Abstract
Background
Macrolide resistance is common in pediatric Mycoplasma pneumoniae pneumonia (MPP), but its relationship with clinical phenotype, short-term in-hospital course, and radiographic severity remains uncertain. We aimed to characterize macrolide resistance–associated sites and their clinical correlates in hospitalized children with MPP, focusing on A2063G and pulmonary consolidation.
Methods
This retrospective study included children aged < 14 years hospitalized with MPP at Shantou Central Hospital, China, from January 1 to December 31, 2024. All patients had undergone throat-swab targeted next-generation sequencing within 24 h of admission as part of routine clinical diagnostic work-up. This retrospective study used secondary data extracted from clinical diagnostic reports and electronic medical records. Four macrolide resistance–associated sites were interrogated: A2063G, A2064G, A2067G, and C2617G. Clinical, laboratory, radiographic, and short-term in-hospital outcome variables were compared by A2063G resistance-site status and by pulmonary consolidation. Multivariable logistic regression was performed for A2063G resistance-site status and pulmonary consolidation. Firth penalized logistic regression was used as a sensitivity analysis for the A2063G model.
Results
Among 402 hospitalized children with MPP, A2063G was detected in 362 (90.0%), whereas A2064G, A2067G, and C2617G were not detected. Monthly case counts peaked during June–August, while the proportion of A2063G remained consistently high throughout the year. Pulmonary consolidation was present in 103 patients (25.6%) and was less frequent in A2063G-positive than in wild-type cases (23.2% vs. 47.5%, P = 0.002). In multivariable analysis, pulmonary consolidation was independently associated with lower odds of A2063G positivity (OR 0.370, 95% CI 0.187–0.732; P = 0.004). For pulmonary consolidation, A2063G positivity remained independently associated with lower odds after adjustment for age, Tmax_24h, and CRP (OR 0.378, 95% CI 0.190–0.752; P = 0.006). No clear differences were observed by resistance-site status in systemic inflammatory profile, overall clinical course, or in-hospital resource use. Overall, short-term in-hospital outcomes were favorable, with no deaths.
Conclusions
In hospitalized children with MPP from the Chaoshan region of southern China in 2024, A2063G was the dominant macrolide resistance–associated site. In this cohort, A2063G positivity was not accompanied by more frequent pulmonary consolidation, a more severe clinical phenotype based on the available indicators, or worse short-term in-hospital outcomes. These findings suggest that, in pediatric MPP, predominance of a resistance-associated site, radiographic severity, and short-term clinical course may not necessarily vary in parallel.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12887-026-07351-y.
Keywords: Mycoplasma pneumoniae pneumonia, Macrolide resistance, A2063G resistance site, Pediatric pneumonia, Pulmonary consolidation, Co-infection, Hospitalization outcomes
Introduction
Mycoplasma pneumoniae is a major cause of community-acquired pneumonia in children and remains an important pathogen in hospitalized pediatric patients [1–6]. In the post-COVID-19 period, several regions, including parts of China, reported a marked resurgence of pediatric M. pneumoniae infection, followed by temporal and regional fluctuation [7–11]. This changing epidemic pattern has created practical challenges for pediatric inpatient care.
Macrolides remain the standard first-line treatment for pediatric Mycoplasma pneumoniae pneumonia (MPP), while macrolide resistance-associated sites have been increasingly detected, particularly in East Asia [12–18]. Resistance is mainly associated with mutations in domain V of the 23 S rRNA gene, among which A2063G is the most frequently reported and clinically relevant site [13–18]. In clinical practice, identification of a resistance-associated site may influence treatment planning because clinicians need to judge whether it is associated with greater inflammatory burden, more prominent pulmonary involvement, or a less favorable short-term course. Whether these molecular markers are actually associated with such features, however, remains uncertain [12, 18, 19].
Pulmonary consolidation is a clinically important radiographic phenotype in pediatric MPP because it usually reflects more substantial parenchymal involvement and is often accompanied by greater inflammatory activity and a more complicated inpatient course [2–6, 19–22]. In addition, co-detection or mixed infection is not uncommon in hospitalized children with MPP and may further complicate clinical interpretation [23–26]. Whether this phenotype is associated with macrolide resistance-associated sites, particularly A2063G, remains unclear.
In this retrospective study, we investigated hospitalized children with tNGS-confirmed MPP in Chaoshan, southern China, during 2024. We aimed to describe the distribution of macrolide resistance-associated sites and to examine the clinical, laboratory, radiographic, and short-term in-hospital correlates of A2063G, with particular focus on pulmonary consolidation.
Materials and methods
Study design and setting
This retrospective observational study included children (< 14 years) hospitalized with Mycoplasma pneumoniae pneumonia (MPP) at Shantou Central Hospital (Shantou, Guangdong, China) between January 1 and December 31, 2024. The study used secondary data extracted from routine clinical diagnostic reports and electronic medical records. The study was approved by the Ethics Committee of Shantou Central Hospital, Shantou, Guangdong, China (Approval No. [2025] 119), which waived the need for consent to participate because of the retrospective design and the use of de-identified clinical data.
Participants
Hospitalized children meeting the screening criteria during the study period were retrospectively and consecutively screened. Inclusion criteria were: (1) clinical features consistent with pneumonia with radiographic evidence of pneumonia; (2) M. pneumoniae detected by targeted next-generation sequencing (tNGS) from throat swabs collected within 24 h of admission; and (3) estimated M. pneumoniae load > 1 × 10⁶ copies/mL.
Exclusion criteria were: (1) rehospitalization for MP infection within 1 month; (2) unresolved severe pneumonia from a prior episode at the time of screening; (3) congenital bronchopulmonary malformations or chronic pulmonary dysfunction; and (4) other conditions considered unsuitable by investigators due to incomplete data or potential misclassification.
