Maria Chiara Pellegrin

Effect of Thalidomide on Clinical Remission in Children and Adolescents With Refractory Crohn Disease: A Randomized Clinical Trial

IMPORTANCE Pediatric-onset Crohn disease is more aggressive than adult-onset disease, has high rates of resistance to existing drugs, and can lead to permanent impairments. Few trials have evaluated new drugs for refractory Crohn disease in children. OBJECTIVE To determine whether thalidomide is effective in inducing remission in refractory pediatric Crohn disease. DESIGN, SETTING, AND PATIENTS Multicenter, double-blind, placebo-controlled, randomized clinical trial of 56 children with active Crohn disease despite immunosuppressive treatment, conducted August 2008-September 2012 in 6 pediatric tertiary care centers in Italy. INTERVENTIONS Thalidomide, 1.5 to 2.5 mg/kg per day, or placebo once daily for 8 weeks. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks. All responders continued to receive thalidomide for an additional minimum 52 weeks. MAIN OUTCOMES AND MEASURES Primary outcomes were clinical remission at week 8, measured by Pediatric Crohn Disease Activity Index (PCDAI) score and reduction in PCDAI by ≥25% or ≥75% at weeks 4 and 8. Primary outcomes during the open-label follow-up were clinical remission and 75% response. RESULTS Twenty-eight children were randomized to thalidomide and 26 to placebo. Clinical remission was achieved by significantly more children treated with thalidomide (13/28 [46.4%] vs 3/26 [11.5%]; risk ratio [RR], 4.0 [95% CI, 1.2-12.5]; P = .01; number needed to treat [NNT], 2.86). Responses were not different at 4 weeks, but greater improvement was observed at 8 weeks in the thalidomide group (75% response, 13/28 [46.4%] vs 3/26 [11.5%]; RR, 4.0 [95% CI, 1.2-12.5]; NNT = 2.86; P = .01; and 25% response, 18/28 [64.2%] vs 8/26 [30.8%]; RR, 2.1 [95% CI, 1.1-3.9]; NNT = 2.99; P = .01). Of the nonresponders to placebo who began receiving thalidomide, 11 of 21 (52.4%) subsequently reached remission at week 8 (RR, 4.5 [95% CI, 1.4-14.1]; NNT = 2.45; P = .01). Overall, 31 of 49 children treated with thalidomide (63.3%) achieved clinical remission, and 32 of 49 (65.3%) achieved 75% response. Mean duration of clinical remission in the thalidomide group was 181.1 weeks (95% CI, 144.53-217.76) vs 6.3 weeks (95% CI, 3.51-9.15) in the placebo group (P < .001). Cumulative incidence of severe adverse events was 2.1 per 1000 patient-weeks, with peripheral neuropathy the most frequent severe adverse event. CONCLUSIONS AND RELEVANCE In children and adolescents with refractory Crohn disease, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and longer-term maintenance of remission in an open-label follow-up. These findings require replication to definitively determine clinical utility of this treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00720538.

Acute febrile cholestatic jaundice in children: keep in mind Kawasaki disease.

ABSTRACT Kawasaki disease (KD) is characterized by persistent fever in addition to 4 of 5 signs of mucocutaneous inflammation. Although gastrointestinal involvement does not belong to the classic diagnostic criteria, it has been often associated with KD onset. We reviewed patients who were admitted for febrile cholestatic jaundice between 2003 and 2010 in 2 tertiary pediatric care centers. KD was the second most frequent cause (21%) after viral infections. Considering the relative high frequency of this condition, a high index of suspicion of KD should be maintained in patients presenting with febrile cholestatic jaundice.

Effect of thalidomide on clinical remission in children and adolescents with ulcerative colitis refractory to other immunosuppressives: Pilot randomized clinical trial

