Safety of Rotavirus Vaccination in Preterm Infants Admitted in Neonatal Intensive Care Units in Sicily, Italy: A Multicenter Observational Study

Rotavirus (RV) is among the most common vaccine-preventable diseases in children under five years of age. Despite the severity of rotavirus pathology in early childhood, rotavirus vaccination for children admitted to the neonatal intensive care unit (NICU), who are often born preterm and with various previous illnesses, is not performed. This multicenter, 3-year project aims to evaluate the safety of RV vaccine administration within the six main neonatal intensive care units of the Sicilian Region to preterm infants. Methods: Monovalent live attenuated anti-RV vaccination (RV1) was administered from April 2018 to December 2019 to preterm infants with gestational age ≥ 28 weeks. Vaccine administrations were performed in both inpatient and outpatient hospital settings as a post discharge follow-up (NICU setting) starting at 6 weeks of age according to the official immunization schedule. Any adverse events (expected, unexpected, and serious) were monitored from vaccine administration up to 14 days (first assessment) and 28 days (second assessment) after each of the two scheduled vaccine doses. Results: At the end of December 2019, 449 preterm infants were vaccinated with both doses of rotavirus vaccine within the six participating Sicilian NICUs. Mean gestational age in weeks was 33.1 (±3.8 SD) and the first dose of RV vaccine was administered at 55 days (±12.9 SD) on average. The mean weight at the first dose was 3388 (SD ± 903) grams. Only 0.6% and 0.2% of infants reported abdominal colic and fever above 38.5 ◦C in the 14 days after the first dose, respectively. Overall, 1.9% EAEs were observed at 14 days and 0.4% at 28 days after the first/second dose administration. Conclusions: Data obtained from this study confirm the safety of the monovalent rotavirus vaccine even in preterm infants with gestational age ≥ 28 weeks, presenting an opportunity to improve the vaccination offer both in Sicily and in Italy by protecting the most fragile infants who are more at risk of contracting severe rotavirus gastroenteritis and nosocomial RV infection

Efficacy of a new technique - INtubate-RECruit-SURfactant-Extubate - "IN-REC-SUR-E" - in preterm neonates with respiratory distress syndrome: Study protocol for a randomized controlled trial

Background: Although beneficial in clinical practice, the INtubate-SURfactant-Extubate (IN-SUR-E) method is not successful in all preterm neonates with respiratory distress syndrome, with a reported failure rate ranging from 19 to 69 %. One of the possible mechanisms responsible for the unsuccessful IN-SUR-E method, requiring subsequent re-intubation and mechanical ventilation, is the inability of the preterm lung to achieve and maintain an "optimal" functional residual capacity. The importance of lung recruitment before surfactant administration has been demonstrated in animal studies showing that recruitment leads to a more homogeneous surfactant distribution within the lungs. Therefore, the aim of this study is to compare the application of a recruitment maneuver using the high-frequency oscillatory ventilation (HFOV) modality just before the surfactant administration followed by rapid extubation (INtubate-RECruit-SURfactant-Extubate: IN-REC-SUR-E) with IN-SUR-E alone in spontaneously breathing preterm infants requiring nasal continuous positive airway pressure (nCPAP) as initial respiratory support and reaching pre-defined CPAP failure criteria. Methods/design: In this study, 206 spontaneously breathing infants born at 24+0-27+6 weeks' gestation and failing nCPAP during the first 24 h of life, will be randomized to receive an HFOV recruitment maneuver (IN-REC-SUR-E) or no recruitment maneuver (IN-SUR-E) just prior to surfactant administration followed by prompt extubation. The primary outcome is the need for mechanical ventilation within the first 3 days of life. Infants in both groups will be considered to have reached the primary outcome when they are not extubated within 30 min after surfactant administration or when they meet the nCPAP failure criteria after extubation. Discussion: From all available data no definitive evidence exists about a positive effect of recruitment before surfactant instillation, but a rationale exists for testing the following hypothesis: a lung recruitment maneuver performed with a step-by-step Continuous Distending Pressure increase during High-Frequency Oscillatory Ventilation (and not with a sustained inflation) could have a positive effects in terms of improved surfactant distribution and consequent its major efficacy in preterm newborns with respiratory distress syndrome. This represents our challenge. Trial registration: ClinicalTrials.gov identifier: NCT02482766. Registered on 1 June 2015

