ABSTRACT
Importance
Although macrolides combined with glucocorticoid therapy have demonstrated efficacy in preventing long‐term pulmonary lesions of severe Mycoplasma pneumoniae pneumonia (MPP), evidence regarding glucocorticoid dose is lacking.
Objective
To evaluate the effects of low‐ and high‐dose methylprednisolone on the risk of long‐term pulmonary lesions for children with severe MPP when combined with azithromycin.
Methods
This randomized, parallel‐controlled, multicenter clinical trial was conducted in mainland China and enrolled pediatric patients hospitalized with severe MPP. A total of 424 enrolled patients were randomized (allocation ratio of 1:1) to azithromycin combined with either a low‐dose [2 mg/(kg·d)] or a high‐dose [10 mg/(kg·d)] methylprednisolone treatment for 3 d followed by tapering over 12 d. The primary outcome was the incidence of composite adverse outcomes, including atelectasis, bronchiectasis, or bronchiolitis obliterans 6 months after treatment.
Results
A total of 118 (27.8%) developed adverse pulmonary lesions at 6 months after treatment; 66 of 211 (31.3%) in the high‐dose methylprednisolone group and 52 of 213 (24.4%) in the low‐dose group, respectively. The risk ratio of long‐term pulmonary lesions in a high‐dose group to those in a low‐dose group was 1.28 (95% confidence interval [95% CI]: 0.94–1.75). In addition, the risk of hypertension in the high‐dose group (8.1%, 17 of 211) was higher than that in the low‐dose group (1.4%, three of 213), with a risk ratio of 5.72 (95% CI: 1.70–19.23)
Interpretation
Azithromycin combined with low‐dose methylprednisolone demonstrates non‐inferior efficacy in reducing pulmonary lesions at 6‐month follow‐up compared to combined with high‐dose methylprednisolone while exhibiting a more favorable safety profile.
Keywords: Children, Glucocorticoids, Long‐term pulmonary lesions, Mycoplasma pneumoniae, Pneumonia
Although macrolides combined with glucocorticoids can prevent long‐term pulmonary lesions by severe Mycoplasma pneumoniae pneumonia (MPP), evidence regarding glucocorticoid dose is lacking. We found that high‐dose methylprednisolone compared to low‐dose did not reduce long‐term pulmonary lesions of severe MPP in Chinese children, but significantly increased the rates of systemic hypertension.
INTRODUCTION
Mycoplasma pneumoniae (M. pneumoniae) is one of the major causes of community‐acquired pneumonia (CAP) in children, with its prevalence ranging from 14% to 48.7%. 1 , 2 , 3 , 4 , 5 Notably, the incidence of severe M. pneumoniae pneumonia (MPP) has risen markedly over the past decade. One study showed the rate of severe MPP was up to 42.6% of all MPP cases. 4 Studies reported that severe pediatric MPP which required intensive treatment accounted for nearly 4.6%–12% of cases. 6 , 7 , 8 The first global prospective surveillance study of M. pneumoniae (ESGMAC MAPS study) 9 from 45 sites in 24 countries includes the four regions: Europe, Asia, the Americas, and Oceania, showed a significant surge in severe cases and extrapulmonary manifestations following three years of coronavirus disease 2019 pandemic restrictions. 10 , 11 Beyond acute damage, parts of children demonstrate serious long‐term pulmonary lesions such as bronchiolitis obliterans, bronchiectasis, or atelectasis despite appropriate antibiotic therapy.
While the precise pathogenesis of severe MPP is not fully understood, excessive cytokine release, activation of cell‐mediated immune responses, along the development of macrolide resistance, play a role. Glucocorticoids are believed to exert their beneficial effects by acting on the important mechanism of inflammation that causes severe or refractory MPP, 12 , 13 and are more effective than using azithromycin alone. 14 , 15 Nevertheless, there is no consensus on the optimal dosages. 16 , 17 , 18 , 19 Additionally, most existing studies are retrospective and focus on short‐term outcomes rather than long‐term lesions. 14 , 15 , 20 , 21 The long‐term pulmonary outcomes and the impact of different doses of glucocorticoids on these outcomes in children with severe MPP remain unclear.
To address these evidence gaps, we conducted a multicenter randomized controlled trial (RCT) to assess the efficacy and safety of low‐dose versus high‐dose methylprednisolone in reducing long‐term pulmonary lesions in children with severe MPP. The study aims to determine the optimal dosage of glucocorticoid therapy for severe MPP, providing strong evidence for clinical practice.
