Respiratory syncytial virus (RSV) is one of the most frequent causes of lower respiratory tract infection in infants and young children.1 Most children have been infected at least once by 24 months of age,2 and 1%–3% require hospitalization. The morbidity and mortality related to RSV infection is greater in prematurely born infants, particularly those with chronic lung disease1,3,4 and infants with hemodynamically relevant congenital heart disease.5,6
On the basis of these high risk groups, the American Association of Pediatrics recommended criteria for prophylaxis with the humanized monoclonal antibody palivizumab.7 For infants born between 32 and 35 weeks of gestation the policy statement referred to “epidemiologic data” and recommended considering additional risk factors: “child care attendance, school-aged siblings, exposure to environmental air pollutants, congenital abnormalities of the airways, or severe neuromuscular disease.”7 The primary aim of this study was to evaluate whether hospitalized RSV-infected children with clinically relevant neuromuscular impairment (NMI) are at an increased risk for a complicated course of RSV infection.
MATERIALS AND METHODS
The DMS RSV Paed Database.
In November 1999, a specific software tool (DMS RSV Paed) developed at our institution for the targeted surveillance of hospitalized RSV-infected pediatric patients was made available for data entry. The primary purpose of the surveillance was to facilitate the collection and analysis of detailed information on the population of hospitalized children with RSV infection in Germany. Inclusion criteria and details of the surveillance protocol have been published recently.8 All pediatric inpatients with virologically confirmed RSV infection were included irrespective of age, underlying diseases, comorbidities and whether the infection had been acquired in the hospital or in outpatients.
The clinical syndrome related to the RSV infection (bronchitis, bronchiolitis, central pneumonia, lobar pneumonia, respiratory failure, etc.) was allocated by the attending physicians to a final clinical category comprising the whole episode of the RSV infection. Vital factors were compared with age-related normal values to identify tachypnea or hypoxemia.
The study protocol was approved by each local study review board and ethics committee. Before enrolment and data entry into the database, informed consent was obtained from parents or the patients' legal guardians.
NMI was an item to be checked in the primary database by the local study nurse and the attending physician. In addition, we used information obtained from free text fields (admission note, discharge summary) to identify all RSV-infected children with NMI.
Taking into account the incubation period which lasts 3–5 days in most patients, a RSV infection was defined as nosocomial if the patient became symptomatic on day 5 or later after admission9 and community acquired otherwise.
A lower respiratory tract infection was only documented as “pneumonia” only if a chest radiograph confirmed the clinical diagnosis.10 Perihilar and peribronchial infiltration led to the diagnosis of “central pneumonia.” Lobar or segmental infiltrates were documented as “other pneumonia.” Mortality attributable to RSV infection was calculated as the proportion of events in which the patient died because of RSV-related complications or in which the RSV infection contributed to the adverse clinical course ultimately leading to the death of the patient.
All RSV infections included were microbiologically confirmed but the study protocol did not stipulate the precise method of detection. This would have been an important obstacle to participate for many centers, since each center followed the preferences of the local virologic laboratories. The methods involved were antigen detection11 (membrane-based ELISA, Becton Dickinson & Co., Sparks, Maryland; alternatively Abbott TestPack RSV Abbott Laboratories, North Chicago, IL)12 and cell culture using MS cells (permanent monkey-derived cell line).13 In some participating institutions, RSV infection was detected following in-house PCR-based diagnostic protocols. The diagnostic specimens (nasopharyngeal aspirate, NPA) were collected in a suction trap after nasal washing with 2–3 mL isotonic sodium chloride solution. This procedure was performed by skilled health care personnel and yielded an aspirate volume of 2–3 mL.14
The collection of the NPA was performed on each patient with clinical signs of respiratory tract infection during the surveillance period. The protocol appointed to perform the RSV detection assay from these NPA within 6 hours after sampling.
