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Severe Respiratory Syncytial Virus Infection in Hospitalized Children
Archives of Medical Research 50 (2019) 377e383
ORIGINAL ARTICLE
Severe Respiratory Syncytial Virus Infection in Hospitalized Children Ana M. Gonzalez-Ortiz,a Sofıa Bernal-Silva,b,c Andreu Comas-Garcıa,b,c Marıa Vega-Morua,a Marıa E. Garrocho-Rangel,b and Daniel E. Noyolab a
Hospital del Ni~no y la Mujer, Dr. Alberto Lopez Hermosa, San Luis Potosı, Mexico Departamento de Microbiologıa, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, San Luis Potosı, Mexico c Centro de Investigaci on en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, San Luis Potosı, Mexico b
Received for publication May 28, 2019; accepted October 18, 2019 (ARCMED_2019_464).
Background. Lower respiratory tract infections (LRTI) are one of the most common causes of death worldwide. Respiratory syncytial virus (RSV) is a leading cause of LRTI in children. Despite of its epidemiological importance, there is limited information regarding the impact of this virus in Latin America. Aims of the study. We carried out a prospective study to establish the frequency and characteristics of RSV infections in hospitalized Mexican children. Methods. 1,252 children hospitalized between November, 2012 and December, 2015 because of LRTI were included in the study. A respiratory sample was obtained for RSV detection by RT-PCR and information regarding clinical presentation, hospital course, and outcome was recorded. Results. RSV was detected in 43.7% of children admitted with LRTI, in 43.3% of those admitted to the intensive care unit (ICU), and in 36.4% of those who died. Infants with RSV infection were younger, were diagnosed with bronchiolitis more frequently, and were less likely to have underlying disorders than those with RSVnegative LRTI. Among RSV-positive infants, admission to the ICU was associated with the presence of underlying conditions, pneumonia diagnosis, and young age. Four (0.73%) of the 547 infants with RSV infection died; death was more common in those with underlying disorders than previously healthy infants (3.8 vs. 0.2%, respectively; p 5 0.02). Conclusion. RSV contributes to a large proportion of LRTI hospital admissions. Most children admitted with RSV infection do not have underlying conditions. However, severe infection requiring ICU admission and death are more common in those with underlying disorders. Ó 2019 IMSS. Published by Elsevier Inc. Key Words: Respiratory syncytial virus, Bronchiolitis, Pneumonia, Acute respiratory infection.
Introduction Lower respiratory tract infections (LRTI) are the fifth most common cause of death worldwide (1). Results of the Global Burden of Disease Study indicate that LRTI caused 2.74 million deaths globally in 2015 (1). In addition, respiratory infections often trigger life-threatening exacerbations
Address reprint requests to: Daniel E. Noyola, Microbiology Department, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, Avenida Venustiano Carranza 2405, San Luis Potosı, 78210, Mexico; Phone: (þ52) (444) 8262344; ext. 6656; E-mail: [email protected]
of chronic respiratory and cardiac diseases, resulting in a greater impact than LRTI-associated mortality alone (2). Respiratory syncytial virus (RSV, recently renamed as Human orthopneumovirus) is the most common respiratory pathogen in children with acute LRTI (3,4). A global systematic review estimated that during 2015, 33.1 million RSV-LRTI episodes occurred in children younger than 5 years, resulting in approximately 3.2 million hospital admissions and 59,600 in-hospital deaths; 45% of these hospital admissions and in-hospital deaths are estimated to have occurred in children younger than 6 months (5). In the United States it is estimated that each year RSV infections result in 1 in 334 hospitalizations, 1 in 38 visits to an
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emergency department, and 1 in 13 visits to a primary care office in children !5 years of age (6). Despite the increasing awareness of the impact of RSV as a cause of hospitalizations and mortality, available data about the impact of RSV in Latin America is limited. A review published in 2014 found that the proportion of RSV detection among Latin American children 0e59 months of age with LRTI was 27.5% (7). However, studies that have analyzed data of young infants report higher detection rates of RSV in hospitalized patients. For instance, a study from Brazil that included infants !3 years of age with LRTI identified the presence of RSV in 53.5% of them (8); in Argentina, RSV infection was confirmed in 65.5% of infants !12 months of age admitted with a respiratory infection during the RSV season (9). Data on population-based incidence of RSV-LRTI in Latin American countries is scarce; recent estimates report figures ranging between 40.3 episodes/1,000 children ! 5 years of age in Costa Rica and 54.6 episodes/1,000 children !5 years of age in El Salvador (5). Overall, estimated RSV-hospitalization rates in Latin America are significantly higher than those estimated for children !5 years of age in the United States (3/1,000) (6). In addition, in spite of the clinical impact of RSV there is limited information regarding case-fatality rates on a global scale, as well as the characteristics of fatal RSV cases (10). The objective of this study was to determine the contribution of RSV as a cause of LRTI in hospitalized children, and to describe the characteristics of children infected with this virus in Mexico.
Materials and Methods The study was carried out at a second-level hospital which provides specialized pediatric and gyneco-obstetric medical care to mid and low-income populations. The hospital has 45 pediatric beds and 45 gynecology-obstetrics beds, as well as 10 neonatal intensive care unit beds and 8 intensive care beds. Most of the population that receives medical care at this hospital is protected by a governmental health insurance system (Seguro Popular). Children admitted to the hospital with LRTI between November 15, 2012 and December 12, 2015 were eligible for study participation. Patients admitted for other diagnoses and who developed acute respiratory infection symptoms in the hospital were excluded from analysis. Patients were enrolled Monday through Friday and enrollment hours were 7:00e15:00. All pediatric wards, the emergency department, and intensive care units were visited to identify patients admitted with LRTI diagnosis. Patients were considered to have LRTI if they presented with respiratory symptoms (such as cough, rhinorrea, nasal congestion, sneezing) and signs of lower respiratory tract involvement (respiratory distress, crackles, wheezing, or chest-x ray
infiltrates). Diagnostic categories were based on the diagnosis established by the treating physician. In general, patients were diagnosed with pneumonia when they had presence of crackles or respiratory distress and x-ray pneumonic infiltrates; bronchiolitis was diagnosed in patients with wheezing or respiratory distress and x-ray finding consistent with this diagnosis (air trapping, rib horizontalization); and whooping cough was considered in patients with characteristic cough episodes, apnea, cyanosis, or lymphocytosis. Viral detection was carried out in respiratory samples. A nasopharyngeal wash was obtained by instillation of 0.5 mL of sterile saline solution using a disposable feeding catheter followed by aspiration. RSV detection was performed using an end-point one-step RT-PCR protocol. This assay is an adaptation of a previously described real-time RT-PCR assay using the Access RT-PCR System (Promega Corporation, Madison, WI, USA) and primers that target the L gene (forward 50 -TCTTCATCACCATACTTTTC TGTTA-3’; reverse 50 -GCCAAAAAATTGTTTCCACAA TA-30 ) (11,12). The amplification program included a retrotranscription step at 50 C for 30 min, followed by 94 C for 2 min, 45 cycles of 20 s at 94 C, 20 s at 55 C, 30 s at 72 C, and a final extension at 72 C for 10 min. PCR products were subjected to electrophoresis on 2.5% agarose gels and digitally documented. Demographic and clinical information were obtained at the time of admission and through review of the medical records and registered in a database. The research protocol was approved by the hospital’s Research and Ethics Committee and signed informed consent was obtained from parents prior to enrollment of children in the study. The characteristics of patients with and without RSV infection were compared. In addition, for RSV positive patients, the characteristics of those admitted to the ICU were compared to those not admitted to the ICU. Comparisons of patient groups were carried out using OpenEpi online software (http://www.openepi.com) and SPSS for Windows (version 25). Categorical variables were compared using Fisher’s exact test or chi-squared test; continuous variables were compared using the Mann-Whitney U test.