Specimen collection and tNGS testing
Throat-swab tNGS testing had been performed as part of routine inpatient diagnostic work-up. Throat swabs were obtained by trained clinicians within 24 h after admission, placed in transport medium, and submitted to Guangzhou KingMed Diagnostics for clinical diagnostic tNGS testing. The present study retrospectively extracted processed diagnostic outputs from clinical reports and medical records; no additional sample collection or sequencing was performed specifically for this study. Raw diagnostic tNGS reads were generated and retained by the third-party clinical diagnostic laboratory and were not provided to the hospital or the study investigators as part of routine clinical reporting. The assay used multiplex PCR targeting conserved regions of a respiratory pathogen panel, followed by next-generation sequencing and reference database alignment for pathogen identification. The pathogen spectrum included in the panel is summarized in Supplementary Table S1. Pathogen load was estimated by the testing laboratory based on normalized sequence reads and internal calibration. In addition to pathogen identification and load estimation, the assay interrogated four macrolide resistance–associated sites in M. pneumoniae: A2063G, A2064G, A2067G, and C2617G.
Pathogen co-detection categories
Based on tNGS results, patients were categorized into three pathogen co-detection groups:
MP-only: M. pneumoniae detected without additional viral or bacterial detections;
MP + virus: M. pneumoniae plus ≥ 1 viral pathogen, with or without bacterial detections;
MP + bacteria: M. pneumoniae plus ≥ 1 bacterial pathogen in the absence of viral detections.
This classification was adopted because viral detections often reflect the dominant antecedent respiratory process in mixed detections, whereas bacterial signals from upper-airway specimens may represent secondary infection or colonization; therefore, mixed viral–bacterial detections were grouped within the virus-related category.
Definitions of key variables
A2063G resistance-site status: Macrolide resistance–associated site status was defined by detection of the A2063G resistance site (A2063G vs. wild-type).
Radiologic assessment and pulmonary consolidation: All participants underwent chest radiography, which served as the primary modality for defining pulmonary consolidation. Consolidation was defined as lobar/segmental air-space opacity consistent with consolidation (with or without air bronchogram) as documented in the official radiology report. Chest CT was performed in selected severe cases and used as supportive evidence to confirm or further characterize consolidation, but was not required for cohort inclusion. Treating clinicians reviewed images and reports as part of routine care. For study abstraction, consolidation status was extracted using a standardized form; discrepant or equivocal cases were resolved by consensus with radiology input. Because this was a retrospective study based primarily on routine clinical radiology reports, formal blinded duplicate image review was not performed, and some degree of interobserver variability cannot be excluded.
Temperature variables: Tmax_24h was defined as the maximum axillary temperature recorded within the first 24 h after admission.
Time to defervescence: Time to defervescence (hours) was defined as the interval from admission to sustained normothermia based on ward nursing temperature records.
Bronchoalveolar lavage (BAL): BAL was performed according to institutional practice informed by the Chinese guideline for pediatric MPP. It was considered early in severe cases with suspected mucus plug obstruction or plastic bronchitis, and in bronchiolitis-pattern airway involvement with imaging evidence of mucus impaction (large or small airways) accompanied by wheeze and/or persistent high fever despite other treatments. Given the small BAL subgroup, BAL-related findings are reported descriptively (Supplementary Table S2).
Doxycycline exposure: Treatment was categorized as azithromycin-only or any doxycycline exposure, the latter including switching from azithromycin to doxycycline and doxycycline monotherapy.
Data collection
Data were extracted from electronic medical records, including demographics (age, sex, BMI), symptom durations prior to admission (fever duration, cough duration, and time since onset), clinical course and severity indicators within the first 24 h (Tmax_24h and oxygen therapy), laboratory markers obtained within 24 h (WBC, PLT, CRP, LDH, and NLR), tNGS outputs (pathogen category and MP load metrics), treatments (intravenous glucocorticoids and antibiotic regimen), and outcomes (time to defervescence, length of stay, and hospitalization cost). Severe in-hospital respiratory support events were also reviewed descriptively; invasive mechanical ventilation occurred in only one patient in the total cohort and was therefore not analyzed as a formal comparative endpoint.
Statistical analysis
Analyses were conducted using SPSS (version 21.0) and R (version 4.3.0). Continuous variables are presented as median (Q1–Q3) and were compared using the Mann–Whitney U test for two-group comparisons or the Kruskal–Wallis test for three-group comparisons. Categorical variables are presented as n (%) and were compared using the chi-square test or Fisher’s exact test, as appropriate. All tests were two-sided, and P < 0.05 was considered statistically significant.
Multivariable logistic regression was performed for two pre-specified outcomes: (1) A2063G resistance-site status and (2) pulmonary consolidation. Candidate predictors were selected based on clinical relevance, availability and reliability in the retrospective dataset, and evidence of association in univariable analyses, while restricting model complexity to reduce overfitting. Disease-timing variables and baseline clinical indicators were considered in descriptive and univariable analyses; variables entered into the final multivariable models were limited to those with stronger statistical support and clinical interpretability. Treatment-related variables were not included in the primary multivariable models because they were guided by clinical condition and treatment response and could represent downstream management pathways rather than baseline characteristics. Continuous predictors were modeled on their original scales. Collinearity was assessed using variance inflation factors (VIFs). Sensitivity analysis for the A2063G model was conducted using Firth penalized logistic regression to mitigate small-sample bias arising from the imbalanced outcome distribution (Supplementary Table S3).
