Mycoplasma pneumoniae (MP) is a major pathogen of pediatric community-acquired pneumonia. Many refractory, severe, fulminant, or even fatal cases who were not responsive to macrolide antibiotics or susceptible antibiotics have been reported mainly in east Asia (Lee et al., 2006; Tamura et al., 2008; You et al., 2014; Liu et al., 2018; Liu et al., 2018; Yang et al., 2019; Zhang et al., 2021). The host’s cell-mediated immunity plays a key role in the development of pulmonary lesions in MP pneumonia (MPP). It is confirmed that corticosteroid could effectively initiate the rapid improvement of clinical symptoms and chest radiographic findings (Lee et al., 2006; Tamura et al., 2008; You et al., 2014; Yang et al., 2019). However, corticosteroid resistance has been reported in some MPP patients with more serious radiological findings (Yan et al., 2016; Liu et al., 2019). Successful methylprednisolone pulse therapy (30 mg/kg/day) has been reported in some patients with severe MPP (SMPP) (Tamura et al., 2008; Shen et al., 2013; You et al., 2014; Liu et al., 2019). Unfortunately, many patients with refractory MPP (RMPP) and SMPP inevitably developed sequelae, mainly atelectasis, bronchiectasis, and bronchiolitis obliterans due to bronchiolitis-associated lesions (Zhao et al., 2017; Wen et al., 2018) and bronchitis obliterans due to pulmonary consolidation (Leong et al., 1997; Zhao et al., 2017; Liu et al., 2018; Liu et al., 2019), although they were treated with susceptible antibiotics, high-dose corticosteroid, and bronchoscopy lavage therapy (BLT).

Yang et al. reported that early corticosteroid therapy might prevent disease progression, and anti-MP antibiotics might have limited effects on MPP (Yang et al., 2019), which was consistent with our clinical experience. However, the definition of “early” is unclear. In addition, there is a wide range of methylprednisolone (1–30 mg/kg/day) doses in the treatment of MPP (Tamura et al., 2008; Yang et al., 2019). Therefore, many factors of MPP about corticosteroid therapy remain unclear, such as which day the optimal starting time is, and how much the ideal initial dose is. Elucidating these issues is important to help guide standard treatment and reduce sequelae.

During the autumn and winter epidemic in 2019 in North China, to improve the prognosis and avoid the sequelae (Zhao et al., 2017; Liu et al., 2018; Liu et al., 2019), we had the plan to use “early” corticosteroid empirically for MPP patients who had pulmonary infiltrations on imaging within 5 days of disease course, and the dose of methylprednisolone was decided according to the severity of the disease. In addition, the clinical features of MPP were reviewed.

Pediatric MPP is a significant public health problem in China, and it is typically mild and even self-limited. However, in recent years, more and more patients with SMPP, RMPP, bronchiolitis-associated MPP, and MPP-associated sequela have been reported (Zhao et al., 2017; Wen et al., 2018; Liu et al., 2019; Liu et al., 2020; Zhang et al., 2021), posing great challenges to pediatricians. It is mandatory to recognize RMPP and SMPP in the early stage, and timely effective anti-MP therapy and immunomodulating therapy are the main strategies for RMPP (Tong et al., 2022). However, the negative rate of anti-MP-IgM at the early stage was high, up to 66.2% ( Table 4 ), and the MP-PCR test takes time and is not be available in some hospitals; thus, early pathogenic diagnosis cannot be achieved in some patients. Therefore, early recognition of the clinical features of MPP, rapid MP-PCR testing, and timely empirical therapy are extremely important.

