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Mycoplasma pneumoniae is a common cause of community‐acquired pneumonia (CAP), among school‐age children and adolescents.14 Though pneumonia caused by M. pneumoniae is typically self‐limited, severe illness may occur.5 M. pneumoniae has also been implicated in airway inflammation, which may lead to the onset and development of chronic pulmonary disease.610 Few studies have directly addressed appropriate treatment strategies for M. pneumoniae pneumonia,11 and, despite its high prevalence and potential for causing severe complications, treatment recommendations remain inconsistent.
The efficacy of macrolide therapy in particular for M. pneumoniae remains unclear. In vitro susceptibility studies have shown bacteriostatic activity of erythromycin, clarithromycin, and azithromycin against M. pneumoniae.1218 Additionally, several small retrospective studies have shown that among children with atypical CAP (including M. pneumoniae pneumonia), those treated with macrolides were less likely to have persistence or progression of signs and symptoms after 3 days of therapy.19, 20 Lu et al21 found a shorter duration of fever among macrolide recipients compared with non‐recipients. In adults, Shames et al22 found a shorter duration of fever and hospitalization among erythromycin recipients compared with controls. Other randomized controlled trials have also addressed the use of macrolides in treatment of M. pneumoniae, but the ability to draw meaningful conclusions is limited by small samples sizes and by lack of details about the number of patients with M. pneumoniae.11
In addition to their antimicrobial effect, macrolides also have anti‐inflammatory properties.2327 The importance of these anti‐inflammatory properties is supported by studies showing clinical cure in patients treated with macrolides despite persistence of M. pneumoniae organisms,2831 clinical improvement despite the administration of doses that provide tissue levels below the minimum inhibitory concentration of the organism,3234 and clinical cure in patients with macrolide‐resistant M. pneumoniae.18, 35
The objectives of the current study were to examine the impact of macrolide therapy on the length of stay (LOS) and short‐ and longer‐term readmissions, including longer‐term asthma‐related readmissions, in children hospitalized with M. pneumoniae pneumonia.
METHODS
Data Source
Data for this retrospective cohort study were obtained from the Pediatric Health Information System (PHIS), which contains administrative data from 38 freestanding children's hospitals. Data quality and reliability are assured through a joint effort by the Child Health Corporation of America (Shawnee Mission, KS) and PHIS‐participating hospitals as described previously.36, 37 Encrypted medical record numbers allow for tracking of individual patients across hospitalizations. This study was reviewed and approved by the Committees for the Protection of Human Subjects at The Children's Hospital of Philadelphia (Philadelphia, PA).
Patients
Children 6‐18 years of age with CAP were eligible if they were discharged from a participating hospital between January 1, 2006 and December 31, 2008. Subjects were included if they received antibiotic therapy on the first day of hospitalization and if they satisfied one of the following International Classification of Diseases, 9th revision (ICD‐9) discharge diagnosis code criteria: 1) Principal diagnosis of M. pneumoniae pneumonia (483.0); 2) Principal diagnosis of a pneumonia‐related symptom (eg, fever, cough) (780.6 or 786.00‐786.52 [except 786.1]) and a secondary diagnosis of M. pneumoniae pneumonia; or 3) Principal diagnosis of pneumonia (481‐483.8 [except 483.0], 485‐486) and a secondary diagnosis of Mycoplasma (041.81).
Children younger than 6 years of age were excluded due to the low prevalence of M. pneumoniae infection.2, 38 Patients with comorbid conditions predisposing to severe or recurrent pneumonia (eg, cystic fibrosis, malignancy) were excluded using a previously reported classification scheme.39 In addition, we excluded patient data from 2 hospitals due to incomplete reporting of discharge information; thus data from 36 hospitals were included in this study.
Validation of Discharge Diagnosis Codes for Mycoplasma pneumoniae
To assess for misclassification of the diagnosis of M. pneumoniae, we reviewed records of a randomly selected subset of subjects from The Children's Hospital of Philadelphia; 14 of 15 patients had signs of lower respiratory tract infection in conjunction with a positive M. pneumoniae polymerase chain reaction test from nasopharyngeal washings to confirm the diagnosis of M. pneumoniae pneumonia. Hence, the positive predictive value of our algorithm for diagnosing M. pneumoniae pneumonia was 93.3%.
