Acute lower respiratory infection (ALRI) is the most common reason for outpatient visits, school absenteeism and hospitalizations among children.1,2 In Argentina, it is an important cause of mortality as well as hospital admissions during the winter months in all age groups, particularly in children under 5 years of age and adults older than 65 years of age. Most of these infections are viral in origin generating significant morbidity and mortality in individuals with risk factors.3 Respiratory syncytial virus (RSV) is the main cause of bronchiolitis and pneumonia in infants and young children worldwide.4 Primary infection usually occurs in young children 6 weeks to 2 years of age2,5–9 and is a leading cause of death in infants under 6 months of age. Mortality rates are higher in developing countries than in developed countries, particularly in children less than 5 years of age.10
RSV is spread through direct or indirect contact with nasal and oral secretions of infected individuals. Children are primarily responsible for transmission because they have higher viral loads than adults.11 Reinfections can occur in any stage of life and are usually mild or asymptomatic in adults, but can cause severe disease in the elderly.12 RSV is also an important pathogen in other risk groups such as preterm infants and children with bronchopulmonary dysplasia or hemodynamically unstable congenital heart disease (CHD).13 Worldwide, this virus is responsible for 30 million episodes of ALRI and for more than 50,000 deaths per year in children under 5 years of age.14 A recent publication on global RSV mortality, which included data from our hospital, estimated that the virus causes one-third of all deaths in children less than 1 year of age.15 In Argentina, based on information provided by the National Laboratory-based Surveillance System (SNVS-SIVILA), of 30,949 positive respiratory samples collected in 2017 between epidemiologic weeks 1 and 44, RSV was the main pathogen found in 61.4% (n = 18,738) of samples, followed by influenza viruses (IF) 20.8% (n = 6349).16
Given the global burden of RSV disease in children, the aim of this study was to describe the clinical and epidemiologic characteristics of RSV-ALRI and estimate case fatality risk factors in patients admitted to our hospital.
We conducted a prospective, cross-sectional study. Patients with ALRI acquired in the community admitted to the Ricardo Gutierrez Children’s Hospital, Buenos Aires, between 2000 and 2017 were identified through an active surveillance program.
All children less than 18 years of age hospitalized for ALRI acquired in the community, namely those presenting bronchiolitis or pneumonia, were included. Both definitions met World Health Organization criteria for ALRI.17
Patients admitted for other causes who developed ALRI during hospitalization were excluded.
Data were collected using a specific case-report form and included date of admission, demographics (age, sex, city of residence), clinical presentation (bronchiolitis, pneumonia), previous hospitalizations for respiratory diseases, readmission within the same episode, co-morbidities, history of close contact with individuals presenting acute respiratory symptoms of probable viral origin (runny nose, cough and/or fever), perinatal respiratory disorders, complications during hospitalization, treatment, length of stay and outcome (discharged home, transferred to another hospital or died). Comorbidities included chronic or recurrent respiratory disease, moderate-to-severe malnourishment, CHD, genetic or neurologic diseases and immunodeficiency.
Chronic or recurrent respiratory disease was also reported, namely, recurrent obstructive bronchitis or asthma (2 or more episodes of bronchial-obstruction), gastroesophageal reflux disease, cystic fibrosis, bronchopulmonary dysplasia, recurrent laryngitis and pneumonia, as were in-hospital complications such as nosocomial infections, sepsis, persistent atelectasis, pneumothorax, pleural effusion, pulmonary bullae, lung abscesses, ear infections, diarrhea, seizures and meningitis.
Nosocomial infection was defined as exacerbation of respiratory symptoms not present at admission (even if incubation was a possibility), diagnosed in patients hospitalized for ≥48 hours, presenting fever, increased oxygen requirement or changes in radiologic pattern.
World Health Organization guidelines were used for clinical and radiologic diagnosis of bronchiolitis and pneumonia.17 Viral diagnosis was performed in all cases by indirect fluorescent antibody testing on nasopharyngeal specimens. After real-time polymerase chain reaction assay became available in 2009, it has been used together with indirect fluorescent antibody test to detect RSV, IF A and B, parainfluenza and adenovirus. Commercially available kits were used in all cases.
