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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 2  |  Page : 46-51

Viruses and hospitalization for childhood lower respiratory tract infection in Malaysia: A prospective study


1 Department of Paediatrics, University Malaya Medical Centre; University Malaya Paediatric and Child Health Research Group, University of Malaya, Kuala Lumpur, Malaysia
2 Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia
3 Department of Medical Microbiology, University Malaya Medical Centre, Kuala Lumpur, Malaysia
4 Department of Medical Microbiology, University Malaya Medical Centre; Tropical Infectious Diseases Research and Education Centre, Kuala Lumpur, Malaysia

Date of Web Publication30-Jun-2017

Correspondence Address:
Jessie Anne deBruyne
Department of Paediatrics, University Malaya Medical Centre, 50603 Kuala Lumpur
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/prcm.prcm_2_17

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  Abstract 

Context: Viruses are the main causes of acute lower respiratory tract infections (ALRIs) in childhood and its impact on hospital admission is largely unknown. Aims: The aim of this study is to determine (a) virus detection, (b) risk factors for admission, particularly virus detection, and (c) differential clinical responses to viral infections, in children attending pediatric emergency department (PED) with an ALRI in Malaysia. Subjects and Methods: This prospective study included children ≤2 years who presented to PED between September 1, 2010, and March 6, 2012, with features of lower respiratory tract infection. Nasopharyngeal aspirates (NPAs) were tested using a multiplex polymerase chain reaction (PCR) for 11 respiratory viruses. Results: Two hundred children were recruited in the study. Two-thirds (65.5%) of them were admitted. NPA-PCR was positive in 54% of all patients: 50.4% of those admitted and 60.9% of those discharged. The most common viruses detected were respiratory syncytial virus (RSV) (49.1%), rhinovirus (30.6%), and parainfluenza viruses (12.0%). Five patients had mixed infections. RSV detection was associated with previous history of wheeze (odds ratio, 2.05 [95% confidence interval 1.06, 4.00]). Viruses were detected in all severely ill patients and patients with apnea. Multivariate analysis showed that virus detection was not associated with the need for admission, but female sex, lack of breastfeeding and, attending nursery were associated with hospitalization. Conclusions: Half of the children who presented to the emergency room with ALRI had viruses detected in their NPA. There was no association between virus detection and hospitalization. RSV was associated with history of wheeze. Female gender, lack of breastfeeding, and nursery attendance were associated with hospitalization.

Keywords: Acute respiratory infections, etiology, bronchiolitis, children, emergency department, Malaysia, pneumonia, viruses


How to cite this article:
Nathan AM, Qiao YL, Jafar FL, Chan YF, Eg KP, Thavagnanam S, Bakar SA, Sam IC, deBruyne JA. Viruses and hospitalization for childhood lower respiratory tract infection in Malaysia: A prospective study. Pediatr Respirol Crit Care Med 2017;1:46-51

How to cite this URL:
Nathan AM, Qiao YL, Jafar FL, Chan YF, Eg KP, Thavagnanam S, Bakar SA, Sam IC, deBruyne JA. Viruses and hospitalization for childhood lower respiratory tract infection in Malaysia: A prospective study. Pediatr Respirol Crit Care Med [serial online] 2017 [cited 2017 Sep 25];1:46-51. Available from: http://www.prccm.org/text.asp?2017/1/2/46/209261




  Introduction Top


Viruses are the main cause for acute lower respiratory tract infection (ALRI), whether in the developing or developed countries. Factors determining hospitalization are important for health and economic reasons. Many studies focus on etiology of ALRI in admitted patients,[1],[2],[3] but few studies focus on children attending the pediatric emergency department (PED) alone [4],[5] to determine the factors associated with admission, especially positive virus detection and coinfections.

The aim of this study was to determine the risk factors for admission in children attending the PED with an ALRI.