Additional exploratory stratified analyses were performed according to A2063G resistance-site status and doxycycline exposure, because doxycycline use was guided by clinical condition and treatment response.
Results
Patient selection and baseline characteristics
The patient selection process is shown in Fig. 1. During the study period, 2,503 hospitalized children with clinically diagnosed pneumonia were screened, 607 had Mycoplasma pneumoniae detected by throat-swab testing, and 402 met the final inclusion criteria. Thus, the analyzed cohort represented 16.1% of the screened hospitalized pneumonia population and 66.2% of the M. pneumoniae-positive screened patients. A total of 402 hospitalized children with MPP were included in the final analysis (Table 1). Among them, 158 (39.3%) had MP-only infection, 121 (30.1%) had viral co-detection, and 123 (30.6%) had bacterial co-detection. Pulmonary consolidation was present in 103 patients (25.6%), and the A2063G resistance site was detected in 362 patients (90.0%), indicating clear predominance of A2063G in this cohort.
Fig. 1.
Flowchart of patient selection and final cohort classification in children hospitalized with Mycoplasma pneumoniae pneumonia
Table 1.
Cohort characteristics and pathogen groups
| Category | Option | Number | Percentage (%) |
|---|---|---|---|
| Pathogen grouping | MP only | 158 | 39.3 |
| Co-viral | 121 | 30.1 | |
| Co-bacterial | 123 | 30.6 | |
| Gender | Male | 230 | 57.21 |
| Female | 172 | 42.79 | |
| Age group | < 3 years | 97 | 24.13 |
| 3–5 years | 140 | 34.83 | |
| ≥ 6 years | 165 | 41.04 | |
| Lung consolidation | Present | 103 | 25.62 |
| Absent | 299 | 74.38 | |
| A2063G | Positive | 362 | 90.05 |
| Negative | 40 | 9.95 | |
| Total | 402 | 100 |
As shown in Fig. 2, monthly case counts fluctuated over time, with a clear peak during June–August and the highest number of cases in July. In contrast, the monthly proportion of the A2063G resistance site remained consistently high throughout the year, with only modest month-to-month variation.
Fig. 2.
Monthly distribution of hospitalized children with Mycoplasma pneumoniae pneumonia (MPP) and the monthly proportion of the A2063G resistance site in 2024. (A) Monthly number of MPP cases; (B) Monthly proportion of cases carrying the A2063G resistance site
Clinical characteristics according to A2063G resistance-site status
Categorical variables
Categorical comparisons by A2063G resistance-site status are shown in Table 2. The distribution of pathogen co-detection categories differed significantly between wild-type and A2063G groups (P = 0.023), with the highest proportion of A2063G observed in the MP + virus group and the lowest in the MP + bacteria group. Sex and age-group distributions did not differ significantly between the two groups.
Table 2.
Categorical variables by A2063G resistance-site status
| Variable | Total (n = 402) | Wild-type (n = 40) | A2063G (n = 362) | A2063G rate, n/N (%) | Test | P |
|---|---|---|---|---|---|---|
| Etiology, n (%) | χ²=7.55 | 0.023 | ||||
| MP only | 158 (39.30) | 15 (37.50) | 143 (39.50) | 143/158 (90.5) | ||
| MP + virus | 121 (30.10) | 6 (15.00) | 115 (31.77) | 115/121 (95.0) | ||
| MP + bacteria | 123 (30.60) | 19 (47.50) | 104 (28.73) | 104/123 (84.6) | ||
| Sex, n (%) | χ²=0.00 | 1.000 | ||||
| Male | 230 (57.21) | 23 (57.50) | 207 (57.18) | 207/230 (90.0) | ||
| Female | 172 (42.79) | 17 (42.50) | 155 (42.82) | 155/172 (90.1) | ||
| Age group, n (%) | χ²=1.07 | 0.586 | ||||
| <3 years | 97 (24.13) | 7 (17.50) | 90 (24.86) | 90/97 (92.8) | ||
| 3–5 years | 140 (34.83) | 15 (37.50) | 125 (34.53) | 125/140 (89.3) | ||
| ≥6 years | 165 (41.04) | 18 (45.00) | 147 (40.61) | 147/165 (89.1) | ||
| Pulmonary consolidation, n (%) | χ²=9.92 | 0.002 | ||||
| With consolidation | 103 (25.62) | 19 (47.50) | 84 (23.20) | 84/103 (81.6) | ||
| Without consolidation | 299 (74.38) | 21 (52.50) | 278 (76.80) | 278/299 (93.0) | ||
| IV glucocorticoids, n (%) | χ²=0.00 | 1.000 | ||||
| Not used | 186 (46.27) | 19 (47.50) | 167 (46.13) | 167/186 (89.8) | ||
| Used | 216 (53.73) | 21 (52.50) | 195 (53.87) | 195/216 (90.3) | ||
| Oxygen therapy, n (%) | χ²=0.05 | 0.817 | ||||
| Not used | 361 (89.80) | 35 (87.50) | 326 (90.06) | 326/361 (90.3) | ||
| Used | 41 (10.20) | 5 (12.50) | 36 (9.94) | 36/41 (87.8) | ||
| Bronchoalveolar lavage, n (%) | Fisher’s exact | 0.019 | ||||
| Not performed | 385 (95.77) | 35 (87.50) | 350 (96.69) | 350/385 (90.9) | ||
| Performed | 17 (4.23) | 5 (12.50) | 12 (3.31) | 12/17 (70.6) |
Values are n (%). Percentages in the wild-type and A2063G columns are column percentages. “A2063G rate” indicates the within-category (row) proportion of patients with A2063G. P values were calculated using the chi-square test, except for bronchoalveolar lavage, for which Fisher’s exact test was used because of small cell counts
Pulmonary consolidation was more common in wild-type than in A2063G cases (47.5% vs. 23.2%, P = 0.002). Intravenous glucocorticoid use and oxygen therapy did not differ significantly between groups. BAL was more frequent in wild-type than in A2063G cases overall (12.5% vs. 3.3%, P = 0.019), although this finding required further interpretation after stratification by pulmonary consolidation.