Results There were 1,252 children hospitalized with LRTI included during the 38 month study period. The median age of study participants was 7.1 months old (IQR, 3e13.4), 514 (49%) were female, and an underlying disease was present in 264 (21.1%). Sixty (4.8%) patients required admission to the ICU and 11 (0.9%) died. RSV was detected in 547 (43.7%) patients. The most common admission diagnosis was bronchiolitis (48.2%), followed by pneumonia (42.4%); other LRTI diagnoses (such as whooping cough) were registered in 9.3% of patients.
Respiratory Syncytial Virus in Children
RSV showed a seasonal pattern with 97% of RSV-positive hospitalizations occurring between October and March (Figure 1). The highest proportion of RSV-positive cases was detected in December (35.6%), followed by January (22.9%), November (13.0%), and February (12.1%). The characteristics of patients with and without RSV detection are shown in Table 1. RSV-positive children were younger (6.1 months old vs. 7.9 months old; p !0.001). Infants !3 months of age showed the highest proportion (50%) of RSV-positive cases (Figure 2). The proportion of RSV positive cases remained high in infants between 3 and 18 months of age, and this tended to decrease in older children. In general, RSV-positive patients were less likely to have underlying diseases than RSV-negative patients (14.3 vs. 26.4%, respectively; p !0.001). Particularly prematurity, asthma, and bronchopulmonary dysplasia were less frequent in RSV-positive than in RSV-negative patients (Table 1). Bivariate analysis taking into account age as a covariate showed similar results. Overall, symptoms in patients with and without RSV infection were similar (Table 2). However, some differences were noted: RSV-positive patients had a higher frequency of rhinorrhea (83.4 vs. 73.2%, p !0.001), nasal congestion (76.2 vs. 70.4%, p 5 0.02), sneezing (64.5 vs. 56.9%, p 5 0.006), wheezing (76.8 vs. 60.7%, p !0.001), and cough (97.6 vs. 92.9%, p !0.001) than RSV-negative patients. OR estimates, adjusted for age, confirmed that rhinorrhea (OR 1.97, 95% CI, 1.48e2.62; p !0.001), sneezing (OR 1.32, 95% CI, 1.05e1.67; p 5 0.016), wheezing (OR 2.17, 95% CI, 1.69e2.79; p !0.001), and cough (OR 3.18, 95% CI, 1.7e5.49; p !0.001) were associated with RSV infection.
379
Table 1. Characteristics of children admitted with and without RSVassociated LRTI RSV positive RSV negative (n [ 547) (n [ 705) Sex Female Male Age, months (median, IQR) Underlying disease a Prematurity Asthma Bronchopulmonary dysplasia Congenital heart disease Down syndrome Tobacco smoke exposure Siblings !5 years old Attends daycare center Discharge LRTI diagnosis Bronchiolitisb Pneumoniab Whooping cough Other Received antibiotics during hospitalization ICU admission ICU admission duration, days (median, IQR) Mechanical ventilation Hospitalization duration (days) (median, IQR) Death Time between admission and RSV testing (days)
225 322 6.1 78 46 14 13 13 4 94 180 14
(41.1%) (58.9%) (2.4e11.7) (14.3%) (8.4%) (2.6%) (2.4%) (2.4%) (0.7%) (17.1%) (32.9%) (2.6%)
289 416 7.9 186 97 62 33 31 8 133 234 20
289 222 34 2 365
(52.8%) (40.6%) (6.2%) (0.4%) (66.7%)
303 352 47 3 440
p
(41%) 0.99 (59%) (3.3e14.7) !0.001 (26.4%) !0.001 (13.8%) 0.002 (8.8%) !0.001 (4.7%) 0.04 (4.4%) 0.05 (1.1%) 0.46 (18.9%) 0.44 (33.2%) 0.92 (2.8%) 0.77 0.007 (43.0%) (49.9%) (6.7%) (0.4%) (62.4%) 0.11
26 (4.8%) 34 (4.8%) 8 (4.0e11.7) 5 (3.0e10.7)
0.96 0.42
23 (4.2%) 4 (3e6.5)
26 (3.7%) 4 (2e6)
0.64 0.96
4 (0.7%) 1 (1e2)
7 (1%) 1 (1e2)
0.65 0.47
a
Some infants had more than one underlying disease. p !0.005.
b
Figure 1. Weekly number RSV detections in children hospitalized with LRTI.
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Figure 2. Age groups of children admitted to the hospital with RSV-positive and RSV-negative LRTI.
Bronchiolitis was the most frequent diagnosis in RSVpositive children (52.8%) and pneumonia in RSV-negative children (49.9%). Patients received antibiotics frequently, and no significant difference was found between those with and without RSV-associated infection. Overall, children with pneumonia diagnosis received antibiotics more frequently than those with bronchiolitis (77.4 vs. 47.7%, respectively; p !0.001). Infants with RSV-bronchiolitis were younger than those with RSV-pneumonia (Table 3). There were no differences in the frequencies of underlying conditions between both groups; however, infants with RSV-bronchiolitis were exposed to tobacco smoke more frequently than those with RSV-associated pneumonia.
Table 2. Symptoms of children admitted with and without RSVassociated LRTI RSV positive (n [ 547) Respiratory distress Cough Rhinorrhea Nasal congestion Wheezing Sneezing Rales Cyanosis Vomiting Diarrhea Apnea Contact with another sick person
535 534 455 417 420 353 308 169 179 76 17 218
(97.8%) (97.6%) (83.4%) (76.2%) (76.8%) (64.5%) (56.3%) (30.9%) (32.7%) (13.9%) (3.1%) (39.9%)
RSV negative (n [ 705) 683 655 516 496 428 401 424 233 212 106 31 217
(96.9%) (92.9%) (73.2%) (70.4%) (60.7%) (56.9%) (60.1%) (33%) (30.1%) (15%) (4.4%) (30.8%)
p 0.32 !0.001 !0.001 0.02 !0.001 0.006 0.17 0.42 0.31 0.57 0.24 0.001
Overall, RSV-pneumonia cases were more severe than bronchiolitis cases; admission to the ICU was required in 10.8% of those with pneumonia compared to 0.7% of those with bronchiolitis and duration of hospitalization was longer.