Clinical variables were prematurity, birth before gestational age of 32 and 28 weeks, respectively, birth weight below 1500 g, CLD plus (chronic lung disease of prematurity and treatment within the last 6 months before the diagnosis of the RSV infection),15 congenital heart disease, neurologic or NMI and nosocomial infection.8 The different outcomes were need for intensive care treatment [pediatric intensive care unit (PICU)], need for mechanical ventilation due to RSV infection, radiologically confirmed pneumonia and death due to RSV infection (only attributable mortality). Since partial outcome events were rare and clinical variables were nonnormally distributed, exact and wherever possible nonparametric methods were used throughout for data description and analysis despite the large sample size.16
Exact logistic regression was used for both univariate and multivariate analysis of associations of a set of 8 predefined clinical variables with 4 different outcomes. For multivariate analysis, the stepwise forward variable selection procedure was chosen, which starts with a model with only the variable most significantly associated in univariate analysis, and resulting in a model incorporating all variables significantly and independently associated with the respective outcome. SPSS (SPSS 11.0; SPSS Inc., Chicago, IL) was used for data description, LogXact-6 for exact logistic regression and StatXact-6 for the remaining exact analyses (both from Cytel Software Corp., Cambridge, MA).
In 6 consecutive RSV-seasons (1999–2005) 1568 RSV infections were prospectively documented in 1541 pediatric patients by a total of 14 pediatric treatment centers (see Table 6). Twenty-seven patients had 2 RSV-related hospitalizations after a symptom free interval of at least 4 weeks, 3 of them from the NMI group.
Subgroups With and Without NMI.
A clinically relevant NMI was present in 73 episodes (NMI-group) of 70 patients. The NMI group included children with hydrocephalus (n = 3), cerebral palsy and central hypoventilation syndromes (n = 41), genetic defects/chromosomal abnormalities (n = 8), neuromuscular disorders (n = 8), severe developmental delay (n = 5), peripheral nerve defects (n = 2) and other NMI as CNS neoplasia or epilepsy (n = 3). The 1495 RSV infections in 1471 patients without NMI formed the control group. Both groups included children with risk factors other than NMI. The age distribution of both groups is shown in Figure 1. The median age at diagnosis was significantly higher in children with NMI (14 vs. 5 months; P < 0.001), and 33% of the NMI patients were older than 24 months at diagnosis (versus 9% in the controls). Significantly more children in the NMI-group than in the control group displayed ≥2 risk factors for a complicated clinical course of the RSV infection (35.6% vs. 7.0%, P < 0.001). Detailed characteristics of both groups are shown in Table 1.
Table 2 shows the distribution of selected symptoms and complications related to the RSV infection in both groups. The incidence of wheezing, tachypnea and seizures was significantly higher in NMI patients. In the NMI group, 21% developed radiologically confirmed pneumonia (central pneumonia 15%, other pneumonia 6%), compared with 23% in the control group (central pneumonia 14%, other pneumonia 12%).
These differences were not significant. The clinical severity grading according to McIntosh and coworkers 199317 (and its recent extension8) is shown in Figure 2. Intensive care (PICU) treatment and mechanical ventilation related to the infection (McIntosh grade 1) was required significantly more often in children with NMI (P < 0.05 and P = 0.001, respectively). A significantly higher proportion of all patients in the NMI group was mechanically ventilated at the time of diagnosis due to other reasons (grade 4, extended McIntosh classification)8 or eventually died related to the RSV infection (P < 0.001 for both). The median length of stay was significantly longer in the NMI group (Table 1); if only RSV-positive days (days with viral shedding, tested once a week) were counted, the difference decreased to a single inpatient day (P < 0.001).
Results of the Univariate and Multivariate Regression Analysis.
In univariate logistic regression analysis (Table 3), the chronic medical conditions that were significantly associated with both an increased risk of PICU treatment and of respiratory failure included prematurity, birth before gestational age of 32 and 28 weeks, birth weight <1500 g, chronic lung disease CLD plus, congenital heart disease, NMI and nosocomial infection. To exclude bias due to colinearity of the different clinical variables, we performed a multivariate logistic regression analysis (Table 4).
Prematurity, birth before gestational age of 32 weeks, congenital heart disease, NMI and nosocomial infection remained significantly and independently associated with PICU admission, whereas only prematurity, CLD plus and NMI remained significantly associated with respiratory failure. NMI was not associated with radiologically confirmed pneumonia, neither in the univariate nor in the multivariate model.
The overall attributable mortality was 0.45% with 3 fatal cases related to RSV infection in the control group (0.2%) and 4 (5.5%) in the NMI group (P < 0.001).