METHODS
Ethical approval
This study was approved by the Ethics Committee of Beijing Children's Hospital, Capital Medical University (2017‐k‐1); Capital Center for Children's Health, Capital Medical University (SHERLL2017005); Shengjing Hospital of China Medical University (2015PS172K); and Shanxi Children's Hospital (IRB‐KY‐2017). All patient guardians and children aged 8 and above gave informed consent for participation in the study.
Study design and setting
This multicenter single‐blind, non‐inferiority randomized parallel‐controlled trial, was conducted in Beijing Children's Hospital, Capital Medical University; Capital Center for Children's Health, Capital Medical University; Shengjing Hospital of China Medical University; Shanxi Children's Hospital; and Baoding Hospital of Beijing Children's Hospital, Capital Medical University from December 2014 to October 2019. The first aim of this trial is to evaluate the efficacy of low‐dose versus high‐dose methylprednisolone for reducing long‐term pulmonary outcomes of pediatric patients with severe MPP. Our research hypothesis is that the efficacy of low‐dose glucocorticoids combined with azithromycin in improving the long‐term poor prognosis of severe MPP is not inferior to that of high‐dose glucocorticoids. The second aim is to demonstrate the safety of low‐dose and high‐dose methylprednisolone in treating children with severe MPP. The trial protocol is provided in Files S1 and S2. All authors ensure the accuracy and completeness of the data and analyses of the trial protocol, which had been published. 22 The study was registered in the ClinicalTrials (registration No. NCT02303587). Reporting followed Consolidated Standards of Reporting Trials guidelines.
Participants
Children aged less than 18 years who met the following inclusion and exclusion criteria were enrolled. The inclusion based on clinical manifestations (fever, cough, and wheezing), physical examination and imaging, and evidence for M. pneumoniae infection, including serum M. pneumoniae antibody ≥ 1:160 with positive RNA of M. pneumoniae or seroconversion (antibody titer increase of ≥ 4‐fold between paired sera), or single titers of serum M. pneumoniae antibody ≥ 1:320; excluding pneumonia caused be by other pathogens (bacteria, fungi, and viruses), chronic lung disease and asthma. Severe MPP refers to patients with one of the following: cyanosis, difficulty in breathing, multilobar or ≥2/3 lung involvement, pleural effusion, extrapulmonary complications, and transcutaneous oxygen saturation in room air ≤92%. 17 Detailed inclusion and exclusion criteria are shown in Table S1.
Randomization
The randomization code list is generated centrally by the Center for Clinical Epidemiology and Evidence‐based Medicine, Beijing Children's Hospital. Patients who meet the criteria for enrollment are randomized (1:1). Details are shown in File S2. After the assignment of the randomization code, researchers and trial monitors were un‐blinded to the treatment dosage of methylprednisolone, while the patients, data analysts, and staff for outcomes evaluation were blinded.
Interventions
Patients in the low‐dose group received 2 mg/(kg·d) up to a maximum dose of 60 mg/d of intravenous methylprednisolone for 3 d, followed by tapering over 12 d. If fever (>38°C) persists 12–24 h after starting, methylprednisolone dose is increased to 4 mg/(kg·d) on day 2 for 3 d, followed by tapering over 12 d. Patients in the high‐dose group received 10 mg/(kg·d) up to a maximum dose of 300 mg/d of intravenous methylprednisolone for 3 d, followed by tapering over 12 d (Table S2). When methylprednisolone was reduced to 10–20 mg/d, patients received a change to an oral formula and were discharged if necessary. A combination of basic azithromycin treatments was used in both groups.
Recruitment and clinical follow‐up
All enrolled children underwent daily clinical assessments during hospitalization, followed by scheduled outpatient evaluations at 1, 3, and 6 months post‐discharge. Items to be monitored at follow‐up included clinical manifestations, adverse events, and adverse drug reactions, such as hyperglycemia, hypertension, and intraocular pressure. The details regarding data collection for the study are described in Table S3. Assessment of symptoms, signs, and long‐term pulmonary lesions—including atelectasis, bronchiectasis, and bronchiolitis obliterans—was performed at the 6‐month follow‐up. Patients with persistent abnormalities at 6 months continued follow‐up until complete resolution of all pathological findings.
