Annual and seasonal patterns in etiologies of pediatric community-acquired pneumonia due to respiratory viruses and Mycoplasma pneumoniae requiring hospitalization in South Korea

Lower respiratory tract infections, including pneumonia, are a group of diseases that constitute a leading worldwide cause of pediatric morbidity, requiring hospitalization, and mortality [1, 2]. Childhood pneumonia causes diverse long-term sequelae, such as restrictive or obstructive lung disease, as well as bronchiectasis, particularly in a considerable proportion of children hospitalized due to community-acquired pneumonia (CAP) [3].

The etiologies of CAP affect the disease burden, development of long-term sequelae, and mortality [3, 4]. The mortality, severity, and disease burden due to CAP differ by age [3, 5]. Therefore, prediction of the causative pathogens and clinical courses before the identification of respiratory pathogens in children with CAP is needed to improve disease outcomes. There are annual and seasonal variabilities in the respiratory pathogens that cause CAP. In addition, the characteristics of these pathogens, including susceptibility to antibiotics, change over time. Assessments of the annual and seasonal variabilities and pathogen characteristics could provide important information needed to establish a direction for vaccine development and health care policies. However, comprehensive studies on these topics are scarce.

The most common causes of pediatric CAP in high-income countries, which differ according to age, are Mycoplasma pneumoniae (MP) and respiratory viruses [6]. Epidemics of MP infections are repeated on a 3–7 year cycle; the last epidemic in Korea was in 2015 [7‐9]. After 2000, macrolide-resistant MP pneumonia rapidly emerged, especially in Asia [7]. MP infections in children are often self-limiting, even in patients with macrolide-resistant MP pneumonia [10]. More than 80% of patients with macrolide-sensitive MP (MSMP) have shown defervescence within 48–72 h after the initiation of macrolide treatment; this occurs in approximately 30% of patients with macrolide-resistant MP pneumonia [11]. Despite its high prevalence, large-scale epidemiologic studies of macrolide-resistant MP pneumonia are scarce.

In the present study, we aimed to identify the annual and seasonal patterns of respiratory pathogens in pediatric CAP requiring hospitalization and the prevalence of MP pneumonia according to the clinical responses to macrolides. In addition, we compared the clinical characteristics according to respiratory pathogens in patients with pediatric CAP.

We evaluated the annual and seasonal patterns in respiratory etiologies of pediatric CAP requiring hospitalization between 2010 to 2015 in a nationwide retrospective cohort study. The most common causes of hospitalization due to pediatric CAP were MP and RSV, with peaks in October–November and November–December, respectively. There were two epidemics of MP pneumonia (2011 and 2015) during the study period. In children hospitalized with CAP due to MP pneumonia, the monthly rates of clinical MRMP and MLEP pneumonias showed increasing trends, together comprising up to 36% of the total cases of MP pneumonia during the study period. In children less than 2 years of age, RSV was the most common cause of pediatric CAP requiring hospitalization, whereas the most common cause was MP in children older than 2 years as well as in adolescents. The rate of children admitted to the intensive care unit was highest in children with RSV pneumonia, followed by those with AdV pneumonia. Ventilator care was most commonly needed in children with AdV pneumonia, followed by those with RSV pneumonia. The results of the present study provide fundamental data on the periodicity of epidemics of pathogens that cause pediatric CAP requiring hospitalization.

In the present study, we found that RSV was the most common cause of CAP in children younger than 2 years of age, which is consistent with the findings of other studies performed in other countries, regardless of the detection methods used or national income levels of the children who were analyzed [6, 14]. The immune response in RSV infection differs according to age [15]. Notably, inefficient and ineffective immune responses in early life contribute to more severe clinical courses and higher incidence of RSV infection; this is especially problematic in infants, who are most frequently affected by RSV pneumonia [15]. These findings may be valuable to guide therapeutic approaches, such as application of immune-modulatory drugs for enhancement of immune responses, and preventive strategies for children with CAP; moreover, the results of the present study suggest that the development of strategies to prevent RSV infection, especially in infants and younger children, might aid in decreasing the worldwide disease burden due to CAP.

The number of children hospitalized with MP pneumonia was typically highest between October and November. In the previous studies, the peak incidence of MP pneumonia showed a similar pattern to that observed in the present study, regardless of age [14, 16]. However, in the 2011 Korean epidemic, the peak rate of hospitalization due to MP pneumonia in children occurred in September, whereas the peak rate in the 2015 epidemic occurred in November. In addition, the number of children hospitalized with MP pneumonia in the 2015 epidemic was smaller than that in the 2011 epidemic. These findings were consistent with the results of another study [16]. The reasons for these phenomenon may be associated with exposure to MP in the previous epidemic [7].

