Analysis of national surveillance of respiratory pathogens for community-acquired pneumonia in children and adolescents

Pneumonia is an infection of the lower airways, and community-acquired pneumonia (CAP) specifically refers to clinical signs and symptoms of pneumonia acquired outside a hospital setting [1]. In the United States, CAP is the most common cause of hospitalization among children, with an annual incidence of 15.7–22.5 hospitalizations per 100,000 children [2, 3]. According to statistics from the Health Insurance Review and Assessment Service, nearly half (44.6%) of the 1.59 million pneumonia patients in 2015 were reported to be children under the age of 10, and in 2018, children under the age of 10 often have respiratory system diseases, which are the most common diseases for outpatient and inpatient visits, with pneumonia ranking second among the causes of inpatient visits [4]. These respiratory diseases are mainly caused by bacterial or viral infections, and treatments should be selected depending on the pathogen that causes them. However, clinical symptoms alone cannot distinguish the pathogens, so they should be assessed via laboratory tests. In most CAPs, empirical treatment is provided in that the causes of pneumonia vary widely depending on individual sensitivity, the dynamics of the community, and seasons. It is difficult to obtain samples for microbiological diagnosis. Thus, epidemiological data on clinical patterns and causes of childhood pneumonia will help care, including determining the direction of treatment [5].

The development of the Haemophilus influenzae type b (Hib) vaccine and protein binding pneumococcal conjugate vaccine (PCV) has rapidly decreased the incidence of Hib pneumonia and pneumococcal pneumonia [6]. Data on changes in the serologic type of S. pneumoniae and antimicrobial susceptibility following the introduction of the pneumococcal vaccine are insufficient. Additionally, the data on pneumonia caused by other bacterial pathogens are insufficient.

Pneumonia by Mycoplasma pneumoniae is also a major infectious illness for children in kindergarten and school age, and it continues to be prevalent every 3 to 4 years [7‐9]. The incidence of mycoplasma infection increased in 2007, and the incidence rate soared from 2010 to 2011 [7]. M. pneumoniae is often accompanied by pleural fluid and shows lobar pneumonia, which is difficult to differentiate from bacterial pneumonia by referring to clinical patterns and chest radiologic findings [8]. Recently, macrolide-resistant M. pneumoniae in Korea has been reported, and it is necessary to determine the nationwide status of the disease, the effectiveness of antibiotic treatment, and the degree of resistance.

There have been reports of the distribution of pathogens, epidemic trends, and antibiotic resistance of bacterial pathogens to respiratory infections in adults, but there have been no nationwide reports in children and adolescents in Korea. In particular, CAP in children and adolescents accounts for more than 50% of all cases, the pathogen of pneumonia is different from that of adults, and recent vaccination has resulted in changes in pathogens. For this reason, a nationalized study is needed to analyze the prevalence, epidemic characteristics, and pathogens of pneumonia in children and adolescents. Therefore, the purpose of this study is to establish a monitoring network for CAP among children in connection with community-based cooperative hospitals and the Korea Disease Control and Prevention Agency (KDCA). In addition, we studied the distribution of pathogens, epidemic trends of CAP, and antibiotic usage and resistance of bacterial pathogens.

Most studies about the causative agents of CAP in children are limited by the difficulty of obtaining adequate specimens. This study is meaningful because it was the first prospective extensive study investigating respiratory pathogens in children with CAP in Korea. In this study, the rate of pathogen detection in children with CAP was 70.5%. However, it could not be confirmed whether the bacterial culture results were the causative pathogen of CAP, and it is highly likely that they were colonized. There are studies about the causative agents of CAP in many countries. In the Taiwanese study, at least one pathogen was identified in 68.3% of children with CAP [10], and in the Chinese study, the causative pathogen was identified in 70.1% of the hospitalized children with CAP at one hospital [11]. In a 3-year US-based study, the causative pathogen was identified in 81% of patients under the age of 18 hospitalized with CAP [2]. In a study conducted in Finland, the causative pathogen was detected in 85% of hospitalized children with pneumonia [12]. The difference in detection rate in each country seems to be due to the difference in sample types and methods. The sample types collected in this study were nasopharyngeal swabs/aspirates and sputum, and the causative pathogens were identified through PCR and cultures. To detect viruses, the same method (PCR test) is used through nasopharyngeal swabs/aspirates in other countries. However, unlike in this study, most tests for bacterial detection were conducted through blood and pleural fluid cultures or blood PCR tests. As a result, it is thought that the detection rate of the pathogen in each study is different.