Outcomes measures
The primary outcome was the composite incidence of atelectasis, bronchiectasis, or bronchiolitis obliterans at the 6‐month follow‐up evaluated by chest computed tomography (CT). This outcome was measured independently by two radiologists. Secondary outcomes included recovery time of the patient's temperature, proportion of pulmonary lesions improvement, length of hospital stay, number of participant(s) requiring intensive care, or with acute respiratory distress syndrome, and any adverse event/severe adverse event. Safety monitoring included blood glucose, blood pressure, intraocular pressure, and bone mineral density to comprehensively evaluate adverse reactions related to methylprednisolone. These parameters were evaluated during hospitalization and at scheduled follow‐up visits (1, 3, and 6 months post‐treatment).
Estimated sample size
The sample size for this two‐arm trial was calculated based on the comparison between high‐dose and low‐dose methylprednisolone treatment. Based on our previous pilot study with a small sample size, we assumed a rate of long‐term pulmonary lesions of 35% in the high‐dose methylprednisolone group and 50% in the low‐dose methylprednisolone group. To achieve a statistical power of 80% (two‐sided, type 1 error of 5%), the calculated sample size for each treatment group was 167 patients per treatment group (334 in total). Considering an expected loss to follow‐up of at least 20%, 424 patients in total were required.
Statistical analysis
Analyses of all endpoints were based on the full analysis set (all randomized patients) following the intention‐to‐treat (ITT) principle. The primary composite outcomes of the high‐dose and low‐dose methylprednisolone groups at the 6‐month follow‐up were compared by Chi‐squared test with two‐sided analyses at the 5% level of significance. The relative risk ratio (RR) and its 95% confidence interval (95% CI) were estimated at the same time.
Considering the difficulties of long‐term follow‐up, especially the parents’ concerns about the impacts of CT examination on children, we have determined the plan to deal with the missing data in advance. Missing values for the primary outcome were addressed by multiple imputations with 10 replicate sets using the monotone discriminant function method. 23 Moreover, results from maximum imputation (all missing data are regarded as outcomes), minimum imputation (all missing data are regarded as non‐outcomes), best scenario imputation (all missing data in the low‐dose group are regarded as outcomes and all missing data in the high‐dose group are regarded as non‐outcomes), worst scenario imputation (all missing data in the low‐dose group are regarded as non‐outcomes and all missing data in the high‐dose group are regarded as outcomes), and last observation carried forward (LOCF) imputation were also provided. Furthermore, if the prevalence of missing data is more than 40%, then analyses will be considered as preliminary and hypothesis‐generating.
In addition, pre‐specified subgroup analyses were conducted based on stratification by age (<6 or ≥6 years), fever history (<10 or ≥10 d), fever after treatment (<48 or ≥48 h), C‐reactive protein (CRP) at baseline (<50/100 mg/L or ≥50/100 mg/L), abnormal alanine aminotransferase (ALT) at baseline (defined as ALT >40 U/L; yes or no), pleural effusion at baseline (yes or no), and consolidation at baseline (yes or no).
Per‐protocol (PP) analysis was conducted as the sensitivity analysis. Since the missing proportion of the primary outcome was high, conditional power was calculated based on the observed data and different trend assumptions in the patients who lost to follow‐up, so that the confidence of conclusions could be assessed under different hypotheses. A P‐value < 0.05 was statistically significant with a two‐sided alternative. All statistical analyses were performed with SAS 9.4 (SAS Institute Inc.).
RESULTS
Characteristics of the patients
From an initial screening of 648 patients, 424 eligible participants with severe MPP were under randomization and received the study treatment at least once. Among the participants included in the ITT analysis, 213 were treated with low‐dose methylprednisolone combined with azithromycin and 211 received high‐dose methylprednisolone combined with azithromycin (Figure 1). During treatment, only 2 patients in the low‐dose group were adjusted to 4 mg/(kg·d) of methylprednisolone. The baseline characteristics of participants among the two groups are comparable (Table 1).
FIGURE 1.
Study design and Consolidated Standards of Reporting Trials (CONSORT) diagram. ITT, intention‐to‐treat.
TABLE 1.