MP type 1 was the predominant genotype from 2008 to 2012 in Beijing, and a shift from type 1 to type 2 began to occur in 2013 (Zhao et al., 2015). In our present study, MP type 1 was still the main genotype; however, the rate of MP genotype 2 increased to 24.2% ( Table 4 ) higher than our previous study (Liu et al., 2019; Guo et al., 2022). In addition, 7 patients had co-infection with type 1 and type 2 MP isolates ( Table 4 ), which has been reported in only a few studies (Zhao et al., 2015; Li et al., 2021). The total MR MP rate was high, up to 100% ( Table 4 ), which was consistent with the previously reported rate (Liu et al., 2019; Zhao et al., 2020; Guo et al., 2022). Positive MP culture in the BALF of Case 2 and positive MP-RNA in samples of patients who received metatranscriptomic sequencing testing suggested that MP could be easy to survive in vitro, because these samples had been stored at 4–8°C for at least 36 h. Furthermore, the metatranscriptomic sequencing performed revealed positive MP-RNA (unique reads: 26 and 59) in the pleural effusion of two patients, which suggested that there could be a few live MP in pleural effusion that have not been reported previously. Most of our patients were treated with macrolides within 5 days and were unresponsive. MP was difficult to clear even by sensitive anti-MP antibiotics (Liu et al., 2019; Zhao et al., 2020), which may explain the long-term positive MP-IgM such as Case 5. The pathogenesis of MPP is mainly attributed to cell-mediated immunity and cytokine responses against the pathogens (Shimizu et al., 2011). Host genetic background was also found to be important for the severity of MPP (Fonseca-Aten et al., 2005; Meyer Sauteur et al., 2018). Therefore, corticosteroid therapy has been confirmed to be very important in hospitalized MPP patients (Liu et al., 2012; Chen et al., 2014; Yang et al., 2019).

Children under 3 years old were more easily prone to have bronchiolitis-associated MPP (Group A) than consolidation-associated MPP (Group B) ( Table 1 ). Patients in Group A were more easily prone to have allergy histories and present with hypoxemia, wheezing sound, and wet rales on auscultation than those in Group B ( Table 1 ), which was consistent with our pervious study (Zhao et al., 2017; Wen et al., 2018). Pleural effusion was more likely to occur in Group B ( Table 4 ). In addition, inflammatory markers such as CRP and LDH in Group B were higher than that in Group A ( Table 1 ), which suggested that inflammation and corticosteroid dose in Group B could be higher than that in Group A.

In this study, we found that pulmonary infiltration could occur within 5 days of illness in MPP, and rapid, serious, and even fulminant clinical deterioration occurred after 5 days of illness onset in our present ( Figures 3 – 6 ) and reported studies (Liu et al., 2012). Therefore, there is an urgent need for lung ultrasound to dynamically detect lung lesions and prevent frequent radiation. The ideal starting time of corticosteroid treatment is 5–10 days after disease onset in SMPP (Version 2023, published by National Health Commission of the People’s Republic of China, http://www.gov.cn/zhengce/zhengceku/2023-02/16/content_5741770.htm). RMPP patients with fever >7 days, CRP >40 mg/L, and consolidation >2/3 pulmonary lobe have been suggested to receive a timely corticosteroid treatment (Liu et al., 2012). Fever ≥10 days, CRP ≥137 mg/L, and consolidation >2/3 pulmonary lobe may predict the occurrence of sequela in MPP (Predictive factors for sequela of bronchitis obliterans in refractory mycoplasma pneumoniae pneumonia, to be published in Zhonghua Er Ke Za Zhi). Methylprednisolone pulse therapy had been prescribed in 21 patients with SMPP; however, sequela of BO had not been avoided in 13 who received treatment with corticosteroid after 9 days of onset (Liu et al., 2019), which was consistent with our present Case 7 and suggested that the rapid irreversible airway remodeling could occur within 9 days of onset. Therefore, earlier corticosteroid treatment (<9 days even 7 days) should be initiated in SMPP ( Table 2 ). Treatment with 2 mg/kg/day methylprednisolone may be ineffective in some patients with high fever >7 days, CRP ≥110 mg/L, and consolidation > whole pulmonary lobe (Chen et al., 2014). In our present study ( Table 3 ), initial corticosteroid therapy on the 5 days of the disease course in Cases 3 and 6, and 1–5 mg/kg/day of initial methylprednisolone dose in Cases 3–7, failed to prevent the deterioration of the disease (higher CRP and more severe pulmonary injury), which further suggested that very early treatment (on day 5) and an insufficient starting dose of corticosteroid could not prevent a subsequent rapidly progressive pulmonary inflammatory storm in patients with ≥1 lobar consolidation. Therefore, the ideal starting time of corticosteroid treatment might be 6–7 days (important window period) of disease course ( Table 2 ). Initial adequate dose of corticosteroid should be decided according to the severity of disease. Pulmonary infiltration particularly lobar consolidation and CRP > 30 mg/L ( Tables 1 , 3 ) within 5 days of illness, and fever duration >5 days, were important clues for recognizing RMPP and SMPP. Persistent high fever, hypoxemia, CRP > 100 mg/L, diffuse bronchiolitis-associated lesions, or whole lobar consolidation on imaging ( Tables 2 , 3 , Figures 3 – 6 ) suggested that possible critical MPP would require corticosteroid pulse therapy.