There are few studies about the causative agent of children with CAP in Korea. In 2009, respiratory viruses were identified in 49.6% of severe lower respiratory tract infections in children [13]. However, unlike in our study, there were no data for bacterial infections. Recently, there was also a study on the seasonal pattern in etiologic viruses and M. pneumoniae in children hospitalized with CAP in Korea; it showed that M. pneumoniae was the most commonly identified pathogen [14]. It was noticeable that bacterial pathogens as well as viruses were also tested. In general, the common bacterial pathogens of CAP in children are S. pneumoniae, H. influenzae type b, and S. aureus. To differentiate true pathogens from colonization in CAP, cultures from blood/pleural fluid samples or urinary S. pneumoniae antigen tests using immunochromatography are better than nasopharyngeal samples [1, 12]. In the current study, we did not use this method; we used bacterial cultures or PCR from nasopharyngeal swabs/aspirates. The detection rate of bacteria from blood cultures in CAP is very low, and pleural cultures are limited to only children with parapneumonic effusion. Urinary S. pneumoniae antigen tests can be positive in children if S. pneumoniae is colonized in the nasopharynx. S. pneumoniae and H. influenzae are common flora in the upper respiratory tract, and up to two-thirds of children younger than 5 years are colonized with common bacterial pathogens in the upper respiratory tract. The identification of bacteria from the upper respiratory tract does not always determine the pathogen of CAP; therefore, physicians should consider clinical relevance for ascertaining the bacterial etiologies of pneumonia [15]. It is difficult to identify bacteria that cause bacterial pneumonia, because the introduction of the National Immunization Program (NIP) vaccine has reduced bacterial pneumonia and invasive bacterial infection. Although the results of bacterial culture in the upper respiratory tract sample in children are highly likely to be colonized, there are studies that suggest the association between bacteria colonizing the upper respiratory tract and lower respiratory tract infection in young children [16]. Also, analysis of antibiotic resistance and serotype of bacteria detected in the upper respiratory tract can obtain important information that can be used clinically. Therefore, the present study that reported these results is meaningful.

Over the past 20 years, more than 20 cases of B. pertussis have been reported every year in Korea. During 2001–2007, there was an average of 11.3 cases of B. pertussis per year [17], and a gradual increase from 2009 to 2012 was reported [18]. In particular, 24.5% of Korean adolescents and adults with chronic cough were positive for B. pertussis in 2015 [19]. Due to the lack of data on B. pertussis in pediatric patients in Korea, it was important to obtain epidemiological data on B. pertussis through the results of the surveillance network study. In this study, B. pertussis was isolated from five children, which was less than we expected. All cases were observed between January and April, and two of the patients were younger than 3 months old, while the other three were aged 1, 6 and 9 years old. Due to the NIP by the Korean government, the incidence of B. pertussis is low in children, but a gradual increase in adolescents and adults requires the need for a booster injection. Based on these data, it will be necessary to accumulate various epidemiological data on pertussis through the construction of a continuous monitoring network in children and adolescents in Korea.

The common pathogen of CAP in adults was S. pneumoniae in a prospective multicenter study in Korea, and in other study, S. pneumoniae was most frequent pathogen, atypical pathogens such as M. pneumoniae, and C. pneumoniae were the second most common pathogens [20, 21]. Unlike with adults, the most common cause of CAP in children varies according to age. Several studies have previously reported that respiratory viruses are the leading cause of CAP, which can be detected in more than 50% of the cases [22, 23]. However, these results may vary by study and age group. Similar to our research, in a study of Peru patients under the age of 18 who were hospitalized for pneumonia, M. pneumoniae was more frequently detected than respiratory viruses [24]. Additionally, in the Taiwanese study, S. pneumoniae was the most common pathogen, and the detection rate of pneumococcus was much higher than that in our study [10]. This may be attributed to relatively lower vaccination rates in Taiwan. Vaccination programs for causative pathogens of pneumonia in Korea are as follows. In 2003, a 7-valent pneumococcal protein-binding vaccine (PCV) was first introduced in Korea, and in June 2010, a 10-valent and a 13-valent PCV were introduced. Currently, Korean government has started pneumococcal vaccination for every infants at 2, 4, 6, and 15 months of age as NIP since 2014, which may rapidly decrease the frequency of S. pneumoniae pneumonia. H. influenzae type b vaccine is also provided as a NIP since 2013. The Hib vaccine is also given at 2, 4, and 6 months of age as a primary vaccinations and at 12–15 months of age as a booster shot. Pertussis vaccination is also included in a NIP as Diphtheria–tetanus–acellular pertussis vaccine (DTaP) or booster tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap). After three primary vaccinations at 2, 4, and 6 months of age, booster vaccinations are performed at 15–18 months old and 4–6 years old, respectively. In our study, 39 (3.8%) patients were not vaccinated, 86 (8.4%) were unsure whether they were vaccinated. And the rest of subjects (87.8%) were all vaccinated.