MECASERMIN TREATMENT OF A CHILD WITH CONGENITAL HYPERINSULINISM LINKED TO INS-R MUTATION

Objectives: Mecasermin is recombinant human insulin-like growth factor 1 (IGF1) which is approved for the treatment of short stature in children with documented primary IGF1 deficiency. Leprechaunism, also known as Donohue syndrome, is a severe disease, secondary to a severe congenital insulin resistance, with prenatal and neonatal growth retardation, typical dysmorphic features, glycaemic dysregulation characterized by hyperinsulinemia and hyperandrogenism. These patients have a poor prognosis with death in the first year of life. Methods: We describe the case of a 3.5 years child, born at 35,4 weeks, with severe fetal growth restriction (weight 1149 gr; length: 38 cm; cranial circumference: 28 cm), typical facial features with low implant ears, low implant hairs, hypertrichosis, hypertrophic external genitalia, postnatal growth failure, and severe hyperglycaemia (327 mg/dl) alternated with hypoglycaemia (10 mg/dl) also during i.v. infusion of glucose; significant hyperinsulinism (1000 mcU/dl) with elevated C peptide levels (43,41 ng/ml), persistent hypertension (113/74 mmHg). He has consanguineous parents (cousins) and the mother underwent abortions before the baby was born. Results: A treatment with diazoxide (5 mg/kg/day) was tried with limited efficacy. He was treated with ACE-inhibitor (Captopril) at the dose of 0,02 mg/kg/day with a low response. The Captopril dose was increased at 0,04 mg/kg/day with a regulation of the blood pressure (76/54 mmHg). The genetic study of INS-R was showed a homozygote mutation in the insulin receptor (INS-R) gene. The mutation reported was c.3289C>T (CAG->TAG) p.Gln1097Stop (Q1097X). For the growth delay and the hypotrophic muscular masses he started a off-label treatment with mecasermin at increasing doses. He had no adverse events linked to the treatment. Otherwise, he improved growth and muscular strength. Conclusions: The singular case is of relieve for the rarity of the disease and for the good response to the treatment with mecasermin, the real opportunity for these children with a severe disease otherwise with a poor prognosis

TERAPIA CON MECASERMINA IN UN BAMBINO CON IPERINSULINISMO CONGENITO DA MUTAZIONE DI INS-R

PRESENTAZIONE DEL CASO, STORIA CLINICA E SINTOMATOLOGIA L’uso per fi ni terapeutici della Mecasermina, insulin-like growth factor 1 (IGF1) umano ricombinante trova indicazione nella terapia della bassa statura di bambini con un defi cit primitivo documentato di IGF-1. Il Leprecaunismo, noto come S. di Donohue, è una rara patologia congenita caratterizzata da insulino-resistenza, severo defi cit accrescitivo intra-uterino e post-natale, fenotipie caratteristiche, alterazione del controllo dell’assetto glicemico, con iperinsulinismo e iperandrogenismo associato. L’outcome prognostico è segnato da morte entro il primo anno di vita in quasi tutti i pazienti descritti. Descriviamo l’outcome di un bambino che attualmente ha 3,5 anni, nato a 35,4 settimane con un ritardo di crescita endouterino severo (peso alla nascita: 1149 gr; lunghezza: 38 cm; circonferenza cranica: 28 cm). Alla nascita presentava facies dismorfi ca caratteristica, con orecchie a basso impianto, attaccatura bassa dei capelli, ipertricosi, lipoatrofi a sottocutanea, ipotrofi a muscolare, macrogenitalismo. Dopo la nascita la crescita è stata estremamente stentata con iperglicemia (327 mg/dl) alternata a ipoglicemia (10 mg/dl) anche durante l’infusione endovenosa di glucosio, iperinsulinismo (1000 mcU/dl)ed elevato C peptide (43,41 ng/ml), ipertensione refrattaria alla terapia farmacologica (113/74 mmHg). La madre ha avuto molti aborti precedenti la nascita del piccolo e i genitori sono consanguinei. Ha iniziato terapia con diazossido alla dose di 5mg/kg/die ed ACE inibitore alla dose do 0,02 mg/kg/die con una risposta parziale. IPOTESI DIAGNOSTICHE Nel sospetto di Iperinsulinismo congenito, è stato avviato lo stidio del gene del recettore per l’insulina (INS-R). INDAGINI DI I E II LIVELLO Lo studio del gene dell’INS-R ha dimostrato una mutazione in omozigosi: c.3289C>T (CAG->TAG) p.Gln1097Stop (Q1097X). DIAGNOSI ED EVENTUALE TERAPIA Il defi cit accrescitivo ponderale e lineare e l’ipotrofi a muscolare si sono accentuate col trascorrere dei mesi epertanto è stata iniziata terapia con mecasermina (0,04 mg/kg bis in die). Non sono stati segnalati eventi avversi. La dose del farmaco è stata progressivamente aumentata con incremento della crescita e della forza muscolare. La rarità del caso clinico e la terapia off-label somministrata con buona risposta anche in termini auxologici, identificano nella mecasermina una prospettiva terapeutica in una sindrome con una prognosi estremamente severa

