Risk factors of severe hospitalized respiratory syncytial virus infection in tertiary care center in Thailand

Abstract Aim To determine factors associated with severe hospitalized Respiratory syncytial virus (RSV)‐associated LRTI and to describe management in tertiary care center. Methods Retrospective medical record review was conducted among children under 5 years old hospitalized with RSV‐associated LRTI at King Chulalongkorn Memorial Hospital. Severe RSV‐associated LRTI was defined as death, mechanical ventilator, or positive pressure ventilation use, prolonged hospitalization >7 days. Factors associated with severe RSV were analyzed using univariate and multivariate logistic regression. Results From January 2011 to December 2016, 427 children were hospitalized. Median age was 10 months (IQR 4.2‐23.0). One hundred seventy‐four (41%) patients had severe RSV (11 deaths, 56 mechanical ventilators, 19 positive pressure ventilation, and 88 prolonged hospitalization). Factors associated with severe RSV were chronic lung disease (aOR 15.16 [4.26‐53.91]), cirrhosis/biliary atresia (aOR 15.01 [3.21‐70.32]), congenital heart disease (aOR 5.11 [1.97‐13.23]), chemotherapy (aOR 4.7 [1.34‐16.56]), and pre‐term (aOR 2.03 [1.13‐3.67]). Oxygen therapy was mainly low flow oxygen delivery. 88% of cases received bronchodilator. Parenteral antibiotics were prescribed in 37.9% of cases. Conclusions Children with co‐morbidities have higher risk of severe RSV‐associated LRTI. More than two‐third of patients received bronchodilator, of which was not recommended by American Academy of Pediatrics. The specific treatment and prevention for RSV are urgently needed.


| INTRODUC TI ON
Respiratory syncytial virus (RSV) infection is well-known for childhood hospitalization from acute lower respiratory tract infection (LRTI) especially young children in developing country. 1 About 200 000 deaths occurred from RSV-associated LRTI worldwide each year. 2 High incidence of hospitalization due to RSV-associated LRTI is associated with higher risk of in-hospital mortality. 3 In Thailand, incidence of acute RSV-associated LRTI in year 2008-2011 was 85/100 000 persons/year particularly children age 5 years. 4 Seasonality of RSV was usually occurred during July to October. [4][5][6] After 3-7 days of incubation period, patient with RSV-associated LRTI may have common symptoms such as fever, runny nose, cough, wheezing, or difficult breathing. 2 Confirmation usually be done by RSV Ag rapid test on sample collected from nasopharyngeal swab. 3 Risk factors for severe RSV-associated LRTI have been described in many studies such as infant, prematurity, cardiopulmonary disease, bacterial co-infection, proximity of birth to RSV season, exposure to environmental smoking, male sex, and familial atopy. [7][8][9][10][11] Also laboratory finding, thrombocytosis at time of diagnosis is one of predictors for severe RSV-associated LRTI. 12 Nosocomial infection is one of the factors associated with intensive care unit and mortality. 13,14 Currently, there is immunoprophylaxis for RSV, a humanized monoclonal antibody called palivizumab, and it has been used in many developed country but only for pre-term infant gestational age <29 weeks, infant with chronic lung disease, and children with hemodynamically significant heart disease. 7 However, the availability in developing countries is limited.
As RSV-associated LRTI responsible for majority of acute lower respiratory tract infection, many treatment modalities were used.
For RSV-associated LRTI, American Academy of Pediatrics (AAP) recommended treatment is mainly supportive (oxygen supplement to maintain oxygen saturation and fluid therapy), and other treatments such as bronchodilators, epinephrine, corticosteroid, hypertonic saline, and antibiotics are not useful. 7 However, there is limited information of pattern of treatment in developing country including

Thailand.
This study aimed to determine factors associated with severe hospitalized RSV-associated LRTI and to describe pattern of management in tertiary care center in Thailand. [BIPAP]), or prolong length of hospital stay in community-acquired RSV-associated LRTI (more than 7 days) and in-hospital death which would be discussed separately. Co-morbidity or underlying disease was condition of patient prior to RSV-associated LRTI. Chronic lung disease such as bronchopulmonary dysplasia was determined regardless of home oxygen use. Immunocompromised status included congenital immunodeficiency, HIV, on immunosuppressive medication, or chemotherapy. Perinatal history, pre-term was defined as patient born at gestational age <37 weeks. Low birthweight was <2500 g.

| MATERIAL AND ME THODS
Physical examination was from initial presentation. Diagnosis of RSV was made by attending physician. Lower respiratory tract infection was bronchitis, bronchiolitis, and pneumonia. Thrombocytosis was defined as platelet count more than 400 000/µL. Oxygen therapy was analyzed from maximum oxygen delivery use as low flow oxygen, high flow oxygen, non-invasive positive pressure ventilation, and invasive ventilation, respectively.
Factors associated with severe hospitalized community-acquired RSV-associated LRTI included host factors and clinical presentation.
Host factors such as demographic data, perinatal history, and underlying disease were collected. Clinical presentation determined as presenting symptoms and initial physical examination, and initial laboratory findings determined as complete blood count. Outcome of patient at discharged was categorized as discharge without readmission or readmission within 1 month with the same diagnosis or in-hospital death.
For hospital-acquired RSV-associated LRTI, patient who was diagnosed of RSV-associated LRTI later during hospital stay, after 72 hours after admission, was recorded as hospital-acquired RSVassociated LRTI. Data were extracted and compared with community-acquired RSV-associated LRTI.