  Subjects and Methods Top


Ethics

Ethical approval was obtained from the hospital's Medical Ethics Committee (No. 996.3) and informed parental consent was obtained. However, no assent was obtained from patients aged above 7 years. Patients' information was anonymized and de-identified before analysis.

Study site

This study was conducted in a 1068-bedded tertiary general hospital in Kuala Lumpur, Malaysia, which serves an urban population of 1.7 million. In our center, we have 100 pediatric beds, including a 10-bed Pediatric Intensive Care Unit.

Study type and patient selection

This is a prospective study of children, 2 years old and younger, who presented to the PED, between September 1, 2010, and March 6, 2012, with ALRIs. ALRI was defined as symptoms (either cough or shortness of breath) and signs (wheeze and/or crepitation and/or recession and/or respiratory distress) of a lower respiratory tract infection. Children with a diagnosis of asthma and those attending the PED during the weekends were excluded from the study.

Data collection

Basic demographic data including comorbidities, birth history, concurrent medications, family history of asthma and atopy, antenatal and postnatal exposure of cigarette smoke, breastfeeding (total duration and exclusive), history of wheezing, current weight, presenting symptoms and signs, and outcome were collected prospectively, using a preprepared data collection sheet.

Specimen processing

All children had nasopharyngeal aspirates (NPAs) collected by trained nurses after nebulization of either 3% NaCl or salbutamol to enhance the chance of virus detection. The exact choice was at the discretion of the attending doctor samples being kept at −20°C before testing. RNA was extracted from 140 μl of each sample using QIAmp Viral RNA Mini Kit (QIAGEN, Germany) following the manufacturer's protocol and eluted in 50 μL of sterile water. Complementary DNA was synthesized using Superscript III RT (Invitrogen, USA). Each reaction was carried out with 0.25 μL of 20X reverse transcriptase-primer mix (500 μg/ml), 1 μl of dNTPs (10 mM each), and 3 μL of RNA template (1 μg/μL) and heated at 65°C for 5 min. The solution was equilibrated at 4°C and mixed with 1 μL of 5X first-strand buffer and 0.25 μL of 0.1 M DTT and incubated at 25°C for another 5 min. Finally, 0.25 μL (50 units) of Superscript II Reverse transcriptase was added to the solution with a final volume of 5 μL, which was then incubated at 50°C for 1 h, before inactivation at 70°C for 15 min. The final products were stored at −20°C until testing using a multiplex polymerase chain reaction (PCR) assay, RespiDetect (Tropical Infectious Diseases Research and Education Centre, Malaysia), following the manufacturers' protocol. This assay is based on dual-priming oligonucleotide technology and detects 11 respiratory viruses: respiratory syncytial virus (RSV), influenza A and B, parainfluenza virus 1–3, adenovirus, human metapneumovirus, human rhinovirus (HRV), coronavirus, and bocavirus. PCR products of the expected size were identified by gel electrophoresis.

Definitions of variables and outcomes

The main outcome measured was admission versus discharge as decided by the PED physician. Oxygen is usually supplied if the saturation is <95% in room air or if there are signs of respiratory distress. Each patient's weight was measured and computed into Z score using gender- and age-specific cutoff points proposed by the World Health Organization guidelines.[4] Life-threatening pneumonia was defined as children who require intensive care treatment and/or noninvasive ventilatory support, for example, bilevel continuous positive airway pressure or high-flow nasal cannula oxygen. Low birth weight was defined as birth weight <2.5 kg. Prematurity was defined as gestation <37 weeks. Environmental tobacco smoke (ETS) exposure was defined as presence of any smoker in the family or caregiver's household.

