To date, lower respiratory infections (LRTIs) remain one of the main causes of death in children.1 LRTIs can present as bronchiolitis, croup, exacerbations of wheezing or asthma as well as pneumonia;2 with most of these latter being of viral origin.3 The most common viruses implicated in LRTIs in children include influenza A/B, parainfluenza virus, adenovirus and respiratory-syncytial-virus (RSV).3 Although most infected children with acute LRTIs fully recover, a subset develop chronic respiratory symptoms.1 However, mild disease can be managed with supportive treatment; moderate and severe cases need hospital admission. Depending on climatic conditions, season, geographical location as well as demographic patterns and the country’s health care system, the degree of involvement of each respiratory virus in the annual disease outbreaks varies.4 Despite the significance of viral LRTIs, little is known about the epidemiology of different respiratory viruses in Saudi children. The aim of this study is thus to explore the viral etiology of LRTIs in children less than 2 years of age, who were admitted to the emergency pediatric unit of a major tertiary care center in Riyadh, Saudi Arabia.

MATERIALS AND METHODS Study Population

This is a retrospective study conducted at King Fahad Medical City Children Hospital, Riyadh, Kingdom of Saudi Arabia. Following institutional review board approval (IRB 20-263), the medical records of all children ≤2 years of age and who were hospitalized with a diagnosis of LRTI from January 1, 2017, to December 31, 2019, were reviewed. Patients were excluded if the infectious agent is solely of bacterial origin. Recurrent infection is defined as an LRTI with a respiratory virus after the documented first infection during the study period. Recurrent wheezing on the other hand is defined as at least 2 episodes with difficulty in breathing and a whistling sound associated with breathing after the documented first infection. Hospital readmission is defined as when the patient was admitted at King Fahad Medical City after the first admission due to LRTI with a respiratory virus during the study period. Mortality due to respiratory virus infection was defined as a patient dying of respiratory failure.

Laboratory Detection of Respiratory Viruses

Nasopharyngeal aspirate samples of included patients were collected and subjected to a multiplex real-time polymerase chain reaction using the Biofire Film Array instrument and the multiplex respiratory panel (Biomerieux diagnostics) that detects the 14 most common respiratory pathogens: adenovirus, coronaviruses 229E, HKU1, NL63, OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A virus, influenza B virus, parainfluenza virus 1-4, RSV A and B subtypes and human bocavirus.

Statistical Analysis

A descriptive analysis was carried out, and continuous variables were expressed as means ± standard deviation. Statistical analysis was performed via SPSS software (version 25, SPSS Inc, Chicago, Illinois, USA). P < 0.05 was considered statistically significant.

RESULTS Study Population Characteristics

Of 331 admitted patients, 217 met the inclusion criteria and thus were included in the analysis. The majority of patients were males and ≥1 year of age. The most common comorbidities observed were congenital heart disease and congenital renal disease. Only 16.1% had associated bacterial infections. The average length of hospital stay was 12 days. More than 50% of the studied population received antibiotics whereas only 15 children had prior receipt of palivizumab (Table, Supplemental Digital Content 1, https://links.lww.com/INF/F25).

Association of Morbidity and Mortality with Age Group

Based on morbidity, patients were divided into 2 age groups: ≤12 months and ≥13 months. Statistical analysis revealed that the mortality rate and intubation requirement were significantly higher in children less than 12 months compared to those greater than 12 months of age (P = 0.03 and 0.04, respectively). No statistical significant difference was observed for the other variables (Table, Supplemental Digital Content 2, https://links.lww.com/INF/F25).

Respiratory Viruses Detected and Mortality

Rhinoviruses (RV) followed by RSV and influenza were the most common respiratory viruses detected as single infections. On the other hand, co-infections were most commonly observed with rhinovirus, RSV and adenoviruses. The detection of 2 viruses in the same patient was more common than the detection of 3 or more viruses in the same subject (Tables, Supplemental Digital Content 3, https://links.lww.com/INF/F25 and Supplemental Digital Content 4, https://links.lww.com/INF/F25). Patients in whom only Rhinovirus was detected had a higher mortality rate compared to those with multiple infections (Table, Supplemental Digital Content 5, https://links.lww.com/INF/F25).

Age Distribution of Respiratory Viruses

As shown in Figure 1, rhinovirus was the most common virus detected in children of all ages, with the highest detection rate being in those of 18 months old. A decline in the prevalence of both RSV and rhinovirus among children of 12 months was noted. For coronaviruses, the detection rate among children greater than 12 months was higher than those less than 12 months old. For all other viruses, the rates of detection fluctuated among all ages without a clear trend (Fig. 1).

FIGURE 1.:

Distribution of detected respiratory viruses over age.

Seasonal Distribution of Respiratory Viruses

Seasonality in the Riyadh region is as follows: Winter, January–March; Spring, April–June; Summer, July–September; Autumn, October–December. RSV and influenza were most commonly detected in winter, and adenovirus and metapneumovirus in summer. Although only 2 cases, H1N1 was only detected in winter (Fig. 2 and Table, Supplemental Digital Content 8, https://links.lww.com/INF/F25).

FIGURE 2.:

Seasonal detection rate of respiratory viruses..

