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.

Differing Performance of the Warning Signs for Immunodeficiency in the Diagnosis of Pediatric Versus Adult Patients in a Two-Center Tertiary Referral Population.

PURPOSE: Primary immunodeficiency (PID) represents disorders with a spectrum of clinical presentations. The medical community seeks clinical features to prompt evaluation for immunodeficiency given improved prognosis with early identification. We hoped to identify clinical characteristics that would improve the diagnostic accuracy of the widely disseminated Jeffrey Modell Foundation warning signs for immunodeficiency. METHODS: We performed a retrospective chart review in a two-center North American cohort of patients with PID. Charts of 137 pediatric and 400 adult patients with PID were evaluated for the presence of these warning signs and compared to controls with normal preliminary biochemical immune evaluation. RESULTS: Fewer than 45% of adults with PID presented with ≥ 2 warning signs, while diagnostic utility was improved in the pediatric population where the warning signs were found to be 64% sensitive. The warning signs found in a significantly increased proportion compared to controls differed for pediatric PID patients (recurrent pneumonia (OR 2.9, p < 0.001), failure to thrive (OR 2.1, p < 0.001), need for IV antibiotics (OR 2.1, p < 0.001), serious bacterial infection (OR 4.8, p < 0.001), recurrent otitis media (OR 1.5, p = 0.027)), versus adult PID patients (recurrent otitis media (OR 2.9, p < 0.001), recurrent sinusitis (OR 2.1, p < 0.001), diarrhea with weight loss (OR 2.2, p < 0.001), recurrent viral infection (OR 3.3 p < 0.001)). In evaluation for additional criteria to promote identification of immunodeficiency, linear regression models showed slightly improved diagnostic accuracy of the warning signs with the addition of autoimmunity in our pediatric PID cohort (8.7% v 2.8%, p < 0.001, ROC 0.58). Adult PID patients demonstrated atopy more frequently than controls (48.0% vs 40.3%, p = 0.011), while atopy was found to have a negative association with the presence of PID in the pediatric age group (OR 0.3, p < 0.01). No improvement in diagnostic accuracy of the warning signs was found with the addition of allergic disease, autoimmunity, or malignant and benign proliferative disease in the adult cohort. CONCLUSIONS: We demonstrate poor diagnostic performance of warning signs for immunodeficiency in patients with PID in a retrospective chart review. Divergent warning signs of statistically significant diagnostic utility were found in pediatric versus adult patients. We suggest education of physicians on differing presentations of possible immunodeficiency between age groups, and expansion of the warning signs to include non-infectious comorbidities such as autoimmunity in pediatric patients.

Racial differences in the clinical presentation of pediatric eosinophilic esophagitis.

BACKGROUND: Analysis of current data suggests that 80% to 90% of children diagnosed with eosinophilic esophagitis are white. Little data exist regarding the presentation of eosinophilic esophagitis and potential clinical differences in minority children. OBJECTIVE: This study compared the clinical presentation of eosinophilic esophagitis in African American children with white children treated at an urban allergy referral center. METHODS: At an urban allergy clinic, a 2-year retrospective chart review was performed of 50 consecutive pediatric patients diagnosed with eosinophilic esophagitis. Presenting symptoms, age at diagnosis, coexisting atopic disease, and laboratory parameters were compared between races. RESULTS: Most of the 50 children identified were boys (74%), as previously described. However, unlike prior literature, most were nonwhite (42% white, 42% African American, 4% Asian, and 12% other). African American children compared with white children had (1) a significantly higher frequency of failure to thrive (P < .01) and vomiting (P < .01) as presenting symptoms, (2) a higher frequency of comorbid atopic dermatitis (P < .01), (3) a younger mean age of symptom presentation and formal diagnosis (3.7 vs 9.1 years; P < .01), and (4) a trend toward a longer interval between symptom onset and formal diagnosis. However, after adjusting for confounding variables of age and insurance type, several of these racial differences were no longer significant. CONCLUSION: African American children in this series had a larger burden of eosinophilic esophagitis than previously described as well as differences in clinical presentation compared with white patients. Analysis of these findings suggests that providers be aware of this potential diagnosis in young, atopic African American children with symptoms of esophageal dysfunction.