Table 3. Characteristics of patients with RSV pneumonia and bronchiolitis Pneumonia (n [ 223) Sex Female Male Age months (median, IQR) Underlying disease a Prematurity BPD Asthma Congenital heart disease Down Syndrome Tobacco smoke exposure Siblings !5 years old Attends daycare center Contact with other sick person Antibiotic use during hospitalization ICU admission Mechanical ventilation Duration of hospitalization days (median, IQR) Death a
96 127 7.9 39 16 5 9 8 4 28 66 8 85 180
(43%) (57%) (3.1e15.5) (17.5%) (7.2%) (2.2%) (4.0%) (3.6%) (1.8%) (12.6%) (29.6%) (3.6%) (38.1%) (80.7%)
Bronchiolitis (n [ 290)
117 173 5.9 35 26 7 5 5 1 58 100 6 114 157
p
(40.3%) 0.54 (59.7%) (3.0e10.5) 0.005 (12.1%) 0.08 (8.9%) 0.46 (2.4%) 0.89 (1.7%) 0.11 (1.7%) 0.18 (0.3%) 0.23 (20.0%) 0.02 (34.5%) 0.24 (2.1%) 0.29 (39.3%) 0.82 (54.1%) !0.001
24 (10.8%) 21 (9.4%) 5.0 (3.0e7.0)
2 (0.7%) 2 (0.7%) 4.0 (3.0e6)
!0.001 !0.001 0.003
4 (1.8%)
0 (0%)
0.07
Some infants had more than one underlying disease.
Respiratory Syncytial Virus in Children
381
Table 4. Characteristics of patients with RSV-associated LRTI admitted and not admitted to the ICU ICU admission (n [ 26) Sex Female Male Age months (median, IQR) Underlying diseasea Prematurity BPD Asthma Congenital heart disease Down Syndrome Tobacco smoke exposure Siblings !5 years old Attends daycare center Contact with other sick people Antibiotic use during hospitalization Mechanical ventilation Duration of hospitalization days (median, IQR) Discharge LRTI diagnosis Bronchiolitisb Pneumoniab Whooping cough Other Death
Not admitted to the ICU (n [ 521)
10 16 2.4 10 6 1 1 3 0 2 4 0 11 21 23 13
(38.5%) (61.5%) (1.6-7.5) (38.5%) (23.1%) (3.8%) (3.8%) (11.5%) (0%) (7.7%) (15.4%) (0%) (42.3%) (80.8%) (88.5%) (8-16.2)
215 306 6.3 68 40 12 13 10 4 92 176 14 207 344 0 4
(41.3%) (58.7%) (2.5-12.0) (13.1%) (7.7%) (2.3%) (2.5%) (1.9%) (0.8%) (17.7%) (33.8%) (2.7%) (39.9%) (66.0%) (0.0%) (3-6)
2 24 0 0 4
(7.7%) (92.3%) (0%) (0%) (15.4%)
287 198 34 2 0
(55.1%) (38.0%) (6.5%) (0.4%) (0%)
p
0.78 !0.001 !0.001 0.02 0.47 0.49 0.04 1.0 0.28 0.05 1.0 0.57 0.12 !0.001 !0.001 0.007
!0.001
a
Some infants had more than one underlying disease. p !0.005.
b
Sixty patients were admitted to the ICU; children with underlying disorders were more likely to require ICU admission (9.5%) compared to those without underlying diseases (3.5%; p !0.001). Infants with congenital heart disease had the highest ICU admission rate (15.9%), followed by those with bronchopulmonary dysplasia (10.9%). Twenty-six (4.8%) of the 547 patients with RSV infection required admission to the ICU. The characteristics of these patients and of those that were not admitted to the ICU are compared in Table 4. RSV-positive patients that required intensive care treatment were more likely to have underlying diseases (38.5 vs. 13.0%; p !0.001) and were younger (2.4 vs. 6.7 months old; p !0.01) than those not admitted to the ICU; 60% of infants with RSV infection who required admission to the ICU were under 6 months old. Regarding underlying disorders, the most notable differences between children admitted and not admitted to the ICU were the history of prematurity (23.1 vs. 7.7%; p 5 0.02) and diagnosis of congenital heart disease (11.5 vs. 1.9%; p 5 0.04). In the bivariate analysis adjusted for age, the history of any underlying disease (OR 4.22, 95% CI, 1.83e9.74; p 5 0.001), congenital heart disease (OR 7.65, 95% CI, 1.9e30.75; p 5 0.004), and a history of prematurity (OR 3.17; 95% CI, 1.19e8.41; p 5 0.02) were associated with ICU admission in children with RSV infection. Pneumonia was the most common diagnosis in RSVpositive children who were admitted to the ICU (69.2%);
in contrast, bronchiolitis was more frequent in children who did not require intensive care (55.1%). As such, pneumonia diagnosis was associated with severe infection (OR adjusted by age of 5.07, 95% CI, 2.014e12.01; p !0.001) compared to other diagnoses (including bronchiolitis). The median total hospitalization duration for children who required admission to the ICU was 13 d (IQR, 8e13) compared to 4 d (IQR, 3e6; p !0.001) for children who did not require ICU admission. Four (15.4%) of the 26 RSV-positive patients that were admitted to the ICU died. All of them had a diagnosis of pneumonia, two were female, and the median age on admission was 9.3 months (IQR, 2.8e19.1). Three of these children (75%) had an underlying disease (two with heart disease and one with history of prematurity). The overall case-fatality rate for children admitted with RSV infection was 0.73% (4 of 547 patients). Infants with underlying conditions had a higher mortality rate (3.8%) compared to previously healthy infants (0.2%; p 5 0.02).
Discussion This study describes the characteristics of RSV infections in Mexican children hospitalized with LRTI. With the use of molecular detection methods, we identified the presence of RSV in 43.7% of LRTI cases. In a review of studies carried out in Latin America, the proportion of RSV detection in children 0e59 months of age with LRTI was 27.5% (7).