Continuous variables
Continuous-variable comparisons are shown in Table 3. Compared with the A2063G group, the wild-type group had a slightly higher Tmax_24h (P = 0.021) and a shorter cough duration before admission (P = 0.046). Other variables, including fever duration before admission, time since onset, time to defervescence, inflammatory markers, length of stay, and hospitalization cost, did not differ significantly between groups.
Table 3.
Continuous variables by A2063G resistance-site status
| Variables | Total (n = 402) | wild-type MP strain (n = 40) | A2063G (n = 362) | P |
|---|---|---|---|---|
| Duration of fever before admission (days) | 5.00 (3.00, 7.00) | 6.00 (4.00, 7.00) | 5.00 (3.00, 7.00) | 0.106 |
| Tmax (within 24 h of admission) (℃) | 39.20 (38.62, 39.70) | 39.50 (39.20, 39.80) | 39.20 (38.60, 39.60) | 0.021 |
| Duration of cough before admission (days) | 6.00 (4.00, 8.00) | 5.00 (4.00, 7.00) | 6.00 (4.00, 8.00) | 0.046 |
| Time since onset (days) | 7.00 (5.00, 8.00) | 6.00 (4.00, 8.00) | 7.00 (5.00, 8.00) | 0.225 |
| Time to defervescence (h) | 13.00 (1.00, 40.75) | 8.50 (1.00, 37.75) | 14.00 (1.00, 40.75) | 0.990 |
| WBC (*10⁹/L) | 8.18 (6.41, 10.36) | 7.34 (6.14, 8.90) | 8.28 (6.45, 10.46) | 0.099 |
| NLR | 2.02 (1.38, 2.96) | 2.03 (1.42, 3.25) | 2.02 (1.36, 2.95) | 0.762 |
| PLT (×10⁹/L) | 267.00 (215.00, 337.50) | 224.00 (199.50, 308.75) | 269.50 (215.00, 338.00) | 0.057 |
| CRP (mg/L) | 11.43 (3.21, 22.85) | 15.75 (7.70, 25.48) | 11.02 (2.89, 22.63) | 0.088 |
| LDH (U/L) | 330.00 (283.25, 390.75) | 335.50 (303.00, 415.25) | 329.50 (281.25, 387.75) | 0.226 |
| Length of hospital stay (days) | 7.00 (6.00, 9.00) | 7.00 (5.00, 9.00) | 7.00 (6.00, 9.00) | 0.274 |
| Hospitalization cost (CNY) | 3990.38 (3141.72, 5103.21) | 3673.30 (2704.81, 5592.37) | 4015.90 (3169.78, 5083.85) | 0.618 |
Multivariable analysis for A2063G resistance-site status
Multivariable logistic regression with A2063G resistance-site status as the outcome is shown in Table 4. Pulmonary consolidation remained independently associated with lower odds of A2063G positivity (OR 0.370, 95% CI 0.187–0.732; P = 0.004). Viral and bacterial co-detection, Tmax_24h, and cough duration were not independently associated with A2063G status.
Table 4.
Multivariable logistic regression for A2063G resistance-site status
| Variable | β (B) | SE | Wald χ² | P | OR | 95% CI for OR | VIF |
|---|---|---|---|---|---|---|---|
| Intercept | 14.602 | 9.016 | 2.623 | 0.105 | NA | NA | |
| Etiology: virus vs. MP only | 0.45 | 0.51 | 0.78 | 0.377 | 1.569 | 0.577–4.261 | 1.797 |
| Etiology: bacteria vs. MP only | -0.657 | 0.379 | 3.016 | 0.082 | 0.518 | 0.247–1.088 | 1.791 |
| Pulmonary consolidation | -0.995 | 0.349 | 8.146 | 0.004 | 0.37 | 0.187–0.732 | 1.371 |
| Tmax within 24 h of admission (°C, per 1 °C) | -0.312 | 0.228 | 1.874 | 0.171 | 0.732 | 0.468–1.144 | 4.1 |
| Cough duration before admission (days, per 1 day) | 0.052 | 0.048 | 1.169 | 0.280 | 1.053 | 0.959–1.158 | 2.346 |
Notes: VIFs were calculated among predictors excluding the intercept. Tmax refers to the maximum axillary temperature recorded within the first 24 h after admission (Tmax_24h). ORs and 95% CIs are not reported for the intercept because it represents the baseline log-odds when all covariates are zero, which is not clinically meaningful for continuous variables
Because of the marked imbalance between A2063G-positive and wild-type cases, Firth penalized logistic regression was further performed as a sensitivity analysis (Supplementary Table S3). The direction of association remained unchanged, and pulmonary consolidation was still independently associated with lower odds of A2063G positivity (OR 0.376, 95% CI 0.193–0.734; P = 0.004).
Clinical characteristics associated with pulmonary consolidation
Categorical variables
Categorical comparisons by pulmonary consolidation status are shown in Table 5. Etiologic group and sex did not differ significantly between patients with and without consolidation. In contrast, age-group distribution differed significantly (P = 0.004), with consolidation rates increasing from 13.4% in children aged < 3 years to 32.1% in those aged ≥ 6 years.
Table 5.
