Paolo Silvani

Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial

BACKGROUND Metachromatic leukodystrophy (a deficiency of arylsulfatase A [ARSA]) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT). METHODS This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure [GMFM] score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov, number NCT01560182. FINDINGS Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18-54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients [grade 3 in four of five patients]). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% [range 14·0-95·6] lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites. INTERPRETATION Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up. FUNDING Italian Telethon Foundation and GlaxoSmithKline.

Pediatric Index of Mortality 2 score in Italy: a multicenter, prospective, observational study.

ObjectivesTo assess the performance of the Pediatric Index of Mortality (PIM) 2 score in Italian pediatric intensive care units (PICUs).DesignProspective, observational, multicenter, 1-year study.SettingEighteen medical–surgical PICUs.PatientsConsecutive patients (3266) aged 0–16 years admitted between 1 March 2004 and 28 February 2005.InterventionsNone.Measurements and main resultsTo assess the performance of the PIM2 score, discrimination and calibration measures were applied to all children admitted to the 18 PICUs, in the entire population and in different groups divided for deciles of risk, age and admission diagnosis. There was good discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.89 (95% CI 0.86–0.91) and good calibration of the scoring system [non-significant differences between observed and predicted deaths when the population was stratified according to deciles of risk (χ2 9.86; 8 df, p = 0.26) for the whole population].ConclusionsThe PIM2 score performed well in this sample of the Italian pediatric intensive care population. It may need to be reassessed in the injury and postoperative groups in larger studies.

A case of severe diazoxide toxicity

Hyperinsulism is a rare cause of persistent hypoglycemia in the neonatal period. Therapy can be accomplished either surgically or pharmacologically. Diazoxide treatment remains the mainstay of medical therapy. Tolerance of diazoxide is usually excellent, but several adverse effects of this drug have been described. A case of severe diazoxide intoxication with fluid retention, congestive heart failure, and respiratory failure is reported. The patient was a 43‐day‐old infant, affected by persistent and severe hypoglycemia. After the diagnosis, hyperinsulinism was established he was treated with diazoxide (17 mg·kg−1 daily) and octreotide (12 μg·kg−1 daily). A few days later he presented with hepatomegaly, severe fluid retention, diffuse edema, congestive heart failure, and respiratory failure requiring mechanical ventilation. After introduction of ACE inhibitors he developed acute renal failure. The clinical condition worsened and he developed pulmonary hypertension requiring high‐frequency oscillatory ventilation. Diazoxide was stopped on the 12th day in spite of poor control of blood sugar. During the next 5 days his hemodynamic status dramatically improved and he was weaned from catecholamines: he lost weight, had a negative fluid balance, and the edema disappeared, a normal diuresis resumed and renal function improved. Improvement of respiratory patterns and gas exchange made it possible to switch back to conventional ventilation and then to extubate the patient. Echocardiography demonstrated reduction of the PA pressure to normal and resolution of atrial enlargement. The patient was scheduled for elective subtotal pancreatectomy. Diagnosis and management of diazoxide intoxication are discussed.

Noninvasive Ventilation Outside the Intensive Care Unit From the Patient Point of View: A Pilot Study

BACKGROUND: Noninvasive ventilation (NIV) is increasingly utilized outside the ICU for patients with acute respiratory failure. However, success and failure risk factors and patient safety aspects have been poorly explored in this setting. So far, no study has evaluated the perspective of the patient, despite the known high relevance of patient participation for NIV success. METHODS: We prospectively interviewed (following a standard questionnaire) the patients successfully treated with NIV for acute respiratory failure outside the ICU. Subjects were interviewed 24–48 hours after NIV suspension. Exclusion criteria: NIV failure, patient not competent, patient unwilling to participate in the study, patient transferred to the ICU. RESULTS: Forty-five consecutive patients were included in the study. Only 20% participated in the initial setting of NIV parameters. More than 40% reported they never had the possibility to discuss the NIV treatment. Eighty percent reported they were never asked to try another interface. All subjects knew how to call for help, but only one fourth had been trained to remove the mask, and 22% reported not being able at all to remove the mask if needed. One half of the subjects reported having received help immediately when needed, but 15% waited more than 3 min. All subjects reported complications, and 18% reported respiratory worsening while on NIV. CONCLUSIONS: Subjects reported a low level of involvement in the initial setting of NIV treatment, low satisfaction about communication with the caring staff, and a suboptimal safety level in case of emergency.

Drug-induced pulmonary hypertension in newborns: a review.

Persistent pulmonary hypertension (PPHN) is a disease characterised by the disruption of the transition from fetal to neonatal circulation with the persistence of high pulmonary vascular resistances and right-to left shunting. This condition, occurring in about 1-2 newborns per 1000 live births, causes severe hypoxemia. Despite significant improvements in treatment, the mortality of PPHN varies from 10 to 20 % of affected newborns. Pulmonary hypertension is frequently observed in some cardiac malformation and in congenital diaphragmatic hernia, in meconium aspiration syndrome, neonatal sepsis, podalic presentation and male sex. Maternal risk factors are tobacco smoking, cesarean section, low socio-economic conditions, diabetes and urinary infections. Another predisposing condition is antenatal or postnatal exposure to some drugs. The medications involved in drug-induced pulmonary hypertension and the mechanisms involved are reviewed.