Statistics

The data were analyzed using IBM Corp. Released 2011. IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp. Data were described using percentage, median, and interquartile range (IQR). The Chi-squared test or Fisher's exact test (where appropriate) was used to perform univariate analysis between the clinical factors and the outcome, i.e. hospitalization or not. Factors included in univariate analysis were as follows: age, gender, presence of any comorbidity (such as chronic lung disease, heart disease, and chronic liver and gut disease), family history of atopy, prematurity, birth weight, current weight percentile <−2 standard deviations, any breastfeeding, attending nursery or daycare, exposure to ETS (antenatal and postnatal), positive respiratory virus PCR result, and PCR positive for more than one virus. Binary logistic regression was performed with factors identified in univariate analysis with P < 0.10. In the final analysis of results, P < 0.05 was considered statistically significant. Association was presented as odds ratios (ORs) with 95% confidence intervals (CIs).


  Results Top


Altogether, 255 children were recruited in the study. Thirty-two NPAs were misplaced and 23 were excluded due to a possible asthma. Finally, 200 episodes of infection were analyzed [Figure 1].
Figure 1: Study flow.

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Demographic data

Characteristics of the patients are shown in [Table 1]. The median age was 8 months with a male predilection. The ethnic distribution is representative of Malaysia. The main comorbid diseases in these children were previous pneumonia (n = 21, 58.3%) and cardiovascular disease (n = 4, 11.1%). The median (IQR) gestational age of the children who were premature was 34 weeks (33–35 weeks). There was a significant exposure to both antenatal and postnatal ETS exposure. More than two-thirds of the children (77%) were breastfed. The most common diagnosis was bronchiolitis (69%) and two-thirds of patients (65.5%) were admitted.
Table 1: Demographic characteristics between those admitted versus discharged

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Pathogen detection

NPA-PCR was positive in 54% of children: 50.4% of those admitted (n = 66/131) and 60.9% of those discharged (n = 42/69). The NPA was positive in 52% (n = 72/138) of children with bronchiolitis and 58% (n = 36/72) of children with pneumonia. Common viruses detected were RSV (n = 53, 49.1%), rhinovirus (n = 33, 30.6%), and parainfluenza virus (n = 13, 12.0%) and altogether these represented 91.7% of all the viruses detected. Five patients (2.5%) had two viruses detected in NPA: RSV + bocavirus (1), RSV + influenza A (1), RSV + HRV (1), HRV + bocavirus (1), and HRV + influenza B (1). Of those admitted patients, 119 NPA samples were sent for bacterial culture and 44 patients had a positive culture (37%).

Risk factors for admission

Virus detection was not associated with hospitalization [Table 2]. In Univariate analysis, factors possibly associated with the need for admission were young age, female gender, Malay ethnicity, attending nursery, diagnosis of pneumonia and not being breastfed [Table 1]. Binary logistic regression identified that female gender, attending nursery, and not being breastfed were independent risk factors for hospitalization [Table 3].
Table 2: Odds ratio of admission for nasopharyngeal aspirates positive viral cases

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Table 3: Binary logistic regression analysis of factors that were significantly associated with admission to hospital

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Clinical responses to viral infections

The following symptoms were not associated with virus infection: fever (P = 0.45, OR 0.79 [95% CI 0.44, 3.42]), rhinitis (P = 0.08, OR 1.87 [95% CI 0.93, 3.75]), shortness of breath (0.65, OR 0.84 [95% CI 0.46, 1.52]), presence of wheezing (P = 0.82, OR 1.06 [95% CI 0.59, 1.91]), and diarrhea (P = 0.35, OR 2.06 [95% CI 0.52, 8.19]).

Only 2 cases of apnea were admitted during this study and RSV and rhinovirus accounted for these two cases. There was a significant association between the symptom of vomiting and virus detection (P < 0.001, OR 4.67 [95% CI 1.94, 11.24]). All the six children who had life-threatening pneumonia had viruses detected in their NPA (influenza [n = 1], RSV [n = 1], rhinovirus [n = 2], rhinovirus + RSV [n = 1], and bocavirus [n = 1]), P = 0.05 (OR 8.37 {95% CI 0.96, 255.2}). None of the children were intubated for their infection and there were no deaths.

