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.

Impact of Steroid Therapy on Early Growth in Infants with Biliary Atresia: The Multicenter Steroids in Biliary Atresia Randomized Trial.

OBJECTIVE: To investigate the impact of corticosteroid therapy on the growth of participants in the Steroids in Biliary Atresia Randomized Trial (START) conducted through the Childhood Liver Disease Research Network. The primary analysis in START indicated that steroids did not have a beneficial effect on drainage in a cohort of infants with biliary atresia. We hypothesized that steroids would have a detrimental effect on growth in these infants. STUDY DESIGN: A total of 140 infants were enrolled in START, with 70 randomized to each treatment arm: steroid and placebo. Length, weight, and head circumference were obtained at baseline and follow-up visits to 24 months of age. RESULTS: Patients treated with steroids had significantly lower length and head circumference z scores during the first 3 months post-hepatoportoenterostomy (HPE), and significantly lower weight until 12 months. Growth trajectories in the steroid and placebo arms differed significantly for length (P < .0001), weight (P = .009), and head circumference (P < .0001) with the largest impact noted for those with successful HPE. Growth trajectory for head circumference was significantly lower in patients treated with steroids irrespective of HPE status, but recovered during the second 6 months of life. CONCLUSIONS: Steroid therapy following HPE in patients with biliary atresia is associated with impaired length, weight, and head circumference growth trajectories for at least 6 months post-HPE, especially impacting infants with successful bile drainage. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00294684.

Idiosyncratic drug reactions and membranous glomerulopathy.

An infant boy with steroid-resistant nephrotic syndrome (idiopathic membranous glomerulonephropathy) achieved remission with ciclosporin but developed eosinophilia and high IgE levels (max 19 000  iU/mL). Conversion to tacrolimus resulted in chronic diarrhoea (eosinophilic gastroenteritis), muscle weakness, polyserositis and failure-to-thrive. In contrast, a trial without tacrolimus resulted in a ciclosporin-responsive relapse, therapy-resistant focal seizures with generalised spikes, worsening muscle weakness and diarrhoea. The patient was weaned off of ciclosporin and completely normalised. In vitro testing demonstrated decreased viability of the patient's cells when incubated with calcineurin inhibitors (ciclosporin, 70%; tacrolimus, 80% compared to control cells), supporting their role in this adverse drug reaction.

Outcome following tranexamic acid exposure during breastfeeding.

OBJECTIVE: This study evaluated the outcome of infants exposed to tranexamic acid during lactation. SUBJECTS AND METHODS: A prospective, controlled observational study design was used. Mothers who contacted the Beilinson Teratology Information Service (BELTIS) regarding use of tranexamic acid while breastfeeding were followed up by phone interview. Data on lactation, neonatal symptoms, and outcomes at the age of 1-3 years were obtained. Mothers' breastfeeding while taking tranexamic acid and their infants were compared with those of a matched control group of breastfeeding mothers using a drug known to be safe during lactation (amoxicillin) and their infants. RESULTS: Follow-up was obtained for 28 of 32 women who sought advice regarding use of tranexamic acid during breastfeeding. Of the 28 women, six did not take the drug, and one refused to participate. The 21 remaining women (study group) were compared with 42 control women. A decreased amount of breastmilk was reported by one woman in the study group versus two women in the control group (p=1.0). Possible adverse drug effects were reported for one of 21 study group infants (restlessness) and for one of 42 control group infants (gastroesophageal reflux) (p=1.0). Growth below the 3rd percentile was found in one of 21 study group infants versus four of 42 control group infants (p=0.66). Development was normal for all study group infants. CONCLUSIONS: No increase in adverse long-term outcomes was found in infants exposed through breastfeeding to tranexamic acid. Our data in conjunction with previous estimates of very low drug exposure support continuation of breastfeeding in women requiring treatment with tranexamic acid.

Case report: heavy metal burden presenting as Bartter syndrome.

CONTEXT: Maternal transfer of heavy metals during fetal development or lactation possibly contributed to the clinical manifestations of Bartter syndrome and developmental delay in the offspring. CASE PRESENTATION: An 11-month-old child diagnosed with Bartter syndrome and failure to thrive was treated concurrently for elevated metal burden while he was undergoing standard medical interventions. Treatment with body-weight doses of meso-2,3-dimercaptosuccinic acid (DMSA) reduced the body burden of lead, beryllium, copper, mercury, and cadmium at the three- and sixth-month follow-up tests. During the course of the six-month treatment, the patient gained 2.4 kg (5.2 lb) and grew approximately 9.5 cm (3.75 in). His weight shifted from significantly below the 5th percentile in weight to within the 5th percentile, and from below the 5th to within the 10th percentile for length. DISCUSSION: The child's acquisition of lead, beryllium, and copper correspond to his mother's history of stained glass assembly and occurred during fetal development or lactation, since there were no other identifiable sources that could have contributed to the heavy metal burden. Tests for known genetic mutations leading to Bartter syndrome were all negative. RELEVANCE TO CLINICAL PRACTICE: This case report highlights the potential benefit of DMSA for treatment of heavy metal body burden in infants who present with Bartter syndrome.