Efficacy of Mecasermin Treatment and Long-Term Survival in a Child with Leprechaunism

Homozygous mutation of Insulin receptor (INS-R) gene cause an extremely rare disease called Leprechaunism, and induce intrauterine growth restriction with poor postnatal growth, hyperinsulinemia, postprandial hyperglycaemia, pre-prandial hypoglycaemia, typical facies, lack of subcutaneous fat, thick skin, hypertrichosis, macrogenitosomia in males. The survival is severely compromised in these patients. Treatment with diazoxide could ameliorate glycaemic control, however these patients are signed by a high precocious lethality into the first 1-2 years of life. Anecdotical cases are described with a longer survival. We describe the clinical case of a child with Leprechaunism, born from consanguineous parents, who had a homozygous mutation of the INS-R gene: c.3289 C>T (CAG->TAG) p.Gln 10975 stop (Q1097X). He was treated with diazoxide (5 mg/kg/day) and captopril (0.04 mg/kg/day), with a reduction of hyperglycaemia and hypertension. However, the stop in ponderal and linear growth induced to try the off-label treatment with mecasermin (0.04 mg/kg bid). The dose was progressively increased to 0.06 mg/kg/bid. After 2 years of treatment with mecasermin, the child increased the weight to 5.9 kg, length to 65 cm, head circumference to 41 cm. His neuromotor development is significantly improved. He performed an encephalic MRI which showed non-specific alterations of the white matter subcortical and periventricular, possible evolution of neonatal prolonged hypoglycaemic events. The peculiar outcome of our patient is linked to the long-term survival and the clinical improvement by mecasermin

The role of a monthly active surveillance programme for multidrug-resistant Gram-negative bacteria in a neonatal intensive care unit: impact evaluation of preventive measures

