probabilities of survival according to the Kaplan-Meier method were 93.3%, 86.7%, 74.3 and 61.9%, respectively at 1 year, 5 years, 10 years and 15 years of age. 3/15 were weaned from parenteral nutrition (PN) with likelihood of weaning being 10% at 5 years and 40% at 10 years. At birth 80% were small for gestational age and the short stature persisted in 60%. Haemophagocytic syndrome was noted in 60% and mild mental retardation was present in 60%. CONCLUSIONS: SD/THE is a rare disease with high morbidity and mortality. Management should be focused on nutrition and immunological defects.

Effectiveness of monovalent and pentavalent rotavirus vaccine.

OBJECTIVE: Previous US evaluations have not assessed monovalent rotavirus vaccine (RV1, a G1P[8] human rotavirus strain) effectiveness, because of its later introduction (2008). Using case-control methodology, we measured the vaccine effectiveness (VE) of the 2-dose RV1 and 3-dose pentavalent vaccine (RV5) series against rotavirus disease resulting in hospital emergency department or inpatient care. METHODS: Children were eligible for enrollment if they presented to 1 of 5 hospitals (3 in Georgia, 2 in Connecticut) with diarrhea of ≤10 days' duration during January through June 2010 or 2011, and were born after RV1 introduction. Stools were collected; immunization records were obtained from providers and state electronic immunization information system (IIS). Case-subjects (children testing rotavirus antigen-positive) were compared with 2 control groups: children testing rotavirus negative and children selected from IIS. RESULTS: Overall, 165 rotavirus-case subjects and 428 rotavirus-negative controls were enrolled. Using the rotavirus-negative controls, RV1 VE was 91% (95% confidence interval [CI] 80 to 95) and RV5 VE was 92% (CI 75 to 97) among children aged ≥8 months. The RV1 VE against G2P[4] disease was high (94%, CI 78 to 98), as was that against G1P[8] disease (89%, CI 70 to 96). RV1 effectiveness was sustained among children aged 12 through 23 months (VE 91%; CI 75 to 96). VE point estimates using IIS controls were similar to those using rotavirus-negative controls. CONCLUSIONS: RV1 and RV5 were both highly effective against severe rotavirus disease. RV1 conferred sustained protection during the first 2 years of life and demonstrated high effectiveness against G2P[4] (heterotypic) disease.

Calcium ameliorates diarrhea in immunocompromised children.

Treatment of infectious diarrheas remains a challenge, particularly in immunocompromised patients in whom infections usually persist and resultant diarrhea is often severe and protracted. Children with infectious diarrhea who become dehydrated are normally treated with oral or intravenous rehydration therapy. Although rehydration therapy can replace the loss of fluid, it does not ameliorate diarrhea. Thus, during the last decades, there has been continuous effort to search for ways to safely stop diarrhea. Herein, we report 3 immunocompromised children who developed severe and/or protracted infectious diarrhea. Their diarrheas were successfully "halted" within 1 to 2 days following the administration of calcium.

Duration of protection of pentavalent rotavirus vaccination in Nicaragua.

OBJECTIVE: To evaluate the duration of protection of pentavaent rotavirus vaccine (RV5) against rotavirus hospitalizations in Nicaragua, a developing country in Central America. METHODS: We conducted a case-control study at 4 hospitals from 2007 through 2010, including 1016 children hospitalized with laboratory-confirmed rotavirus diarrhea, 4930 controls with nonrotavirus diarrhea (ie, "test-negative"), and 5627 controls without diarrhea. All cases and controls were aged ≥ 6 months and born after August 2006. Outcomes included odds of antecedent vaccination between case-patients and controls, and effectiveness of vaccination (1 - adjusted odds ratio [OR] × 100). Duration of protection was assessed by comparing effectiveness among children aged <1 year compared with ≥ 1 year. RESULTS: Indicators of socioeconomic conditions and nonrotavirus vaccination (oral polio vaccine and diphtheria/tetanus/pertussis/hepatitis A/hepatitis B) for test-negative controls were more comparable to the rotavirus case-patients than nondiarrhea controls. RV5 vaccination was associated with a significantly lower risk of rotavirus hospitalization by using test-negative controls (OR: 0.55; 95% confidence interval [CI]: 0.41-0.74) and nondiarrhea controls (OR: 0.30; 95% CI: 0.22-0.40). Risk of rotavirus hospitalization was twofold lower among RV5 vaccinated children aged <1 year (OR: 0.36; 95% CI: 0.22-0.57) compared with RV5 vaccinated children aged ≥ 1 year (OR: 0.70; 95% CI: 0.47-1.05). CONCLUSIONS: RV5 provided good protection against severe rotavirus disease in Nicaragua during the first year of life, when most severe and fatal rotavirus disease in developing countries occurs. However, the decline in protection with age warrants monitoring of disease among older children and consideration of a booster dose evaluation at the end of infancy.

The importance of breastfeeding in rotaviral diarrhoeas.

Globally, rotaviral vaccines in use today have contributed to the reduction of the incidence of rotaviral diarrhoeas. Despite the substantial protection conferred by the current vaccines against the rotaviral strains, it is only prudent to recognise that other protective factors, like breastfeeding, also provide some degree of protection against this disease. This article has attempted to review some important mechanisms of protection in breast milk against the rotaviruses and highlight the oft forgotten non-immunoglobulin fraction in breast milk as an additional tool of protection against rotavirus disease. The adaptive capacity of breast milk to environment is another compelling reason to continue breastfeeding as it can usefully complement and be significant in the use of many vaccines. Vital immunoprotective constituents in breast milk beneficially protect the infant by initiating and strengthening many immune responses and should be borne in mind as essential tools of defence even in an era where vaccines play a pivotal role in the combat against certain diseases. It is impressive that besides nutritive advantages, the suckling infant enjoys appreciable immunoprotection via exclusive breastfeeding.