Categorical variables were analyzed using the χ2 test with Yates correction. We used the Wilcoxon test for median age comparison. Odds ratio with 95% confidence interval was used for association analysis; a bivariate analysis was performed initially to identify significant associations, and multivariate logistic regression was subsequently carried out to establish independent predictors of case fatality. P values <0.05 were considered statistically significant. STATA/SE version 13 (StataCorp LLC, TX) was used for the analysis.
A logistic regression model was constructed to identify the predictors of mortality by RSV. The variables with significant association with death in the crude analysis and/or those considered clinically relevant were added one at a time in the multivariate model, and only those significantly associated with the outcome in the multivariable context (Wald test) were retained in the final model. We checked the changes on the coefficients to find confounding variables.
Calibration and Discrimination
The calibration and discrimination of the model were evaluated with the Hosmer–Lemeshow goodness-of-fit test and the area under the receiver operating characteristic curve.
RSV season onset and offset were calculated as described by Panozzo et al in 2007.18
Privacy rights of patients were observed in all cases in accordance with the World Medical Association Declaration of Helsinki International Code of Ethics for experiments involving humans. Patient’s informed consent is not applicable in this study because data were obtained from a routine epidemiologic surveillance activity included in the framework of Argentinean Law 15465/60. The study was approved by the Ethics and Research Committees of the Ricardo Gutierrez Children’s Hospital. This study will not affect human rights, nor will it cause damage to the environment, animals and/or future generations.
A total of 15,451 patients were admitted for ALRI acquired in the community over a period of 18 years, from them 13,033 (84%) children were tested for respiratory viruses and 5831 (45%) had positive results (see Figure, Supplemental Digital Content 1, http://links.lww.com/INF/D397).
RSV predominated throughout the entire study period (4738, 81.3%), followed by IF (440, 7.6%), parainfluenza (402, 6.9%) and adenovirus (251, 4.3%).
RSV had a seasonal epidemic pattern (viral activity onset and offset 18 and 33 epidemiologic weeks, respectively) coinciding with months of lowest median temperature and highest relative humidity (May to July). (Figure 1)
In our study population, there was a slight predominance of boys (56.5%), and the median age was 7 months (interquartile range: 2–12); almost two-thirds were infants less than 12 months and 42% less than 6 months of age.
The distribution of the different clinical and epidemiologic characteristics of patients with RSV disease and their relationship with the outcome (death) is expressed in Table 1, comparing nonfatal and fatal cases.
RSV case fatality rate was 1.7% (82/4687).
The annual mortality rate distribution was not stable over the study period with the highest mortality in the year 2002. (Figure 2)
In fatal cases, the most frequent complications were respiratory distress (80.5%), nosocomial infections (45.7%), sepsis (31.7%) and atelectasis (13.4%) (Table 2).
Independent predictors of RSV mortality were moderate-to-severe malnourishment, chronic neurologic disease, CHD and the age less than 6 months (Table 3).
The final model achieved good calibration (P=0.85) and discrimination with an area under the receiver operating characteristic curve of 0.712.
In this study, we evaluated the characteristics and outcome of patients with RSV-ALRI based on active surveillance and systematic data collection over a period of 18 years. Active surveillance of ALRI is crucial for rapid detection of increase in number of cases, identification of high risk groups and to determine the frequency, distribution and characteristics of disease-causing agents.19,20
RSV was the most frequent pathogen found in positive samples from the patients included in our center (81.3%) and that incidence was highest in infants less than 1 year of age (74% of cases). These results are similar to those of other epidemiologic studies carried out in the region.21–23
RSV circulation showed a seasonal epidemic pattern as seen in temperate climate regions. Onset and offset of viral activity were registered during epidemiologic weeks 18 and 33, respectively, coinciding with months of lowest median temperature and highest relative humidity in Argentina (May–July).23 Kamigaki et al found that mean temperature and specific humidity were also positively associated with influenza and RSV at Philippine sites.24 In addition, Meerhoff et al, reported that the combination of both (temperature and humidity) contribute more to RSV activity than each factor independently.25 Furthermore, Walton et al showed that real-time weather forecasts have the potential to predict RSV outbreaks.26 Although we found a similar epidemic seasonal pattern, a proper time-series analysis is needed to draw robust conclusions as mentioned by the authors.