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Of note, this review included reports that used immunofluorescence and viral culture, which are less sensitive than RT-PCR. A multicenter study that included 1,404 Mexican children !5 years of age with pneumonia identified RSV (either alone or in combination with other viruses) in 38.1% of them (3). A study carried out in Guatemala reported detection of RSV in 32.3% of children !5 years old hospitalized with respiratory infection (13). Analyses restricted to younger infants have reported higher proportions of RSV infections (8,9). Therefore, the contribution of RSV to LRTI requiring admission to the hospital in our region may be higher than previously estimated figures. High detection rates of RSV in hospitalized children have also been found in developed countries; for example, in a study carried out in Canada, this virus was detected in 63.6% of infants !3 years old hospitalized with respiratory tract infections (14). As such, the leading role of RSV as a cause of LRTI admissions is noteworthy worldwide. In concordance with other studies, age under 6 months old, history of prematurity, and the presence of underlying conditions were the most frequent factors associated with severe RSV infection (14e17). Although the frequency of bronchopulmonary dysplasia and congenital heart disorders was low among children included in the present study, the frequency of prematurity was similar to that reported by other authors. The ICU admission rate (4.8%) and case fatality rate (0.73%) for infants admitted with RSV infection in the present study are similar to those reported at a General Hospital in Mexico (5.2 and 1.04%, respectively) (18). In a study from Argentina, the case fatality rate for RSV LRTI cases was 0.9%, and RSV was detected in 54% of children with LRTI who died after the neonatal period who were tested for this virus (9). In the present study, 36.3% of the children with LRTI who died had RSV confirmed infection. These figures underscore the potential severity of RSV infections. In our study, the majority of RSV cases that required ICU admission did not have an underlying disorder (61.5%); however, three of the four fatal RSV cases occurred in infants with underlying conditions. In a study carried out at a third-level hospital in Mexico City 12 of 14 children (85.7%) who died among those with diagnosis of RSV infection had an underlying condition (19). A recent report indicated that underlying conditions were present in 70% of fatal RSV cases in high-income countries, while these were reported in only 28% of fatal cases in low-income or lower-middle-income countries (10). Although Mexico is classified as an upper middle-income country, several characteristics of children with severe disease in the present study were similar to those reported for high-income countries; however, it is noteworthy that the number of fatal cases in our study was small. In the present study 96% of RSV infections were detected between October and March. This seasonal pattern is similar to the one previously reported from other studies
carried out in different cities in Mexico (3,18,20). Our results provide further support regarding the seasonal pattern for RSV in Mexico. A limitation of our study is that, in addition to RSV detection, no further characterization of this virus was carried out. Previous studies in Mexico have shown that both RSV A and B may circulate during the same season (21). While RSV A is detected more frequently than RSV B, during some seasons RSV B can be the predominant virus (22,23). Previous studies in Mexico have shown that during the 2012e2013 winter season RSV A was the most common RSV group, while RSV B predominated during the 2013e2014 and 2014e2015 seasons (20,24). As such, it is likely that infections by both RSV A and B may have occurred in our study population. Of note, although several studies have assessed whether severity of illness may be associated with the viral genotype, most studies have not found a major difference between infections caused by RSV A and RSV B viruses (20,24e27). Another limitation is that virological testing was carried out only for RSV. Although information regarding the role of other respiratory pathogens as the cause of LRTI is of great interest, this project was focused on RSV, since it is known to be the major etiological agent for severe respiratory infections in young children (3,4,13). In summary, our results indicate that, in our community, RSV causes a large proportion of LRTI in children. The majority of infants admitted with infection due to this virus do not have underlying disorders. Almost 5% of children admitted with RSV required ICU admission and the case fatality rate was 0.73%. In the present study the history of prematurity, congenital heart disease, having contact with another sick person, and the diagnosis of pneumonia were the most significant factors associated with severe RSV infection. These results contribute to the assessment of the impact of this virus as a cause of morbidity and mortality in Mexico and Latin America. Potential Conflicts of Interest AMGO, ACG, SBS, MVM, and MEGR declare that there are no conflicts of interest regarding the publication of this manuscript. DEN has participated as a member of the speakers’ bureau of AbbVie and speakers’ bureau and advisory board for Sanofi Pasteur. References 1. GBD 2015 LRI Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infection in 195 countries: a systematic analysis of the Global Burden of Disease Study 2015. Lancet Infect Dis 2017;17: 1133e1161. 2. Tang JW, Lam TT, Zaraket H, et al. Global epidemiology of noninfluenza RNA respiratory viruses: data gaps and a growing need for surveillance. Lancet Infect Dis 2017;17:e320ee326.
Respiratory Syncytial Virus in Children 3. Wong-Chew RM, Garcıa-Leon ML, Noyola DE, et al. Respiratory virus detected in Mexican children younger than 5 years old with community-acquired pneumonia: a national multicenter study. Int J Infect Dis 2017;19:e01256ee01316. 4. Jain S, Williams DJ, Arnold SR, et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N Engl J Med 2015;372:835e845. 5. Shi T, McAlister DA, O’Brien KL, et al. Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study. Lancet 2017;390:946e958. 6. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360: 588e598. 7. Bardach A, Rey-Ares L, Cafferata ML, et al. Systematic review and meta-analysis of respiratory syncytial virus infection epidemiology in Latin America. Rev Med Virol 2014;24:76e89. 8. Da Silva ER, Pitrez MC, Arruda E, et al. Severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors. BMC Infect Dis 2013;13:41. 9. Geoghegan S, Erviti A, Caballero MT, et al. Mortality due to respiratory syncytial virus. burden and risk factors. Am J Respir Crit Care Med 2017;195:96e103. 10. Scheltema NM, Gentile A, Lucion F, et al. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series. Lancet Glob Health 2017;5:e984ee991. 11. Whiley DM, Syrmis MW, Mackay IM, Sloots TP. Detection of human respiratory syncytial virus in respiratory samples by LightCycler reverse transcriptase PCR. J Clin Microbiol 2002;40:4418e4422. 12. Montejano-Elıas L, Alpuche-Solıs AG, Zarate-Chavez V, et al. Human metapneumovirus and other respiratory viral infections in children attending a day care center. Pediatr Infect Dis J 2009;28:1024e1026. 13. McCracken JP, Prill MM, Arvelo W, et al. Respiratory syncytial virus infection in Guatemala, 2007e2012. J Infect Dis 2013;208(Suppl 3): S197eS206. 14. Papenburg J, Hamelin ME, Ouhoummane N, et al. Comparison of risk factors for human metapneumovirus and respiratory syncytial virus disease severity in young children. J Infect Dis 2012;206:178e189. 15. Rodrıguez DA, Rodriguez-Martinez CE, Constanza Cardenas A, et al. Predictors of severity and mortality in children hospitalized with respiratory syncytial virus infection in a tropical region. Pediatr Pulmonol 2014;49:269e276.