Mercury poisoning: a rare but treatable cause of failure to thrive and developmental regression in an infant.

An infant presented with failure to thrive and developmental regression. Physical examination revealed an irritable child with swollen, erythematous extremities, and elevated blood pressure. Extensive investigations, including a metabolic work-up and neuroimaging, were unrevealing. Exposure to self-purchased medication was initially denied. The physical signs were suggestive of acrodynia. Mercury poisoning was ultimately established by measuring paired blood and urine mercury levels. On further enquiry, it was revealed that the child had been given a Chinese medicinal product for 4 months. He responded well to a chelating agent. Acrodynia is a childhood disease considered to be of historical interest only, but making a diagnosis of mercury poisoning is rewarding because the response to treatment is good. This case highlights the common misconception that alternative medicines are safe and benign.

Cushing's syndrome induced by misuse of moderate- to high-potency topical corticosteroids.

OBJECTIVE: To report a case of Cushing's syndrome caused by continuous use of moderate- to high-potency topical corticosteroids over several months. CASE SUMMARY: An 11-month-old patient with atopic dermatitis received uninterrupted treatment with moderate- to high-potency topical corticosteroids. He presented with several food allergies and was admitted to the hospital after atopic dermatitis worsened. Signs of growth retardation, which had begun at 6 months of age, were also noted during the child's hospital stay. An endocrinologist concluded that a lower-than-normal bone density scan and growth retardation on both weight and growth curves were due to suppression of the hypothalamicpituitary-adrenal (HPA) axis and a multifactorial failure to thrive. DISCUSSION: This is a case of an infant overexposed to topical corticosteroid treatment who developed Cushing's syndrome within a few months. Local treatment of atopic dermatitis is classically based on the use of topical corticosteroids in combination with an emollient or other drugs. To limit local and general damaging effects, the choice of topical corticosteroid must be made in terms of patient age, severity and site of the rash, and the extent of skin involvement. Several factors influence the systemic absorption of topical corticosteroids. While our literature review indicated the possibility of a multifactorial origin of the child's growth retardation, the use of topical corticosteroids was shown to have contributed to suppression of the HPA axis. Application of the Naranjo probability scale indicated a probable relationship between the continuous and sustained administration of topical corticosteroids over several months and suppression of the HPA axis. Although topical corticosteroids are widely used and can be perceived by parents and patients to be safe, daily documentation of agents used and body surfaces exposed should be done during long-term treatment. CONCLUSIONS: Continuous use of moderate- to high-potency topical corticosteroids over several months can contribute to Cushing's syndrome. Growth and development as well as cortisol levels should be monitored in children on long-term topical corticosteroid treatment.

Substantia nigra MR imaging signal changes and cardiomyopathy following prenatal exposure to cocaine and heroin.

Exposure to cocaine in utero results in behavioral and neurodevelopmental abnormalities that persist into adulthood. Conventional MR imaging has generally failed to reveal the expected structural lesions to explain these clinical findings. We report a case of focal MR imaging signal-intensity changes in the substantia nigra, locus ceruleus, and other selected nerve tracts and nuclei in a child exposed prenatally to cocaine and other drugs. The patient also had dilated cardiomyopathy.

Preoperative steroid-related complications in Japanese pediatric patients with ulcerative colitis.

PURPOSE: This study was designed to clarify a limit for steroid therapy in patients with ulcerative colitis through analyzing the preoperative major steroid-related complications and to define when alternative therapies, including surgery, should be performed in pediatric ulcerative colitis patients. METHODS: The medical records of 28 pediatric and 57 adult patients with ulcerative colitis who underwent total proctocolectomy and ileal J-pouch-anal anastomosis were reviewed. The relationship between the preoperative dose of glucocorticoids and major steroid-related complications, as well as the surgery variables, was evaluated. RESULTS: Significantly higher incidences of growth retardation, osteoporosis, glaucoma, and cataracts were noted in pediatric patients than in adult patients. In pediatric patients, major steroid-related complications occurred at a significantly lower preoperative total dosage of glucocorticoids/body weight (mg/kg) or preoperative total dosage of glucocorticoids/body surface area (mg/m2) than in adult patients. A similar surgical procedure was performed in both pediatric and adult patients. The presence of major steroid-related complications can lower a patient's long-term quality of life. CONCLUSIONS: Evidence-based guidelines for the recommended dose of glucocorticoids according to body weight or body surface area are needed. To allow patients to feel well and maintain a good quality of life, early introduction of alternative treatments, including surgery, should be considered.