Crohn's disease presenting as a neutrophilic dermatosis in a 5-month-old boy.

A 5-month-old boy with a previous history of failure to thrive and poor feeding was admitted to the hospital with failure to thrive, oral ulcers, and a generalized vesiculopustular rash that demonstrated a subcorneal pustule and neutrophilic infiltrate on histology. Esophagogastroduodenoscopy and flexible sigmoidoscopy biopsies demonstrated chronic active colitis with granulomas, consistent with the diagnosis of Crohn's disease. Our case represents, to our knowledge, the youngest person reported with this condition in association with Crohn's disease.

Placental inflammatory response is associated with poor neonatal growth: preterm birth cohort study.

OBJECTIVE: We sought to determine whether placental markers of intrauterine inflammation were associated with poor weight gain among premature infants in the neonatal period. METHODS: We reviewed 697 preterm births prospectively enrolled as part of an ongoing molecular epidemiological study. Placental markers and serial weight gain were analyzed for premature infants who were hospitalized for >/=21 days (N = 256). Placentas were examined for maternal inflammatory response (MIR), defined as subchorionitis, chorioamnionitis, deciduitis, or free membranitis, and fetal inflammatory response (FIR), defined as inflammation extending to the umbilical cord or chorionic plate. Multivariate linear regression and stratified analyses were performed. RESULTS: Decreases in weight gain at day 21 were associated with the presence of either MIR or FIR (beta coefficient = -4.63 +/- 1.41; P = .001). The association was stronger with FIR than MIR (P for trend = .0027) and persisted in the remaining hospitalized infants at day 28 (n = 223; beta coefficient = -5.53 +/- 1.85; P = .0028). Mean body weights were similar among the 3 groups by corrected age of 36 weeks or discharge, whichever came first. Associations between placental inflammation and poor growth persisted among infants with prenatal corticosteroid exposure and/or neonatal complications and remained marginally significant in the nonexposed groups. Among infants without intrauterine growth restriction, significant association persisted (n = 186; beta coefficient = -5.68 +/- 1.56; P = .0003). CONCLUSIONS: Placental inflammation is associated with poor neonatal growth. MIR and FIR may be useful markers for identifying infants at risk for postnatal growth failure.

Otitis media as a presenting complaint in childhood immunodeficiency diseases.

Otitis media is one of the most common childhood infections and may result from a variety of underlying problems. Suspicion of immunodeficiency should increase when ear infections are frequent; suppurative; unresponsive to antibiotics; caused by unusual organisms; or seen in the context of other frequent infections, severe eczema, or failure to thrive. Humoral immune deficiencies, particularly with an inability to make antibody to encapsulated organisms, are the immunodeficiencies most likely to cause increased otitis media. Immune system evaluation should concentrate on humoral immunodeficiency disorders, but the presenting history and physical findings also should be considered when designing the work-up. Treating the underlying immune deficiency is usually necessary to adequately control the ear infections.

The efficacy of amino acid-based formulas in relieving the symptoms of cow's milk allergy: a systematic review.

The aim of this systematic review was to evaluate the efficacy of amino acid-based formulas (AAF) in patients with cow's milk allergy (CMA). Studies were identified using electronic databases and bibliography searches. Subjects eligible for inclusion were patients of any age with CMA or symptoms suggestive of it. Comparisons of interest were AAF vs. extensively hydrolysed formula (eHF), AAF vs. soy-based formula (SF) and AAF vs. cow's milk or cow's milk-based formula. Outcomes of interest were gastrointestinal (GI), dermatological, respiratory and behavioural symptoms as well as growth. A total of 20 studies [three head-to-head randomized controlled trials (RCTs), three cross-over challenge RCTs, seven clinical trials (CTs) and seven case reports (CRs)] were included in the review. In infants with confirmed or suspected CMA, the use of an AAF was shown to be safe and efficacious. Findings from RCT comparisons of AAF with eHF showed that both formulas are equally efficacious at relieving the symptoms of CMA in confirmed or suspected cases. However, infants in specific subgroups (e.g. non-IgE mediated food-induced gastro-enterocolitis-proctitis syndromes with failure to thrive, severe atopic eczema, or with symptoms during exclusive breastfeeding) were more likely overall to benefit from AAF, as intolerance to eHF may occur. In such cases, symptoms persisting despite eHF feeding usually remit on AAF, and catch-up growth may be seen. Meta-analysis of the findings was not possible due to lack of homogenous reporting of outcomes in the original trials. This systematic review shows clinical benefit from use of AAF in both symptoms and growth in infants and children with CMA who fail to tolerate eHF. Further studies are required to determine the relative medical or economic value of initial treatment with AAF in infants at high risk of eHF intolerance.

