Giovanna Ventura

Lupus nephritis in children and adolescents: results of the Italian Collaborative Study

BACKGROUND Lupus nephritis (LN) strongly affects the outcome in children with systemic lupus erythematosus (SLE). Many patients, however, have renal disease at onset, but lack a sufficient number of criteria to be diagnosed as SLE and develop delayed symptoms over time (d-SLE). Data on the clinical course, long-term outcome and predictors of disease progression in children with LN are scant. METHODS The Italian Collaborative Study included 161 paediatric patients with LN who were followed up for a mean of 96 months (range 6-296) in seven paediatric nephrology units. Cox-Mantel regression models were used to identify predictors of disease remission, relapse and progression. RESULTS At 1 year, the proportion of patients in remission was 83.2% (partial) and 53.5% (complete). Renal flares occurred in >50% of patients within 10 years. The intensity of induction treatment correlated significantly with the achievement of remission, while d-SLE, class IV LN and younger age were associated with poor response to treatment and/or with progression to chronic renal failure. CONCLUSIONS The current study provides outcome data on a large paediatric population with LN and underlines the importance of prescribing appropriate induction treatment to all children, regardless of the presence of enough SLE criteria, which may develop several years after the initial diagnosis.

Human Colostrum and Breast Milk Contain High Levels of TNF-Related Apoptosis-Inducing Ligand (TRAIL)

Background: TNF-related apoptosis inducing ligand (TRAIL) is a pleiotropic cytokine, which plays a key role in the immune system as well as in controlling the balance of apoptosis and proliferation in various organs and tissues. Objective: To investigate the presence and levels of soluble TRAIL in human colostrum and milk. Methods: The levels of soluble human TRAIL were measured in human colostrum (day 2 after delivery) and breast milk (day 5 after delivery). The presence of TRAIL was also measured in infant formula. Results: Levels of soluble TRAIL in the colostrum and mature human milk were, respectively, at least 400 and 100 fold higher than those detected in human serum. No TRAIL was detected in formula. Conclusion: Human soluble TRAIL is present at extremely high levels in human colostrum and human milk and might have a significant role in mediating the anti-cancer activity of human milk.

Orofacial granulomatosis in children: Think about Crohn's disease

BACKGROUND The term orofacial granulomatosis is conventionally used to describe patients with granulomatous lesions affecting the orofacial tissues, in absence of intestinal lesions. Lip swelling and facial swelling are the most common clinical signs. Despite the fact that histologically it is not distinguishable from Crohns disease, and that both diseases have a chronic/recurrent course, the relationship between orofacial granulomatosis and Crohns disease is still debated. METHODS Herein we present five cases of orofacial granulomatosis. RESULTS All patients presented concomitant Crohns disease, supporting the hypothesis that orofacial granulomatosis and Crohns disease may be one single disease. Thalidomide was effective in inducing remission of oral and intestinal symptoms in all five cases and could be considered a valid treatment opportunity for these patients. CONCLUSIONS Orofacial granulomatosis and Crohns disease may be part of the same disease; both may respond to thalidomide.

Outcome of childhood-onset full-house nephropathy

Background Patients with full-house nephropathy (FHN) present renal lesions that are indistinguishable from those of lupus nephritis (LN) but lack the systemic features necessary to meet diagnostic criteria for systemic lupus erithematosus (SLE). Some have been reported to develop a delayed SLE with time. The clinical outcome of children having FHN without SLE has never been reported. Methods Children with biopsy-proven FHN were selected after excluding SLE cases by the absence of America College of Rheumatology criteria. The proportion of patients with complete (proteinuria <0.5 g/day) or partial remission (proteinuria ≤50% from baseline), relapse (estimated glomerular filtration rate <25% and/or proteinuria ≥50% from baseline) and progression to Stage III chronic kidney disease (CKD) was described according to age and gender groups with the Kaplan-Meier curve and compared with the Log-rank test. Entity of treatment was summarized by a score at induction (0-6 months) and maintenance (6-18 months). Cox-regression model was performed to test predictors of remission, relapse and progression to CKD. Results Among 42 patients (28 pre-pubertal) who met the inclusion criteria, 39 (92.9%) achieved partial and 32 (76.2%) complete remission of nephropathy over 2.78 and 7.51 months of follow-up. At 10 years, the probability of progressing to CKD was 4.8%. Of those achieving remission, 18% had a renal flare mainly within 4 years after remission. Pre-pubertal males achieved complete remission more frequently than other patients but often relapsed; pre-pubertal females were treated more aggressively. Cox-regression analysis did not find independent predictors of remission or relapse. Conclusions The outcome of the patients with FHN we investigated was encouraging. Recurrences are limited to the first 4 years following diagnosis, allowing progressive withdrawal of immunosuppression in patients achieving remission. Evaluation of risk factors for adverse outcome is necessary especially in pre-pubertal children.

