Central apneas are a serious and well-known complication in infants with acute bronchiolitis. Previous studies among hospitalized infants found rates of apnea ranging from 23.8% to 1.2%,1 and prematurity and young age have been identified as risk factors for its development. However, these previous studies focused on children with respiratory syncytial virus (RSV) infection. Some case reports have described the development of apnea with infection by other respiratory viruses,2,3 but few studies have examined the overall frequency and clinical characteristics of apnea in bronchiolitis by different viral etiologies. The aims of this study were to determine the frequency of apnea in infants admitted for bronchiolitis and to describe the respiratory viruses involved and the clinical characteristics of these patients. Secondarily, the apneic infants were compared according to RSV status (positive against negative).
MATERIAL AND METHODS
Prospective study of infants <12 months with apnea in the context of acute bronchiolitis (concomitantly or developing after the onset of apnea) admitted to Hospital Sant Joan de Deu, Barcelona, Universitat de Barcelona, from January 20, 2006, to October 15, 2008.This is a 342-bed children’s center for the south-Barcelona area with a pediatric population of around 200,000 children.
Central apnea is defined as a respiratory pause of ≥20 seconds or a shorter respiratory pause associated with bradycardia, cyanosis, pallor and/or marked hypotonia.4 We also considered apnea as any respiratory pause observed at home by the caretaker, regardless of the duration of the respiratory event, with associated changes in appearance (pallor, cyanosis or hypotonia) and any respiratory pause associated with oxygen desaturation <90% reported by a physician or a nurse during hospitalization. Bronchiolitis was diagnosed according to the presence of the first acute respiratory tract infection characterized by respiratory distress, cough, widespread crackles or wheezing or both, associated with signs of viral infection (coryza). Exclusion criteria were: demonstrated obstructive sleep apnea, apnea secondary to documented gastroesophageal reflux or epilepsy and primary apnea without bronchiolitis.
In the emergency room or within 24 hours after admission, a nasopharyngeal aspirate was collected and processed for polymerase chain reaction (PCR) virus detection at the Virology Unit of the Microbiology Department of Hospital Clinic (Barcelona). Nucleic acids from either RNA/DNA viruses were extracted from 200 μL of specimen using Nucli-Sense easyMAG (BioMérieux, NL-5281 RM Boxtel, The Netherlands) according to manufacturer’s instructions. Two independent multiplex nested reverse transcriptase PCR assays were carried out using techniques described by Coiras et al.5 First reverse transcriptase PCR assay detected influenza A, B and C viruses, RSV A and B and adenovirus. Another reverse transcriptase PCR examined human parainfluenza1, 2, 3 and 4, human coronavirus 229E and OC43, enterovirus and rhinovirus (RV). To detect human metapneumovirus, extracted RNA was used as a template for cDNA synthesis by random primers according to the manufacturer’s instructions (First Strand cDNA Synthesis Kit, Roche Diagnostics, Mannheim, Germany). Amplification reaction was carried out using specific primers amplifying a conserved fragment of 170 bp in the polymerase gene as described elsewhere.6
The following data were collected for each patient: gender, gestational age and underlying illnesses; chronological and postconceptional ages; weight, temperature, respiratory and cardiac rates at admission; need for pediatric intensive care unit support, length of stay and respiratory support provided (invasive or noninvasive mechanical ventilation); respiratory virus detected and results of bacterial cultures if performed and clinical characteristics of apnea (self-terminating or recurrent, onset of apnea before or after development of respiratory distress). The ethics committees of both the Hospital Clinic and Hospital Sant Joan de Deu approved the study protocol.
Statistical analysis was performed with SPSS statistical software for Windows v. 17.0.2 (SPSS Inc., Chicago, IL). Continuous variables were compared using Student t or Mann-Whitney U tests, according to data distribution. Discrete variables were compared using Pearson χ2 tests or Fisher’s exact test. P ≤ 0.05 was considered statistically significant.
During the 34 months of the study, 989 infants <12 months with bronchiolitis were admitted and 51 of them had apnea. The overall rate of apnea was 5.16% (confidence interval 95% 3.94–6.72). Virologic and clinical characteristics of the apneic infants are shown in the Table (Supplemental Digital Content 1, http://links.lww.com/INF/B885).
Thirty seven (72.5%) of the infants with apneas had a postconceptional age <44 weeks. Seven infants had received palivizumab (100% of those in whom it was indicated according to 2003 American Academy of Pediatrics recommendations). In 17 (33.3%) of the infants, apnea was the first manifestation of bronchiolitis appearing before the development of respiratory distress and/or crackles or wheezing. The other 34 (66.7%) infants developed apnea with apparent respiratory symptoms, with a median duration of bronchiolitis in these infants of 2 days (range: 0.5–10 days). Forty-one infants (80.4%) had recidivant apneas.