Clinical responses to specific viruses

Children ≤6 months were not more likely to be infected with RSV (P = 0.25, OR 1.49 [95% CI 0.79, 2.82]). Both HRV detection (P = 0.16, OR = 2.03 [95% CI 0.83, 4.96]) and RSV detection (P = 0.40, OR = 0.75 [95% CI 0.39, 1.45]) were not associated with current wheezing. However, RSV detection was significantly associated with a previous history of wheeze (P = 0.03, OR 2.05 [95% CI 1.06, 4.00]). This association was not seen with HRV (P = 0.85, OR 1.17 [95% CI 0.54, 2.0].


  Discussion Top


In this prospective study, half of the young children presenting to the PED with ALRI were positive for a respiratory virus, but there was no significant association between virus detection and hospitalization. However, all six severely ill children had viruses detected in their NPA. We found three significant clinical factors associated with admission: female sex, nursery attendance, and lack of breastfeeding. RSV, and not HRV, was detected more frequently in children with a previous history of wheezing. Symptom of vomiting was significantly associated with viral detection.

This study was conducted in a tertiary hospital, located in an urban city, with a high attendance of children presenting with respiratory infections, and only young children with ALRI were included. All samples were NPAs, the optimal specimen for viral detection.[6],[7] Half of the samples (50.7%) were positive for a virus and 2.5% had mixed viral infections. A retrospective study from the Netherlands, done in the accident and emergency department during two winter seasons, showed that 82% of 274 samples were positive for a single virus and 23% had mixed viral infections.[5] In another study from France about childhood upper and lower respiratory tract infections, 89% of samples were positive.[4] A possible reason for the extremely high positivity rate in the study from the Netherlands was the sampling period, when viral infections would be at its peak. In a tropical climate like Malaysia, it was shown that RSV had its peak season from September to December but generally viruses are prevalent throughout the year.[8],[9] In a study in Beijing, China, which included both inpatients and outpatients, using reverse transcriptase PCR to detect viruses, 61.7% of patients were positive for a virus, a rate similar to ours.[10] RSV was the most common virus detected in those who were admitted while influenza was most common in those who were discharged, and being positive for any virus was not associated with admission (69% in those admitted versus 54% in those discharged).[10] In another inpatient-based study, conducted in the Philippines, involving 819 children admitted with severe pneumonia and using PCR to detect viruses, the positivity rate was also 61% with HRV and RSV being the most common viruses detected.[11] This study had a low mixed infection rate of 8%,[11] compared to other studies which found mixed viral infection rates of 14%–40%.[3],[12],[13] In a review of published studies, viruses were found in 43%–67% of children with community-acquired pneumonia in children, although the detection rate will be affected by many factors including type and extent of molecular assay used, season, sample population, indications for testing, and methods of sample collection and processing.[14],[15]

The most common viruses detected in our study were RSV, HRV, and parainfluenza virus, similar to the other studies, both in Asia and Europe.[5],[10],[11] RSV but not rhinovirus was associated with previous history of wheezing, but neither HRV nor RSV was significantly associated with current wheezing. This finding differed from that in the Netherlands, where prior treatment with steroids and salbutamol was associated with HRV.[5] Both HRV and RSV were reported to be associated with increased risk for future wheezing. RSV is more likely an “inducer” by its neuroimmune effect on the airways and not via allergic sensitization whereas HRV is a “trigger” inducing release of chemokines and cytokines that triggers the allergic pathway in a child with a predisposition to asthma.[16] As for severity of disease, while in this study neither RSV nor any other virus was associated with severity of illness, all children who had severe respiratory compromise were virus positive. In the Netherlands, HRV was associated with severe disease while RSV was inversely associated with severity of disease.[5] HRV-C is known to be associated with lower respiratory tract infections while HRV-A and B is associated with upper respiratory tract infections.[17] We did not include the HRV in this study. However, one patient who was HRV positive had a severe ALRI requiring noninvasive ventilation support. There was evidence that HRV might not be all benign.[5]