Cows milk protein enteropathy and granulomatous duodenitis in a newborn.

Cow's milk protein enteropathy is a symptom complex that composed of severe diarrhoea and malnutrition. This disorder is caused by non-immunoglobulin E-mediated food allergy. Its clinical features and natural course have been explained in many reports, of different types of cow's milk and soy reactions. In the present article, we describe a newborn patient who presented with chronic diarrhoea and failure to thrive diagnosed as cow's milk protein enteropathy. The duodenal biopsy revealed granulomatous duodenitis which has not been described before. Her clinical and pathological findings responded well to cow's milk elimination. We suggest that food allergies should be considered in differential diagnosis of patients with chronic diarrhoea and failure to thrive.

Cytomegalovirus esophagitis in a child with human immunodeficiency virus-1 infection presenting as fever of unknown origin and stunted growth.

We report a 12-year old boy with human immunodeficiency virus-1 infection and cytomegalovirus-associated esophagitis, who presented with an indolent clinical course associated with fever of an unknown origin, failure to thrive and weight loss.

Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice.

We describe a model of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in C57BL/6 mice. A clinical isolate of the virus introduced intranasally replicated transiently to high levels in the lungs of these mice, with a peak on day 3 and clearance by day 9 postinfection. Viral RNA localized to bronchial and bronchiolar epithelium. Expression of mRNA for angiotensin converting enzyme 2, the SARS-CoV receptor, was detected in the lung following infection. The virus induced production in the lung of the proinflammatory chemokines CCL2, CCL3, CCL5, CXCL9, and CXCL10 with differential kinetics. The receptors for these chemokines were also detected. Most impressively, mRNA for CXCR3, the receptor for CXCL9 and CXCL10, was massively up-regulated in the lungs of SARS-CoV-infected mice. Surprisingly Th1 (and Th2) cytokines were not detectable, and there was little local accumulation of leukocytes and no obvious clinical signs of pulmonary dysfunction. Moreover, beige, CD1-/-, and RAG1-/- mice cleared the virus normally. Infection spread to the brain as it was cleared from the lung, again without leukocyte accumulation. Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice. These data indicate that C57BL/6 mice support transient nonfatal systemic infection with SARS-CoV in the lung, which is able to disseminate to brain. In this species, proinflammatory chemokines may coordinate a rapid and highly effective innate antiviral response in the lung, but NK cells and adaptive cellular immunity are not required for viral clearance.

Failure to thrive in a 14-month-old boy with lymphopenia and eosinophilia.

We describe the case of a 14-month-old boy with delayed-onset SCID due to ADA-deficiency which was masqueraded only by failure to thrive. Remarkably, the child had no serious infections and an adequate immune response. However, absolute lymphopenia, eosinophilia and absent thymus on chest x-ray were indicative for immunodeficiency.

Purine nucleoside phosphorylase deficiency: a new case report and identification of two novel mutations (Gly156A1a and Val217Ile), only one of which (Gly156A1a) is deleterious.

