Flow-Independent Exhaled Nitric Oxide Parameters in Pediatric Lung and Cardiac Transplant Recipients

Abstract

We read with interest the recent letter by Hofer et al. (1) in which airway nitric oxide (NO) in stable lung transplant recipients was compared with healthy controls using fractional exhaled NO (FeNO) measurements at variable exhalation flow rates. FeNO was similar between transplant recipients and controls at each of four fixed exhalation flows used. The authors concluded that further studies were warranted using variable flow rates, as this information could be used to differentiate between alveolar and bronchial NO production. We here provide preliminary data from a study in pediatric lung and cardiac transplant recipients using variable flow FeNO measurements. Lung and cardiac transplant recipients, without clinical or laboratory evidence of acute graft rejection, were recruited during routine hospital visits. Transplant patients were compared with healthy controls who had no history of atopy, respiratory or cardiac disease, and normal pulmonary function testing. Controls were recruited from siblings of patients and community volunteers. Respiratory infection within 3 weeks preceding the FeNO measurements was an exclusion criterion in all groups. The study was approved by the institutional review board. After obtaining written informed consent, subjects completed spirometry (2). FeNO measurements were then completed following previously published guidelines (3). FeNO was measured at expiratory flow rates of 50, 100, and 150 mL/sec using a chemiluminescence NO-analyzer (CLD 88 sp, Eco Physics, Dürnten, Switzerland). The mean of three measurements within 15% variation at each flow were used for further analysis. The flow-independent parameters, bronchial NO flux (JNO), and alveolar NO concentration (Calv) were then determined for each patient using the two-compartment model as described by Tsoukias and George (4). Comparisons were made between pairs of groups using the Mann-Whitney U test and between multiple groups using analysis of variance. Fourteen transplant recipients (7 double lung and 7 cardiac) and 21 controls were included. Mean (±SD) age at time of study was similar between transplant recipients and controls (13.9±2.0 years vs. 12.4±2.9 years). The time from transplant was longer in cardiac compared with lung transplant recipients (46.0±32.6 months vs. 11.2±89 months). Forced expiratory volume in 1 sec in percent of predicted normal values (5) were similar between controls and cardiac transplant recipients (97.2%±12.8% vs. 89.4%± 8.6%) but was significantly lower in lung transplant recipients (67.4%±22.0%, P<0.004). Similarly, forced vital capacity was comparable between controls and cardiac transplant recipients (94.6%± 12.2% vs. 85.9%±8.0%) but significantly lower in lung transplant recipients (71.1%±13.3%, P<0.003). In healthy controls, FeNO measurements were 10.8±4.0 ppb, 6.5±2.2 ppb, and 4.8±1.4 ppb at constant flows of 50, 100, and 150 mL/sec, respectively. These were not significantly different from the transplant population (12.7±4.5 ppb, 8.3±3.0 ppb, and 6.7±2.0 ppb). Subgroup analysis of the lung and cardiac groups did not demonstrate differences in FeNO (lung: 13.3±5.8 ppb, 7.9±3.5 ppb, and 6.4±1.7 ppb; cardiac: 12.1±3.1 ppb, 8.8±2.7 ppb, and 7.0±2.3 ppb). When flow-independent parameters were compared, JNO and Calv were similar between all transplant patients and controls. When lung and cardiac transplant recipients were compared separately with controls, no differences were found in JNO. However, Calv was significantly elevated in cardiac transplant recipients when compared with controls (5.5±4.0 ppb vs. 1.7±0.6 ppb, P<0.027). No such increase was seen in the lung transplant group (2.5±1.0 ppb vs. 1.7±0.6 ppb) (Figure 1).FIGURE 1.: The alveolar concentration (Calv) of nitric oxide in healthy controls, lung transplant and cardiac transplant recipients. Calv is shown for each control, lung transplant recipient, and cardiac transplant recipient. The mean Calv of each group is depicted as a line.Our preliminary data support the previously published results showing normal FeNO in lung transplant recipients (1) or cardiac transplant recipients (6) at fixed exhalation flows. However, in this pediatric population, we show a significant increase in the flow-independent NO parameter Calv in cardiac transplant recipients. The underlying cause of the increase in peripheral airways NO production in pediatric cardiac transplant recipients remains unclear, and further studies in this area are required. Our data do, however, reinforce the fact that differences in NO production in the peripheral airways may not be detected by measurements of FeNO at constant flows. The calculation of flow-independent parameters using variable exhalation flows may be needed to detect differences between groups. These parameters may become a useful tool to help diagnose clinical conditions such as bronchiolitis obliterans syndrome, infection or acute cellular rejection in lung transplant recipients noninvasively, as previous studies had suggested that these conditions may result in altered airway NO production (7–9). Larger studies will be needed to further characterize flow- independent NO parameters in solid organ transplant populations. Glenda N. Bendiak Fiona Kritzinger Anne I. Dipchand Vicky L. Ng Melinda Solomon Hartmut Grasemann Transplant Centre, Department of Pediatrics Hospital for Sick Children ON, Canada, Toronto ON, Canada University of Toronto Toronto ON, Canada