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16. Shi T, Balsells W, Wastnedge W, et al. Risk factors for respiratory syncytial virus associated with acute lower respiratory infection in children under five years: Systematic review and meta-analysis. J Glob Helath 2015;5:020416. 17. Zhou L, Xiao W, Zhao Y, et al. The impact of viral dynamics on the clinical severity of infants with respiratory syncytial virus bronchiolitis. J Med Virol 2015;87:1276e1284. 18. Vizcarra-Ugalde S, Rico-Hernandez M, Monjaras-Avila C, et al. Intensive care unit admission and deaths rates of infants admitted with respiratory syncytial virus lower respiratory tract infection in Mexico. Pediatr Infect Dis J 2016;35:1199e1203. 19. Rodrıguez-Auad JP, Nava-Frıas M, Casasola-Flores J, et al. The epidemiology and clinical characteristics of respiratory syncytial virus infection in children at a public pediatric referral hospital in Mexico. Int J Infect Dis 2012;16:e508ee513. 20. Gami~no-Arroyo AE, Moreno-Espinosa S, Llamosas-Gallardo B, et al. Epidemiology and clinical characteristics of respiratory syncytial virus infections among children and adults in Mexico. Influenza Other Respir Viruses 2017;11:48e56. 21. Tirado R, Sarmiento RE, Bustos J, Thompson O, Gomez B. Occurrence of respiratory syncytial virus subtypes in Mexican infants with acute lower respiratory tract disease. Arch Med Res 1995;26: 121e126. 22. Heikkinen T, Ojala E, Waris M. Clinical and socioeconomic burden of respiratory virus infection in children. J Infect Dis 2017;15:17e23. 23. Mlinaric-Galinovic G, Vojnovic G, Cepin-Bogovic J, et al. Does the viral subtype influence the biennial cycle of respiratory syncytial virus? Virol J 2009;6:133. 24. Comas-Garcıa A, Noyola DE, Cadena-Mota S, Rico-Hernandez M, Bernal-Silva S. Respiratory syncytial virus-A ON1 genotype emergence in Central Mexico in 2009 and evidence of multiple duplication events. J Infect Dis 2018;217:1089e1098. 25. Savon C, Goyenechea A, Valdes O, et al. Respiratory syncytial virus group A and B genotypes and disease severity among Cuban children. Arch Med Res 2006;37:543e547. 26. Martinello RA, Chen MD, Weibel C, Kahn JS. Correlation between respiratory syncytial virus genotype and severity of illness. J Infect Dis 2002;186:839e842. 27. Sato M, Saito R, Sakai T, et al. Molecular epidemiology of respiratory syncytial virus infections among children with acute respiratory symptoms in a community over three seasons. J Clin Microbiol 2005;43: 36e40.
ORIGINAL ARTICLE
Severe Respiratory Syncytial Virus Infection in Hospitalized Children Ana M. Gonzalez-Ortiz,a Sofıa Bernal-Silva,b,c Andreu Comas-Garcıa,b,c Marıa Vega-Morua,a Marıa E. Garrocho-Rangel,b and Daniel E. Noyolab a
Hospital del Ni~no y la Mujer, Dr. Alberto Lopez Hermosa, San Luis Potosı, Mexico Departamento de Microbiologıa, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, San Luis Potosı, Mexico c Centro de Investigaci on en Ciencias de la Salud y Biomedicina, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, San Luis Potosı, Mexico b
Received for publication May 28, 2019; accepted October 18, 2019 (ARCMED_2019_464).
Background. Lower respiratory tract infections (LRTI) are one of the most common causes of death worldwide. Respiratory syncytial virus (RSV) is a leading cause of LRTI in children. Despite of its epidemiological importance, there is limited information regarding the impact of this virus in Latin America. Aims of the study. We carried out a prospective study to establish the frequency and characteristics of RSV infections in hospitalized Mexican children. Methods. 1,252 children hospitalized between November, 2012 and December, 2015 because of LRTI were included in the study. A respiratory sample was obtained for RSV detection by RT-PCR and information regarding clinical presentation, hospital course, and outcome was recorded. Results. RSV was detected in 43.7% of children admitted with LRTI, in 43.3% of those admitted to the intensive care unit (ICU), and in 36.4% of those who died. Infants with RSV infection were younger, were diagnosed with bronchiolitis more frequently, and were less likely to have underlying disorders than those with RSVnegative LRTI. Among RSV-positive infants, admission to the ICU was associated with the presence of underlying conditions, pneumonia diagnosis, and young age. Four (0.73%) of the 547 infants with RSV infection died; death was more common in those with underlying disorders than previously healthy infants (3.8 vs. 0.2%, respectively; p 5 0.02). Conclusion. RSV contributes to a large proportion of LRTI hospital admissions. Most children admitted with RSV infection do not have underlying conditions. However, severe infection requiring ICU admission and death are more common in those with underlying disorders. Ó 2019 IMSS. Published by Elsevier Inc. Key Words: Respiratory syncytial virus, Bronchiolitis, Pneumonia, Acute respiratory infection.
Introduction Lower respiratory tract infections (LRTI) are the fifth most common cause of death worldwide (1). Results of the Global Burden of Disease Study indicate that LRTI caused 2.74 million deaths globally in 2015 (1). In addition, respiratory infections often trigger life-threatening exacerbations
Address reprint requests to: Daniel E. Noyola, Microbiology Department, Facultad de Medicina, Universidad Autonoma de San Luis Potosı, Avenida Venustiano Carranza 2405, San Luis Potosı, 78210, Mexico; Phone: (þ52) (444) 8262344; ext. 6656; E-mail: [email protected]
of chronic respiratory and cardiac diseases, resulting in a greater impact than LRTI-associated mortality alone (2). Respiratory syncytial virus (RSV, recently renamed as Human orthopneumovirus) is the most common respiratory pathogen in children with acute LRTI (3,4). A global systematic review estimated that during 2015, 33.1 million RSV-LRTI episodes occurred in children younger than 5 years, resulting in approximately 3.2 million hospital admissions and 59,600 in-hospital deaths; 45% of these hospital admissions and in-hospital deaths are estimated to have occurred in children younger than 6 months (5). In the United States it is estimated that each year RSV infections result in 1 in 334 hospitalizations, 1 in 38 visits to an
0188-4409/$ - see front matter. Copyright Ó 2019 IMSS. Published by Elsevier Inc. https://doi.org/10.1016/j.arcmed.2019.10.005
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emergency department, and 1 in 13 visits to a primary care office in children !5 years of age (6). Despite the increasing awareness of the impact of RSV as a cause of hospitalizations and mortality, available data about the impact of RSV in Latin America is limited. A review published in 2014 found that the proportion of RSV detection among Latin American children 0e59 months of age with LRTI was 27.5% (7). However, studies that have analyzed data of young infants report higher detection rates of RSV in hospitalized patients. For instance, a study from Brazil that included infants !3 years of age with LRTI identified the presence of RSV in 53.5% of them (8); in Argentina, RSV infection was confirmed in 65.5% of infants !12 months of age admitted with a respiratory infection during the RSV season (9). Data on population-based incidence of RSV-LRTI in Latin American countries is scarce; recent estimates report figures ranging between 40.3 episodes/1,000 children ! 5 years of age in Costa Rica and 54.6 episodes/1,000 children !5 years of age in El Salvador (5). Overall, estimated RSV-hospitalization rates in Latin America are significantly higher than those estimated for children !5 years of age in the United States (3/1,000) (6). In addition, in spite of the clinical impact of RSV there is limited information regarding case-fatality rates on a global scale, as well as the characteristics of fatal RSV cases (10). The objective of this study was to determine the contribution of RSV as a cause of LRTI in hospitalized children, and to describe the characteristics of children infected with this virus in Mexico.