Baseline characteristics of the two groups of children
| Characteristics |
Low‐dose group (n = 213) |
High‐dose group (n = 211) |
P |
|---|---|---|---|
| Demographic characteristics | |||
| Male sex | 115 (54.0) | 98 (46.4) | 0.120 |
| Age (y) | 6.8 (5.3–8.7) | 7.2 (5.8–8.9) | 0.126 |
| Age category (y) | 0.182 | ||
| <3 | 8 (3.8) | 8 (3.8) | |
| 3–<6 | 63 (29.6) | 46 (21.8) | |
| ≥6 | 142 (66.6) | 157 (74.4) | |
| Clinical symptoms | |||
| Fever | 213 (100.0) | 210 (99.5) | 0.237 |
| Cough | 213 (100.0) | 210 (99.5) | 0.237 |
| Expectoration | 89 (41.8) | 98 (46.4) | 0.088 |
| Wheezing | 8 (3.8) | 8 (3.8) | 0.977 |
| Chest pain | 4 (1.9) | 6 (2.8) | 0.511 |
| Retraction of the chest wall | 2 (0.9) | 3 (1.4) | 0.981 |
| Rash | 5 (2.3) | 5 (2.4) | 0.417 |
| CNS involvement | 6 (2.8) | 4 (1.9) | 0.496 |
| Physical examinations | |||
| Max temperature (°C) | 39.6 (39.2–40.0) | 39.8 (39.0–40.1) | 0.560 |
| Respiratory rate (breaths/min) | 25 (23–28) | 25 (22–28) | 1.000 |
| Decreased oxygen saturation (≤92%) | 42 (19.7) | 50 (23.7) | 0.343 |
| Retraction of the chest wall | 2 (0.9) | 3 (1.4) | 0.981 |
| Pulmonary auscultation | |||
| Moist rale | 95 (44.6) | 96 (45.5) | 0.934 |
| Wheeze | 8 (3.8) | 8 (3.8) | 0.984 |
| Laboratory tests | |||
| WBC (×109/L) | 7.6 (6.2–9.1) | 7.9 (6.4–9.9) | 0.772 |
| Neutrophil（%) | 64.2 (54.3–71.0) | 64.3 (56.9–73.1) | 0.267 |
| HB (g/L) | 127.0 (122.3–133.0) | 128.0 (121.0–135.0) | 0.381 |
| CRP (mg/L) | 20.0 (11.0–42.0) | 21.6 (11.6–49.0) | 0.448 |
| ALT abnormal | 36 (16.9) | 41 (19.4) | 0.499 |
| CKMB abnormal | 36 (16.9) | 37 (17.5) | 0.863 |
| Radiographic characteristics | |||
| Consolidation | 209 (98.1) | 206 (97.6) | 0.725 |
| Atelectasis | 9 (4.2) | 13 (6.2) | 0.279 |
| Interstitial lesions | 2 (0.9) | 7 (3.3) | 0.083 |
| Pleural effusion | 109 (60.6) | 97 (46.0) | 0.636 |
Data are presented as n (%) or median (interquartile range).
Abbreviations: ALT, alanine aminotransferase (Abnormal: >40 U/L); CKMB, creatine kinase MB (Abnormal: ≥25 U/L); CNS, central nervous system; CRP, C‐reactive protein; HB, hemoglobin; WBC, white blood cell count.
As expected in advance, the number of lost patients increased with the extension of follow‐up time, although various attempts were made by the research staff. It has been shown in Table S4 that the risk of pulmonary lesions decreased with time after therapy based on the PP dataset. The median healing time was close to 6 months, and a total of 98 cases with severe MPP have a long‐term adverse prognosis, including pulmonary atelectasis (8), bronchiolitis obliterans (27), and bronchiectasis (8) (Figure 2).
FIGURE 2.
Chest computed tomography (CT) scans for pediatric patients of severe Mycoplasma pneumoniae pneumonia with long‐term pulmonary lesions at 6‐month follow‐up. Patient 1. (A) Chest CT showed consolidations in the left lung; (B) Six months later, mosaic and bronchial wall thickening on chest CT and obstructive changes with air trapping were clearly shown. Patient 2. (C) Chest CT showed consolidations in the right lung, then bronchiectasis and mosaic were shown 6 months later (D). Patient 3. (E) Chest CT showed consolidation and atelectasis in the right lung; (F) Six months later, atelectasis remained.