Study Definitions
We identified children with asthma in 2 ways. Asthma‐related hospitalizations were identified by an ICD‐9 code for asthma (493.0‐493.92) in any discharge diagnosis field during any hospitalization in the 24 months prior to the current hospitalization. Baseline controller medications were identified by receipt of inhaled corticosteroids (eg, fluticasone) or leukotriene receptor antagonists on the first day of hospitalization.
Systemic corticosteroids (either oral or intravenous) included dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Measures of disease severity included admission to the intensive care unit within 48 hours of hospitalization, and administration of vancomycin or clindamycin, vasoactive infusions (epinephrine, norepinephrine, dopamine, and dobutamine), and invasive (endotracheal intubation) and noninvasive (continuous positive airway pressure) mechanical ventilation within 24 hours of hospitalization, as previously described.40, 41 Viral respiratory season was defined as October through March.
Measured Outcomes
The primary outcomes of interest were hospital LOS and all‐cause readmission within 28 days and 15 months after index discharge. We examined readmissions for asthma 15 months after index discharge as a secondary outcome measure because of the potential role for M. pneumoniae infection in long‐term lung dysfunction, including asthma.42 The 15‐month time frame was selected based on longitudinal data available in PHIS for the entire study cohort.
Measured Exposures
The main exposure was early initiation of macrolide therapy, defined as receipt of erythromycin, clarithromycin, or azithromycin on the first day of hospitalization.
Data Analysis
Continuous variables were described using median and interquartile range (IQR) or range values, and compared using the Wilcoxon rank‐sum test. Categorical variables were described using counts and frequencies, and compared using the chi‐square test. Multivariable linear (for LOS) and logistic (for readmission) regression analyses were performed to assess the independent association of macrolide therapy with the primary outcomes. Because the LOS data had a skewed distribution, our analyses were performed using logarithmically transformed LOS values as the dependent variable. The resulting beta‐coefficients were transformed to reflect the percent difference in LOS between subjects receiving and not receiving macrolide therapy.
Building of the multivariable models began with the inclusion of macrolide therapy. Variables associated with primary outcomes on univariate analysis (P < 0.20) were also considered for inclusion as potential confounders.43 These variables were included in the final multivariable model if they remained significant after adjusting for other factors, or if their inclusion in the model resulted in a 15% or greater change in the effect size of the primary association of interest (ie, macrolide therapy).44 Because corticosteroids also have anti‐inflammatory properties, we assessed for interactions with macrolide therapy. There was no interaction between macrolide and systemic corticosteroid therapy (P = 0.26, Likelihood ratio test), therefore our primary model adjusted for systemic corticosteroids.
Despite adjusting for systemic corticosteroid therapy in our primary analysis, residual confounding by indication for corticosteroid therapy might exist. We therefore repeated the analysis after stratifying by receipt or non‐receipt of systemic corticosteroid therapy. Because the benefit of macrolides in preventing long‐term dysfunction may be limited to those without a prior diagnosis of asthma, we repeated the analysis of readmissions within 15 months of index discharge (any readmission and asthma‐related readmissions) while limiting the cohort to those without evidence of asthma (ie, no prior asthma‐related hospitalizations and no chronic asthma medications). Because children with underlying conditions or circumstances that would predispose to prolonged hospitalizations may have been included, despite our restriction of the cohort to those without an identified chronic complex condition, we also repeated the analysis while limiting the cohort to those with a LOS 7 days. Finally, all analyses were clustered on hospital using the robust standard errors of Huber and White to account for the correlation of exposures and outcomes among children within centers.
Data were analyzed using Stata version 11 (Stata Corporation, College Station, TX). Statistical significance was determined a priori as a two‐tailed P value <0.05.
RESULTS
Patient Characteristics
During the study, 690 children ages 6 to 18 years met inclusion criteria. Characteristics of these patients are shown in Table 1. The median age was 10 years (IQR, 7‐13 years). Ten patients (1.4%) also had a concomitant discharge diagnosis of pneumococcal pneumonia, while 19 patients (2.7%) had a concomitant discharge diagnosis of viral pneumonia; 1 of these patients had discharge diagnoses of both viral and pneumococcal pneumonia.