Categorical variables by pulmonary consolidation status
| Variable | Total (n = 402) | No consolidation (n = 299) | Consolidation (n = 103) | Consolidation rate, n/N (%) | Test | P |
|---|---|---|---|---|---|---|
| Etiology, n (%) | χ²=2.98 | 0.225 | ||||
| MP only | 158 (39.30) | 111 (37.12) | 47 (45.63) | 47/158 (29.7) | ||
| MP + virus | 121 (30.10) | 96 (32.11) | 25 (24.27) | 25/121 (20.7) | ||
| MP + bacteria | 123 (30.60) | 92 (30.77) | 31 (30.10) | 31/123 (25.2) | ||
| Sex, n (%) | χ²=0.46 | 0.499 | ||||
| Male | 230 (57.21) | 174 (58.19) | 56 (54.37) | 56/230 (24.3) | ||
| Female | 172 (42.79) | 125 (41.81) | 47 (45.63) | 47/172 (27.3) | ||
| Age group, n (%) | χ²=11.31 | 0.004 | ||||
| <3 y | 97 (24.13) | 84 (28.09) | 13 (12.62) | 13/97 (13.4) | ||
| 3–5 y | 140 (34.83) | 103 (34.45) | 37 (35.92) | 37/140 (26.4) | ||
| ≥6 y | 165 (41.04) | 112 (37.46) | 53 (51.46) | 53/165 (32.1) | ||
| A2063G site, n (%) | χ²=9.92 | 0.002 | ||||
| Wild-type | 40 (9.95) | 21 (7.02) | 19 (18.45) | 19/40 (47.5) | ||
| A2063G | 362 (90.05) | 278 (92.98) | 84 (81.55) | 84/362 (23.2) | ||
| IV glucocorticoids, n (%) | χ²=13.71 | < 0.001 | ||||
| Not used | 186 (46.27) | 155 (51.84) | 31 (30.10) | 31/186 (16.7) | ||
| Used | 216 (53.73) | 144 (48.16) | 72 (69.9) | 72/216 (33.3) | ||
| Oxygen therapy, n (%) | χ²=0.00 | 1.000 | ||||
| Not used | 361 (89.80) | 269 (89.97) | 92 (89.32) | 92/361 (25.5) | ||
| Used | 41 (10.20) | 30 (10.03) | 11 (10.68) | 11/41 (26.8) |
Notes: Values are n (%). Percentages in the two consolidation-status columns are column percentages. “Consolidation rate” is the within-category proportion with consolidation. P values are from χ² tests; percentages may not sum to 100% due to rounding
A2063G resistance-site status was also significantly associated with pulmonary consolidation. The consolidation rate was 47.5% in wild-type cases and 23.2% in A2063G-positive cases (P = 0.002). Intravenous glucocorticoid use was more frequent in the consolidation group (P < 0.001), whereas oxygen therapy did not differ between groups.
Continuous variables
Continuous comparisons are shown in Table 6. Compared with patients without consolidation, those with consolidation had a higher Tmax_24h, higher CRP, longer length of stay, and higher hospitalization cost (all P ≤ 0.006). Other variables, including fever duration, cough duration, time since onset, BMI, WBC, NLR, PLT, LDH, and tNGS uniform sequence counts, did not differ significantly.
Table 6.
Continuous variables by pulmonary consolidation status
| Variables | Total (n = 402) | No pulmonary consolidation (n = 299) | With pulmonary consolidation (n = 103) | P |
|---|---|---|---|---|
| Duration of fever, M (Q1, Q3) | 5.00 (3.00, 7.00) | 5.00 (3.00, 7.00) | 6.00 (4.00, 7.00) | 0.134 |
| Tmax (within 24 h of admission)℃ | 39.20 (38.62, 39.70) | 39.20 (38.55, 39.60) | 39.50 (38.90, 39.85) | 0.006 |
| Duration of cough (days) | 6.00 (4.00, 8.00) | 6.00 (4.00, 8.00) | 6.00 (4.00, 7.00) | 0.153 |
| Time since onset | 7.00 (5.00, 8.00) | 7.00 (5.00, 8.00) | 7.00 (5.00, 7.00) | 0.262 |
| BMI | 14.63 (13.77, 15.98) | 14.64 (13.76, 16.09) | 14.61 (13.78, 15.68) | 0.641 |
| WBC (*109/L) | 8.18 (6.41, 10.36) | 8.21 (6.29, 10.58) | 8.14 (6.63, 9.85) | 0.758 |
| NLR | 2.02 (1.38, 2.96) | 1.94 (1.30, 2.95) | 2.27 (1.62, 2.98) | 0.086 |
| PLT (*109/L) | 267.00 (215.00, 337.50) | 273.00 (215.00, 347.50) | 244.00 (210.50, 315.00) | 0.057 |
| CRP (mg/L) | 11.43 (3.21, 22.85) | 10.60 (1.64, 20.76) | 15.00 (8.34, 29.41) | < 0.001 |
| LDH | 330.00 (283.25, 390.75) | 330.00 (280.50, 388.00) | 328.00 (290.50, 399.50) | 0.329 |
| Length of hospital stay (days) | 7.00 (6.00, 9.00) | 7.00 (6.00, 9.00) | 8.00 (6.00, 10.00) | < 0.001 |
| Hospitalization cost (CNY) | 3990.38 (3141.72, 5103.21) | 3797.63 (3047.16, 4664.57) | 4781.68 (3537.80, 6681.10) | < 0.001 |
Overall, short-term in-hospital outcomes were generally favorable in this cohort, with no deaths. Severe respiratory support was uncommon; only one child in the total cohort underwent invasive mechanical ventilation. Figure 3 presents representative pre- and post-treatment chest radiographs from three children with pulmonary consolidation, showing radiographic improvement after treatment.
