Epidemiology and clinical characteristics of respiratory syncytial virus infections among children and adults in Mexico

Background Respiratory syncytial virus (RSV) is a leading etiological agent of acute respiratory tract infections and hospitalizations in children. However, little information is available regarding RSV infections in Latin American countries, particularly among adult patients. Objective To describe the epidemiology of RSV infection and to analyze the factors associated with severe infections in children and adults in Mexico. Methods Patients ≥1 month old, who presented with an influenza‐like illness (ILI) to six hospitals in Mexico, were eligible for participation in the study. Multiplex reverse‐transcriptase polymerase chain reaction identified viral pathogens in nasal swabs from 5629 episodes of ILI. Patients in whom RSV was detected were included in this report. Results Respiratory syncytial virus was detected in 399 children and 171 adults. RSV A was detected in 413 cases and RSV B in 163, including six patients who had coinfection with both subtypes; 414 (72.6%) patients required hospital admission, including 96 (16.8%) patients that required admission to the intensive care unit. Coinfection with one or more respiratory pathogens other than RSV was detected in 159 cases. Young age (in children) and older age (in adults) as well as the presence of some underlying conditions were associated with more severe disease. Conclusions This study confirms that RSV is an important respiratory pathogen in children in Mexico. In addition, a substantial number of cases in adults were also detected highlighting the relevance of this virus in all ages. It is important to identify subjects at high risk of complications who may benefit from current or future preventive interventions.


| INTRODUCTION
Respiratory syncytial virus (RSV) is the major infectious cause of lower respiratory tract illness in infants and young children around the world. 1,2 It has also been recognized as an important etiologic agent of pneumonia and other respiratory tract infections in adults and elderly patients. 3,4 The clinical presentation of this infection varies widely, from mild upper respiratory tract disease to bronchiolitis and pneumonia. 5 This virus is responsible for the majority of bronchiolitis cases and causes approximately 50% of pneumonia cases during the first years of life. 6 In children, host factors such as young age, prematurity, and chronic cardiopulmonary diseases have been associated with severe disease. In addition, other factors such as lower socioeconomic status, exposure to cigarette smoke, air pollution, crowded households, and the lack of breastfeeding have also been associated with severe disease. 7 Viral factors associated with virulence leading to severe disease are not sufficiently understood. 8 Human RSV is a member of the Paramyxoviridae family. Outbreaks of RSV infections occur between fall and spring in temperate climates and tend to last up to 5 months. 9,10 RSV isolates can be divided into two groups: group A and group B based on antigenic and genetic characteristics. 8 These two groups cocirculate in the human population, with group A being more prevalent. Several studies have compared the severity of disease between infants infected with RSV group A and group B with mixed results. Most studies have not found significant clinical differences between both subtypes. 8  Despite the recognized importance of RSV as a cause of respiratory illness, the information regarding the epidemiology of this virus in Latin America, particularly among adults, is limited. 11 In the present study, 570 cases of RSV infection identified during four epidemic years in Mexico were evaluated to clarify the epidemiology of this infection and to assess the possible variations in demographic and clinical characteristics according to viral groups. Results from patients enrolled during the first year of the study have previously been described. 6 In this report, we analyzed the characteristics of 570 patients (399 children and 171 adults) with confirmed RSV infection included in the study during a 4-year period.

| Case definition and selection criteria
Patients ≥1 month old who presented with an ILI to any of the participating hospitals were eligible for participation in the study. ILI was defined by the presence of at least one respiratory symptom (e.g., shortness of breath, nasal congestion, and cough) and one of the two following criteria: (i) fever ≥38°C on examination, or self-reported fever, or feverishness in the past 24 hours; (ii) one or more nonrespiratory symptoms (e.g., malaise, headache, myalgia, or chest pain).
In order to rule out a nosocomial infection, patients who had been hospitalized for more than 48 hours at the time of symptom onset were excluded from the study.

| Study procedures
Subjects were interviewed and examined at the time of enrollment, a nasopharyngeal swab was obtained for the detection of respiratory pathogens, and a blood sample for the complete blood counts and chemistry analysis were obtained. When available, the results of other tests obtained for standard clinical care were extracted from medical records. Subjects were evaluated again on day 28 after enrollment, and follow-up information was also obtained by a telephone call on day 14 after the enrollment. At each follow-up visit, clinical information (symptoms, rehospitalizations, and death) was assessed. These visits allowed the ascertainment of the final disposition of the study patients (outpatient, emergency room, hospital ward, or intensive care unit [ICU]).

| Laboratory diagnostics
Nasopharyngeal swab specimens were collected from enrolled patients, placed in a tube with viral transport media, and maintained under refrigeration until they were sent to the Molecular Biology

| Ethical considerations
Verbal consent was obtained from parents/legal tutor and subjects before screening to determine eligibility. Once a patient was determined to be eligible for study participation, written informed consent and assent (for children older than 8 years) were obtained.
The protocol was approved by the institutional review board of each hospital.