| Empiric Macrolide Therapy | ||||
|---|---|---|---|---|
| Variable | All Subjects | Yes | No | P |
| ||||
| Demographics | ||||
| Male sex | 356 (51.6) | 200 (49.4) | 156 (54.7) | 0.166 |
| Race | ||||
| Black | 135 (19.6) | 81 (20.0) | 54 (19.0) | 0.506 |
| White | 484 (70.1) | 287 (70.9) | 197 (69.1) | |
| Other | 62 (9.0) | 31 (7.7) | 31 (10.9) | |
| Missing | 9 (1.3) | 6 (1.5) | 3 (1.1) | |
| Presentation during viral respiratory season | 420 (60.9) | 242 (59.8) | 178 (62.5) | |
| Prior asthma hospitalization | 41 (5.9) | 31 (7.7) | 10 (3.5) | 0.023 |
| Intensive care unit admission | 127 (18.4) | 74 (18.3) | 53 (18.6) | 0.914 |
| Laboratory tests and procedures | ||||
| Additional radiologic imaging* | 24 (3.5) | 13 (3.2) | 11 (3.9) | 0.646 |
| Arterial blood gas | 116 (17.3) | 72 (18.5) | 44 (15.6) | 0.316 |
| Complete blood count | 433 (64.4) | 249 (64.0) | 184 (65.0) | 0.788 |
| Blood culture | 280 (41.7) | 167 (42.9) | 113 (39.9) | 0.436 |
| Mechanical ventilation | 16 (2.3) | 5 (1.2) | 11 (3.86) | 0.024 |
| Medications | ||||
| Chronic asthma medication | 116 (16.8) | 72 (17.8) | 44 (15.4) | 0.419 |
| Beta‐agonist therapy | 328 (47.5) | 215 (53.1) | 113 (39.7) | 0.001 |
| Vasoactive infusions | 22 (3.2) | 13 (3.2) | 9 (3.2) | 0.969 |
| Systemic corticosteroids | 252 (36.5) | 191 (47.2) | 61 (21.4) | <0.001 |
| Clindamycin or vancomycin | 86 (12.5) | 24 (5.9) | 62 (21.8) | <0.001 |
Macrolide therapy was administered to 405 (58.7%) patients. Systemic corticosteroid therapy was administered to 252 (36.5%) patients. Overall, 191 (27.7%) of the 690 patients received both macrolides and systemic corticosteroids empirically, while 224 (32.5%) received neither; 61 (8.8%) received corticosteroids but not macrolides, while 214 (31.0%) received macrolides but not corticosteroids. Asthma hospitalization within the 24 months prior to admission was more common among those receiving macrolides (N = 60/405, 14.8%) than among those not receiving macrolides (N = 30/285, 10.5%) (P = 0.023). Macrolide recipients also more commonly received concomitant systemic corticosteroids (N = 191/405, 47.2%) than macrolide non‐recipients (N = 61/285, 21.4%) (P < 0.001) and more commonly received beta‐agonist therapy (N = 215/405, 53.1%) than macrolide non‐recipients (N = 113/285, 39.7%) (P = 0.001).
Length of Stay
The overall median LOS was 3 days (IQR, 2‐6 days); the median LOS was 3 days (IQR, 2‐5 days) for empiric macrolide recipients and 4 days (IQR, 2‐9 days) for non‐recipients (P < 0.001). Overall, 22.9% (N = 158) of children had an LOS 7 days and 8.8% (N = 61) of children had an LOS 14 days. The LOS was 7 days for 15.3% (N = 62) of macrolide recipients and 33.7% (N = 96) of non‐recipients. LOS was 7 days for 17.5% (N = 44) of systemic steroid recipients and 26% (N = 114) of non‐recipients. In unadjusted analysis, macrolide therapy (beta‐coefficient, 0.49; 95% confidence interval [CI]: 0.72 to 0.25; P < 0.001) and systemic corticosteroid administration (beta‐coefficient, 0.26; CI: 0.37 to 0.14; P < 0.001) were associated with shorter hospital LOS (Appendix 1).