Adrenal suppression and failure to thrive after steroid injections for periocular hemangioma.

PURPOSE: To evaluate the effects of steroid injections for periocular capillary hemangioma on adrenal function and body composition. DESIGN: Noncomparative, interventional case series. PARTICIPANTS: Four patients with periocular hemangioma. METHODS: Four white female infants with sight-threatening periocular hemangiomata received a combination of steroid injections of triamcinolone and betamethasone. In the first 2 cases, injections were perilesional and in the other 2, intralesional. MAIN OUTCOME MEASURES: The infants were monitored by serial measurements of basal serum cortisol concentrations, responses to the Synacthen stimulation test, measurement of growth and of weight gain, and, in one case, more detailed anthropometric measures of body composition. RESULTS: Prolonged suppression of circulating serum cortisol concentrations and cortisol responses to the Synacthen stimulation test were noted in 3 cases, and marked failure to thrive was noted in all 4 cases. CONCLUSIONS: Adrenal suppression after steroid injection for periocular capillary hemangioma is a potentially life-threatening complication. Failure to thrive is also a frequent side effect of treatment. Ophthalmologists should undertake the above treatment in consultation with a pediatric endocrinologist.

[Zidovudine-associated mitochondriopathy: three possible observations in Abidjan, Côte d'Ivoire]. / Mitochondriopathie associée à la zidovudine. A propos de 3 cas possibles à Abidjan, Côte d'Ivoire.

In Africa, prevention of mother-to-child transmission of HIV (PMTCT) with antiretrovirals is becoming a key component of the response to the pandemic. Toxicity issues remain however a concern and require careful monitoring. We report here three observations of mild neurological deterioration among children for whom a diagnosis of mitochondrial dysfunction was considered possible. These children were identified within a PMTCT research program (ANRS 049) conducted in Abidjan, Côte d'Ivoire, and evaluating a short regimen of maternal zidovudine monotherapy for PMTCT of HIV type 1. Maternal HIV-1 infection was diagnosed during pregnancy before enrolment in the randomised trial (two cases) or in the subsequent open cohort (one case). These three women had been allocated to the ZDV group and had no particular medical history. Pregnancy check-up was negative except the diagnosis of HIV-1 infection. The three children were diagnosed as uninfected by HIV-1. Symptoms developed by the age of six months (two cases) and 13 months (one case): growth failure, anthropometric abnormalities, impaired psycho-motor development, generalised and repeated seizures. The evolution of these three HIV-uninfected children was favourable after 12 to 18 months. The transient nature of these abnormalities is compatible with mild complications of mitochondrial dysfunction. We conclude however that the anticipated benefits of PMTCT with antiretrovirals in Africa greatly outweigh the potential risks and should not lead to reconsider their public health interest

Alcohol, tobacco and marijuana use among pregnant teenagers: 6-year follow-up of offspring growth effects.

This prospective study evaluated the relations between maternal alcohol, tobacco and marijuana use during pregnancy and children's growth at 6 years. In this cohort of pregnant teenagers and their offspring, mothers were recruited from an urban prenatal clinic between 1990 and 1995, and observed from their fourth prenatal month. At the delivery assessment, there were 413 live-born singletons. At the 6-year visit, 345 children and mothers were evaluated. Prenatal alcohol and marijuana exposure were significantly associated with growth deficits, after controlling statistically for other prenatal substance use, current maternal substance use, current environmental tobacco exposure (ETS) and sociodemographic and growth-related covariates. There was a significant negative association between the second and third trimester alcohol exposure and offspring height. Third trimester alcohol exposure predicted reduced skinfold thickness. Exposure to any prenatal marijuana in the second trimester was significantly associated with shorter stature. First trimester tobacco exposure was associated with increased skinfold thickness among the 6-year-olds. The effects of prenatal alcohol exposure on growth at birth persisted in older children despite a low level of exposure during gestation. Effects of prenatal marijuana exposure on reduced height were not anticipated and occurred only when use was categorized as any/none. These data are consistent with an emerging body of evidence indicating that, by contrast to the growth deficits associated with smoking during pregnancy, which are evident at birth, the shorter stature associated with prenatal alcohol exposure continues to be evident during childhood.

Effects of sodium arsenite exposure on development and behavior in the rat.