Children under 5 years are at risk for tuberculosis after occasional contact with highly contagious patients: outbreak from a smear-positive healthcare worker

The World Health Organization (WHO), jointly with experts from tuberculosis (TB) low-incidence countries, developed a framework for TB elimination [1, 2]. Children under 5 years of age are at risk for tuberculosis after occasional contact with highly contagious patients http://ow.ly/RqAn30fKdGk

Leonardo da vinci meets celiac disease

Background and Aim: Leonardo da Vincis face symmetry derives from 3 equal craniofacial segments: trichion-nasion (tn), which represents the superior third of the face, nasion-subnasal (ns) that is the medium third of the face, and subnasal-gnathion (sg) that is the length of the lower third of the face. It has been reported that adult subjects with celiac disease (CD) can be identified on the basis of a greater extension of the forehead in comparison to the medium third of the face, with a high tn/ns ratio. The aim of the present study was to investigate the correlation between facial asymmetry and CD in childhood and adulthood. Methods: We studied 126 biopsy-proven patients with CD (76 children and 50 adults) and 102 healthy controls (43 children and 59 adults). Their faces were photographed; the pictures were edited using a software program to calculate the facial segments. Results: The tn length was significantly different between adult celiac and adult controls (7.43 ± 1.46 cm vs 6.38 ± 1.73 cm, P = 0.001). The cutoff of 6.5 cm tn, derived from receiver operating characteristic curve analysis, identified 43 of 50 patients (sensitivity 86%), but 34 of 59 controls were positive (specificity 54.2%). The positive predictive value was 56%; however, the tn/ns ratio was not significantly different between celiacs and controls. Neither the tn length nor the tn/ns ratio in celiacs correlated to the time of gluten exposure. Conclusions: Adults, but not children, with celiac disease show a forehead extension significantly greater than controls, but this tests specificity appears too low to be used in the screening of CD.

A Boy with Acute Strabismus

Figure 2. Magnetic resonance imaging shows a lesion occupying one-half of the sphenoidal sinus with no involvement of other sinuses. A 12-year-old boy was admitted to the hospital with a 3-day history of strabismus, diplopia, and worsening of a headache of which he had been complaining for 3 months, without nocturnal awakenings. The headache worsened during the previous 2 weeks, after an upper respiratory tract infection, such that the analgesic therapy (paracetamol and codeine) was not effective anymore. There was no history of vomiting. In the previous period, he never had been febrile. On neurologic examination, we found a left esotropia without alterations of ocular movements (Figure 1), a faltering walk probably due to diplopia, and a bilateral papilledema; visual acuity was normal. Blood tests revealed only a mildly elevated erythrocyte sedimentation rate. A magnetic resonance imaging scan ruled out a brainstem tumor but showed homogeneous semifluid material completely occupying half the sphenoid sinus, with no enhancement after contrast, in keeping with a flogistic event (Figure 2). A computerized tomography scan of the paranasal sinuses highlighted a well-delineated cystic formation with loss of bone continuity next to the sella turcica, a radiologic image compatible with a mucocele (Figure 3; available at www.jpeds.com). This diagnostic suspectwas confirmedby surgery (endoscopic sphenoidotomy). Sphenoid sinus mucocele is a rare condition accounting for 1%-2% of paranasal sinus mucoceles. The etiology is unknown; it could be due to sinus ostium obstruction following chronic sinus inflammation, polyposis, infections, or tumors. The highest incidence of sphenoid sinus mucocele is reported during the fourth decade of life, whereas it is rare in childhood when cystic fibrosis must be ruled out. Useful for