Around the world, 1%–3% of healthy children are hospitalized as result of RSV respiratory infections during the first year of life.2,3,6,27 In our study, although most patients were healthy children younger than 1 year of age, patients with underlying conditions such as prematurity, CHD, malnutrition and chronic neurologic disease showed higher rates of mortality.28,29 In a meta-analysis on incidence and mortality of RSV infections in children, Stein et al concluded that the virus was an important cause of hospitalization and mortality, and that gestational age was a critical determinant of disease severity in the first year of life.30 Unfortunately, as we have not recorded gestational age data in the whole series, we could not include this variable in the analysis.
Although being a boy was found to be a risk factor in some studies,31 we did not observe significant gender differences in our population. Regarding CHD, a 20-year systematic review was undertaken across studies reporting data for hospital visits/admissions for RSV infection among children with CHD, concluding that young children with CHD have a significant risk for RSV mortality.32 This risk is specially for severe disease and hospitalization and, in some instances, may require admission to the intensive care unit, supplemental oxygen therapy and prolonged mechanical ventilation.33,34
In a study based on national data sets, Byington et al also found children with complex chronic conditions accounted for most RSV-associated deaths.35 Scheltema et al also found that more than half of all children included in the RSV Gold RSV-associated study had a weight for age of less than −2 standard deviations.15 García et al describe several factors that independently correlated with the severity of illness as trisomy 21, lower weights on admission, neuromuscular disorders.28
Death from RSV infection was more common in patients requiring mechanical ventilation, longer hospital length of stay, presenting sepsis and atelectasis, in line with other regional studies.36,37 Most deaths were associated with complex chronic conditions or acute disorders such as sepsis or respiratory failure. Moreover, many children have more than 1 complication during hospitalization.
Case fatality rate was 1.7% (82/4687) similar to values reported by Nair et al who found rates of 0.3% and 2.1% in children under 5 years and 0.7% and 2.1% in infants (<1 year of age) for industrialized and developing countries, respectively.38
One of the strengths of this study lies in its methodologic design, a prospective active surveillance based on robust epidemiologic data, a sample large enough that allows statistical robust conclusions and individual data of each patient. The model showed good calibration and discriminative capacity in the studied population.
In addition, indirect immunofluorescence test is recommended for rapid detection and diagnosis of respiratory viruses. This method is widely used because it is a simple, quick, low-cost test with high specificity and sensitivity detecting viruses that usually cause ALRI, namely RSV, IF, parainfluenza and adenovirus.38–41
As a limitation, this study was conducted in a single tertiary hospital, so the complexity of our patients makes it difficult to extrapolate results to the general population. The high proportion of comorbidities in our patients perhaps overestimates the more severe RSV symptoms when we analyzed complications. Moreover, hospital case-fatality ratios cannot be translated to population-based mortality.
Around 60 different strategies to prevent RSV infection are being developed involving candidate vaccines and human monoclonal antibodies, of which 16 are currently undergoing phase I–III studies.42 The data afforded by this epidemiologic study and other similar investigations will be crucial to assess the effectiveness and impact of new RSV vaccines, as well as for establishing age-specific immunization strategies and harmonizing health care policies.43
In conclusion, multiple independent characteristics have been identified, which significantly increase the risk of death in the population studied.
1. Russ C, Ellis A; Sociedad Argentina de Pediatría. Sincicial Respiratorio. In: Libro Azul de Infectología Pediátrica. 2012.4th ed. Buenos Aires: Sociedad Argentina de Pediatria.