Purine nucleoside phosphorylase (PNP) deficiency results in an autosomal recessive immunodeficiency disease characterized by initial involvement of cellular immunity and neurological manifestations with subsequent abnormalities of humoral immunity. The initial presentation and clinical course has varied widely in the relatively few published cases. The molecular basis has been reported in only 10 patients, precluding evaluation of phenotype-genotype relationships. We now report clinical, immunologic, and molecular findings in a new case of relatively early onset that emphasizes hypotonia and developmental delay as early manifestations. The patient carried two novel missense mutations (Gly56A1a and Val217Ile) on the same allele in apparent homozygosity. Expression of each of the mutant enzymes in vitro demonstrated that the Gly156A1a mutation abolished enzyme activity while the Val217Ile mutation was without obvious effect and is therefore a normal variant. Such "normal" polymorphisms might be associated with a variable response to the immunosuppressive PNP inhibitors currently in clinical trials.

Flow cytometric immunophenotyping in the diagnosis and follow-up of immunodeficient children.

From time to time, paediatricians are confronted with children who might suffer from a primary immunodeficiency disease. For practical purposes, these children can be divided into four main clinical categories: (1) a relatively large group of children with recurrent ear-nose and throat and lower respiratory tract infections, in some cases caused by deficiencies of antibodies or complement; (2) children with failure to thrive, intractable diarrhoea or an opportunistic infection which can be caused by a T-lymphocyte or combined immunodeficiency; (3) children with infections with pyogenic bacteria or fungi as seen in case of granulocyte/monocyte function deficiency; and (4) a small heterogeneous group of children with recurrence of particular infections. Also, acquired immunodeficiency becomes a more common problem in paediatric practice. Flow cytometric immunophenotyping of leucocytes appears to be an efficient and rapid tool in the diagnosis and follow-up of immunodeficient patients, supporting early recognition, before serious infections have compromised the child's general condition. This technique can now be performed in many hospitals. In this review, we give directions for the use of flow cytometric immunophenotyping of leucocytes in the diagnosis and follow-up of immunodeficient children according to the four main clinical categories.

[Immunology in medical practice. XXXV. Screening of suspected immunodeficiency: diagnostic protocols for patients with opportunistic or recurrent severe infections, wasting and failure to thrive]. / Immunologie in de medische praktijk. XXXV. Diagnostiek bij vermoeden van een afweerstoornis: onderzoeksprotocollen voor patiënten met opportunistische of recidiverende ernstige infecties, sterke vermagering en niet-gedijen ('failure to thrive').

With a multistage laboratory protocol immunodeficiencies can be efficiently identified. The article presents a diagnostic protocol that consists of three schemes. Scheme 1 describes the diagnostic protocol for the large group of patients with recurrent pulmonary and ENT-infections, where an antibody deficiency can occasionally be found. Scheme 2 presents the diagnostic protocol for the much smaller group of patients with opportunistic infections, wasting or failure to thrive. Several of these patients suffer from a severe T-lymphocyte disorder. Early diagnosis and treatment is important for the prognosis in these patients. Scheme 3 shows the diagnostic protocol for patients with recurrent infections of surface areas and deeper organs; these patients may suffer from a phagocyte disorder.

Morphological picture of the mucosa of small intestine in children with food allergy.

40 children aged from 1 to 8 years with failure to thrive, suspected of food allergy were examined. In the small intestine biopsy, normal mucosa or atrophy of intestinal villi of various intensity were found. Eosinophilic infiltration in the submucosa was present. In children over the 3rd year of life, "prick" skin test was performed, confirming polyallergy. Total IgE level was tested in all patients but only in 25% of children was it elevated.

Immunoreactive trypsin in Shwachman's syndrome.

We studied two infants with Shwachman's syndrome in whom the immunoreactive trypsin concentration was found to be abnormally low. Experience with several hundred assays for immunoreactive trypsin has not shown this low concentration. This finding is probably specific for pancreatic acinar deficiency at this age and strongly suggests Shwachman's syndrome.

Syndrome of erythroderma, failure to thrive, and diarrhea in infancy: a manifestation of immunodeficiency.

Five infants with a triad of symptoms comprising generalized erythroderma, failure to thrive, and diarrhea are presented. All of these children demonstrated significant immunologic abnormalities. This is a recognizable clinical syndrome that reflects immunodeficiency; however, the responsible immunodeficiencies do not appear to be the same in every case. Early investigation and appropriate therapy may considerably reduce morbidity, and mortality in children with this syndrome.