Primary and secondary outcomes
The proportion of long‐term pulmonary lesions at 6 months was numerically lower in the low‐dose group (52/213, 24.4%) compared to the high‐dose group (66/211, 31.3%), though this difference did not reach statistical significance (P = 0.115; Table 2). The overall RR was 1.28 (95% CI: 0.94 to 1.75) for the high‐dose versus low‐dose group, and the corresponding risk difference was 6.9% (95% CI: −1.6% to 15.4%). Results from other imputation approaches are provided in Table S5.
TABLE 2.
Primary and secondary outcomes in the trial
| Outcome |
Low‐dose group (n = 213) |
High‐dose group (n = 211) |
Risk ratio (95% CI) |
P |
|---|---|---|---|---|
| Primary outcome | ||||
| Pulmonary lesions at 6‐month follow‐up | 52 (24.4) | 66 (31.3) | 1.28 (0.94, 1.75) | 0.115 |
| Secondary outcomes | ||||
| Recovery of the patient's temperature | ||||
| Treatment for 24 h | 168 (78.9) | 176 (83.4) | 1.06 (0.96, 1.16) | 0.232 |
| Treatment for 48 h | 185 (86.9) | 190 (90.0) | 1.04 (0.97, 1.11) | 0.303 |
| Treatment for 72 h | 189 (88.7) | 196 (92.9) | 1.05 (0.99, 1.11) | 0.139 |
| Treatment for 96 h | 195 (91.5) | 194 (91.9) | 1.00 (0.95, 1.06) | 0.883 |
| Recovery of the patient's cough | ||||
| Treatment for 3 d | 130 (61.0) | 144 (68.0) | 1.12 (0.97, 1.29) | 0.120 |
| Treatment for 7 d | 202 (94.8) | 199 (94.3) | 0.99 (0.95, 1.04) | 0.812 |
| Pulmonary lesions improvement when discharged | 213 (100.0) | 211 (100.0) | – | 1.000 |
| Length of hospital stay (d) | 10 (8–12) | 11 (9–13) | – | 0.255 |
| Transfer to the intensive care unit | 2 (0.9) | 1 (0.5) | 0.49 (0.05, 5.41) | 0.556 |
Data are presented as n (%) or median (interquartile range).
Additional results regarding secondary outcomes are provided in Table 2. The recovery rate of the patient's temperature after treatment for 24, 48, 72, and 96 h was not significantly different between the two dose groups. The median time from enrollment to hospital discharge was 10 d (interquartile range, 8–12 d) in the low‐dose group and 11 d (interquartile range, 9–13 d) in the high‐dose group (P = 0.255). We also observed no significant difference between groups in the proportion of intensive care unit admissions and invasive ventilation support required during the trial.
The pre‐specified subgroup analyses failed to suggest any credible subgroup effects (Table 3). However, exploratory analyses suggested fever history (10 d) and CRP 100 mg/L might be the potential predictors for high‐dose methylprednisolone treatment. These observations were consistent in both the intention‐to‐treat and per‐protocol analyses (Table 3 and Table S6, respectively), though the associations did not reach predefined thresholds for statistical significance after adjustment for multiple comparisons.
TABLE 3.
Subgroup analysis for developing primary composite outcome when follow‐up at 6 months
| Subgroup | n | Risk ratio (95% CI) | P for interaction |
|---|---|---|---|
| Demographic characteristics | |||
| Age (y) | 0.408 | ||
| <6 | 125 | 1.58 (0.88, 2.84) | |
| ≥6 | 299 | 1.17 (0.82, 1.69) | |
| Clinical symptoms | |||
| Fever history (d) | 0.094 | ||
| <10 | 300 | 1.08 (0.74, 1.58) | |
| ≥10 | 124 | 1.84 (1.08, 3.13) | |
| Fever after treatment (h) | 0.414 | ||
| <48 | 49 | 0.93 (0.43, 2.04) | |
| ≥48 | 375 | 1.37 (0.97, 1.92) | |
| Laboratory tests | |||
| CRP (mg/L) | 0.488 | ||
| <50 | 345 | 1.20 (0.84, 1.72) | |
| ≥50 | 79 | 1.51 (0.80, 2.84) | |
| CRP (mg/L) | 0.056 | ||
| <100 | 400 | 1.19 (0.86, 1.64) | |
| ≥100 | 24 | 4.20 (1.06, 16.68) | |
| Abnormal ALT | 0.603 | ||
| Yes | 77 | 1.39 (0.79, 2.45) | |
| No | 347 | 1.22 (0.85, 1.76) | |
| Radiographic characteristics | |||
| Pleural effusion | 0.778 | ||
| Yes | 206 | 1.33 (0.91, 1.96) | |
| No | 218 | 1.28 (0.77, 2.12) | |
| Consolidation | 0.978 | ||
| Yes | 415 | 1.27 (0.93, 1.73) | |
| No | 9 | – | |
Abbreviations: ALT, alanine aminotransferase (Abnormal >40 U/L); CRP, C‐reactive protein (Normal range: <8 mg/L).