Background:In a randomized controlled trial, thalidomide has shown to be effective in refractory Crohns disease in children. This pilot study aimed at evaluating thalidomide in refractory pediatric ulcerative colitis (UC). Methods:Double-blind, placebo-controlled randomized clinical trial on thalidomide 1.5 to 2.5 mg/kg/day in children with active UC despite multiple immunosuppressive treatments. In an open-label extension, nonresponders to placebo received thalidomide for an additional 8 weeks; all responders were followed up for a minimum of 52 weeks. Results:Twenty-six children with refractory UC were randomized to thalidomide or placebo. Clinical remission at week 8 was achieved by significantly more children treated with thalidomide {10/12 (83.3%) versus 2/11 (18.8%); risk ratio, 4.5 (95% confidence interval [CI], 1.2–16.4); P = 0.005; number needed to treat, 1.5}. Of the nonresponders to placebo who were switched to thalidomide, 8 of 11 (72.7%) subsequently reached remission at week 8 (risk ratio, 4.0 [95% CI, 1.1–14.7]; number needed to treat, 2.45; P = 0.01). Clinical remission in the thalidomide group was 135.0 weeks (95% CI, 32–238), compared with 8.0 weeks (95% CI, 2.4–13.6) in the placebo group (P < 0.0001). Cumulative incidence of severe adverse events was 3.1 per 1000 patient-weeks. Peripheral neuropathy and amenorrhea were the most frequent adverse events. Conclusions:In this pilot randomized controlled trial on cases of UC refractory to immunosuppressive therapy, thalidomide compared with placebo resulted in improved clinical remission at 8 weeks of treatment and in longer term maintenance of remission. These findings require replication in larger clinical studies evaluating both thalidomide efficacy and safety.

Hypoxaemia as a Mortality Risk Factor in Acute Lower Respiratory Infections in Children in Low and Middle-Income Countries: Systematic Review and Meta-Analysis.

Objective To evaluate the association between hypoxaemia and mortality from acute lower respiratory infections (ALRI) in children in low- and middle-income countries (LMIC). Design Systematic review and meta-analysis. Study Selection Observational studies reporting on the association between hypoxaemia and death from ALRI in children below five years in LMIC. Data Sources Medline, Embase, Global Health Library, Lilacs, and Web of Science to February 2015. Risk of Bias Assessment Quality In Prognosis Studies tool with minor adaptations to assess the risk of bias; funnel plots and Egger’s test to evaluate publication bias. Results Out of 11,627 papers retrieved, 18 studies from 13 countries on 20,224 children met the inclusion criteria. Twelve (66.6%) studies had either low or moderate risk of bias. Hypoxaemia defined as oxygen saturation rate (SpO2) <90% associated with significantly increased odds of death from ALRI (OR 5.47, 95% CI 3.93 to 7.63) in 12 studies on 13,936 children. An Sp02 <92% associated with a similar increased risk of mortality (OR 3.66, 95% CI 1.42 to 9.47) in 3 studies on 673 children. Sensitivity analyses (excluding studies with high risk of bias and using adjusted OR) and subgroup analyses (by: altitude, definition of ALRI, country income, HIV prevalence) did not affect results. Only one study was performed on children living at high altitude. Conclusions The results of this review support the routine evaluation of SpO2 for identifying children with ALRI at increased risk of death. Both a Sp02 value of 92% and 90% equally identify children at increased risk of mortality. More research is needed on children living at high altitude. Policy makers in LMIC should aim at improving the regular use of pulse oximetry and the availability of oxygen in order to decrease mortality from ALRI.

A case of Rubinstein‐Taybi syndrome associated with growth hormone deficiency in childhood