Predictors of Recurrence Wheezing, Asthma and Mortality

Multiple logistic regression analysis revealed that recurrent wheezing in children with body weight 2–5.9 kg is increased compared to those weighing 6–8.9 kg. The administration of palivizumab monoclonal antibody was found to be protective against recurrent wheezing. On the other hand, our results showed that rhinovirus was associated up to 2 times in children with asthma compared to those without. Patients with congenital renal disease were found to be 6 times more likely to have asthma attacks than others without renal disease. Moreover, a lower body weight (2.0–5.9 kg) increased the possibility of having asthma up to 3 times in the high-risk group than in the other group (6.0–8.9kg). Furthermore, the probability of an intensive care unit admission is twice likely in patients with asthma than in nonasthmatics. For mortality, our analysis revealed that the risk of death is increased 6 times in males compared to females. In the group of children that are less than 1 year of age, the odds of mortality are increased up to 13 times compared to the age group of more than 1 year. Most deaths with respiratory viral infections were associated with deterioration in respiratory function requiring intubation, a factor that is 27 times more likely associated with mortality (Table 1).

TABLE 1. - Logistic Regression Analysis of Factors Associated with Recurrent Wheezing, Asthma and Mortality 95% CI SE Sig. Exp (B) Lower Upper Recurrent Wheezing Received palivizumab 0.633 0.005 0.167 0.048 0.578 Weight 2.0–5.9 kg 0.427 0.003 3.59 1.553 8.296 Weight 6.0–8.9 kg 0.498 0.03 2.952 1.113 7.83 Asthma Rhinovirus 0.334 0.023 2.136 1.11 4.111 Congenital renal disease 0.8 0.022 6.236 1.299 29.936 ICU admission 0.337 0.004 2.658 1.373 5.146 Weight 2.0–5.9 kg 0.378 0 3.863 1.842 8.102 Weight 6–8.9 kg 0.444 0.17 1.839 0.771 4.386 Mortality Male 0.89 0.042 6.095 1.066 34.854 Intubation requirement 0.754 0 27.612 6.298 121.052 Age 1–12 months 1.143 0.024 13.213 1.407 124.07

CI indicates confident interval; ICU, intensive care unit; SE, standard error.

DISCUSSION

Although most children fully recover, LRTIs remain among the most common causes of death in those less than 5 years of age.1 In our study, most of the LRTIs occurred in children less than 1 year of age. This observation is similar to a recent study, where the rate of LRTIs was found to be higher among children aged less than 1 year.5 In our study, rhinovirus was the most common detected virus followed by RSV and influenza. These 3 viruses were often reported as among the most common causative agents of LRTIs in children. Similar to our findings, in a recent study conducted in Thailand, it was reported that the influenza virus was the most common pathogen in hospitalized children with LRTI, followed by RSV.6 In Kingdom of Saudi Arabia, it was found RSV followed by influenza A and metapneumovirus are highly prevalent in this subpopulation.4

It is worth mentioning that Middle East Respiratory Syndrome-related Coronavirus (MERS-CoV) is not included in the respiratory panel test in our hospital. Indeed, Khan et al.7 found that the MERS-CoV infection ratio have significantly declined during 2016–2019 with the least infected ages on average being below 20 years old (ref).

Interestingly, in 31% of our studied subjects, 2 or more respiratory viruses were detected in a single patient. The highest co-detection rate was found for RV-RSV-adenovirus. While some studies have suggested that the presence of multiple respiratory viruses adversely affects clinical outcomes, others have reported minimal or no impact on the pathogenesis of respiratory diseases. In a single-center study conducted over a 2-year period at a children’s hospital in the USA, the detection of multiple respiratory viruses was associated with increased use of noninvasive ventilation, increased likelihood of experiencing moderate to severe illness as well as increased mortality.8 Interestingly some studies even found that co-infected patients are less likely to develop severe disease.9 In our analysis, rhinovirus-mono-infected patients had an increased mortality rate compared to those with rhinovirus-multiple-infections. In our study, the presence of rhinovirus, intensive care unit (ICU) admission as well as a congenital renal disease were associated with asthmatic patients. In fact, studies have suggested that RV can contribute to the development of asthma as well as its exacerbation, both in children and adults.10 The increased risk of ICU admission observed in children with asthma in our study was documented by a study conducted in Denmark, where it was found that having asthma symptoms for less than 1 week was a significant factor associated with higher odds of pediatric ICU admission.11 Regarding the factors associated with increased mortality, lower age that is, less than 1 year was associated with increased odds of death. This is similar to a study where it was found that the mortality of pneumonia was the highest in patients less than 1 year old.6

In conclusion, our findings suggest that both Rhinovirus and RSV are frequent causes of LRTI in hospitalized children in Saudi Arabia. Rhinovirus is associated with adverse clinical outcomes with an increased likelihood in asthmatic patients. Future multicenter surveillance studies are necessary to evaluate the role of mono-infection and co-infection with viral pathogens detected in lower respiratory viral infections. Such studies are even more important in the era of the COVID-19 pandemic; this is in addition to determining if the molecular epidemiology of respiratory viral infections, as well as the prevalence of different respiratory viruses including MERS-CoV in causing LRTI, has been altered in children in this era.

ACKNOWLEDGMENTS

We acknowledge the Pathology and Clinical Laboratory Medical Administration at King Fahad Medical City, Riyadh for the support and providing the relevant data.

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