Afebrile seizures in infants: Never forget magnesium!: Seizures due to hypomagnesaemia

A 5-month-old girl presented to the Emergency Department (ED) because of two self-remitting episodes of loss of consciousness and generalised jerking that lasted 2 min each, separated by a 15-min interval. On admission the baby was afebrile, pale and slightly hyporeactive, but made adequate eye interaction. No vomiting or diarrhoea was reported. Physical examination was unremarkable, and non-dysmorphic, skeletal abnormalities or focal neurological signs were not noted. Her past medical history was unremarkable: Her parents were non-consanguineous and she was delivered after a full-term pregnancy, no perinatal issues were reported. She had been both breast and bottle fed and she had begun her weaning 2 weeks earlier. Her immunisation state was up-todate and she had been assuming daily supplementary vitamin D (400 IU). After her arrival, she presented another generalised seizure; intravenous midazolam (0.1 mg/kg) was administered and the seizure resolved. The baby gained full consciousness but looked unwell. Empirical treatment with intravenous ceftriaxone (100 mg/kg) and acyclovir (1500 mg/m) was started. The interictal electroencephalography did not show epileptic anomalies. Brain computed tomography and magnetic resonance imaging scans were normal. Blood tests, instead, revealed an extremely severe hypomagnesaemia (0.16 mmol/L, normal range 0.75–0.95 mmol/L) associated with a mild hypocalcaemia (HSH) (1.85 mmol/L, normal range 2.18–2.58 mmol/L). Intravenous magnesium sulphate supplementation was started (10 mg/kg/h) and the patient was admitted to the Pediatric Intensive Care Unit (PICU). In the meanwhile, three further seizures occurred. Magnesium blood levels increased to the normal range in 48 h and the girl had no further crisis. Renal magnesium loss was excluded based on the magnesium excretion fraction (1%). No hypercalciuria or nephrocalcinosis was found. An intestinal malabsorption was ruled out by the absence of steatorrhea and by the normal levels of faecal elastases. Magnesium supplementation was eventually shifted from the intravenous to the oral route. Several dose adjustments had been necessary to obtain a stable magnesium level. The final therapeutic schedule consisted of six daily doses of magnesium pidolate (0.75 mg/dose, 0.9 mg/kg/day). Because the clinical picture and blood tests suggested primary hypomagnesaemia, a genetic analysis was performed and showed two mutations in the TRMP6 gene. The former is the known mutation c.2922delA (p.Ala975Glnfs*7), which she inherited from her mother, and the latter, c.5735A>G (p.Tyr1912Cys), is a novel variant, not previously reported in affected or healthy people. This mutation was inherited from her father. Moreover, the c.2922delA (p.Ala975Glnfs*7) involves an amino acid conserved across the species and it is predicted to be pathogenic by different webtools (Mutation Taste, PolyPhen2, PROVEAN, SIFT; J. Craig Venter Institute, La Jolla, CA, USA). Primary hypomagnesaemia with secondary HSH was subsequently diagnosed. One year after, the girl was healthy with a normal psychomotor development and has not presented any further seizure, even if some episodes of tremors and irritability have been reported, all of them concurrent with the detection of low magnesium blood levels.

Nonatopic persistent asthma in children, a missed phenotype of asthma?