Materials and Methods The study was carried out at a second-level hospital which provides specialized pediatric and gyneco-obstetric medical care to mid and low-income populations. The hospital has 45 pediatric beds and 45 gynecology-obstetrics beds, as well as 10 neonatal intensive care unit beds and 8 intensive care beds. Most of the population that receives medical care at this hospital is protected by a governmental health insurance system (Seguro Popular). Children admitted to the hospital with LRTI between November 15, 2012 and December 12, 2015 were eligible for study participation. Patients admitted for other diagnoses and who developed acute respiratory infection symptoms in the hospital were excluded from analysis. Patients were enrolled Monday through Friday and enrollment hours were 7:00e15:00. All pediatric wards, the emergency department, and intensive care units were visited to identify patients admitted with LRTI diagnosis. Patients were considered to have LRTI if they presented with respiratory symptoms (such as cough, rhinorrea, nasal congestion, sneezing) and signs of lower respiratory tract involvement (respiratory distress, crackles, wheezing, or chest-x ray
infiltrates). Diagnostic categories were based on the diagnosis established by the treating physician. In general, patients were diagnosed with pneumonia when they had presence of crackles or respiratory distress and x-ray pneumonic infiltrates; bronchiolitis was diagnosed in patients with wheezing or respiratory distress and x-ray finding consistent with this diagnosis (air trapping, rib horizontalization); and whooping cough was considered in patients with characteristic cough episodes, apnea, cyanosis, or lymphocytosis. Viral detection was carried out in respiratory samples. A nasopharyngeal wash was obtained by instillation of 0.5 mL of sterile saline solution using a disposable feeding catheter followed by aspiration. RSV detection was performed using an end-point one-step RT-PCR protocol. This assay is an adaptation of a previously described real-time RT-PCR assay using the Access RT-PCR System (Promega Corporation, Madison, WI, USA) and primers that target the L gene (forward 50 -TCTTCATCACCATACTTTTC TGTTA-3’; reverse 50 -GCCAAAAAATTGTTTCCACAA TA-30 ) (11,12). The amplification program included a retrotranscription step at 50 C for 30 min, followed by 94 C for 2 min, 45 cycles of 20 s at 94 C, 20 s at 55 C, 30 s at 72 C, and a final extension at 72 C for 10 min. PCR products were subjected to electrophoresis on 2.5% agarose gels and digitally documented. Demographic and clinical information were obtained at the time of admission and through review of the medical records and registered in a database. The research protocol was approved by the hospital’s Research and Ethics Committee and signed informed consent was obtained from parents prior to enrollment of children in the study. The characteristics of patients with and without RSV infection were compared. In addition, for RSV positive patients, the characteristics of those admitted to the ICU were compared to those not admitted to the ICU. Comparisons of patient groups were carried out using OpenEpi online software (http://www.openepi.com) and SPSS for Windows (version 25). Categorical variables were compared using Fisher’s exact test or chi-squared test; continuous variables were compared using the Mann-Whitney U test.
Results There were 1,252 children hospitalized with LRTI included during the 38 month study period. The median age of study participants was 7.1 months old (IQR, 3e13.4), 514 (49%) were female, and an underlying disease was present in 264 (21.1%). Sixty (4.8%) patients required admission to the ICU and 11 (0.9%) died. RSV was detected in 547 (43.7%) patients. The most common admission diagnosis was bronchiolitis (48.2%), followed by pneumonia (42.4%); other LRTI diagnoses (such as whooping cough) were registered in 9.3% of patients.
Respiratory Syncytial Virus in Children
RSV showed a seasonal pattern with 97% of RSV-positive hospitalizations occurring between October and March (Figure 1). The highest proportion of RSV-positive cases was detected in December (35.6%), followed by January (22.9%), November (13.0%), and February (12.1%). The characteristics of patients with and without RSV detection are shown in Table 1. RSV-positive children were younger (6.1 months old vs. 7.9 months old; p !0.001). Infants !3 months of age showed the highest proportion (50%) of RSV-positive cases (Figure 2). The proportion of RSV positive cases remained high in infants between 3 and 18 months of age, and this tended to decrease in older children. In general, RSV-positive patients were less likely to have underlying diseases than RSV-negative patients (14.3 vs. 26.4%, respectively; p !0.001). Particularly prematurity, asthma, and bronchopulmonary dysplasia were less frequent in RSV-positive than in RSV-negative patients (Table 1). Bivariate analysis taking into account age as a covariate showed similar results. Overall, symptoms in patients with and without RSV infection were similar (Table 2). However, some differences were noted: RSV-positive patients had a higher frequency of rhinorrhea (83.4 vs. 73.2%, p !0.001), nasal congestion (76.2 vs. 70.4%, p 5 0.02), sneezing (64.5 vs. 56.9%, p 5 0.006), wheezing (76.8 vs. 60.7%, p !0.001), and cough (97.6 vs. 92.9%, p !0.001) than RSV-negative patients. OR estimates, adjusted for age, confirmed that rhinorrhea (OR 1.97, 95% CI, 1.48e2.62; p !0.001), sneezing (OR 1.32, 95% CI, 1.05e1.67; p 5 0.016), wheezing (OR 2.17, 95% CI, 1.69e2.79; p !0.001), and cough (OR 3.18, 95% CI, 1.7e5.49; p !0.001) were associated with RSV infection.