2. Pickering LK, Baker CJ, et al; American Academy of Pediatrics
. In: Red Book: 2012 Report of the Committee on Infectious Diseases. 2012:Elk Grove Village, IL: American Academy of Pediatrics
3. Direccion General de Informatica Clinica y Epidemiologia (DEIS). Estadisticas Vitales Argentina, 2012. Available at: http://www.deis.gov.ar/
. Accessed: January 22, 2014.
4. Shi T, McAllister DA, O’Brien KL, et al; RSV Global Epidemiology
Network. 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;390:946–958.
5. Hall CB MC. Mandell GL, Bennet JE, Dolin R. Respiratory Syncytial Virus
. In: Principles and Practices of Infectious Diseases 1995:4th ed. NY: Churchill Livingstone, 1501–18.
6. Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus
infection in young children. N Engl J Med. 2009;360:588–598.
7. Prendergast C, Papenburg J. Rapid antigen-based testing for respiratory syncytial virus
: moving diagnostics from bench to bedside? Future Microbiol. 2013;8:435–444.
8. Korppi M, Kotaniemi-Syrjänen A, Waris M, et al. Rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis
. Pediatr Infect Dis J. 2004;23:995–999.
9. Jartti T, Lehtinen P, Vuorinen T, et al. Respiratory picornaviruses and respiratory syncytial virus
as causative agents of acute expiratory wheezing in children. Emerg Infect Dis. 2004;10:1095–1101.
10. UN Inter-Agency Group for Childhood Mortality Estimation. Level & Trends in Child Mortality. 2013. NY, Available at: http://www.childmortality.org
. Accessed June 5, 2014.
11. DeVincenzo JP, Wilkinson T, Vaishnaw A, et al. Viral load drives disease in humans experimentally infected with respiratory syncytial virus
. Am J Respir Crit Care Med. 2010;182:1305–1314.
12. Falsey AR, Hennessey PA, Formica MA, et al. Respiratory syncytial virus
infection in elderly and high-risk adults. N Engl J Med. 2005;352:1749–1759.
13. Fernandez Jonusas S, Albas Maubett D, Satragno D, et al. [Recommendations for palivizumab use. Update 2015]. Arch Argent Pediatr 2016;114(1):84–88.
14. Comite de infecciones Respiratorias. Consenso de la Sociedad Latinoamericana de Infectología Pediátrica sobre neumonia adquirida en la comunidad. Revista de Enfermedades Infecciosas en Pediatria 2010;24(94):1–23.
15. Scheltema NM, Gentile A, Lucion F, et al; PERCH Study Group. Global respiratory syncytial virus
-associated mortality in young children (RSV GOLD): a retrospective case series. Lancet Glob Health. 2017;5:e984–e991.
17. Roth D CL, Ezzati M, Black R. Acute lower respiratory infections in childhood: opportunities for reducing the global burden through nutritional interventions. Bulletin of the World Health Organization 2008;86(5):321–416.
18. Panozzo CA, Fowlkes AL, Anderson LJ. Variation in timing of respiratory syncytial virus
outbreaks: lessons from national surveillance. Pediatr Infect Dis J. 2007;26(11 Suppl):S41–S45.
21. Piñeros JG, Baquero H, Bastidas J, et al. Respiratory syncytial virus
infection as a cause of hospitalization in population under 1 year in Colombia. J Pediatr (Rio J). 2013;89:544–548.
22. Gamiño-Arroyo AE, Moreno-Espinosa S, Llamosas-Gallardo B, et al; Mexico Emerging Infectious Diseases Clinical Research Network (La Red). Epidemiology
and clinical characteristics of respiratory syncytial virus
infections among children and adults in Mexico. Influenza Other Respir Viruses. 2017;11:48–56.
23. Gurgel RQ, Bezerra PG, Duarte Mdo C, et al. Relative frequency, Possible Risk Factors, Viral Codetection Rates, and Seasonality of Respiratory Syncytial Virus
Among Children With Lower Respiratory Tract Infection in Northeastern Brazil. Medicine (Baltimore). 2016;95:e3090.