Dear Editors, Rubinstein-Taybi syndrome (RTS) is a rare autosomal dominant disease. Point mutations or deletions of the cAMPresponse element-binding protein-BP (CREBBP) (50–60% of the cases) or the homologous gene E1A-binding protein (EP300) (5%) are involved in RTS. RTS patients show intellectual disability, distinctive clinical characteristics (such as broad and sometimes laterally deviated thumbs and halluces), short stature, and craniospinal and posterior fossa abnormalities. We describe the case of a girl delivered at term with mild perinatal asphyxia. At birth, weight and length were 2630 g ( 1 73 SDS) and 47 5 cm ( 1 34 SDS), respectively. A clinical diagnosis of RTS was performed in the first days of life because of broad thumbs and toes, downslating palpebral fissures and malpositioned ears with dysplastic helices. The molecular analysis showed a frameshift mutation of the CREBBP gene due to a duplication of 20 nucleotides (c.5838_5857dup20). This mutation, never described before, involves the exon 31 of the CREBBP gene and leads to a stop codon (p.Pro1953HisfsX30) with a resulting truncated protein of 1982 aminoacids (the wild-type protein is of 2442 aminoacids). In the following years, she showed growth impairment and development delay. She was referred to our attention at the age of 3 years because of short stature (86 5 cm, 2 1 SDS, 25–50° percentile following RTS growth charts). The growth velocity in the last year was 5 69 cm/year ( 1 67 SDS). The weight was between 10° and 25° percentile (between 25 and 50°pc following RTS growth charts). Tanner pubertal stage was Ph1 B1, and the bone age showed a delay of 2 years. Clinical examination showed features consistent with RTS and cutaneous neuromas. Cortisol levels at 8:00 a.m., thyroid, hepatic and renal functions were normal. Two arginine provocative tests for growth hormone (GH) secretion were performed. GH peak levels were 5 57 lg/l and 6 69 lg/l (n.v. >10 lg/l), respectively, revealing a GH deficiency. The IGF-1 levels were 22 27 nmol/l (n.v. 13 88– 32 75 nmol/l). A brain magnetic resonance (MRI) showed normal pituitary height (3 8 mm with a normal height range for age and sex of 4 25 0 68 mm) and volume, normal anatomy of the stalk, normal position of the posterior pituitary, and normal anatomy of the hypothalamic region. A thinning of the corpus callosum was evident. She started GH therapy (0 033 mg/kg/day) when she was 3 5 years old, with good improvement of growth velocity (the patient’s growth charts are shown in Fig. 1a and b). At last follow-up, the patient was 9 9 years old and her stature was 134 6 cm (+0 58 SDS according Italian charts and 90–97°percentile according RTS growth charts). At the present time, the GH dose is 0 022 mg/kg/day with a growth velocity of 6 95 cm/year (+1 90 SDS). Pubertal stage is Ph1 B1. IGF-1 levels are 49 38 nmol/l (n.v. 16 50–34 19 nmol/l). The bone age shows a retardation of 16 months. The thyroid function is normal. TSH levels are 3 35 mIU/l (n.v. 0 27–4 20 mIU/l), Ft4 levels are 13 64 pmol/l (n.v. 11 9–21 8 pmol/l), and Ft3 levels are 0 059 pmol/l (n.v. 0 027–0 070 pmol/l). She did not presented any side effects to GH therapy. In individuals with RTS, short stature is considered a classic feature of the syndrome and indirect measures of growth hormone secretion have been usually reported as normal. Therefore, these patients do not usually undergone dynamic testing to detect growth hormone deficiency. In literature, we found a single case report of RTS female patient with GH deficiency associated with a CREBBP frameshift mutation. The diagnosis of GH deficiency was performed when she was 11 years old. She was treated with GH therapy for 5 years with good improvement in growth velocity (reaching the 3° percentile of height for the normal population growth chart and the 75° percentile of height for the RTS growth chart) without any side effects. Interestingly, this patient presented also pituitary hypoplasia, Arnold Chiari malformation type 1 and double syringomyelic cavity. This fact underlines the possibility that GH deficiency could play a role in the short stature of RTS patients with CREBBP mutation and that the replacement therapy could lead to improvement of stature. Another RTS patient with GH deficiency and short stature is present in the population of Spena et al. and this patient showed a frameshift CREBBP mutation leading to a stop codon at aminoacid 107. Unfortunately, no more auxological data and information about a possible therapy are available. Herein, we report a precocious diagnosis of GH deficiency (performed when the patient was 3 5 years old) associated with a new CREBBP mutation. Our case report shows a GH replacement therapy started early in life in RTS patients with GH deficiency leading to an important improvement of stature (her height reached the 25° percentile according normal population and 90–97° percentile according RTS growth charts) without any side effects. Unlike the patient previously described, our patient did not present pituitary hypoplasia. The hypothesis of the linkage between short stature and GH deficiency in RTS patients with CREBBP mutations is supported by previous studies in mice and in vitro. cAMP-response element-binding protein (CREB) is one of the first transcription factors that showed an impact on somatic growth. CREB is required for the efficient production of GHRH in hypothalamus and GH in pituitary gland. In fact, CREBmutant mice present reduced postnatal growth consistent with dwarfism caused by GH deficiency. CREBBP, involved in RTS pathogenesis, is a nuclear factor named for its ability to bind CREB. It is possible that CREBBP mutations affect the CREB–CREBBP interaction, determining an impaired CREB-binding protein both at hypothalamic and at pituitary level, with consequent reduction in GH levels. In addition, at pituitary level, CREBBP interacts as cofactor with Pit-1. Pit-1 is an important transcription factor that promotes growth hormone and stimulates somatic growth. Therefore, an impairment of CREBBP/Pit-1 interaction could affect pituitary GH secretion. Considering all the GH secretion steps in whom CREBBP could be implicated, we suppose that in RTS patients without

Endoscopic and Histologic Healing in Children With Inflammatory Bowel Diseases Treated With Thalidomide

