A comparative study of general and severe mycoplasma pneumoniae pneumonia in children

Severe pneumonia is the leading infectious disease that causes death in children under five years of age. It is estimated that 740,180 deaths occur annually worldwide due to severe pneumonia, accounting for 22% of deaths in children under 5 years of age [1]. Mycoplasma pneumoniae has long been considered an important aetiology of pneumonia and is commonly isolated from children [2]. Although most children with M. pneumoniae pneumonia (MPP) appreciably recover, some present with worsening clinical symptoms and imaging findings, defined as severe MPP (SMPP) [3]. In 2022, MPP was detected in most of children with pneumonia and caused a substantial increase in hospitalisations, severe illnesses, even deaths [4]. Research on active surveillance of hospitalised children suffering from SMPP in China is scarce [5, 6]. In order to improve treatment and to reduce morbidity and mortality, it is vital to recognize the factors contributing to the severity of MPP [7]. This study sought to characterise the demographic and clinical features of paediatric SMPP patients in 2022, which has been rarely described in the literature.

Although M. pneumoniae often causes community-acquired pneumonia, the epidemiology of severe infections that pose a life-threatening risk in children is poorly characterized [7]. Here, we explored the severity of MPP and its related factors in children with MPP from January and December 2022 and present the following key findings: 1) half of the MPP cases were severe and occurred mainly in winter, 2) a greater proportion of children with SMPP received antibiotics other than macrolides, and 3) higher levels of pro-inflammatory ILs, gastrointestinal complications as well as duration of fever were risk factors for severe MPP.

MPP can cause severe pulmonary infections and extrapulmonary complications in adults and children [11]. During the 2010–2013 M. pneumoniae epidemic, the hospital mortality rate of adult patients with MPP admitted to intensive care was 29.4% [3]. A large study of paediatric patients with MPP from 2011–2019 in Taiwan revealed emerging cases requiring extracorporeal membrane oxygenation [12]. Carrim et al. treated 103 hospitalised patients with MPP and found that an age of <6 years was an independent risk factor of severe pneumonia [13]. In this study, we observed a severe rate of more than half of hospitalised children with MPP, and extrapulmonary complications included digestive, cardiovascular, and neurological system complications. A series of 332 paediatric patients hospitalised with MPP between 2007–2017 revealed that 25.6% (85/332) of the children experience complications related to the skin, digestion, nervous system, and cardiovascular system [14]. A study conducted in China found that 55.9% (33/59) of children with MPP between 2013-2014 had myocardial damage [15]. In our study, myocardial damage, pericardial effusion, and heart failure were observed especially in the SMPP group. Kammer et al. showed that 24.7% (22/89) of paediatric patients hospitalised in Germany between 2000-2013 had neurological symptoms and signs [16]. We observed febrile seizures, epilepsy, and encephalitis only in the SMPP group. Mia et al. reported that in 2010–2011, 33% (246/746) of children with MPP admitted to a paediatric hospital in Denmark had nausea or vomiting complications [17]. Othman et al. reported children with MPP exhibited coryza, diarrhoea and vomiting especially in children less than 5 years[18]. We observed that the gastrointestinal complication was a dependent risk factor for SMPP. These data suggest that extrapulmonary complications of MPP are common in children and are more frequent in severe cases. Therefore, the management of extrapulmonary complications should be a critical part of the therapeutic regimens for MPP.

In this report, elevated leukocyte levels with a predominance of neutrophils were observed in children with severe pneumonia. Shimizu et al. reported that after M. pneumoniae infection, the M. pneumoniae lipid-associated membrane proteins can activate the toll-like receptor, leading to an increase in neutrophils [19]. CRP and PCT are sensitive indicators of the acute phase of inflammation. They are useful in identifying severe disease caused by MPP [20]. CRP levels are correlated with infection severity [21]. In the present study, patients with SMPP had a lower percentage of NK cell abnormalities than those with GMPP. Genome pathway analysis revealed that the NK cell-mediated cytotoxicity pathway was significantly upregulated in children with MPP [22]. Another study found that the number of NK cells and the expression of CD158b on their surface were altered in patients with severe acute respiratory syndrome and correlated with disease severity [23]. The study found that patients with severe disease had a significantly lower percentage of NK cells compared to those with GMPP. This suggests that NK cells may serve as a marker of disease severity; however, further mechanistic studies are required.