| Statistical analysis
Means and standard deviation were used to summarize the quantitative variables, while frequencies and percentages were used for the qualitative variables. Comparisons between groups were made using Student's t-test for quantitative variables and the chi-squared or Fisher's exact test for qualitative variables. Multivariate logistic regression analysis was used to determine the factors associated with hospitalization and ICU admission. Data were analyzed with the use of pspp and OpenEpi. A P value <.05 was considered as statistically significant.

| RESULTS
Between 2010 and 2014, there were 5662 subjects enrolled in the ILI-002 study; 33 patients did not have respiratory samples available F I G U R E 1 Respiratory syncytial virus infections in subjects included during four seasons in the ILI-002 study F I G U R E 2 Respiratory syncytial virus seasonality according to the viral subtype and presence of coinfection for viral testing, and therefore, the final sample size for analysis was 5629 subjects. Of these subjects, there were 570 (10.7%) cases with RSV infection: 407 with RSV A infection, 157 with RSV B, and six in whom both RSV A and B were detected (Fig. 1).
RSV cases were detected throughout the study period. However, a marked seasonality was observed with a high number of cases during the fall and winter and a decrease in detections during spring and summer (Fig. 2). RSV A was the predominant virus between 2010 and 2012, but in seasons between 2012 and 2014, both RSV subtypes circulated simultaneously.
The characteristics of patients with RSV infection were compared to those of all other patients enrolled in the ILI-002 study ( Table 1).
The age group affected more frequently by RSV was that of children 0-5 years of age; 66.84% of RSV infections occurred in children in this age group, while 30% occurred in adults and 3.16% in children 6-17 years of age; 24.6% (381/1550) of respiratory tract infections in children <5 years were caused by RSV as compared to 4.7% (18/379) of children older than 5 years and 4.6% (171/3700) of adults. Also, the proportion of cases seen as outpatients was lower in patients with RSV infection compared to those in which this virus was not detected, while the proportion of ICU admissions was higher (Table 1).
We compared the characteristics of infections caused by RSV A and RSV B to assess whether there were significant clinical differences between them (Table 2); the six cases with coinfection with RSV A and B were excluded from this analysis. We did not find any differences in the medical history between patients with RSV A and RSV B infections. We also compared the frequency of each symptom between patients with RSV A and RSV B infections; no significant differences were observed for any of the symptoms that were recorded (including fever, cough, sore throat, fatigue, headache, myalgias, eye symptoms, sneezing, rhinorrhea, shortness of breath, nausea, vomiting, diarrhea, confusion, malaise, and irritability) (data not shown).
In addition, we compared the clinical characteristics of patients with and without coinfection with other pathogens (Table 3).
Differences in the age group distribution were noted between cases with and without coinfection with other pathogens: The proportion of pediatric cases was higher for those infections caused by RSV only, while a larger proportion of coinfections was noted in adults. Most symptoms were as frequent in patients with infections caused by RSV only compared to those with coinfections (data not shown); however, there were differences in the frequencies of some symptoms:

| DISCUSSION
We present the characteristics of RSV infections detected in a prospective, multicenter study of children and adults seeking clinical care.
Our data obtained over four seasons provide a description of the epi- children with RSV infection in whom other pathogens were detected were hospitalized less frequently than those infected by RSV only.
However, among hospitalized children, the presence of another respiratory pathogen was associated with admission to the ICU. In order to interpret these results, it is important to take into account that there was a wide variety of coinfecting pathogens and that in some cases two and even three viruses, in addition to RSV, were detected.
One of the main objectives of the study was to identify the factors associated with severe disease leading to RSV hospitalization in our country. Approximately 40% of subjects with RSV infection that were enrolled in the study had at least one underlying disorder. The most frequent conditions included congenital malformations/congenital syndromes, cardiovascular disorders, chronic lung disease, and asthma. We observed significant differences in the factors associated with hospitalization between children and adults; while multivariate logistic regression analysis indicated that young age was the main variable associated with hospitalization in children, adults showed an association between additional factors and the requirement of hospitalization. In this age group, multivariate logistic regression analysis showed an association between RSV infection and age, the presence of any underlying condition, and asthma. In their global study of respiratory tract viral infections in elderly adults, Falsey et al. 15 found that congestive heart failure, other cardiopulmonary diseases, and noninflammatory cerebrovascular/neurological disorders appeared to be associated with RSV infection; however, on multivariate analysis, no specific factors were associated with this virus.
In the group of children, multivariate logistic regression analysis showed an association between the risk of ICU admission and the presence of coinfection with other respiratory pathogens, cardiovas- Other limitations include the fact that the presence of underlying conditions (including history of prematurity and other chronic diseases) was based on patient self-report, which might not be totally reliable.
Also, we did not collect data on palivizumab use which might be relevant in infants; however, access to this prophylaxis is limited in Mexico because of the high cost and, therefore, the number of patients that may have received it is likely to be low.
On the other hand, strengths of our study include the participa-