BACKGROUND & AIMS: Mucosal healing, determined by endoscopic evaluation, is one of the most important prognostic markers for patients with inflammatory bowel diseases. Findings from histologic evaluation, however, could complement findings from endoscopy in assessing mucosal responses to treatment. We analyzed long‐term results of children treated with thalidomide to determine the association between clinical response and histology and endoscopy findings. METHODS: We collected data from 2 multicenter trials of 70 children with refractory Crohn’s disease (CD) or ulcerative colitis (UC) (2–18 years old; ileocolonic or colonic disease) given thalidomide or placebo (NCT00720538). Clinical remission and clinical response at 8 weeks were defined as a pediatric CD activity index scores 10 points or lower and a decrease of at least 50% from baseline, respectively, for patients with CD; and as a pediatric UC activity index score below 10 and a decrease of at least 20 points from baseline, respectively, for patients with UC. Patients with a clinical response to 8 weeks’ treatment with thalidomide underwent endoscopic examination with biopsy collection at study weeks 12 and 52. Severity of inflammation in patients with UC was assessed by Mayo score and in patients with CD by 4‐grade system. Biopsies were assessed for signs of active inflammation, erosion or ulceration, and crypt abscesses and assigned a histologic score. RESULTS: Clinical remission was observed in 42 patients (60.0%) and clinical response in 45 patients (64.2%) at Week 8. At Week 52, a total of 38 patients (54.3%) were still in clinical remission or still had a clinical response; 29 patients (41.4%) had mucosal healing, defined as complete healing of erosions or ulcerations, and 20 patients (27.7%) had histologic healing, defined as complete absence of markers of inflammation. Of patients with clinical remission or clinical response, 75.3% also had mucosal healing and 52.6% also had histologic healing. The probability of achieving mucosal healing decreased significantly with increasing values of erythrocyte sedimentation rate (adjusted odds ratio, 0.96; 95% CI, 0.93–0.98; P = .006). CONCLUSIONS: In a long‐term analysis of data from 2 clinical trials of pediatric patients with CD or UC, 52 weeks’ treatment with thalidomide led to clinical remission in 54.3% of patients with ileocolonic or colonic disease; of these patients, 75.3% had mucosal healing and 52.6% also had histologic healing. Further studies are needed to determine how thalidomide therapy affects long‐term progression of inflammatory bowel diseases. (ClinicalTrials.gov number NCT00720538).

Corrigendum to “Comparison of non-HDL-cholesterol versus triglycerides-to-HDLcholesterol ratio in relation to cardiometabolic risk factors and preclinical organ damage in overweight/obese children: The CARITALY study” [Nutr Metab Cardiovasc Dis 25 (2015) 489–494]

a Department of Internal Medicine, Pozzuoli Hospital (Napoli), Naples, Italy Department of Movement Sciences and Wellness, Parthenope University, Naples, Italy c Division of Auxology, Italian Auxological Institute, Verbania, Italy Department of Pediatrics, AORN Santobono-Pausilipon, Naples, Italy e Pediatric Diabetes and Metabolic Disorders Unit, Department of Life & Reproduction Sciences, University of Verona, Verona, Italy f Bambino Gesù Children’s Hospital, Rome, Italy g Department of Woman, Child and General and Specialized Surgery, Second University of Napoli, Naples, Italy Department of Pediatrics and Child Neuropsychiatry, Sapienza University of Rome, Rome, Italy i Department of Pediatrics, University of Trieste, Trieste, Italy j Pediatric Unity, AOU Udine, Udine, Italy k Endocrinology and Diabetes, Department of Medical Sciences, University of Cagliari, Cagliari, Italy l Department of Experimental Medicine, Sapienza University of Roma, Rome, Italy