Fig. 3.
Representative pre- and post-treatment chest radiographs in three children with pulmonary consolidation
Cases 1 and 2 were wild-type, whereas Case 3 was A2063G resistance-site positive. For each case, panel A shows the pre-treatment radiograph and panel B shows the post-treatment radiograph. The images are presented as representative examples of radiographic improvement after treatment.
Age-adjusted and multivariable analyses for pulmonary consolidation
To assess whether age confounded the association between A2063G and pulmonary consolidation, stepwise logistic regression models were constructed (Table 7). In the crude model, A2063G positivity was associated with lower odds of pulmonary consolidation (OR 0.334, 95% CI 0.171–0.651; P = 0.001). This association remained significant after adjustment for age (OR 0.356, 95% CI 0.181–0.701; P = 0.003), while age itself was positively associated with consolidation.
Table 7.
Association of A2063G resistance-site status with pulmonary consolidation: crude, age-adjusted, and primary multivariable logistic regression models
| Model | Predictor | β (B) | SE | Wald χ² | P | OR | 95% CI for OR | VIF |
|---|---|---|---|---|---|---|---|---|
| Crude | A2063G (yes vs. no) | -1.097 | 0.340 | 10.401 | 0.001 | 0.334 | 0.171–0.651 | |
| Age-adjusted | A2063G (yes vs. no) | -1.032 | 0.345 | 8.956 | 0.003 | 0.356 | 0.181–0.701 | |
| Age (months) | 0.008 | 0.003 | 6.483 | 0.011 | 1.008 | 1.002–1.014 | ||
| Primary multivariable | A2063G (yes vs. no) | -0.972 | 0.351 | 7.686 | 0.006 | 0.378 | 0.190–0.752 | 1.016 |
| Age (months) | 0.005 | 0.003 | 2.447 | 0.118 | 1.005 | 0.999–1.012 | 1.150 | |
| Tmax (°C, per 1 °C) | 0.174 | 0.150 | 1.347 | 0.246 | 1.190 | 0.888–1.594 | 1.169 | |
| CRP (mg/L, per 1 mg/L) | 0.014 | 0.006 | 5.345 | 0.017 | 1.014 | 1.002–1.026 | 1.118 |
Notes: Model 1 was unadjusted. Model 2 was adjusted for age (months). Model 3 was the primary multivariable model including age, A2063G resistance-site status, Tmax_24h, and CRP. VIFs are shown for the primary multivariable model only. Tmax_24h denotes the maximum axillary temperature within the first 24 h after admission
In the primary multivariable model including age, Tmax_24h, and CRP, A2063G positivity remained independently associated with lower odds of pulmonary consolidation (OR 0.378, 95% CI 0.190–0.752; P = 0.006), whereas CRP remained independently associated with higher odds of consolidation (OR 1.014, 95% CI 1.002–1.026; P = 0.017). These findings indicate that the lower consolidation frequency in A2063G-positive cases cannot be explained simply by differences in age distribution.
Supplementary analysis of BAL
Supplementary analysis of BAL is provided in Supplementary Table S2. Overall, 17/402 (4.2%) patients underwent BAL, and all BAL procedures occurred in patients with pulmonary consolidation. In the overall cohort, BAL was more frequent in wild-type than in A2063G cases (12.5% vs. 3.3%, P = 0.019). However, when the analysis was restricted to patients with pulmonary consolidation, this difference was no longer statistically significant (26.3% vs. 14.3%, P = 0.301).
Exploratory treatment-stratified analyses
Exploratory treatment-stratified analyses are shown in Supplementary Tables S4 and S5. Because doxycycline use was guided by clinical condition and treatment response, and the wild-type + any doxy subgroup was very small (n = 3), these findings should be interpreted descriptively rather than causally.
Within the A2063G-positive stratum (Supplementary Table S4), patients with any doxycycline exposure were older, had higher Tmax_24h, and had longer time to defervescence than those receiving azithromycin only (all P < 0.001), whereas CRP, LDH, pulmonary consolidation, glucocorticoid use, oxygen therapy, length of stay, and hospitalization cost did not differ significantly. No significant differences were observed between azithromycin-only and any-doxy groups within the wild-type stratum, although interpretation was limited by the very small sample size.
When stratified by treatment pattern (Supplementary Table S5), wild-type cases in the azithromycin-only subgroup had a higher Tmax_24h and a higher proportion of pulmonary consolidation than A2063G-positive cases. Within the any-doxy subgroup, no significant differences were observed, although inference was again limited by the very small number of wild-type cases.
Overall, these exploratory analyses did not materially alter the main finding that A2063G positivity was not accompanied by more frequent pulmonary consolidation. Instead, they suggest that doxycycline exposure and treatment switching were more likely influenced by age, initial fever severity, and clinical response over time.
Discussion
In this hospitalized pediatric MPP cohort from 2024, A2063G was the dominant resistance-associated site and remained prevalent throughout the year. The main contribution of this study is not simply the confirmation of a high A2063G prevalence, but the characterization of its clinical and radiographic correlates in the post-COVID-19 period. Specifically, we examined whether epidemic predominance of A2063G was paralleled by more frequent pulmonary consolidation, greater systemic inflammatory burden, or a worse short-term in-hospital course. Within this cohort, A2063G positivity was not accompanied by such a pattern, and the exploratory treatment-stratified analyses did not materially change this overall observation. This genotype–phenotype perspective may help refine the clinical interpretation of resistance-site results in pediatric MPP.
Pulmonary consolidation and short-term in-hospital outcomes were used as clinically available indicators related to disease severity in this retrospective cohort. These indicators were selected because they were consistently recorded and relevant to inpatient assessment and management of pediatric Mycoplasma pneumoniae pneumonia, but they should not be interpreted as comprehensive measures of disease severity.