In multivariable analysis, macrolide therapy remained associated with a shorter LOS (Table 2; Appendix 2). Systemic corticosteroid administration was associated with a 23% shorter LOS (adjusted beta‐coefficient, 0.26; 95% CI: 0.39 to 0.14; P < 0.001). In contrast, previous hospitalization for asthma was associated with a 31% longer LOS (adjusted beta‐coefficient, 0.27; 95% CI: 0.09‐0.045; P = 0.004). Receipt of beta‐agonist therapy or chronic asthma medications were not associated with significant differences in LOS. In analysis stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy, empiric macrolide therapy remained associated with a significantly shorter LOS in both systemic corticosteroid recipients and non‐recipient (Table 4). When the cohort was restricted to subjects with a LOS 7 days, macrolide therapy remained significantly associated with a shorter LOS (adjusted percent change, 20%; 95% CI: 32% to 5%; P = 0.015).
| Association of Empiric Macrolide Therapy With Outcomes* | |
|---|---|
| |
| Length of stay (days) | |
| Adjusted beta‐coefficient (95 % CI) | 0.38 (0.59 to 0.17) |
| Adjusted percent change (95% CI) | 32% (45% to 15%) |
| P value | 0.001 |
| Any readmission within 28 days | |
| Adjusted odds ratio (95% CI) | 1.12 (0.22 to 5.78) |
| P value | 0.890 |
| Any readmission within 15 mo | |
| Adjusted odds ratio (95% CI) | 1.00 (0.59 to 1.70) |
| P value | 0.991 |
| Asthma hospitalization within 15 mo | |
| Adjusted odds ratio (95% CI) | 1.09 (0.54 to 2.17) |
| P value | 0.820 |
Readmission
Overall, 8 children (1.2%) were readmitted for pneumonia‐associated conditions within 28 days of index discharge. Readmission occurred in 1.2% of macrolide recipients and 1.1% of non‐recipients (P = 0.83) (Table 4). In unadjusted analysis, neither macrolide therapy (odds ratio [OR], 1.18; 95% CI: 0.25‐5.45; P = 0.84) nor systemic corticosteroid administration (OR, 1.04; 95% CI: 0.27‐4.10; P = 0.95) was associated with 28‐day readmission (Appendix 3). In multivariable analysis, empiric macrolide therapy was not associated with 28‐day readmission in the overall cohort (Table 2; Appendix 4)), or when the analysis was stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy (Table 3).
| Concomitant Systemic Corticosteroid Therapy* | ||
|---|---|---|
| Yes | No | |
| ||
| Length of stay | ||
| Adjusted beta‐coefficient (95% CI) | 0.40 (0.74 to 0.07) | 0.37 (0.58 to 0.16) |
| Adjusted percent change (95% CI) | 33% (52% to 7%) | 31% (44% to 15%) |
| P value | 0.020 | 0.001 |
| Readmission within 28 days | ||
| Adjusted odds ratio (95% CI) | 1.09 (0.05 to 26.7) | 1.50 (0.21 to 10.8) |
| P value | 0.960 | 0.687 |
| Readmission within 15 mo | ||
| Adjusted odds ratio (95% CI) | 1.57 (0.65 to 3.82) | 0.81 (0.45 to 1.46) |
| P value | 0.32 | 0.49 |
| Asthma hospitalization within 15 mo | ||
| Adjusted odds ratio (95% CI) | 1.51 (0.58 to 3.93) | 0.85 (0.36 to 1.97) |
| P value | 0.395 | 0.700 |
| Empiric Macrolide Therapy | ||
|---|---|---|
| N/Total (%) | ||
| Readmission | Yes | No |
| Any readmission within 28 days | ||
| Overall | 5/405 (1.2) | 3/285 (1.1) |
| Systemic corticosteroid therapy | 2/186 (1.1) | 1/66 (1.5) |
| No systemic corticosteroid therapy | 3/177 (1.7) | 2/261 (0.8) |
| Any readmission within 15 mo | ||
| Overall | 96/405 (23.7) | 64/285 (22.5) |
| Systemic corticosteroid therapy | 52/186 (28.0) | 17/66 (25.8) |
| No systemic corticosteroid therapy | 32/177 (18.1) | 59/261 (22.6) |
| Asthma hospitalization within 15 mo | ||
| Overall | 61/405 (15.1) | 34/285 (11.9) |
| Systemic corticosteroid therapy | 39/186 (21.0) | 13/66 (19.7) |
| No systemic corticosteroid therapy | 14/177 (7.9) | 29/261 (11.1) |
Overall, 160 children (23.2%) were readmitted within 15 months of index discharge; 95 were readmitted for asthma during this time (Table 3). Overall readmission occurred in 23.7% of macrolide recipients and 22.5% of macrolide non‐recipients (P = 0.702). Asthma readmission occurred in 15.1% of macrolide recipients and 11.9% of macrolide non‐recipients (P = 0.240). In unadjusted analysis, empiric macrolide therapy was not significantly associated with any readmission within 15 months (OR, 1.07; 95% CI: 0.69‐1.68; P = 0.759) or with asthma‐related readmission within 15 months (OR, 1.31; 95% CI: 0.73‐ 2.36; P = 0.369). In multivariable analysis, neither any readmission nor asthma readmission within 15 months was associated with empiric macrolide therapy overall (Table 2) or when stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy (Table 3).