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Table 1. Characteristics of children admitted with and without RSVassociated LRTI RSV positive RSV negative (n [ 547) (n [ 705) Sex Female Male Age, months (median, IQR) Underlying disease a Prematurity Asthma Bronchopulmonary dysplasia Congenital heart disease Down syndrome Tobacco smoke exposure Siblings !5 years old Attends daycare center Discharge LRTI diagnosis Bronchiolitisb Pneumoniab Whooping cough Other Received antibiotics during hospitalization ICU admission ICU admission duration, days (median, IQR) Mechanical ventilation Hospitalization duration (days) (median, IQR) Death Time between admission and RSV testing (days)
225 322 6.1 78 46 14 13 13 4 94 180 14
(41.1%) (58.9%) (2.4e11.7) (14.3%) (8.4%) (2.6%) (2.4%) (2.4%) (0.7%) (17.1%) (32.9%) (2.6%)
289 416 7.9 186 97 62 33 31 8 133 234 20
289 222 34 2 365
(52.8%) (40.6%) (6.2%) (0.4%) (66.7%)
303 352 47 3 440
p
(41%) 0.99 (59%) (3.3e14.7) !0.001 (26.4%) !0.001 (13.8%) 0.002 (8.8%) !0.001 (4.7%) 0.04 (4.4%) 0.05 (1.1%) 0.46 (18.9%) 0.44 (33.2%) 0.92 (2.8%) 0.77 0.007 (43.0%) (49.9%) (6.7%) (0.4%) (62.4%) 0.11
26 (4.8%) 34 (4.8%) 8 (4.0e11.7) 5 (3.0e10.7)
0.96 0.42
23 (4.2%) 4 (3e6.5)
26 (3.7%) 4 (2e6)
0.64 0.96
4 (0.7%) 1 (1e2)
7 (1%) 1 (1e2)
0.65 0.47
a
Some infants had more than one underlying disease. p !0.005.
b
Figure 1. Weekly number RSV detections in children hospitalized with LRTI.
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Figure 2. Age groups of children admitted to the hospital with RSV-positive and RSV-negative LRTI.
Bronchiolitis was the most frequent diagnosis in RSVpositive children (52.8%) and pneumonia in RSV-negative children (49.9%). Patients received antibiotics frequently, and no significant difference was found between those with and without RSV-associated infection. Overall, children with pneumonia diagnosis received antibiotics more frequently than those with bronchiolitis (77.4 vs. 47.7%, respectively; p !0.001). Infants with RSV-bronchiolitis were younger than those with RSV-pneumonia (Table 3). There were no differences in the frequencies of underlying conditions between both groups; however, infants with RSV-bronchiolitis were exposed to tobacco smoke more frequently than those with RSV-associated pneumonia.
Table 2. Symptoms of children admitted with and without RSVassociated LRTI RSV positive (n [ 547) Respiratory distress Cough Rhinorrhea Nasal congestion Wheezing Sneezing Rales Cyanosis Vomiting Diarrhea Apnea Contact with another sick person
535 534 455 417 420 353 308 169 179 76 17 218
(97.8%) (97.6%) (83.4%) (76.2%) (76.8%) (64.5%) (56.3%) (30.9%) (32.7%) (13.9%) (3.1%) (39.9%)
RSV negative (n [ 705) 683 655 516 496 428 401 424 233 212 106 31 217
(96.9%) (92.9%) (73.2%) (70.4%) (60.7%) (56.9%) (60.1%) (33%) (30.1%) (15%) (4.4%) (30.8%)
p 0.32 !0.001 !0.001 0.02 !0.001 0.006 0.17 0.42 0.31 0.57 0.24 0.001
Overall, RSV-pneumonia cases were more severe than bronchiolitis cases; admission to the ICU was required in 10.8% of those with pneumonia compared to 0.7% of those with bronchiolitis and duration of hospitalization was longer.
Table 3. Characteristics of patients with RSV pneumonia and bronchiolitis Pneumonia (n [ 223) Sex Female Male Age months (median, IQR) Underlying disease a Prematurity BPD Asthma Congenital heart disease Down Syndrome Tobacco smoke exposure Siblings !5 years old Attends daycare center Contact with other sick person Antibiotic use during hospitalization ICU admission Mechanical ventilation Duration of hospitalization days (median, IQR) Death a
96 127 7.9 39 16 5 9 8 4 28 66 8 85 180
(43%) (57%) (3.1e15.5) (17.5%) (7.2%) (2.2%) (4.0%) (3.6%) (1.8%) (12.6%) (29.6%) (3.6%) (38.1%) (80.7%)
Bronchiolitis (n [ 290)
117 173 5.9 35 26 7 5 5 1 58 100 6 114 157
p
(40.3%) 0.54 (59.7%) (3.0e10.5) 0.005 (12.1%) 0.08 (8.9%) 0.46 (2.4%) 0.89 (1.7%) 0.11 (1.7%) 0.18 (0.3%) 0.23 (20.0%) 0.02 (34.5%) 0.24 (2.1%) 0.29 (39.3%) 0.82 (54.1%) !0.001
24 (10.8%) 21 (9.4%) 5.0 (3.0e7.0)
2 (0.7%) 2 (0.7%) 4.0 (3.0e6)
!0.001 !0.001 0.003
4 (1.8%)
0 (0%)
0.07
Some infants had more than one underlying disease.
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Table 4. Characteristics of patients with RSV-associated LRTI admitted and not admitted to the ICU ICU admission (n [ 26) Sex Female Male Age months (median, IQR) Underlying diseasea Prematurity BPD Asthma Congenital heart disease Down Syndrome Tobacco smoke exposure Siblings !5 years old Attends daycare center Contact with other sick people Antibiotic use during hospitalization Mechanical ventilation Duration of hospitalization days (median, IQR) Discharge LRTI diagnosis Bronchiolitisb Pneumoniab Whooping cough Other Death
Not admitted to the ICU (n [ 521)
10 16 2.4 10 6 1 1 3 0 2 4 0 11 21 23 13
(38.5%) (61.5%) (1.6-7.5) (38.5%) (23.1%) (3.8%) (3.8%) (11.5%) (0%) (7.7%) (15.4%) (0%) (42.3%) (80.8%) (88.5%) (8-16.2)
215 306 6.3 68 40 12 13 10 4 92 176 14 207 344 0 4
(41.3%) (58.7%) (2.5-12.0) (13.1%) (7.7%) (2.3%) (2.5%) (1.9%) (0.8%) (17.7%) (33.8%) (2.7%) (39.9%) (66.0%) (0.0%) (3-6)
2 24 0 0 4
(7.7%) (92.3%) (0%) (0%) (15.4%)
287 198 34 2 0
(55.1%) (38.0%) (6.5%) (0.4%) (0%)
p
0.78 !0.001 !0.001 0.02 0.47 0.49 0.04 1.0 0.28 0.05 1.0 0.57 0.12 !0.001 !0.001 0.007
!0.001
a
Some infants had more than one underlying disease. p !0.005.