Adverse events and adverse drug reactions
The most common methylprednisolone‐related adverse drug reactions were hypertension, hyperglycemia, and high intraocular pressure. A marked difference was observed in hypertension incidence between groups, occurring in 1.4% (3/213) of low‐dose recipients versus 8.1% (17/211) of high‐dose recipients (RR 5.72, 95% CI: 1.70–19.23; P = 0.001) (Table S7). Notably, no fractures or decreased bone density were observed in either group, and there were no significant differences in the incidence of other adverse events or serious adverse events. All methylprednisolone‐related adverse effects resolved following treatment cessation. Importantly, no mortality events occurred in either group.
Conditional power, which refers to the probability of detecting statistically significant results if all the patients were followed up, is provided in Table S8. Under most hypotheses, the conditional power was not high, indicating that high‐dose methylprednisolone was likely not to reduce the long‐term pulmonary lesions of severe MPP in Chinese children, compared to low‐dose methylprednisolone.
DISCUSSION
This multicenter RCT was first performed to evaluate the efficacy and safety of a strategy of azithromycin combined with low‐dose or high‐dose methylprednisolone treatment for long‐term pulmonary lesions in children with severe MPP. Azithromycin combined with high‐dose methylprednisolone compared to that with low doses did not reduce long‐term pulmonary lesions of severe MPP in Chinese children but significantly increased the rates of systemic hypertension.
Excessive inflammatory reaction is one of the pathogenes of severe MPP. Studies have shown that severe MPP patients had high levels of cytokines in the serum and bronchoalveolar lavage fluid, 24 , 25 which is one of the causes of long‐term pulmonary lesions. Our study showed that the proportion of long‐term pulmonary lesions was up to 27.8% (118/424) at the 6‐month follow‐up. Such long‐term lesions could potentially impair pulmonary function into adulthood and increase susceptibility to chronic obstructive pulmonary diseases. 26 While glucocorticoids are commonly employed during acute severe MPP management due to their anti‐inflammatory effects, optimal dosing remains controversial. Retrospective studies 20 , 21 , 27 suggested that patients with refractory MPP treated with high‐dose glucocorticoids or pulse therapy could achieve defervescence earlier and achieve a shorter hospitalization than with low‐dose glucocorticoids. However, the majority of these studies were limited by their retrospective design, single‐center nature, small sample sizes, and lack of long‐term outcome assessment.
Our study, a rigorously designed multicenter RCT, demonstrated that the efficacy of azithromycin combined with low‐dose methylprednisolone was not inferior to the high‐dose group. Specifically, the high‐dose group failed to show a reduction in long‐term pulmonary lesions or improvements in clinical outcomes such as time to fever resolution transfer to the intensive care unit and hospital discharge duration. Importantly, the high‐dose methylprednisolone group was associated with a significantly higher incidence of systemic hypertension. Furthermore, corticosteroids, even at lower doses, have been associated with adverse effects such as hypertension, gastrointestinal bleeding, neuropsychiatric disorders, muscle weakness, hypernatremia, and secondary infections, which aligns with evidence from other RCTs evaluating glucocorticoids in patients with community‐acquired‐pneumonia (CAP). 28 , 29 Contemporary research supports the use of lower glucocorticoid doses for severe pulmonary infections, as they maintain therapeutic efficacy while substantially reducing adverse event profiles. 30 , 31 Consistent with these findings, our study showed that low‐dose methylprednisolone is a safer and equally effective option compared to high‐dose regimens. Therefore, we recommend the use of low‐dose methylprednisolone to treat severe MPP in children, achieving a balance between efficacy and reducing the risk of adverse events.