The role of mixed viral infections could not be evaluated in this study due to the small number of positive samples. Nonetheless, globally, its impact on ALRIs was also not clear.[18] This is due to the high sensitivity of PCR, which may detect asymptomatic infections or low levels of virus from recent, resolved infections, hence resulting in over detection of “innocent” pathogens, especially rhinovirus.[19] Nevertheless, some studies showed an association between mixed viral infections with increased severity of illness.[10],[12]

The other important finding of our study was the three clinical factors significantly associated with the need for admission: female gender, nursery care, and lack of breastfeeding. Other factors such as age and exposure to ETS were not significant. The protective effect of breastfeeding against ALRI confirmed findings in other studies.[2],[20] Care outside the home, if more than 6 children are in attendance, was shown to be associated with hospitalization for an ALRI.[21]

Finally, in this study, children with a clinical presentation of vomiting were more likely to have viruses detected in their NPA. Vomiting is a known sign of an infection in a child and is not specific to the gastrointestinal system.[22]

The main strength of this study is that it is a prospective study and looks at the impact of viruses in the Emergency Department of a developing country.

Limitations to this study included the small sample size with only 200 patients recruited as patients who attended during the weekends were excluded from the study. We recognize the possible impact of bacterial–viral infections on increasing severity of illness; however, we cannot report on this as only children who were admitted had bacterial cultures done. This study was also done in a tertiary hospital, and hence, the results may not be extrapolated to the rest of Malaysia.


  Conclusions Top


Detection of viruses in children presenting to the PED was not associated with hospitalization for an ALRI. About half of the children presenting to PED were positive for a respiratory virus. All children who were severely ill, requiring noninvasive ventilation, had viruses detected in their NPA. Three clinical factors significantly associated with the need for admission were being female, attending nursery, and lack of breastfeeding. RSV but not HRV was detected more frequently in children with a previous history of wheeze.

Acknowledgement

We thank Ardalinah Hassan, Siti Sarah Nor'E and Boon Teong Teoh for technical assistance. We would like to thank Dr Ju Vern Ew for her help in preparation of this article.

Financial support and sponsorship

This study was funded by the University Malaya Research Grant (No. UM.TNC2/RC/HTM/RP026-14HTM) and High Impact Research Grant (No. UM.C/625/1/HIR/MOHE/MED/42) from University Malaya. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Tiewsoh K, Lodha R, Pandey RM, Broor S, Kalaivani M, Kabra SK. Factors determining the outcome of children hospitalized with severe pneumonia. BMC Pediatr 2009;9:15.  Back to cited text no. 1
    
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Nathan AM, Rani F, Lee RJ, Zaki R, Westerhout C, Sam IC, et al. Clinical risk factors for life-threatening lower respiratory tract infections in children: A retrospective study in an urban city in Malaysia. PLoS One 2014;9:e111162.  Back to cited text no. 2
    
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García-García ML, Calvo C, Pozo F, Villadangos PA, Pérez-Breña P, Casas I. Spectrum of respiratory viruses in children with community-acquired pneumonia. Pediatr Infect Dis J 2012;31:808-13.  Back to cited text no. 3
    
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Gooskens J, van der Ploeg V, Sukhai RN, Vossen AC, Claas EC, Kroes AC. Clinical evaluation of viral acute respiratory tract infections in children presenting to the emergency department of a tertiary referral hospital in the Netherlands. BMC Pediatr 2014;14:297.  Back to cited text no. 5
    
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Khor CS, Sam IC, Hooi PS, Quek KF, Chan YF. Epidemiology and seasonality of respiratory viral infections in hospitalized children in Kuala Lumpur, Malaysia: A retrospective study of 27 years. BMC Pediatr 2012;12:32.  Back to cited text no. 9
    
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Anderson LJ, Parker RA, Strikas RA, Farrar JA, Gangarosa EJ, Keyserling HL, et al. Day-care center attendance and hospitalization for lower respiratory tract illness. Pediatrics 1988;82:300-8.  Back to cited text no. 21
    
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