Background: Antimicrobial resistance is a public health threat. Neonatal Intensive Care Unit (NICU) patients are particularly at risk, due to the large use of invasive devices and antimicrobial treatment. Since 2014 an active surveillance program of multidrug-resistant organisms is in place in the five NICUs of Palermo, Italy. High prevalence of multidrug-resistant Gram-negative bacteria (MDR-GNB) carriage observed in one NICU suggested the need of a long-lasting approach to achieve effective control of MDR-GNB circulation. Materials/methods: Rectal swabs were obtained every month from each hospitalized new-born. Samples were enriched in liquid cultures, plated in McConkey Agar with three antimicrobial discs (amoxicillin-clavulanate, meropenem, ceftazidime). Resistant colonies were isolated, identified and submitted for antimicrobial susceptibility testing and ESBL detection. Molecular characterization of MDR-GNB was performed using pulsed-field gel electrophoresis (PFGE). From November 2017 multiple intervention measures were done: - Strengthening of sample collection for two months; - Stakeholders meetings; - Standardized protocols for antimicrobial therapy and common procedures. Prevalence of MDR-GNB carriage between the pre-intervention (November 2016-October 2017) and the post-intervention period (November 2017-October 2018) was compared by chi-square test. Clinical features were analysed in a subgroup of patients to identify possible risk factors. All associated variables with p-values <0.25 were included in a multivariate logistic regression model. P<0.05 was considered significant. Results: 39 patients were included in the 2 months of strengthened microbiological surveillance. MDR-GNB and ESBL-Klebsiella pneumoniae (KP) were detected in rectal swabs (34.8%; 23.2%), nasal swabs (24.6%; 14.5%), oral swabs (14.5%; 5.4%), milk samples (32.1%; 17.9%) soother swabs (30.8%; 17.9%). ESBL-KP was also detected from a sub-intensive room surface. Thirteen ESBL-KP strains isolated from clinical and environmental samples showed identical or closely related PFGE patterns suggesting a common origin for all tested strains. Prevalence of MDR-GNB and ESBL-KP carriage after intervention significantly decreased compared to the year before (61.1% vs 20.6%; p<0.001 and 94.5% vs 53.8%; p<0.001). Admission in post-intervention period significantly reduced the risk of MDR-GNB carriage (OR=0.15, p=0.01). Conclusions: MDR-GNB broadly circulate in NICU setting, can colonize different body sites and spread by various vehicles. Cooperation between epidemiologist and clinicians can effectively reduce diffusion of antimicrobial-resistant bacteria

Lung recruitment before surfactant administration in extremely preterm neonates with respiratory distress syndrome (IN-REC-SUR-E): a randomised, unblinded, controlled trial

Background: The importance of lung recruitment before surfactant administration has been shown in animal studies. Well designed trials in preterm infants are absent. We aimed to examine whether the application of a recruitment manoeuvre just before surfactant administration, followed by rapid extubation (intubate-recruit-surfactant-extubate [IN-REC-SUR-E]), decreased the need for mechanical ventilation during the first 72 h of life compared with no recruitment manoeuvre (ie, intubate-surfactant-extubate [IN-SUR-E]). Methods: We did a randomised, unblinded, controlled trial in 35 tertiary neonatal intensive care units in Italy. Spontaneously breathing extremely preterm neonates (24 + 0 to 27 + 6 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 h of life were randomly assigned (1:1) with a minimisation algorithm to IN-REC-SUR-E or IN-SUR-E using an interactive web-based electronic system, stratified by clinical site and gestational age. The primary outcome was the need for mechanical ventilation in the first 72 h of life. Analyses were done in intention-to-treat and per-protocol populations, with a log-binomial regression model correcting for stratification factors to estimate adjusted relative risk (RR). This study is registered with ClinicalTrials.gov, NCT02482766. Findings: Of 556 infants assessed for eligibility, 218 infants were recruited from Nov 12, 2015, to Sept 23, 2018, and included in the intention-to-treat analysis. The requirement for mechanical ventilation during the first 72 h of life was reduced in the IN-REC-SUR-E group (43 [40%] of 107) compared with the IN-SUR-E group (60 [54%] of 111; adjusted RR 0·75, 95% CI 0·57–0·98; p=0·037), with a number needed to treat of 7·2 (95% CI 3·7–135·0). The addition of the recruitment manoeuvre did not adversely affect the safety outcomes of in-hospital mortality (19 [19%] of 101 in the IN-REC-SUR-E group vs 37 [33%] of 111 in the IN-SUR-E group), pneumothorax (four [4%] of 101 vs seven [6%] of 111), or grade 3 or worse intraventricular haemorrhage (12 [12%] of 101 vs 17 [15%] of 111). Interpretation: A lung recruitment manoeuvre just before surfactant administration improved the efficacy of surfactant treatment in extremely preterm neonates compared with the standard IN-SUR-E technique, without increasing the risk of adverse neonatal outcomes. The reduced need for mechanical ventilation during the first 72 h of life might facilitate implementation of a non-invasive respiratory support strategy. Funding: None