Duc Long Phi Minh Manh To Kieu Dung Le Tien Dat Pham Cao Thanh Vu Khanh Linh Duong Thi Loi Dao Van Thuan Hoang ^*

• Thai Binh University of Medicine and Pharmacy, Thái Bình, Vietnam

We have read with great interest the publication by Chen et al. (1) on the co-infection of adenovirus and Mycoplasma pneumoniae among children with severe community-acquired pneumonia (CAP). We especially appreciate the findings about risk factors of severe disease. Several studies have showed whether M. pneumoniae infection contributes to more severe clinical outcomes than other pathogens (2)(3)(4)(5). However, the role of M. pneumoniae shoud be considered along with other factors such as age, gender, and co-infection with different pathogens. In this Commentary, we report no association between M. pneumoniae, but an association with age, and severe pneumonia in children.M. pneumoniae is a common cause of respiratory infections, particularly in children and young adults. Despite its prevalence, the role of M. pneumoniae in the disease severity among children remains controversial (6)(7)(8)(9). As a bacterium without a cell wall, M. pneumoniae spreads via respiratory droplets, causing mild, self-limiting infections. It is common in school-aged children and can cause outbreaks in community settings (10,11).M. pneumoniae accounts for 10-40% of pediatric CAP cases with peaks in children aged 5 to 15.Epidemiological studies suggest cyclical outbreaks of M. pneumoniae infections every 4-7 years, with regional and seasonal variation. Severe cases are more common in children with underlying health conditions (12). Research findings on the link between M. pneumoniae and severe pneumonia have been mixed, as summarized in a recent systematic review (9). From 01/06/2023 to 31/05/2024, 2040 children with atypical pneumonia were hospitalized at Thai Binh Pediatric Hospital, Thai Binh. The proportion of severe pneumonia was 11.9% (243/2040).Due to limitations in equipment and the fact that health insurance does not cover molecular biological tests for diagnosing respiratory pathogens, the identification of M. pneumoniae infection in children in Thai Binh is only performed using serological methods. The serum samples were quantitatively analyzed for IgM antibodies against Mycoplasma pneumoniae using the Virion/Serion ELISA kit (GmbH Germany, catalog number ESR127M). The antibody levels were expressed in units per milliliter (U/ml). According to the manufacturer's guidelines, the interpretation criteria for M. pneumoniae IgM were as follows: positive (>17 U/ml), negative (< 13 U/ml), and borderline (13-17 U/ml). All ELISA assays were carried out strictly following the instructions provided by the manufacturer. A total of 1070 (52.4%) patients were positive with IgM. The distribution of ill children gradually decreased with age.Univariate and multivariate analysis using logistic regression showed no association between M. pneumoniae infection and male gender with severe pneumonia among children (adjusted OR = 0.98, p = 0.91, and aOR = 1.21, p = 0.18, respectively). However, age was a risk factor closely related to the severity of pneumonia. Compared to children aged ≥5 years old, those aged 2 -<12 months were associated with 7 times of risk for severe disease (aOR = 6.87, p <0.0001), patients aged 12 -<36 months and 36 -<60 months were associated with 4 times and twice of risk for severe pneumonia (aOR = 3.39, p <0.0001 and aOR = 1.84, p = 0.002, respectively) (Table 1). The heterogeneity in study designs, populations, and diagnostic methods contributes to the variability in the results assessing the role of M. pneumoniae in severe pediatric pneumonia (6).One of the primary challenges in establishing a clear association is the presence of confounding factors. Children with severe pneumonia are more likely to undergo extensive diagnostic testing, including polymerase chain reaction (PCR) assays, leading to a detection bias. Additionally, coinfections with other respiratory pathogens, such as viruses or bacteria, can complicate the clinical picture and obscure the role of M. pneumoniae.The lack of a consistent association between M. pneumoniae infection and severity of disease has important implications for clinical practice (7,8). Physicians should consider M. pneumoniae a potential cause of pneumonia in children but not assume it is associated with more severe disease without supporting clinical evidence. Treatment decisions should be guided by the overall clinical picture and not solely based on the presence of M. pneumoniae. Indeed, antibiotic therapy for M. pneumoniae pneumonia typically includes macrolides, such as azithromycin or clarithromycin. However, the emergence of macrolide-resistant M. pneumoniae strains poses a challenge (13,14). Clinicians must remain vigilant for resistance patterns and consider alternative treatments in older children, such as fluoroquinolones or tetracyclines.Further research is needed to clarify the relationship between M. pneumoniae and pneumonia severity in children. Prospective studies with standardized diagnostic criteria, robust case definitions, and comprehensive data collection on co-infections and underlying health conditions are essential.It is also crucial to understand the mechanisms underlying macrolide resistance in M. pneumoniae and develop strategies to minimize its impact. Surveillance programs to monitor resistance patterns and the effectiveness of current treatment regimens can inform clinical guidelines and improve patient outcomes. The findings of our study should be interpreted with caution due to several limitations. Firstly, although the large sample size, this was a retrospective study conducted at a single center, focusing only on the association of severe pneumonia with age, sex, and M. pneumoniae infection. Furthermore, due to limited laboratory resources, M. pneumoniae infection was identified using a single IgM test, whereas paired sera would provide a more accurate diagnosis. However, the reliability of single IgM serological tests and the requirement for paired testing remain inconsistent (15). Additionally, using paired IgG as a reference standard - requiring a second serum sample collected two to four weeks after the initial one - presents challenges in children and has minimal impact on clinical practice and treatment. In conclusion, the current body of evidence does not support a definitive association between M. pneumoniae infection and the severity of pneumonia among children. The variability in study findings highlights the complexity of pneumonia etiology and the influence of multiple factors on disease severity. Clinicians should adopt a holistic approach to diagnosing and managing pediatric pneumonia, considering the potential role of M. pneumoniae without overestimating its impact on disease severity.