The effect of vasoactive drugs on mortality in patients with severe sepsis and septic shock. A network meta-analysis of randomized trials

Purpose: Inotropes and vasopressors are cornerstone of therapy in septic shock, but search for the best agent is ongoing. We aimed to determine which vasoactive drug is associated with the best survival. Materials and methods: PubMed, BioMedCentral, Embase, and the Cochrane Central Register were searched. Randomized trials performed in septic patients with at least 1 group allocated to an inotrope/vasopressor were included. Network meta‐analysis with a frequentist approach was performed. Results: The 33 included studies randomized 3470 patients to 16 different comparators. As compared with placebo, levosimendan (odds ratio [OR], 0.17, 95%; confidence interval [CI], 0.05‐0.60), dobutamine (OR, 0.30; 95% CI, 0.09‐0.99), epinephrine (OR, 0.35; 95% CI, 0.13‐0.96), vasopressin (OR, 0.37; 95% CI, 0.16‐0.89), and norepinephrine plus dobutamine (OR, 0.4; 95% CI, 0.11‐0.96) were significantly associated with survival. Norepinephrine improved survival compared with dopamine (OR, 0.81; 95% CI, 0.66‐1.00). Rank analysis showed that levosimendan had the highest probability of being the best treatment. Conclusions: Among several regimens for pharmacological cardiovascular support in septic patients, regimens based on inodilators have the highest probability of improve survival.

Human protein C concentrates in adult septic patients

Some case reports and case series suggest that protein C concentrates may improve the outcome in patients with congenital or acquired protein C deficiency (not only in those with sepsis induced purpura fulminans). We reviewed the published literature on the use of protein C concentrates in adult septic patients and found that it is limited to less than 70 patients reported in observational studies with a 70% survival, and added our personal experience (two adult patients with sepsis and contraindications to recombinant activated protein C).

A Systematic Review on Levosimendan in Paediatric Patients

Levosimendan is a calcium-sensitizing agent that improves cardiac function, hemodynamic performance, and survival in critically ill adult patient. Few data exist on its off-label use in paediatric patients. We therefore performed a systematic review updated in September 2013 of all the published articles describing the use of levosimendan in paediatric patients. We identified 24 studies published in the period 2004-2013 that included a total of 623 patients, the largest one being a case series of 293 patients. Most of the patients underwent cardiac surgery, other settings consisting of chronic heart failure, primary congenital heart diseases and sepsis and cancer-associated cardiac dysfunction. Most studies reported improvement in ventricular function, central venous oxygen saturation, serum lactate levels or cardiac index. The 5 randomized studies published so far have all been performed in cardiac surgery and suggest a beneficial effect on hemodynamic data with no effect on intensive care unit stay, hospital stay or survival. Side effects (e.g. hypotension) were reported. This inodilator merits to be investigated with further randomized trials focusing on clinically relevant outcomes.

Noninvasive ventilation in H1N1-correlated severe ARDS in a pregnant woman: please, be cautious!

Dear Editor, We read with great interest the report of Djibre et al. [1] on a pregnant woman with H1N1-correlated severe acute respiratory distress syndrome (ARDS) successfully treated with noninvasive ventilation (NIV). We agree that a trial of NIV can be attempted in most cases of acute respiratory failure [2], in particular when the patient is admitted in the ICU; nevertheless, in our opinion the reported case was unfit for a prolonged NIV treatment. The positive outcome was likely due to the high expertise of the authors, but generalization of their decision to avoid tracheal intubation in such critical conditions should be discouraged as too hazardous. The pregnant woman presented with severe ARDS (PaO2/FiO2 ratio \100), and NIV is commonly contraindicated in this condition [3] (above all in the absence of any contraindication to tracheal intubation). Even if the best ventilatory parameters to treat ARDS are still a matter of debate, the authors applied for 72 h a maximal FiO2/minimal PEEP strategy that is very far from standard ARDS treatment. Furthermore, when the patient worsened requiring intermittent NIV after a temporary improvement, bronchoalveolar lavage, transports to perform two CT scans, and caesarean section were performed still avoiding preventive tracheal intubation. We believe that a prudential, elective tracheal intubation, best if preceded by NIV to preoxygenate the patient [4], was indicated by the risk of acute deterioration associated with those maneuvers and by the extremely high risk of severe hypoxia in case of emergent tracheal intubation in an ARDS patient (in particular outside the ICU), aggravated by the potential difficult airway management in pregnant women. The risk of consequences for the fetus was another crucial reason to perform a preventive tracheal intubation. The authors reported that fetal monitoring was always satisfactory, and the infant was in good health; while we congratulate the authors for the successful management, we feel that the fetus was at very high (preventable) risk of permanent consequences in case of maternal sudden deterioration [5]. During a recent influenza A pandemic, pregnant women were shown to be at a relatively high risk of ARDS, and the possibility of future (or even imminent) viral pandemia with analogous characteristics exists. We strongly suggest a more prudential approach to ventilatory support in pregnant women with severe ARDS, preferring elective tracheal intubation whenever emergent intubation could have devastating consequences for the mother and the fetus and to allow a protective ventilatory strategy.

Abnormalities of acid–base balance and predisposition to metabolic acidosis in Metachromatic Leukodystrophy patients

Metachromatic Leukodystrophy (MLD; MIM# 250100) is a rare inherited lysosomal storage disorder caused by the deficiency of Arylsulfatase A (ARSA). The enzymatic defect results in the accumulation of the ARSA substrate that is particularly relevant in myelin forming cells and leads to progressive dysmyelination and dysfunction of the central and peripheral nervous system. Sulfatide accumulation has also been reported in various visceral organs, although little is known about the potential clinical consequences of such accumulation. Different forms of MLD-associated gallbladder disease have been described, and there is one reported case of an MLD patient presenting with functional consequences of sulfatide accumulation in the kidney. Here we describe a wide cohort of MLD patients in whom a tendency to sub-clinical metabolic acidosis was observed. Furthermore in some of them we report episodes of metabolic acidosis of different grades of severity developed in acute clinical conditions of various origin. Importantly, we finally show how a careful acid-base balance monitoring and prompt correction of imbalances might prevent severe consequences of acidosis.