Key notes
• Factor associated with severe hospitalized RSV were pre-term, infant, co-morbidity of cardiopulmonary disease, on chemotherapy, and cirrhosis/biliary atresia.
• Low flow oxygen use was main oxygen therapy. Most of patients were receiving bronchodilator and antibiotics.

| Statistical analysis
The primary objective of this study was to determine factors associated with severe hospitalized RSV-associated LRTI such as underlying disease, perinatal history, clinical presentation, and laboratory findings. Secondary objective was to describe pattern of management in hospitalized RSV infection including oxygen therapy, intravenous hydration, bronchodilator nebulizer, and antibiotics use.
Factors associated with severe hospitalized RSV-associated LRTI were analyzed from community-acquired group. For baseline characteristics of all patients, severe hospitalized RSV-associated LRTI were compared with not severe RSV infection using chi-square for categorical data and Wilcoxon rank-sum test for continuous data.
Factors associated with severe RSV-associated LRTI were analyzed using univariate and multivariate logistic regression if P-value < .1.
Management pattern for RSV infection in study was described as percentage and frequency for categorical data and median for continuous data. Data were managed by Statistical Package for the Social Sciences

| Demographic data
From 2011 to 2016, there were 427 hospitalized RSV-associated LRTI patients in this study, and we stratified into 2 groups of community-acquired RSV-associated LRTI (n = 361 85%) and hospitalacquired (nosocomial) RSV-associated LRTI (n = 66, 15%). Median age of all patients was 10 (IQR 4-23) months old. Majority of patients was 0-6 months of age. Male was 45% of all patients. Less than quarter was pre-term (21%). Half of the patients were having co-morbidities. Most common co-morbidities were chronic lung disease, congenital heart disease, and cirrhosis (19%, 16%, and 6%, respectively). Baseline demographic data are shown in Table 1. Peak of RSV-associated LRTI was in July-September of each year. Seasonal of RSV is shown in Figure 1

| Outcome after hospital stay
Readmission rate within 1 month with the same diagnosis of RSVassociated LRTI was 0.5%. There were 11 dead cases in this study (2.6%). All cases had co-morbidities as presented in Table 3. From all dead cases, 6 cases (1.4% of 361 cases) were community-acquired and 5 cases (7.6% of 66 cases) were hospital-acquired RSVassociated LRTI.  Figure 2. Immunocompromised status such as patient on chemotherapy and hematologic disorder was not different in both severe and not severe RSV-associated LRTI.

TA B L E 3
Risk factor associated with severe community-acquired RSVassociated LRTI in Bangkok, Thailand, 2011-2016 lethal outcome. Characteristic of 11 children with mortality after RSV-associated LRTI showed in Table 4.

| DISCUSS IONS
Almost half RSV-associated LRTI hospitalization were having severe symptoms. Infant is still at high risk of RSV-associated LRTI as majority of RSV-associated LRTI was children 0-6 months old. 15 Gastrointestinal disease such as cirrhosis or biliary atresia was another important risk factors for severe RSV-associated LRTI including resulted as in-hospital death and might be another group to consider for prophylaxis treatment. Other correlate findings for risk factors with previous study were co-morbidities of prematurity, low birthweight, cardiopulmonary disease, gastrointestinal disorder, and neuromuscular impairment. 14,16 Many studies had pointed out other risk factor such as immunocompromised status and Down syndrome [17][18][19] but were not statistically significant associated with severe RSV in our study. Our study found no significant different between male and female sex as in western countries which male as one of risk factor. 20 Other risk factors were maternal smoking during pregnancy, multiparity, and birth during first half of RSV season which might lead to promote of smoking cessation or avoidance. 21  Treatment for RSV-associated LRTI was mainly depend on clinical presentation. Even though desaturation was found in only 28.5% of cases at initial presentation, oxygen therapy was being use in all cases for respiratory support and to decrease work of breathing similar to other study in children with medical complexity that required oxygen during illness. 29 In our study, bronchodilator nebulizer and antibiotics were used which might not be useful and was not recommended by AAP guideline. 7 Even without initial wheezing, wheezing might develop later during hospital stay and might improve since most of salbutamol nebulizer was being continuously used more than 1 day. Most of antibiotic use for RSV-associated LRTI was ceftriaxone or cefotaxime which aimed to cover most of community-acquired bacterial infection which could be Staphylococcus aureus and Pseudomonas aeruginosa. 30 But specific bacterial co-infection could not be proved due to limitation of specimen for bacterial identification.

| Strength and limitation
Subjective information such as history of clinical presentation might be limitation of this study due to retrospective study but we also collect objective data such as physical examination and laboratory findings that were recorded as first presentation. Clinical diagnosis of RSV-associated LRTI was based on attending physician's medical record. Analysis of antibiotic use was limited due to secondary bacterial infection may be suspected in some cases but evidence of bacterial infection was not available in most cases.

| CON CLUS ION
RSV-associated LRTI is high burden disease. Infants or children with co-morbidities especially cardiopulmonary and biliary atresia have higher risk of severe RSV-associated LRTI. No specific treatment is available so treatment is mainly supportive with oxygen therapy, bronchodilator, or other treatment based on clinical presentation and treatment response/outcome.

Thanks to Ms Sineenart Chautrakarn and Mr Padoemwut
Teerawongsakul, MD for assisting with paper work process.

CO N FLI C T O F I NTE R E S T
Potential conflicts of interest. All authors: No conflicts.