The results of this prospective multicenter RSV-surveillance study from Germany confirm that children with NMI have a significantly increased risk of respiratory failure and ICU admission as a result of RSV infection, despite their higher median age at diagnosis. Clinically obvious reasons why children with neurologic impairment may be more severely affected in case of a viral respiratory tract infection are given in Table 5 and have been extensively discussed in a recent review by Panitch.18 Our study did not document higher rates of pneumonia in children with NMI. This suggests that radiologically confirmed pneumonia is not a prerequisite for respiratory failure in these patients. Even infections of the upper respiratory tract lead to an increase in nasopharyngeal and tracheal secretions, which cannot be cleared by the patients because of muscle weakness and an impaired cough mechanism.20 Any acute viral infection, in particular if associated with airway obstruction,21 could aggravate respiratory muscle fatigue and predispose children with NMI to severe hypoxemia and hypercapnia. As shown previously by our group8 and by others,22 even children, who are on prolonged mechanical ventilation for other reasons are at risk for nosocomial RSV infection.
In a subgroup analysis of the Canadian PICNIC RSV-database, Arnold and coworkers23 compared the outcome of RSV infection in children with CLD with that in those having other chronic conditions such as NMI, cystic fibrosis and pulmonary malformation. In that study, the proportions of patients admitted to the intensive care unit and of those mechanically ventilated were not significantly different between prematures with CLD and children with NMI, supporting the hypothesis that children with NMI face an increased risk of complications. These results referred only to 6 retrospectively identified patients (NMI subgroup). Five of these 6 children with NMI were older than 12 months. These data correlate well with our study in which about one third of all NMI patients were older than 24 months. The progressive nature of some neuromuscular diseases, rendering older children even at a higher risk of severe airway infection, may contribute to this observation.
Resch and coworkers24 from Graz/Austria identified 45 prematurely born infants with clinically significant neurologic handicaps in their retrospective single center cohort study, which included 453 infants with a gestational age at birth of 29–36 weeks of gestation. The NMI rate was 26% in infants born at 29–32 weeks of gestation and 5% in those born at 33–36 weeks. In a multivariate analysis, NMI was confirmed as a significant independent risk factor for rehospitalization (21% vs. 9%; OR, 2.93; CI95, 1.44–5.97; P < 0.001). The same group reported in 2006 the results of an Austrian multicenter observational study, in which 801 premature infants with a gestational age at birth of 29–32 weeks were included.25 These children represented 60%–70% of all infants born in Austria in this age group during the surveillance period (2001–2003). Of all these preterms, 84 (10.5%) had neurologic disease and 30 (3.8%) were classified as suffering from “severe neurologic disease.” Although presence of NMI doubled the risk of rehospitalization in the univariate analysis, the CI95of the odds ratio in the multivariate analysis failed to prove a significant difference (OR, 2.16; CI95, 0.77–5.25).25
Sritippayawan et al26 identified pneumonia as the most important reason for acute respiratory failure and for the nonelective initiation of mechanical ventilation (69%) in 73 children with neuromuscular diseases. NMI was cited as a risk factor for severe RSV disease in preterm infants born between 32 and 35 weeks of gestation.7 Speer and coworkers27 used the prospective palivizumab outcomes registry (phase IV surveillance tool of those children, who were receiving palivizumab) to identify children with NMI or congenital airways abnormalities in the 2002–2003 season (published in an abstract). While only 1% (n = 57) of all passively immunized children with neither NMI nor airway abnormalities required hospitalization despite palivizumab prophylaxis, the corresponding proportion was 1.8% (n = 4) in the infants with NMI.
Although the attributable mortality was significantly higher in the NMI group, NMI was not an independent risk factor for RSV-related death in the multivariate model. In multivariate analysis, however, NMI was not significantly associated with the outcome of death independently of other factors. The highly significant association of NMI with attributable mortality in univariate analysis is an indirect one, acting via an increased risk for PICU admission and respiratory failure.
In a landmark study published in JAMA in 2005, Keren and coworkers28 confirmed a strong association between the presence of NMI and the development of respiratory failure in children with influenza virus infection. This was confirmed by a recent 2003–2004 surveillance study of severe pediatric influenza cases (hospitalization in the PICU or death) in California: 23% (36 of 160) children had a neurologic disorder as an underlying condition.29
These findings together with ours suggest that in all children with NMI who have to be hospitalized in the PICU with severe clinical deterioration due to an airway infection at least 1 specimen of nasopharyngeal secretions should be sent as soon as possible to a virologic laboratory to detect viral pathogens and to develop a better understanding how the old and the emerging viral pathogens14,30–32 contribute to acute respiratory deteriorations in children with NMI. According to our results, it seems reasonable to include NMI as an important corisk factor into the decision algorithm for passive immunization in infants and children less than 24 months of age.
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