b
Sixty patients were admitted to the ICU; children with underlying disorders were more likely to require ICU admission (9.5%) compared to those without underlying diseases (3.5%; p !0.001). Infants with congenital heart disease had the highest ICU admission rate (15.9%), followed by those with bronchopulmonary dysplasia (10.9%). Twenty-six (4.8%) of the 547 patients with RSV infection required admission to the ICU. The characteristics of these patients and of those that were not admitted to the ICU are compared in Table 4. RSV-positive patients that required intensive care treatment were more likely to have underlying diseases (38.5 vs. 13.0%; p !0.001) and were younger (2.4 vs. 6.7 months old; p !0.01) than those not admitted to the ICU; 60% of infants with RSV infection who required admission to the ICU were under 6 months old. Regarding underlying disorders, the most notable differences between children admitted and not admitted to the ICU were the history of prematurity (23.1 vs. 7.7%; p 5 0.02) and diagnosis of congenital heart disease (11.5 vs. 1.9%; p 5 0.04). In the bivariate analysis adjusted for age, the history of any underlying disease (OR 4.22, 95% CI, 1.83e9.74; p 5 0.001), congenital heart disease (OR 7.65, 95% CI, 1.9e30.75; p 5 0.004), and a history of prematurity (OR 3.17; 95% CI, 1.19e8.41; p 5 0.02) were associated with ICU admission in children with RSV infection. Pneumonia was the most common diagnosis in RSVpositive children who were admitted to the ICU (69.2%);
in contrast, bronchiolitis was more frequent in children who did not require intensive care (55.1%). As such, pneumonia diagnosis was associated with severe infection (OR adjusted by age of 5.07, 95% CI, 2.014e12.01; p !0.001) compared to other diagnoses (including bronchiolitis). The median total hospitalization duration for children who required admission to the ICU was 13 d (IQR, 8e13) compared to 4 d (IQR, 3e6; p !0.001) for children who did not require ICU admission. Four (15.4%) of the 26 RSV-positive patients that were admitted to the ICU died. All of them had a diagnosis of pneumonia, two were female, and the median age on admission was 9.3 months (IQR, 2.8e19.1). Three of these children (75%) had an underlying disease (two with heart disease and one with history of prematurity). The overall case-fatality rate for children admitted with RSV infection was 0.73% (4 of 547 patients). Infants with underlying conditions had a higher mortality rate (3.8%) compared to previously healthy infants (0.2%; p 5 0.02).
Discussion This study describes the characteristics of RSV infections in Mexican children hospitalized with LRTI. With the use of molecular detection methods, we identified the presence of RSV in 43.7% of LRTI cases. In a review of studies carried out in Latin America, the proportion of RSV detection in children 0e59 months of age with LRTI was 27.5% (7).
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Of note, this review included reports that used immunofluorescence and viral culture, which are less sensitive than RT-PCR. A multicenter study that included 1,404 Mexican children !5 years of age with pneumonia identified RSV (either alone or in combination with other viruses) in 38.1% of them (3). A study carried out in Guatemala reported detection of RSV in 32.3% of children !5 years old hospitalized with respiratory infection (13). Analyses restricted to younger infants have reported higher proportions of RSV infections (8,9). Therefore, the contribution of RSV to LRTI requiring admission to the hospital in our region may be higher than previously estimated figures. High detection rates of RSV in hospitalized children have also been found in developed countries; for example, in a study carried out in Canada, this virus was detected in 63.6% of infants !3 years old hospitalized with respiratory tract infections (14). As such, the leading role of RSV as a cause of LRTI admissions is noteworthy worldwide. In concordance with other studies, age under 6 months old, history of prematurity, and the presence of underlying conditions were the most frequent factors associated with severe RSV infection (14e17). Although the frequency of bronchopulmonary dysplasia and congenital heart disorders was low among children included in the present study, the frequency of prematurity was similar to that reported by other authors. The ICU admission rate (4.8%) and case fatality rate (0.73%) for infants admitted with RSV infection in the present study are similar to those reported at a General Hospital in Mexico (5.2 and 1.04%, respectively) (18). In a study from Argentina, the case fatality rate for RSV LRTI cases was 0.9%, and RSV was detected in 54% of children with LRTI who died after the neonatal period who were tested for this virus (9). In the present study, 36.3% of the children with LRTI who died had RSV confirmed infection. These figures underscore the potential severity of RSV infections. In our study, the majority of RSV cases that required ICU admission did not have an underlying disorder (61.5%); however, three of the four fatal RSV cases occurred in infants with underlying conditions. In a study carried out at a third-level hospital in Mexico City 12 of 14 children (85.7%) who died among those with diagnosis of RSV infection had an underlying condition (19). A recent report indicated that underlying conditions were present in 70% of fatal RSV cases in high-income countries, while these were reported in only 28% of fatal cases in low-income or lower-middle-income countries (10). Although Mexico is classified as an upper middle-income country, several characteristics of children with severe disease in the present study were similar to those reported for high-income countries; however, it is noteworthy that the number of fatal cases in our study was small. In the present study 96% of RSV infections were detected between October and March. This seasonal pattern is similar to the one previously reported from other studies
carried out in different cities in Mexico (3,18,20). Our results provide further support regarding the seasonal pattern for RSV in Mexico. A limitation of our study is that, in addition to RSV detection, no further characterization of this virus was carried out. Previous studies in Mexico have shown that both RSV A and B may circulate during the same season (21). While RSV A is detected more frequently than RSV B, during some seasons RSV B can be the predominant virus (22,23). Previous studies in Mexico have shown that during the 2012e2013 winter season RSV A was the most common RSV group, while RSV B predominated during the 2013e2014 and 2014e2015 seasons (20,24). As such, it is likely that infections by both RSV A and B may have occurred in our study population. Of note, although several studies have assessed whether severity of illness may be associated with the viral genotype, most studies have not found a major difference between infections caused by RSV A and RSV B viruses (20,24e27). Another limitation is that virological testing was carried out only for RSV. Although information regarding the role of other respiratory pathogens as the cause of LRTI is of great interest, this project was focused on RSV, since it is known to be the major etiological agent for severe respiratory infections in young children (3,4,13). In summary, our results indicate that, in our community, RSV causes a large proportion of LRTI in children. The majority of infants admitted with infection due to this virus do not have underlying disorders. Almost 5% of children admitted with RSV required ICU admission and the case fatality rate was 0.73%. In the present study the history of prematurity, congenital heart disease, having contact with another sick person, and the diagnosis of pneumonia were the most significant factors associated with severe RSV infection. These results contribute to the assessment of the impact of this virus as a cause of morbidity and mortality in Mexico and Latin America. Potential Conflicts of Interest AMGO, ACG, SBS, MVM, and MEGR declare that there are no conflicts of interest regarding the publication of this manuscript. DEN has participated as a member of the speakers’ bureau of AbbVie and speakers’ bureau and advisory board for Sanofi Pasteur. References 1. GBD 2015 LRI Collaborators. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infection in 195 countries: a systematic analysis of the Global Burden of Disease Study 2015. Lancet Infect Dis 2017;17: 1133e1161. 2. Tang JW, Lam TT, Zaraket H, et al. Global epidemiology of noninfluenza RNA respiratory viruses: data gaps and a growing need for surveillance. Lancet Infect Dis 2017;17:e320ee326.
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