The rate of M. pneumoniae surged from the fall of 2019, which abruptly ended after the COVID-19 outbreak in 2020. M. pneumoniae is a major pathogen of CAP in children and adolescents [9]. Recent studies showed that mycoplasma was responsible for approximately 20–30% of CAP at the age of 3 to 4 years, and during the epidemic M. pneumoniae infected even children at 2 years old [5, 9, 25]. M. pneumoniae pneumonia epidemics occur every 3 to 5 years [9, 26, 27]. It was reported that epidemics of M. pneumoniae pneumonia occurred in 2007, 2011, and 2015 [28, 29]. According to the trend cycle, the results of this study confirmed that the mycoplasma epidemic had been refloating in 2019. Interestingly, the rate of M. pneumoniae decreased abruptly after COVID-19. This may be attributed to social distancing, mask-wearing, hand washing, and online schooling.

The seasonal difference in detection rates for viruses is consistent with the existing data. We found that the respiratory viruses were composed of major pathogens for CAP in young children under the age of 3 years. It is known that viruses may cause pneumonia, either directly or by rendering the host more susceptible to bacterial infection [11]. In studies of CAP in children, mixed infections were identified in 34–41% of the children with CAP, and mixed viral-bacterial infection showed the highest rate [11, 30‐32]. On the other hand, two US studies reported a lower rate (23–26%) of mixed infection [2, 31]. In this study, the proportion of co-detection was 49.2%, which was higher than in previous studies. The co-detection rate of viruses, bacteria, and atypical bacterial pathogens was 3.6%. It is assumed that the differences in co-detection rate and pattern of co-detection may be related to seasonal, geographical, and racial factors. It may also vary depending on the type of sample or laboratory testing method.

Although viruses are major cause of childhood CAP, a majority of children with pneumonia receive antibiotics. Empiric use of antibiotics remains a cornerstone of treatment in the absence of results in the causative agents of pneumonia. In the U.S. guidelines, amoxicillin is used in previously healthy outpatients who have been properly vaccinated if they suspect mild or moderate bacterial pneumonia. It is recommended to use macrolides if CAP caused by an atypical pneumonia pathogen is suspected [33]. In our study, the empiric antibiotic prescription rate was high, and of them, the macrolide prescription rate was the highest. The high macrolide prescription rate may be attributable to the epidemic of M. pneumoniae in 2019.

The rate of antibiotic resistance in this study showed similar results as previous reports. Penicillin sensitivity of pneumococcus in the study of adult pneumonia was 42.9% in 2001 but 100% in 2010 [20, 21]. According to the treatment guidelines of CAP, S. pneumoniae has a low resistance rate for penicillin and quinolone and a relatively high resistance rate for some cephalosporin and macrolide [34]. Our results also showed high resistance rates for second-generation cephalosporin and macrolide, while low resistance rates for the third-generation cephalosporin, penicillin, and quinolone, which is similar to what was previously reported. In addition, the results of the antibiotic resistance of H. influenzae, P. aeruginosa, K. pneumoniae, and S. aureus were also confirmed to be similar to the 2017 National Antibacterial Resistance Survey Report [35]. These data can be helpful in forming the basis of empiric antibiotic therapy in a child with CAP.

This study established a surveillance network for monitoring respiratory infections in Korean children. This research provided scientific evidence of policies for managing pneumonia in children and adolescents in Korea by identifying trends in the prevalence of pathogens in children and adolescents with CAP. It will also contribute to the analysis of antibiotic resistance status for bacteria and proper treatment guidelines for children’s respiratory infections in Korea. In addition, this nationwide network system can help to search for a novel pathogen and monitor new respiratory infections such as COVID-19 and provide early national strategies in preparation for a new epidemic.