Persistent predominance of A2063G in this cohort
The A2063G resistance site was detected in 90.05% of cases, and its monthly proportion remained consistently high throughout the year, with only limited fluctuation. In hospitalized children with MPP from the Chaoshan region of southern China in 2024, these findings support A2063G as the major macrolide resistance-associated molecular marker. Unlike monthly case counts, which showed a clear seasonal peak, the proportion of A2063G remained relatively stable, suggesting a persistent molecular epidemiologic background rather than a transient rise confined to epidemic months [7–18].
This study interrogated four macrolide resistance-associated sites, namely A2063G, A2064G, A2067G, and C2617G. Among them, only A2063G was detected in this cohort, whereas the other three sites were not observed. Accordingly, the present discussion focuses on the clinical correlates of A2063G as the dominant resistance-site pattern identified in this dataset.
A2063G was not accompanied by more frequent pulmonary consolidation
A key finding of this study was that A2063G-positive cases had a lower frequency of pulmonary consolidation than wild-type cases, and that this difference remained after adjustment for age and further adjustment for Tmax_24h and CRP. In this hospitalized pediatric MPP cohort, A2063G resistance-site status was therefore not accompanied by more frequent pulmonary consolidation.
From the observed data, the wild-type group, despite its relatively small sample size, had a substantially higher proportion of pulmonary consolidation than the A2063G group. This pattern does not support a simple assumption that macrolide resistance necessarily corresponds to a more severe pulmonary radiographic phenotype. Rather, it suggests that the relationship between resistance-site status and lung imaging phenotypes in pediatric MPP may be more complex [12, 18, 19].
One possible explanation is that A2063G primarily reflects target-site–related macrolide resistance rather than enhanced pathogen virulence per se. At the same time, pulmonary consolidation is likely related to multiple factors, including disease stage, host inflammatory response, and patterns of airway and parenchymal involvement [20, 21, 27–29]. Taken together, the present findings are more consistent with a clinicoradiographic association than with a simple severity correspondence.
In addition, CRP, length of hospital stay, and hospitalization cost did not differ significantly between wild-type and A2063G groups. At minimum, these results suggest that, in this cohort, A2063G status was not accompanied by a pattern consistent with greater systemic inflammatory burden or greater inpatient resource use. Together with the absence of deaths and the overall favorable short-term outcomes, A2063G in this study appears to reflect resistance background more than a clearly worse short-term in-hospital prognosis.
A2063G and CRP in relation to pulmonary consolidation
The frequency of pulmonary consolidation increased across age groups, from the lowest rate in children aged < 3 years to the highest rate in those aged ≥ 6 years. However, after adjustment for age, the inverse association between A2063G positivity and pulmonary consolidation remained significant, suggesting that this association was not explained simply by age distribution.
In the primary multivariable model, A2063G positivity remained associated with lower odds of pulmonary consolidation, whereas CRP was associated with higher odds. By contrast, age and Tmax_24h did not remain statistically significant after full adjustment. These findings suggest that, in this cohort, A2063G status and CRP were more closely related to the consolidation phenotype than age or a single temperature measurement.
Both associations should be interpreted cautiously. The inverse association between A2063G positivity and pulmonary consolidation should not be interpreted as evidence of a protective effect of A2063G. It may reflect differences in strain background, host response, illness stage at admission, prior treatment exposure, or admission and referral patterns. Similarly, because the OR for CRP was estimated per 1 mg/L increase and no clinically validated threshold was derived, CRP should not be considered a stand-alone severity marker. Rather, A2063G status and CRP should be interpreted as cohort-level correlates of pulmonary consolidation and considered together with radiographic findings and the overall clinical course [20, 21, 27–29].
Pathogen co-detection patterns differed by resistance-site status, but interpretation remains cautious
The overall distribution of pathogen co-detection categories differed between wild-type and A2063G cases, with the highest proportion of A2063G observed in the virus co-detection group and a lower proportion in the bacteria co-detection group. However, neither viral nor bacterial co-detection remained significant in the multivariable model. These findings should therefore be interpreted cautiously, particularly because mixed detections in upper-airway specimens may be influenced by previous infection, colonization, or disease stage [23–26].
Exploratory treatment-stratified analyses suggest substantial confounding by clinical indication
Additional exploratory analyses stratified by A2063G resistance-site status and doxycycline exposure showed that, within the A2063G-positive stratum, children with any doxycycline exposure were older, had higher Tmax_24h, and had longer time to defervescence, whereas length of stay and hospitalization cost did not differ significantly. Within the azithromycin-only stratum, wild-type cases had a higher Tmax_24h and a higher proportion of pulmonary consolidation than A2063G-positive cases. These findings do not support selecting a treatment strategy on the basis of resistance-site status alone. Rather, they suggest that treatment escalation and doxycycline exposure were shaped by age, initial fever burden, radiographic phenotype, and subsequent clinical response. The treatment-stratified analyses are therefore better understood as exploratory patterns related to clinical treatment pathways rather than as direct comparative evidence of treatment efficacy.
BAL-related results were presented only descriptively. Because BAL was an indication-driven procedural variable and the subgroup size was small, no further inference was made from these findings [30–35]. Severe respiratory support events were also rare in this cohort; only one child underwent invasive mechanical ventilation, which precluded meaningful comparative analysis of this endpoint across resistance-site groups.
