Characterization of tracheobronchomalacia in infants with hypophosphatasia

Raja Padidela,Charles Myer,Omendra Narayan,Robert Yates,Claire Nissenbaum,Stuart Wilkinson,Dan Benscoter,Howard M Saal,M Zulf Mughal,Gary Mcphail,Jaya Nichani,Elaine Chan,Shanggen Zhou

doi:10.1186/s13023-020-01483-9

Abstract

BackgroundPerinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications. Effective management of such complications is of key clinical importance. In some infants with HPP, severe tracheobronchomalacia (TBM) contributes to respiratory difficulties. The objective of this study is to characterize the clinical features, investigations and management in these patients.MethodsWe report a case series of five infants with perinatal HPP, with confirmed TBM, who were treated with asfotase alfa and observed for 3–7 years. Additionally, we reviewed respiratory function data in a subgroup of patients with perinatal and infantile HPP included in the clinical trials of asfotase alfa, who required high-pressure respiratory support (positive end-expiratory pressure [PEEP] ≥6 cm H2O and/or peak inspiratory pressure ≥18 cm H2O) during the studies.ResultsThe case series showed that TBM contributed significantly to respiratory morbidity, and prolonged respiratory support with high PEEP was required. However, TBM improved over time, allowing weaning of all patients from ventilator use. The review of clinical trial data included 20 patients and found a high degree of heterogeneity in PEEP requirements across the cohort; median PEEP was 8 cm H2O at any time and some patients presented with high PEEP (≥8 cm H2O) over periods of more than 6 months.ConclusionIn infants with HPP presenting with persistent respiratory complications, it is important to screen for TBM and initiate appropriate respiratory support and treatment with asfotase alfa at an early stage.Trial registrationClinicalTrials.gov numbers: NCT00744042, registered 27 August 2008; NCT01205152, registered 17 September 2010; NCT01176266, registered 29 July 2010.

Highlights

Perinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications
Hypophosphatasia (HPP) is a rare, systemic, inherited, metabolic disease caused by deficient activity of the tissue non-specific isoenzyme of alkaline phosphatase (TNSA LP), resulting in the extracellular accumulation of its substrates - inorganic pyrophosphate (PPi), pyridoxal-5phosphate (PLP) and phosphoethanolamine (PEA) [1]
Patients with perinatal or infantile HPP and vitamin B6-dependent seizures have high morbidity and mortality in the first 5 years of life [3]; prior to the availability of asfotase alfa (Strensiq®), the only enzyme replacement therapy approved for the treatment of patients with perinatal/infantile- and juvenile-onset HPP, only 42% of infants with HPP survived their first year and only 27% survived to the age of 5 years, with death typically resulting from respiratory complications [2, 4–6]

Summary

Introduction

Perinatal and infantile hypophosphatasia (HPP) are associated with respiratory failure and respiratory complications. Infantile HPP, which is identified in patients before 6 months of age, is characterized by failure to thrive, hypercalcemia, short limbs, limb deformities with abnormal metaphyses, small thoraces with gracile, thin ribs, respiratory complications and vitamin B6-dependent seizures [2]. While asfotase alfa has been shown to improve survival in patients with perinatal and infantile HPP substantially [4], the characterization and management of respiratory complications in these patients remains key to their survival and to optimizing their treatment and clinical outcomes. Multiple factors contribute to respiratory difficulties in infants with HPP These include abnormal chest compliance arising from rachitic chest wall deformities and fractures, hypoplastic lungs, muscle weakness, episodic seizures, increased predisposition to infections secondary to TNSALP deficiency in leukocytes and, in some cases, severe tracheobronchomalacia (TBM) [4, 7–9]. Severe TBM is associated with an imminent risk of death from respiratory failure, complicated pulmonary infections and life-threatening cardiopulmonary arrests; infants with TBM require intensive respiratory support from a broad group of specialists [10]

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