A child with macroscopic crystalluria: Answers

Question 1. The most likely diagnosis is crystalluria secondary to amoxicillin therapy. Amoxicillin was prescribed within the range of the recommended dosage for pneumonia (100 mg/kg/day), but a concomitant acid urine pH and dehydration (the child admitted low fluid intake with, consequently, elevated urinary density) may have played a role in the precipitation of crystals. There were no other predisposing causes, such as urinary tract infection nor structural anomalies of the urinary tract. A differential diagnosis of drug-induced acute tubulointerstitial nephritis (TIN) was very unlikely, considering the preservation of renal function and the absence of rash, arthralgia, and peripheral eosinophilia. Question 2. Comparison of the morphology of the crystals with images of crystals appearing in the literature [1, 2] revealed that the crystals found in the urine of our patient differed remarkably from those more commonly seen in urine, such as uric acid and calcium oxalate crystals. These atypical crystals took on the form of ‘needles,’ and when aggregated looked like ‘sheaves of wheat’, ‘broom bush,’ or ‘sea urchin’ [2]. In a compatible setting, this appearance is diagnostic of amoxicillin crystalluria and does not require further investigations [1]. Subsequent spontaneous recovery after removal of the drug confirmed the diagnosis. Question 3. The correct management of amoxicillin crystalluria is drugwithdrawal and high fluid intake to improve drug solubility in the urine. Once amoxicillin therapy has been stopped, spontaneous and complete recovery occurs rapidly, even in case of renal impairment. Intravenous re-hydration and urine alkalinization are indicated only in more severe and symptomatic cases [1, 2]. In our patient, urinary crystals rapidly disappeared within 24 h after drug discontinuation, without sequelae.

A child with macroscopic crystalluria: Questions

A 9-year-old boy presented to the emergency department with a 2-day history of fever and left-sided chest pain. His past medical history was unremarkable. Upon physical examination the child was well-appearing, with reduced breath sounds and crackles at the left lung base. A chest ultrasound confirmed the diagnosis of community-acquired pneumonia without signs of empyema; findings of the abdominal ultrasound were unremarkable. Laboratory tests showed elevated Creactive protein (7.12 mg/dl, normal range <0.5), leukocytosis (17,730/mmc, predominantly neutrophils 15,200/mmc), with normal electrolyte and serum creatinine levels. A urine dipstick was negative for blood and protein. Treatment with oral amoxicillin (100 mg/kg/day divided in 3 doses) was started. After 2 days, the boy presented once again to the emergency department, complaining about whitish and frothy urine. He was asymptomatic and afebrile during the preceding 24 h. Parents reported a good compliance to antibiotic therapy, without any antipyretic administration during the preceding 36 h. Upon closer examination, the frothy appearance of the urine was seen to be caused by macroscopic massive crystalluria (Fig. 1). By urine dipstick, the pH was 5.5 and the relative density 1030. Direct examination of the urine specimen showed multiple needle-shaped crystals, microhematuria (50 eumorphic red blood cells/mmc), some leucocytes, and no casts (Fig. 2). Physical examination was normal, except for lung crackles on the left lung base. Abdominal ultrasound revealed normal kidneys without dilation of the pelvicalyceal system; renal function was preserved (glomerular filtration rate

Risk Factors and Outcomes of Thalidomide-induced Peripheral Neuropathy in a Pediatric Inflammatory Bowel Disease Cohort

Background: Thalidomide is an effective therapy in children with inflammatory bowel disease refractory to standard treatments, but thalidomide-induced peripheral neuropathy (TiPN) limits its long-term use. We aimed to investigate the risk factors and the outcome of TiPN in children with inflammatory bowel disease. Methods: Within a retrospective multicenter cohort study, we evaluated prevalence and evolution of TiPN. Clinical data and candidate genetic profiles of patients with and without TiPN were compared with detect predisposing factors. Results: One hundred forty-two patients were identified. TiPN was found in 72.5% of patients (38.7% clinical and instrumental alterations, 26.8% exclusive electrophysiological anomalies, and 7.0% exclusive neurological symptoms). Median TiPN-free period of treatment was 16.5 months; percentage of TiPN-free patients was 70.0% and 35.6% at 12 and 24 months of treatment, respectively. The risk of TiPN increased depending on the mean daily dose (50–99 mg/d adjusted hazard ratio 2.62; 95% confidence interval [CI], 1.31–5.21; 100–149 mg/d adjusted hazard ratio 6.16; 95% CI, 20.9–13.06; >150 mg/d adjusted hazard ratio 9.57; 95% CI, 2.6–35.2). Single nucleotide polymorphisms in ICAM1 (rs1799969) and SERPINB2 (rs6103) genes were found to be protective against TiPN (odds ratio 0.15; 95% CI, 0.03–0.82 and 0.36; 95% CI, 0.14–0.88, respectively). TiPN was the cause of drug suspension in 41.8% of patients. Clinical symptoms resolved in 89.2% of cases, whereas instrumental alteration persisted in more than half of the patients during a short follow-up. Conclusions: In children with inflammatory bowel disease, TiPN is common but mild and generally reversible. Cumulative dose seems to be the most relevant risk factor, whereas polymorphisms in genes involved in neuronal inflammation may be protective.