This study has several limitations. First, this was a single-center retrospective cohort of hospitalized children, and the findings may not be generalizable to outpatient settings, milder MPP cases, or broader pediatric CAP populations. Local admission and referral patterns may also have influenced the observed clinical phenotype distribution and the high proportion of A2063G positivity. Second, the A2063G-positive and wild-type groups were markedly imbalanced. Although Firth penalized logistic regression yielded results consistent with the main model, the small wild-type subgroup may still have affected the stability of comparative estimates. Therefore, the inverse association between A2063G positivity and pulmonary consolidation should be interpreted as a cohort-level, hypothesis-generating observation rather than evidence of a protective effect. Third, residual confounding cannot be fully excluded in this retrospective real-world dataset. Disease-timing variables and early clinical indicators were considered where appropriate, but some clinically relevant contextual factors, including pre-admission treatment details and subsequent treatment decisions, could not be reliably reconstructed or incorporated as baseline covariates. Finally, disease severity was assessed using available clinical proxies, mainly pulmonary consolidation and short-term in-hospital outcomes. These measures are clinically relevant but do not fully capture refractory disease evolution, dynamic progression, long-term pulmonary sequelae, or post-discharge outcomes. Severe respiratory support events were rare, with only one child requiring invasive mechanical ventilation, precluding meaningful comparative analysis of this endpoint.
Conclusions
In summary, A2063G was the dominant macrolide resistance-associated site in this cohort of hospitalized children with MPP, but its presence was not accompanied by more frequent pulmonary consolidation or by a pattern consistent with greater short-term in-hospital severity. Instead, pulmonary consolidation was more common in wild-type cases, and this association persisted after age adjustment. These findings suggest that, within this cohort, predominance of a resistance-associated site and radiographic severity did not necessarily vary in parallel. Further prospective multicenter studies with more comprehensive severity assessment and treatment-history data are needed to confirm this observation.
Supplementary Information
Acknowledgements
Not applicable.
Abbreviations
- A2063G
Adenine-to-guanine mutation at position 2063
- BAL
Bronchoalveolar lavage
- BMI
Body mass index
- CI
Confidence interval
- CRP
C-reactive protein
- CT
Computed tomography
- LDH
Lactate dehydrogenase
- MP
Mycoplasma pneumoniae
- MPP
Mycoplasma pneumoniae pneumonia
- NLR
Neutrophil-to-lymphocyte ratio
- OR
Odds ratio
- PLT
Platelet count
- tNGS
Targeted next-generation sequencing
- Tmax_24h
Maximum axillary temperature within the first 24 h after admission
- VIF
Variance inflation factor
- WBC
White blood cell count
Authors’ contributions
Hachao Zhou and Xianyao Wang contributed equally to this work. They were responsible for project conceptualization, clinical data collection, statistical analysis, data interpretation and analysis of the conclusions, and manuscript drafting. Ruiling Ma, Wenshan Zhong, Haipeng Lin, Lingling Jiang and Zhiwei Xiao participated in clinical data acquisition. Yutao Guo and Mingxiang Lin contributed to data interpretation and critical analysis of the conclusions. All authors reviewed and approved the final version of the manuscript.
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Data availability
The present retrospective study analysed secondary data extracted from routine clinical diagnostic reports and electronic medical records. No additional sequencing was performed specifically for this study, and no novel DNA/RNA sequence, genome assembly, or new genetic variation dataset was generated or reported. The tNGS results analysed in this study consisted of processed clinical diagnostic outputs, including pathogen detection, estimated Mycoplasma pneumoniae load metrics, and the presence or absence of predefined macrolide resistance-associated sites. Raw diagnostic tNGS reads were generated and retained by the third-party clinical diagnostic laboratory, Guangzhou KingMed Diagnostics, and were not provided to the hospital or the study investigators as part of routine clinical reporting. Therefore, raw reads were neither available to the investigators nor used in the present retrospective analysis. In addition, raw diagnostic tNGS reads may contain or be linked to patient-related information and are subject to institutional, ethical, and diagnostic laboratory restrictions. De-identified analytical data supporting the findings of this study may be made available from the corresponding author upon reasonable request and subject to approval by the Ethics Committee of Shantou Central Hospital and applicable institutional requirements.
Declarations
Ethics approval and consent to participate
The study protocol was reviewed and approved by the Ethics Committee of Shantou Central Hospital, Shantou, Guangdong, China (Approval No. [2025] 119). The need for consent to participate was waived by the Ethics Committee of Shantou Central Hospital because of the retrospective nature of the study and the use of de-identified clinical data. The study was conducted in accordance with the Declaration of Helsinki and established ethical standards for research involving human participants.
Consent for publication
Not applicable. This manuscript does not contain identifiable individual person’s data or identifiable images.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Hachao Zhou and Xianyao Wang contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The present retrospective study analysed secondary data extracted from routine clinical diagnostic reports and electronic medical records. No additional sequencing was performed specifically for this study, and no novel DNA/RNA sequence, genome assembly, or new genetic variation dataset was generated or reported. The tNGS results analysed in this study consisted of processed clinical diagnostic outputs, including pathogen detection, estimated Mycoplasma pneumoniae load metrics, and the presence or absence of predefined macrolide resistance-associated sites. Raw diagnostic tNGS reads were generated and retained by the third-party clinical diagnostic laboratory, Guangzhou KingMed Diagnostics, and were not provided to the hospital or the study investigators as part of routine clinical reporting. Therefore, raw reads were neither available to the investigators nor used in the present retrospective analysis. In addition, raw diagnostic tNGS reads may contain or be linked to patient-related information and are subject to institutional, ethical, and diagnostic laboratory restrictions. De-identified analytical data supporting the findings of this study may be made available from the corresponding author upon reasonable request and subject to approval by the Ethics Committee of Shantou Central Hospital and applicable institutional requirements.