Introduction

This is the first published report of a young girl with co-inherited sickle cell-β+ thalassemia and cystic fibrosis. Although a small subset of patients with co-inherited cystic fibrosis and other hemoglobinopathies have been reported, this patient developed early hematologic and pulmonary complications that were more severe than the previous cases. To assess pulmonary co-morbidities, we used infant pulmonary function testing through the raised volume rapid thoracoabdominal compression technique as both an established study of early cystic fibrosis and also as a newer study of mechanism for early sickle cell lung disease. This further serves as the first report of the raised volume rapid thoracoabdominal compression technique to determine raised volume forced expiratory flows and fractional lung volumes in a patient with a hemoglobinopathy.

Case presentation

A 2-year-old African-American girl with co-inherited cystic fibrosis and sickle cell-β+ thalassemia developed severe hematologic complications (recurrent vaso-occlusive events, hepatic sequestration, and acute chest syndrome) during periods of cystic fibrosis pulmonary exacerbations and weight loss. Because cystic fibrosis and sickle cell-β+ thalassemia both confer distinct patterns of pulmonary disease, infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique was used to define respiratory pathophysiology and guide treatment options. Infant pulmonary function testing data demonstrated moderate-to-severe lower airways obstruction, moderate air trapping, and no evidence of restrictive lung disease.

Conclusions

Infant pulmonary function testing with the raised volume rapid thoracoabdominal compression technique guided therapy in this patient with cystic fibrosis and sickle cell-β+ thalassemia. Although this is an original case report on a unique patient, this case highlights the need to evaluate early respiratory pathophysiology in a broader population of young patients with hemoglobinopathies and screen those at risk for early pulmonary co-morbidities.

Objective

Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%-50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN.

Methods

The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials.

Results

For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows.

Conclusions

These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.

Rationale

The relationship between respiratory function at hospital discharge and the severity of later respiratory disease in extremely low gestational age neonates is not well defined.

Objectives

To test the hypothesis that tidal breathing measurements near the time of hospital discharge differ between extremely premature infants with bronchopulmonary dysplasia (BPD) or respiratory disease in the first year of life and those without these conditions.

Methods

Study subjects were part of the PROP (Prematurity and Respiratory Outcomes Program) study, a longitudinal cohort study of infants born at less than 29 gestational weeks followed from birth to 1 year of age. Respiratory inductance plethysmography was used for tidal breathing measurements before and after inhaled albuterol 1 week before anticipated hospital discharge. Infants were breathing spontaneously and were receiving less than or equal to 1 L/min nasal cannula flow at 21% to 100% fraction of inspired oxygen. A survey of respiratory morbidity was administered to caregivers at 3, 6, 9, and 12 months corrected age to assess for respiratory disease. We compared tidal breathing measurements in infants with and without BPD (oxygen requirement at 36 wk) and with and without respiratory disease in the first year of life. Measurements were also performed in a comparison cohort of term infants.

Results

A total of 765 infants survived to 36 weeks postmenstrual age, with research-quality tidal breathing data in 452 out of 564 tested (80.1%). Among these 452 infants, the rate of postdischarge respiratory disease was 65.7%. Compared with a group of 18 term infants, PROP infants had abnormal tidal breathing patterns. However, there were no clinically significant differences in tidal breathing measurements in PROP infants who had BPD or who had respiratory disease in the first year of life compared with those without these diagnoses. Bronchodilator response was not significantly associated with respiratory disease in the first year of life.

Conclusions

Extremely premature infants receiving less than 1 L/min nasal cannula support at 21% to 100% fraction of inspired oxygen have tidal breathing measurements that differ from term infants, but these measurements do not differentiate those preterm infants who have BPD or will have respiratory disease in the first year of life from those who do not. Clinical trial registered with www.clinicaltrials.gov (NCT01435187).

Background

With improved survival rates, short- and long-term respiratory complications of premature birth are increasing, adding significantly to financial and health burdens in the United States. In response, in May 2010, the National Institutes of Health (NIH) and the National Heart, Lung, and Blood Institute (NHLBI) funded a 5-year $18.5 million research initiative to ultimately improve strategies for managing the respiratory complications of preterm and low birth weight infants. Using a collaborative, multi-disciplinary structure, the resulting Prematurity and Respiratory Outcomes Program (PROP) seeks to understand factors that correlate with future risk for respiratory morbidity.

Methods/design

The PROP is an observational prospective cohort study performed by a consortium of six clinical centers (incorporating tertiary neonatal intensive care units [NICU] at 13 sites) and a data-coordinating center working in collaboration with the NHLBI. Each clinical center contributes subjects to the study, enrolling infants with gestational ages 23 0/7 to 28 6/7 weeks with an anticipated target of 750 survivors at 36 weeks post-menstrual age. In addition, each center brings specific areas of scientific focus to the Program. The primary study hypothesis is that in survivors of extreme prematurity specific biologic, physiologic and clinical data predicts respiratory morbidity between discharge and 1 year corrected age. Analytic statistical methodology includes model-based and non-model-based analyses, descriptive analyses and generalized linear mixed models.

Discussion

PROP incorporates aspects of NICU care to develop objective biomarkers and outcome measures of respiratory morbidity in the <29 week gestation population beyond just the NICU hospitalization, thereby leading to novel understanding of the nature and natural history of neonatal lung disease and of potential mechanistic and therapeutic targets in at-risk subjects.

Trial registration

Clinical Trials.gov NCT01435187.