The high prevalence of macrolide‐resistant M. pneumoniae strains in China (>90%) presents additional therapeutic challenges. 32 , 33 Clinical studies have demonstrated significantly reduced macrolide efficacy against resistant strains, 34 potentially contributing to poorer outcomes. Given these resistance patterns and recent guideline updates allowing children to use tetracycline, clinicians should consider alternative antibiotics (e.g., doxycycline) either as monotherapy or in combination with low‐dose glucocorticoids for refractory cases.
This trial has several notable strengths, including its multicenter nature and randomized design, which robustly evaluate the efficacy and safety of low‐dose versus high‐dose methylprednisolone in reducing long‐term pulmonary lesions in children with severe MPP. The findings provide valuable evidence to guide glucocorticoid use in severe MPP, suggesting that lower doses may be sufficient while minimizing unnecessary high‐dose exposure in pediatric patients. Despite the rigorous methodology and enhanced generalizability afforded by the multicenter approach, this study possesses several limitations. First, we only studied hospitalized children with severe MPP in mainland China, and the benefit of methylprednisolone in CAP caused by other pathogens and patients in other countries was not evaluated. Second, this study did not include the non‐glucocorticoid group, as current evidence from previous studies 14 , 15 , 17 and our clinical experience consistently demonstrates superior outcomes with combined glucocorticoid and antibiotic therapy compared to antibiotic monotherapy for severe MPP cases. This also has been mentioned in recent Chinese pediatric MPP management guideline, 17 which recommends glucocorticoids use for severe manifestations based on established clinical benefits. Third, in our study methylprednisolone was the only glucocorticoid used to treat severe MPP. There are many available types of glucocorticoids, including hydrocortisone, and dexamethasone, and the appropriate choice of glucocorticoid for treatment is currently controversial. Previous studies 30 , 31 , 35 , 36 have reported the potent anti‐inflammatory effects of methylprednisolone, making it a commonly used treatment for patients with severe pneumonia. Considering this, we opted to utilize methylprednisolone in our study, although the effects of other glucocorticoids still need to be evaluated. Fourth, we did not test macrolide resistance between the two groups because of the high macrolide resistance rate (over 90%) in China. In addition, our study had a high rate of loss to follow‐up, and we were unable to achieve the expected number of enrolled patients by the end of the 6‐month follow‐up period. If we were to recalculate the sample size based on these research results, aiming for 80% power (two‐sided, type 1 error of 5%) to detect a difference between the group proportions of −0.0690, over 1300 pediatric patients would need to be enrolled (with 659 patients in each group). Collecting such a substantial number of pediatric patients poses significant challenges for our clinical trial. Importantly, our findings align with the current understanding of methylprednisolone's anti‐inflammatory properties while providing novel evidence that lower doses achieve similar therapeutic benefits with significantly reduced adverse effects, particularly hypertension risk. These results strongly support clinical guidelines recommending judicious corticosteroid use in pediatric severe MPP, favoring lower‐dose regimens to optimize the balance between therapeutic efficacy and patient safety.
In conclusion, the combination of azithromycin and low‐dose methylprednisolone in the treatment of severe MPP children is not inferior to the combination of high‐dose methylprednisolone in reducing lung lesions at 6 months after treatment and improving short‐term prognosis, with fewer adverse reactions.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
Supporting information
Supporting Information
ACKNOWLEDGMENTS
We thank all the patients and their families who freely participated in this trial. And thank Professor Getu Zhaori for revising the manuscript. We sincerely appreciate the professional support provided by the Peking University Clinical Research Institute for monitoring the research process. This study was supported by the Clinical and Translational Medicine Research Project of the Chinese Academy of Medical Sciences (2023‐I2M‐C&T‐A‐015), High‐level Public Health Talents Training Program of Beijing Municipal Health Commission (2022‐2‐023) and Beijing Municipal Science & Technology Commission (Z171100001017081).
Xu B, Cao L, Shang Y, Liu L, Gao L, Yin J, et al. Low‐dose versus high‐dose methylprednisolone for children with severe Mycoplasma pneumoniae pneumonia (MCMP): A randomized controlled trial. Pediatr Investig. 2025;9:251–261. 10.1002/ped4.70014
Baoping Xu, Ling Cao, Yunxiao Shang, Liping Liu and Liwei Gao contributed equally to this work.
Contributor Information
Baoping Xu, Email: xubaopingbch@163.com.
Xiaoxia Peng, Email: pengxiaoxia@bch.com.cn.
Kunling Shen, Email: kunlingshen1717@163.com.
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