24. Kamigaki T, Chaw L, Tan AG, et al. Seasonality of Influenza and Respiratory Syncytial Viruses and the Effect of Climate Factors in Subtropical-Tropical Asia Using Influenza-Like Illness Surveillance Data, 2010 -2012. PLoS One. 2016;11:e0167712.
25. Meerhoff TJ, Paget JW, Kimpen JL, et al. Variation of respiratory syncytial virus
and the relation with meteorological factors in different winter seasons. Pediatr Infect Dis J. 2009;28:860–866.
26. Walton NA, Poynton MR, Gesteland PH, et al. Predicting the start week of respiratory syncytial virus
outbreaks using real time weather variables. BMC Med Inform Decis Mak. 2010;10:68.
27. Walsh EE. Respiratory Syncytial Virus
Infection: An Illness for All Ages. Clin Chest Med. 2017;38:29–36.
28. García CG, Bhore R, Soriano-Fallas A, et al. Risk factors in children hospitalized with RSV bronchiolitis
versus non-RSV bronchiolitis
29. Andres S, Bauer G, Rodríguez S, et al. Hospitalization due to respiratory syncytial virus
infection in patients under 2 years of age with hemodynamically significant congenital heart disease. J Pediatr (Rio J). 2012;88:246–252.
30. Stein RT, Bont LJ, Zar H, et al. Respiratory syncytial virus
hospitalization and mortality: Systematic review and meta-analysis. Pediatr Pulmonol. 2017;52:556–569.
31. Robledo-Aceves M, Moreno-Peregrina MJ, Velarde-Rivera F, et al. Risk factors for severe bronchiolitis
caused by respiratory virus infections among Mexican children in an emergency department. Medicine (Baltimore). 2018;97:e0057.
32. Checchia PA, Paes B, Bont L, et al. Defining the Risk and Associated Morbidity and Mortality of Severe Respiratory Syncytial Virus
Infection Among Infants with Congenital Heart Disease. Infect Dis Ther. 2017;6:37–56.
33. Medrano López C, García-Guereta L; CIVIC Study Group. Community-acquired respiratory infections in young children with congenital heart diseases in the palivizumab era: the Spanish 4-season civic epidemiologic study. Pediatr Infect Dis J. 2010;29:1077–1082.
34. Butt M, Symington A, Janes M, et al. Respiratory syncytial virus
prophylaxis in children with cardiac disease: a retrospective single-centre study. Cardiol Young. 2014;24:337–343.
35. Byington CL, Wilkes J, Korgenski K, et al. Respiratory syncytial virus
-associated mortality in hospitalized infants and young children. Pediatrics
36. Bardach A, Rey-Ares L, Cafferata ML, et al. Systematic review and meta-analysis of respiratory syncytial virus
in Latin America. Rev Med Virol. 2014;24:76–89.
37. Castillo LM, Bugarin G, Arias JC, et al. One-year observational study of palivizumab prophylaxis on infants at risk for respiratory syncytial virus
infection in Latin America. J Pediatr (Rio J). 2017;93:467–474.
38. Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory syncytial virus
in young children: a systematic review and meta-analysis. Lancet. 2010;375:1545–1555.
39. Portillo C CJ. A quick diagnostic immunofluorescence test in children hospitalized with acute respiratory infections. Arch Argent Pediatr 2000;98(2):99–102.
40. Griffin MR, Walker FJ, Iwane MK, et al; New Vaccine Surveillance Network Study Group. Epidemiology
of respiratory infections in young children: insights from the new vaccine surveillance network. Pediatr Infect Dis J. 2004;23(11 Suppl):S188–S192.
41. Sadeghi CD, Aebi C, Gorgievski-Hrisoho M, et al. Twelve years’ detection of respiratory viruses by immunofluorescence in hospitalised children: impact of the introduction of a new respiratory picornavirus assay. BMC Infect Dis. 2011;11:41.
42. Lucion MF VM, Gentile A. RSV a promising future for vaccines. Rev Hosp Niños 2018;60(268):118–24.
43. Anderson LJ. Respiratory syncytial virus
vaccine development. Semin Immunol. 2013;25:160–171.