Based on in vitro macrolide sensitivity tests, the macrolide resistance rates of MP pneumonia have recently been identified as 50–90% in Asia [7, 8]; these rates differ dramatically among nations. When we defined clinical MSMP, MLEP, and MRMP according to fever duration after the initiation of macrolides in each pneumonia episode, regardless of the results of in vitro macrolide sensitivity tests, the ratios of clinical MLEP and MRMP of total MP pneumonia showed increasing trends after adjustment for monthly time series. However, the estimated clinical MRMP/total MP pneumonia ratio during the study period in the present study (0.0–11.0%) was far lower than that based on in vitro macrolide sensitivity tests (50–90%, especially in Asia) [7, 8]. Therefore, the results of our present study suggest that the clinical response to macrolides in MP pneumonia in the real world might not be as weak as that has been reported, based on in vitro macrolide sensitivity tests, which could partially be due to the self-limiting features of MP infections [17]. Due to the high prevalence of MRMP, there are a great deal of concerns regarding second-line treatment options for MRMP, including tetracycline or fluoroquinolones [7]. Some previous studies have reported no significant differences with respect to clinical and radiologic findings between MRMP and MSMP pneumonia in children [8, 9]. When combined with the results of the present and previous studies [8, 13], a considerable proportion of cases of macrolide-resistant MP pneumonia might be recategorized as clinical MSMP or MLEP pneumonia. Therefore, the first-line treatment for MP pneumonia can be initially started, even in cases of MRMP pneumonia. Considering the exaggerated immune response in children with MP pneumonia [18], the application of immune-modulators, such as corticosteroids or immunoglobulin, rather than antibiotics, might play more important roles in the management of MP pneumonia, even in some cases of MLEP or MRMP pneumonia [19]. When selecting the proper treatment strategy for MLEP and MRMP pneumonia, consideration of diverse clinical courses, including self-limiting features and combined immune responses in each case, might be more important than the results of in vitro sensitivity tests to macrolide.

This study has some limitations. First, there might have been selection bias due to not including all cases of CAP in Korean children. Second, some patients might have been misclassified into the “no MP pneumonia and no respiratory virus detection” group due to a sampling error, including inappropriate sputum specimens or lack of repetitive follow-up of MP-specific IgM in patients with an initial negative result for MP-specific IgM. Due to the retrospective study design, all techniques of RT-PCR for detection of respiratory viruses and MP and serology for MP were not performed in all participants. In the present study, we did not include CAP caused by typical bacterial pathogens; therefore, we could not identify time-dependent changes in the occurrence of CAP caused by typical bacterial pathogens alone or caused by co-infection of typical bacteria and viruses. However, following the introduction of the pneumococcal conjugate vaccine and the Haemophilus influenza type b vaccine, the disease burden due to bacterial pneumonia has been significantly decreased [6, 20]. Therefore, we clinically defined the MSMP, MRMP, and MLEP pneumonia groups solely based on fever duration after initiation of the administration of macrolides, regardless of the results of the in vitro tests for macrolide sensitivity. Because the results of in vitro sensitivity tests to antibiotics do not always correspond with those of in vivo sensitivity tests of the same antibiotics [21] and administration of immune-modulators might play more important roles in the treatment of MP pneumonia in some cases, the application of clinical classifications of MP pneumonia, rather than the results of in vitro macrolide sensitivity tests, might be more helpful in the management of MP pneumonia. This is especially significant in cases of MLEP and MRMP pneumonia, in this era with a high rate of antibiotic-refractory MP.

We identified the annual and seasonal patterns of causative pathogens in children with CAP requiring hospitalization. Throughout the study period, MP and RSV were the most common causes of CAP, with cyclic peaks in specific seasons. The disease burden due to pediatric CAP requiring hospitalization is largely due to RSV pneumonia, especially in infants and young children. The relatively lower rates of clinical MLEP and MRMP pneumonia, contrary to the known high prevalence of macrolide-refractory MP pneumonia, highlights the appropriate treatment strategies for patients with MP pneumonia. The results of the present study may aid in establishing treatment and management strategies for pediatric CAP and policies to reduce the disease burden by improving public health policies for children with CAP.