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Initiation of ECMO for ventilator-dependent respiratory failure in an infant with Pompe's
Abstract
We present a 7-month-old male with Pompe's disease with respiratory failure requiring extracorporeal membrane oxygenation that received enzyme replacement therapy. There are no published cases of the use of extracorporeal membrane oxygenation in a patient with Pompe's disease, or the use of enzyme replacement therapy in the setting of acute respiratory failure.
... Survival was comparable with patients without Trisomy 21 (67% vs. 71%, P=0.09) (24). A recent case report even described the use of ECMO as respiratory support for an infant with Pompe's disease during RSV infection while treatment of the underlying disease with enzyme replacement was co-administered (25). Indeed, there are other scattered case reports describing the experience of the use of ECMO in severe respiratory failure in infants with other genetic conditions (26,27). ...
Infantile Pompe disease resulting from a deficiency of lysosomal acid α-glucosidase (GAA) requires enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA). Cross-reactive immunologic material negative (CRIM-negative) Pompe patients develop high-titer antibody to the rhGAA and do poorly. We describe successful tolerance induction in CRIM-negative patients.
Two CRIM-negative patients with preexisting anti-GAA antibodies were treated therapeutically with rituximab, methotrexate, and gammaglobulins. Two additional CRIM-negative patients were treated prophylactically with a short course of rituximab and methotrexate, in parallel with initiating rhGAA.
In both patients treated therapeutically, anti-rhGAA was eliminated after 3 and 19 months. All four patients are immune tolerant to rhGAA, off immune therapy, showing B-cell recovery while continuing to receive ERT at ages 36 and 56 months (therapeutic) and 18 and 35 months (prophylactic). All patients show clinical response to ERT, in stark contrast to the rapid deterioration of their nontolerized CRIM-negative counterparts.
The combination of rituximab with methotrexate ± intravenous gammaglobulins (IVIG) is an option for tolerance induction of CRIM-negative Pompe to ERT when instituted in the naïve setting or following antibody development. It should be considered in other conditions in which antibody response to the therapeutic protein elicits robust antibody response that interferes with product efficacy.
Unlabelled:
The objective of this study was to describe the characteristics of children who required mechanical ventilation (MV) or extracorporeal membrane oxygenation (ECMO) support for respiratory syncytial virus (RSV) bronchiolitis, and to identify risk factors associated with disease severity assessed by duration of MV, mortality and need for ECMO. Ventilated children under 1 year of age admitted for bronchiolitis were retrospectively studied over the 8-year period 1996-2003. The study population included 151 children. Of these, 38.4% were born prematurely and 8.6% had bronchopulmonary dysplasia (BPD). The mean age at initiation of MV was 61 days (+/-63 days). Infants were ventilated for a mean of 7.8 days (+/-7.5 days). Multivariate analysis revealed that prolonged duration of MV (>6 days, median value) was significantly associated with low gestational age ( P =0.02 for the group <32 weeks), requirement of neonatal oxygen supplementation ( P =0.03), BPD ( P =0.02) and positive tracheal aspiration culture ( P =0.004), in particular for Haemophilus influenzae ( P =0.03). Fourteen infants required ECMO with a mean period of MV before ECMO of 3.9 days (+/-4.5 days). Amongst these infants, the frequency of BPD was significantly higher as compared with the others ( P =0.001). Four infants died (survival rate 71.4%). The mean duration of ECMO for survivors was 12.1 days (+/-3.3 days).
Conclusion:
The data suggest that gestational age, requirement of neonatal oxygen supplementation, bronchopulmonary dysplasia and tracheal colonisation with Haemophilus influenzae are correlated with prolonged mechanical ventilation in children with bronchiolitis. Only bronchopulmonary dysplasia was associated with a need for extracorporeal membrane oxygenation that may provide lifesaving support in infants refractory to conventional management.
Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were ⩽6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc4.Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM-positive patients were deceased or invasively ventilated (p < 0.0001). By age 27.1 months, all CRIM-negative patients and 4/21 (19.0%) CRIM-positive patients were deceased or invasively ventilated. Cardiac function and gross motor development improved significantly more in the CRIM-positive group. IgG antibodies to rhGAA developed earlier and serotiters were higher and more sustained in the CRIM-negative group. CRIM-negative status predicted reduced overall survival and invasive ventilator-free survival and poorer clinical outcomes in infants with Pompe disease treated with rhGAA. The effect of CRIM status on outcome appears to be mediated by antibody responses to the exogenous protein.
Respiratory syncytial virus (RSV) lower respiratory tract disease may present as bronchiolitis, an obstructive lung disease with hyperinflation, or pneumonitis, a restrictive parenchymal disease with diffuse consolidation, a large intrapulmonary shunt and acute respiratory distress syndrome (ARDS). Although a significant proportion of those admitted to hospital will require some form of respiratory support, there have been few randomised studies to determine which is the most beneficial. Studies on the use of continuous positive airway pressure (CPAP), heliox, inhaled nitric oxide, and natural surfactant are reviewed. Current practice regarding ventilator support is largely based on clinical judgment and case reports. Multicentre randomised trials with long-term follow-ups are urgently required.
Pompe's disease is a fatal muscular disorder caused by lysosomal alpha-glucosidase deficiency. In an open-label study, four babies with characteristic cardiomyopathy were treated with recombinant human alpha-glucosidase (rhGAA) from rabbit milk at starting doses of 15 mg/kg or 20 mg/kg, and later 40 mg/kg. The enzyme was generally well tolerated. Activity of alpha-glucosidase normalised in muscle. Tissue morphology and motor and cardiac function improved. The left-ventricular-mass index decreased significantly. We recommend early treatment. Long-term effects are being studied.
Infantile glycogen storage disease type II (GSD-II) is a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). The purpose of this study was to investigate the safety and efficacy of recombinant human GAA (rhGAA) enzyme therapy for this fatal disorder.
The study was designed as a phase I/II, open-label, single-dose study of rhGAA infused intravenously twice weekly in three infants with infantile GSD-II. rhGAA used in this study was purified from genetically engineered Chinese hamster ovary (CHO) cells overproducing GAA. Adverse effects and efficacy of rhGAA upon cardiac, pulmonary, neurologic, and motor functions were evaluated during 1 year of the trial period. The primary end point assessed was heart failure-free survival at 1 year of age. This was based on historical control data that virtually all patients died of cardiac failure by 1 year of age.
The results of more than 250 infusions showed that rhGAA was generally well tolerated. Steady decreases in heart size and maintenance of normal cardiac function for more than 1 year were observed in all three infants. These infants have well passed the critical age of 1 year (currently 16, 18, and 22 months old) and continue to have normal cardiac function. Improvements of skeletal muscle functions were also noted; one patient showed marked improvement and currently has normal muscle tone and strength as well as normal neurologic and Denver developmental evaluations. Muscle biopsies confirmed that dramatic reductions in glycogen accumulation had occurred after rhGAA treatment in this patient.
This phase I/II first study of recombinant human GAA derived from CHO cells showed that rhGAA is capable of improving cardiac and skeletal muscle functions in infantile GSD-II patients. Further study will be needed to assess the overall potential of this therapy.
To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid alpha-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.
We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echocardiograms, growth, and motor and cognitive function.
After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related.
rhGAA improved ventilator-free survival, cardiomyopathy, growth, and motor function in patients with infantile-onset Pompe disease compared with outcomes expected for patients without treatment.
Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease.
Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment.
All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity.
Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.
Chinese hamster ovary cell-derived recombinant human acid alpha-glucosiadse in infantile onset Pompe disease
- Kishnani
- Ps
Kishnani PS et al (2006) Chinese hamster ovary cell-derived recombinant human acid alpha-glucosiadse in infantile onset Pompe disease. J Pediatr 149(1):89–97
Chinese hamster ovary cell-derived recombinant human acid alpha-glucosiadse in infantile onset Pompe disease
- P S Kishnani
- PS Kishnani