Over the 48-week treatment period in the PACT trial, during which continuous therapy with controller medication was provided by the study, the vast majority (81.3%) of NASRA occurred in periods outside of exacerbation. Nights with asthma symptoms requiring albuterol use were often followed the next day by indicators of asthma morbidity, including increased albuterol use, school absence, doctor contact, and occurrence of severe wheeze and/or cough. The relative risks of occurrence of these indicators of morbidity due to NASRA outside of exacerbations were greater than the corresponding relative risks within periods of exacerbation, indicating that nocturnal asthma symptoms have substantial clinical impact on patient’s lives even during periods of relative asthma stability (i.e. not during exacerbation). To our knowledge, such a pattern of nocturnal asthma symptom morbidity has not previously been reported, in part due to the cross-sectional approaches of prior studies12,15
Nearly a quarter of participants with mild to moderate persistent asthma receiving daily controller therapy experienced a NASRA on at least a monthly basis, with the distribution of NASRA similar to the seasonal distribution of exacerbations (fall greatest, summer lowest) 18
. Treatment group assignment significantly affected the occurrence of NASRA, with the fluticasone group having a significantly lower rate of NASRA than the montelukast group. The superiority of fluticasone in reducing NASRA is consistent with the overall effect of fluticasone in terms of asthma control days reported in a previous PACT publication 17
. Similar to the findings in terms of asthma control days, the PACT combination of salmeterol 50µg twice daily with fluticasone 100µg once daily in the morning was not associated with significantly fewer NASRA than fluticasone twice daily, despite the use of a long acting β-agonist in the evening. This finding may have been due to the once daily (morning) dosing of fluticasone during the trial in the combination group rather than the typical twice daily dosing of fluticasone. While salmeterol has been demonstrated to decrease nocturnal awakenings in adults with asthma19
, the clinical efficacy of salmeterol on nocturnal asthma symptoms may differ in children. The inhaled corticosteroid dosing regimen in the combination group did not allow us to examine if the nocturnal administration of inhaled corticosteroid would have resulted in a greater effect on nocturnal symptoms.
NASRA were neither specific nor sensitive indicators nor antecedents of exacerbations requiring oral corticosteroid. Even when NASRA(s) did occur during the week preceding an exacerbation, they generally did not appear until a couple of nights prior to oral corticosteroid start (). Similarly, peak expiratory flows, symptoms and albuterol use during the day were not good indicators of a NASRA that evening, as only about 6% of evenings with a red zone PEF were followed by a NASRA and only about 20% of days before a NASRA included severe cough or wheeze or ≥7 puffs of albuterol use. Only 38.4% of exacerbation periods included a report of at least one NASRA, suggesting that NASRAs are a sign of symptom escalation in a subgroup of subjects.
Parents appear to seek medical attention following some, but not all, NASRAs, and NASRAs that occur during exacerbations were more often followed by a doctor visit. This may be due to the cumulative nature of the symptoms that occur with the exacerbation and a higher likelihood that symptoms during exacerbations may be more severe or less responsive to therapy than those outside of exacerbation periods.
The CAMP trial of children with mild to moderate asthma reported the prevalence of at least one nocturnal awakening during the 28 day albuterol-only and exacerbation-free run-in period to be 33.7% 8
, a finding very similar to the 31.2% of subjects who experienced at least one NASRA during the 2 week PACT albuterol-only run-in period, and not much dissimilar to the 24.3% who had 13 or more NASRA during PACT while taking a controller medication. The current analysis expands on the results from CAMP as it includes a longer period of observation (48 weeks vs. 4 weeks) as well as examining NASRAs that occur both outside and during asthma exacerbations and examining the effects of different treatment regimens on these events. To our knowledge, these observations have not been previously reported in either adults or children.
A limitation of this study is that the diary card did not include separate questions for nocturnal awakenings and nocturnal albuterol use for asthma symptoms. NASRA is likely a suitable surrogate measure of nocturnal awakenings since albuterol use requires being awake. However, our data may underestimate nocturnal awakenings since some nocturnal awakenings may not have been treated with albuterol. The study did not include a placebo group to establish the background frequency of NASRA. Since subjects with very frequent NASRA during the run-in period were excluded from the trial, the trial may have selected for children with fewer NASRA. The education provided by the coordinators and the support from the clinical center teams may have influenced clinical events occurring in days after NASRAs, most likely by decreasing event occurrence. It is possible that some patients experienced poor perception of airflow obstruction and thus did not experience a NASRA. Finally, as with all post hoc subgroup analyses, inadequate statistical power may have resulted in failure to detect significant associations with NASRA.
In conclusion, most NASRA occurred outside exacerbation periods and those NASRA observed during exacerbation periods did not appear to be a clinically useful antecedent of exacerbations. Despite the lack of association with exacerbations, NASRA were associated with morbidity in the form of symptom scores, additional albuterol use, and school absences and doctor contacts outside of exacerbation periods. NASRA frequency appears differentially responsive to controller therapy, with the fluticasone group experiencing the lowest frequency of NASRA and the montelukast group experiencing the greatest frequency. Since NASRA were associated with clinically relevant outcomes and treatment differences, inclusion of nocturnal symptoms as an important outcome measure in future clinical trials, along with further investigation into the etiologies and prevention of nocturnal asthma symptoms, may have substantial clinical implications.
Nocturnal asthma symptoms primarily occurred outside of exacerbation periods and were associated with clinical morbidity. Investigation into the etiologies and prevention of childhood nocturnal symptoms may have substantial clinical implications.