In 39 (76.5%) infants, any respiratory virus was detected (See Table, Supplemental Digital Content 1, http://links.lww.com/INF/B885). In 7 (13.7%) infants, a positive bacterial culture was obtained: 2 urinary tract infections (Klebsiella oxytoca, Streptococcus faecalis) and 5 positive broncho-alveolar lavage culture (Pseudomonas aeruginosa, Serratia marcescens, 3 Streptococcus pneumoniae). None of them had a positive blood culture. The only risks factors for bacterial infection were young age (85.7% were <40 days) and prematurity (57.1% were <37 weeks).
When comparing clinical characteristics depending on RSV status, among the non-RSV group there was a higher proportion of preterm infants (74.1% vs. 33.3%, P = 0.010) with a lower gestational age (mean 33.8 vs. 37.4 weeks; P < 0.0001) and a higher rate of recidivant apnea (92.6% vs. 66.6%; P = 0.033).Although the non-RSV group was older (mean age 57.9 vs. 35.7 days; P = 0.020), the 2 groups had the same postconceptional age (mean 42.1 and 42.0 days, respectively). No differences between the 2 groups were seen in the intubation rate, need for noninvasive respiratory support, rate of bacterial coinfection, length of hospital stay, days of supplementary oxygen or fever. Non-RSV infants tended to have more underlying illnesses (22.2% vs. 4.2%) without reaching statistical significance (P = 0.103). Also, the rate of apnea as the first event before development of clinical bronchiolitis tended to be higher among non-RSV infants (44.4% vs. 20.8%, P = 0.136). A second comparison was made between RSV infants (n = 21) and RV (n = 11), the largest group of other viruses. Coinfections with RSV and RV were excluded (n = 3). The only statistical significant difference was a greater percentage of ex-preterm infants among RV group (90.9% vs. 40%, P = 0.008).
In this prospective study of infants <12 months with bronchiolitis, we found a frequency of apnea of 5.16%, which is much lower than initial reports in the mid-1980s but a bit higher than most recent reports.1 These divergences probably can be explained by differences in the definition of apnea and in the inclusion criteria used; although other reports include infants up to 2 years, we studied younger infants which are more prone to apneas. Secondly, we included all infants that developed bronchiolitis clinically in spite of the RSV status, although most articles report the frequency of apnea only in RSV infants (with or without bronchiolitis). Also, to date, the majority of data regarding apnea frequency have come from retrospective chart reviews.1 In contrast, we performed a prospective study that more readily detects the frequency of apnea, so it is probably more accurate in estimating the true rate of apnea in these infants.
The rate of positive virus detection and the relative frequency of each respiratory virus among apneic infants are similar to what is reported in infants admitted for bronchiolitis in different reports.7 This finding is noteworthy, supporting previous case reports that described the relation between apnea and other respiratory viruses apart from RSV, especially in preterm infants.2,3,8 Our results indicate that young age and prematurity, the classical risk factors for apnea in RSV bronchiolitis, could also be valid for apneas caused by other viruses, as 72.5% of infants with apnea had a postconceptional age of <44 weeks. In infants <2 months with severe RSV infection, there has been demonstrated an acquired dysfunction of the autonomic nervous system that could result from an inflammatory cascade induced by the virus. This has been proposed as the pathogenic mechanism for the development of apnea in RSV bronchiolitis. This mechanism may be common to other respiratory viruses, which should be tested in prospective studies, but it seems a reasonable hypothesis in accordance with the substantial data that demonstrate a relation between respiratory infections and apnea in sudden infant death.10 It is remarkable that non-RSV infants have a higher rate of prematurity and tend to have more underlying illnesses than the RSV group. Moreover, all the extreme preterms are in the non-RSV group that may partially be explained by the use of palivizumab prophylaxis, which might have prevented RSV infection. However, the relative abundance of moderate preterms (32–36 gestational weeks) in the non-RSV group regarding RSV (48.1% vs. 29.2%, respectively) is a matter which deserves further study. Because of the low frequency of apneas, sample size is a limitation to compare specific groups of viruses and to find other significant differences between groups.
In conclusion, our study suggests that other respiratory viruses apart from RSV can play a role in the development of apnea, and that young age and prematurity are the main risk factors for apnea independent of the RSV status.
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