To the Editor: We read with great interest the study by Fitzpatrick et al, showing how, in preschool children with persistent asthma, the type 2 inflammation biomarkers (ie, aeroallergen sensitization and/or increased blood eosinophilic counts) are strong predictors of a positive therapeutic response to daily inhaled corticosteroid treatment. To our knowledge, Fitzpatrick et al’s study is the first to extrapolate and clearly identify a particular phenotype of persistent eosinophilic asthma, without pneumoallergen sensitization. Global Initiative for Asthma 2016 guidelines define it as ‘‘intrinsic asthma,’’ a rare phenotype affecting only adulthood; the PRACTALL consensus report is the only children guideline that mentions persistent asthma in children without relevant allergic sensitization as ‘‘unresolved asthma.’’ We had previously called this specific phenotype of nonallergic eosinophilic asthma in children NAPA (nonatopic persistent asthma). It is now well known that some eosinophilic nonallergic sensitizationdependent bronchial inflammation is controlled by type 2 innate lymphoid cells that are induced as a result of direct stimulation by exogenous agents such as viruses and bacteria. Turato et al analyzed bronchial biopsies obtained in children with multitrigger wheeze (median age, 5 years; range, 2-10 years), and found that airway pathology typical of asthma (thickened basement membrane, increased number of eosinophils, and cytokine expression) is identical in nonatopic and atopic wheezing children. In our reference center for pediatric asthma, we defined persistent (multitrigger) asthma, without aeroallergen sensitization, blood eosinophil counts of 400/mL or greater and/or nasal eosinophilia 10% and/or exhaled nitric oxide level of more than 25 ppb as NAPA. NAPA represented about 8% of cases of persistent asthma (55 of 685) seen in our recent clinical record. In our experience, we observed noticeable differences in the clinical features of NAPA compared with allergic persistent asthma (APA): patients with NAPA lack atopic familiarity and early onset atopic dermatitis; furthermore, NAPA is clinically more severe, requiring hospital admission in 50% versus 10% of patients with APA (P< .001). However, daily low-dose inhaled corticosteroid induces a rapid and good remission of asthma in almost all children. As we previously stated, it is surprising that NAPA in children has not yet been recognized as a separate clinical phenotype in specific medical literature and in guidelines for pediatric asthma. This implies that the NAPA best treatment schedule and natural history are still unknown. In our clinical practice, about 40% of patients recovered after 5 years; a 2-year-old patient completely recovered after 10 months. This evidence suggests that NAPA, despite a more severe clinical onset, could have a milder and non–life-long prognosis than APA. Giorgio Longo, MD Ester Conversano, MD Elisa Panontin, MD Giovanna Ventura, MD Alessandro Ventura, MD From the Univerisity of Trieste and the Institute for Maternal and Child Health, IRCCS ‘‘Burlo Garofolo,’’ Trieste, Italy. E-mail: giorgio.longo@burlo.trieste.it. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

Extremely large air distension of the bowel

A 14-year-old girl presented to our paediatric department in May, 2012, with massive abdominal distension that had developed over the previous 2 years. She reported chronic abdominal discomfort, alternating diarrhoea and constipation, and two previous subocclusive episodes that had resolved with laxative therapy. Plain abdominal radiographs showed substantial large bowel distension and several air–fl uid levels. No air was evident in the rectum or anal canal (fi gure). She underwent surgery, and because no mechanical obstruction was observed a diverting ileostomy was done. Analysis of full-thickness large bowel and rectal biopsy samples obtained during surgery showed a decreased number of ganglion cells and acetylcho linesterase activity compatible with the diagnosis of hypo ganglionosis. In November, 2012, she had large bowel resection, ileorectal anastomosis, and ileostomy repositioning. The postoperative course was character ised by progressive intestinal recanalisation, although she had persistent watery stools with faecal sodium loss. The resulting electrolyte imbalance was corrected with partial parenteral nutrition. The patient was discharged 2 months after the procedure and continued parenteral nutrition at home. She had a gradual reduction of watery diarrhoea so we tapered the partial parenteral nutrition and weaning was possible after 12 months. At last follow-up in July, 2014, the patient reported no more episodes of abdominal distension. Hypoganglionosis is classed as a hypogenetic type of intestinal innervation disorder characterised by very low or absent acetylcholinesterase mucosal activity and a decreased number of ganglion cells within the myenteric and submucosal plexus of a variable intestinal segment. The most common presenting symptoms of hypoganglionosis are acute constipation, intestinal obstruction, and enterocolitis. The disorder thus resembles Hirschsprung’s disease, but clinical pre sentation might be subtle and misdiagnosed as chronic constipation. The median age at diagnosis is usually higher in patients with hypoganglionosis than Hirschsprung’s disease. Defi nitive diagnosis requires the analysis of full-thickness biopsy sample of the aff ected intestinal segment. The treatment is surgical, involving resection of the hypoganglionotic tract of the intestine.