Arsenic is an environmental contaminant found in soil, water and air in some zones of the world. It has been widely studied for its effects as a human carcinogenic agent, but few studies have dealt with neurobehavioral effects. In addition, studies of arsenic effects on development have only addressed its effects on embryotoxicity and teratogenicity after a single oral, gavage or intraperitoneal exposure. Among the behavioral alterations reported after intoxication with arsenic are both increased and decreased locomotor activity and learning deficits in a delayed alternation task [Toxicol. Lett. 54 (1990) 345; Bull. Environ. Contam. Toxicol. 50 (1993) 100; Brain Res. Bull. 55 (2001) 301]. To further characterize developmental and behavioral alterations induced by arsenic exposure, Sprague-Dawley rats were exposed to arsenite (36.70 mg arsenic/l in drinking water) from gestation day 15 (GD 15) or postnatal day 1 (PND 1), until approximately 4 months old. The pregnant or lactating dams received either the arsenic solution or regular drinking water and once pups were weaned, they continued receiving the same solution as drinking water. Animals exposed from GD 15 showed increased spontaneous locomotor activity and both exposed groups showed increased number of errors in a delayed alternation task in comparison to the control group. Total arsenic (TA) content in brain was similar for both exposed groups and significantly different from the control group. These results indicate that rats exposed to arsenic during development present deficits in spontaneous locomotor activity and alterations in a spatial learning task.

Treatment with alpha-galactosylceramide before Trypanosoma cruzi infection provides protection or induces failure to thrive.

Trypanosoma cruzi, a protozoan parasite, chronically infects many mammalian species and triggers a chronic inflammatory disease. Invariant Valpha14 NK T (iNKT) cells are a regulatory subset of T cells that can contribute to protection against pathogens and to control of chronic inflammatory diseases. alpha-Galactosylceramide (alpha-GalCer) is an iNKT cell-specific glycolipid Ag: a single immunization with alpha-GalCer stimulates robust IFN-gamma and IL-4 production by iNKT cells, while multiple immunizations stimulate IL-4 production, but limited IFN-gamma production. We recently demonstrated that iNKT cells help control T. cruzi infection and affect the chronic Ab response. Therefore, alpha-GalCer treatment might be used to increase protection or decrease chronic inflammation during T. cruzi infection. In this report, we show that a single dose of alpha-GalCer before T. cruzi infection decreases parasitemia. This protection is independent of IL-12, but dependent upon iNKT cell IFN-gamma. In addition, alpha-GalCer treatment of the IFN-gamma(-/-) mice exacerbates parasitemia through IL-4 production. Furthermore, a multiple dose regimen of alpha-GalCer before T. cruzi infection does not lower parasitemia and, surprisingly, after parasitemia has resolved, causes poor weight gain. These data demonstrate that during T. cruzi infection glycolipids can be used to manipulate iNKT cell responses and suggest the possibility of developing glycolipid treatments that can increase protection and possibly decrease the chronic inflammatory pathology.

The role of medications in geriatric failure to thrive.

Geriatric failure to thrive (GFTT) is a syndrome associated with functional decline, depression and malnutrition. Adverse drug reactions are cited as one of the most common causes of GFTT. Two distinct drug-related issues should be considered. Firstly, failure to provide appropriate treatment for conditions such as anaemia, depression, nutritional deficiencies and pain may precipitate GFTT. Secondly, drug-induced functional decline and decreased nutrient intake may cause or contribute to the syndrome. Pharmacological intervention may include discontinuing potentially offending agents for a trial period, or drug treatment of anorexia and depression.

Comparative toxicity of selenium from seleno-DL-methionine, sodium selenate, and Astragalus bisulcatus in pigs.

Selenium is an essential micronutrient, although ingestion in excess in pigs can cause disease conditions including neurological dysfunction and chronic skin and hoof lesions. Controlled feeding trials in growing swine, using the same Se content in feed sources, resulted in higher concentrations (p < or = 0.05) of Se in blood and organs of pigs fed seleno-DL-methionine compared with those receiving Astragalus bisulcatus or sodium selenate. Clinical signs of Se toxicity including neurological signs of paralysis were more severe and occurred sooner in the A. bisulcatus group than in the sodium selenate or seleno-DL-methionine groups. All five pigs fed A. bisulcatus developed neurological signs of paralysis, and in four the signs occurred within 5 days of the start of treatment. Four of five pigs fed sodium selenate also developed paralysis, but this occurred 4 to 21 days after treatment began. The fifth pig in the group developed signs of chronic selenosis. Two of five pigs fed seleno-DL-methionine developed paralysis on 9 and 24 days, respectively, and the remaining three developed chronic selenosis. Selenium fed to pigs in three forms [plant (A. bisulcatus), sodium selenate, or seleno-DL-methionine] resulted in neurological dysfunction and lesions of symmetrical poliomyelomalacia. These were most severe in the A. bisulcatus group, which also had polioencephalomalacia. Although seleno-DL-methionine caused the greater increase in tissue and blood Se concentrations, this did not correlate with severity of pathological changes, since animals fed A. bisulcatus developed more severe and disseminated lesions.