MP persistent infection may cause airway obstruction and remodeling in vitro and animal experiments (Fonseca-Aten et al., 2005; Salvatore et al., 2008; Prince et al., 2018). Obstructive pulmonary function ( Table 1 ) and the irreversible BO (Zhao et al., 2017; Liu et al., 2018; Wen et al., 2018; Liu et al., 2019; Zhao et al., 2020) suggested an early rapid airway injury and remodeling in children with SMPP. Therefore, timely and initial adequate dosage of corticosteroid therapy is extremely important in the window period, which can reduce airway inflammation and airway hypersecretion, and prevent rapid airway remodeling. Although the rate of MR MP was 100% in this study, macrolides were still used in most patients, because of their anti-inflammation and anti-remodeling properties (Kang et al., 2016). Sirolimus may also reduce airway inflammation and remodeling (Wang et al., 2020) and it might be a potential therapeutic drug (Liu et al., 2021); therefore, we prescribed sirolimus for 1 month in the recovery stage of Case 5.

The bronchoscopy performed revealed extensive increased sticky secretions in 41 patients of Group A, which may explain the hypoxemia, wheezing, wet rales, and the subsequent possible sequela of bronchiolitis obliterans (Zhao et al., 2017; Wen et al., 2018). Mucus plugs and mucosal necrosis under bronchoscopy were more likely to occur in severe patients of Group B, suggesting subsequent possible atelectasis and bronchitis obliterans (Liu et al., 2018; Liu et al., 2019; Zhao et al., 2020). Therefore, timely and multiple BLT is also extremely important, which can remove airway secretions and prevent lumen obstruction.

In general, patients with MPP admitted in our hospital were more severe than those in most hospitals of China. In this present study, we analyzed the clinical features, “early” corticosteroid treatment outcome, and prognosis of 210 MPP children who had pulmonary infiltrations on imaging within 5 days after onset. Based on our rich clinical experience, the prescribed “early”/on admission (5–10 days, mainly 6–7 days of disease course) corticosteroid with different doses for patients with MPP successfully prevented deterioration in most patients and minimized the sequelae ( Table 2 ). To the best of our knowledge, this is the first study to emphasize the importance of both starting time and the initial dose of corticosteroid treatment in MPP particularly in SMPP.

Patients in Group A were more prone to have allergy histories, hypoxemia, wheezing sounds, and wet rales on auscultation than those in Group B. Pulmonary infiltration within 5 days of illness, fever duration >5 days, and elevated inflammatory markers such as CRP were important clues for recognizing RMPP and SMPP. In hospitalized children with MPP, particularly SMPP (except rare fulminant MPP), the ideal starting time of corticosteroid treatment might be 5–10 days, preferably 6–7 days (important window period) after disease onset. The initial adequate dosage of corticosteroid therapy was extremely important in SMPP and should be decided according to the severity of the disease. MPP patients with both persistent high fever and diffuse bronchiolitis-associated lesions/≥1 pulmonary lobar consolidation can be recommended to receive high-dose corticosteroid therapy ( Table 3 ).

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by The Ethics Committee of Beijing Children’s Hospital, Capital Medical University (No. 2017-23). Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

JL, XZ, and RH conducted the analysis and drafted and revised the initial manuscript. HW advised on the design of the analysis and revised the manuscript. FZ and LL performed MP-related testing, analyzed experimental data, and revised the manuscript. SZ conducted the analysis and revised the initial manuscript. All authors contributed to the article and approved the submitted version.