Cytokines are widely used as markers in children with infectious diseases [24]. In the present study, we observed the elevated serum concentrations of INF-γ, IL-2, IL-5, IL-6, IL-8, and IL-10 in patients with SMPP. ILs are a class of cytokines produced by a various of cells that play important regulatory roles in the immune system and have been implicated in the development and progression of MPP [25‐27]. In severe pneumonia, immune cells in the lungs (e.g., macrophages and neutrophils) release interleukins, leading to an enhanced inflammatory response. M. pneumoniae infection increases IL-6 gene expression and its protein secretion [25]. Serum concentration of IL-6 could potentially indicate the severity and outcomes of MPP [26]. Our results were similar to those of Zhang et al., with the levels of IL-2, IL-10 and IFN-γ being higher in the SMPP group than in the GMPP group (p<.05) [27]. IFN-γ is one of the major cytokines involved in the inflammatory response after M. pneumoniae infection and can increase macrophage lysosomal activity and stimulate macrophage secretion of pro-inflammatory factors to exacerbate the inflammatory response [28]. Esposito et al. discovered that IL-5 was the only cytokine that presented substantially differences in the serum of children with acute M. pneumoniae infection and wheezing [29]. Narita et al. found that in patients with pleural effusion and a persistent fibrotic change in the lungs caused by M. pneumoniae infection, IL-8 was also detected. This indicates the crucial role for IL-8 in the pathogenesis of MPP [30]. It is important to note that the relationship between ILs and severe pneumonia is complex, and that IL levels and actions may be influenced by individual differences, infectious agents, and host immune status. Current strategies for the treatment of severe pneumonia focus on anti-infective therapy and a combination of supportive therapeutic measures [31]. To regulate the inflammatory response, several anti-inflammatory and immunomodulatory drugs need to be investigated for clinical application.

Previous studies have described bacterial co-infection in severely ill children with MPP [32]. In a study aimed at evaluating the frequency and impact of bacterial co-infection in children hospitalised with MPP, Song et al. showed that 2% (173/8612) of children with MPP had bacterial co-infection between 2006–2014, half of which were with S. pneumoniae [33]. In another study, 15.3% (9/59) of hospitalized children with MPP in Korea were found to have bacterial co-infection. In children under the age of 5 years, co-infection with S. pneumoniae was more likely to result in a longer duration of fever and hospital stay, compared to those infected with M. pneumoniae alone [34]. In addition, reports suggest that viruses, such as rhinovirus, may be independent causative agents of pneumonia, including severe pneumonia [35]. Human rhinovirus has emerged as an important cause of pneumonia due to its severity and poor prognosis in adults and children [32, 36]. We observed a substantially increase in the rate of viral and bacterial co-infections in children with SMPP. The results imply that early identification and swift, efficient antibiotic or antiviral treatment in SMPP children is crucial for preventing disease progression. Further investigation is warranted to determine the pathogenic role of this virus and identify specific bacteria that may be the culprit for the severe clinical presentations.

Our study has several limitations. The first one is that it was a retrospective study conducted in a single centre. Second, only inpatients were included, which restricts the generalizability of the results to other patients, particularly those with mild MPP who did not require hospitalization.

Conclusively, a much higher proportion of SMPP children are prone to extrapulmonary complications and viral or bacterial co-infections. Children with severe illness present with elevated inflammation and decreased adaptive immunity. Consequently, hormonal, prophylactic and anticoagulant therapies, as well as the use of antibiotics other than macrolides for bacterial co-infections, could be incorporated into the treatment regimens for the effective management of children with SMPP.