The analyses for readmissions within 15 months of index discharge were repeated while limiting the cohort to those without prior asthma hospitalizations or chronic asthma medications. In this subset of patients, readmissions for any reason occurred in 55 (18.6%) of 295 macrolide recipients and 50 (22.0%) of 227 non‐recipients. The difference was not statistically significant in multivariable analysis (adjusted odds ratio, 0.79; 95% CI: 0.41‐1.51; P = 0.47). Readmissions for asthma occurred in 30 (10.2%) of 295 macrolide recipients and 26 (11.5%) of 227 non‐recipients; this difference was also not significant in multivariable analysis (adjusted odds ratio, 0.83; 95% CI: 0.36‐1.93; P = 0.83). The magnitude of the estimate of effect for 28‐day and 15‐month readmissions, and 15‐month asthma hospitalizations, was similar to the primary analysis when the cohort was restricted to subjects with a LOS 7 days.
DISCUSSION
This multicenter study examined the role of macrolide therapy in children hospitalized with M. pneumoniae pneumonia. Empiric macrolide therapy was associated with an approximately 30% shorter hospital LOS and, in stratified analysis, remained associated with a significantly shorter hospital LOS in both systemic corticosteroid recipients and non‐recipients. Empiric macrolide therapy was not associated with short‐ or longer‐term hospital readmission.
Previous small randomized trials have been inconclusive regarding the potential benefit of macrolide therapy in M. pneumoniae pneumonia.11 Our study, which demonstrated a shorter LOS among macrolides recipients compared with non‐recipients, has several advantages over prior studies including a substantively larger sample size and multicenter design. Animal models support our observations regarding the potential beneficial antimicrobial role of macrolides. M. pneumoniae concentrations in bronchoalveolar lavage specimens were significantly lower among experimentally infected mice treated with clarithromycin, a macolide‐class antibiotic, compared with either placebo or dexamethasone.45 Combination therapy with clarithromycin and dexamethasone reduced histopathologic inflammation to a greater degree than dexamethasone alone.45
While the relative importance of the antimicrobial and anti‐inflammatory properties of macrolides is not known, observational studies of children infected with macrolide‐resistant M. pneumoniae suggest that the antimicrobial properties of macrolides may provide disproportionate clinical benefit. The duration of fever in macrolide recipients with macrolide‐resistant M. pneumoniae (median duration, 9 days) reported by Suzuki et al46 was significantly longer than those with macrolide‐susceptible infections (median duration, 5 days), and similar to the duration of fever in patients with M. pneumoniae infection treated with placebo (median duration, 8 days) reported by Kingston et al.47 Additionally, macrolide therapy was associated with significant improvements in lung function in patients with asthma and concomitant M. pneumoniae infection, but not in patients with asthma without documented M. pneumoniae infection.9 As corticosteroids also have anti‐inflammatory properties, we expect that any anti‐inflammatory benefit of macrolide therapy would be mitigated by the concomitant administration of corticosteroids. The shorter LOS associated with empiric macrolide therapy in our study was comparable among corticosteroid recipients and non‐recipients.
Atypical bacterial pathogens, including M. pneumoniae, are associated with diffuse lower airway inflammation6, 48 and airway hyperresponsiveness,6 and have been implicated as a cause of acute asthma exacerbations.7, 4954 Among patients with previously diagnosed asthma, acute M. pneumoniae infection was identified in up to 20% of those having acute exacerbations.7, 54 Macrolide therapy has a beneficial effect on lung function and airway hyperresponsiveness in adults with asthma.9, 55 Among mice infected with M. pneumoniae, 3 days of macrolide therapy resulted in a significant reduction in airway hyperresponsiveness compared with placebo or dexamethasone; however, after 6 days of therapy, there was no significant difference in airway hyperresponsiveness between those receiving macrolides, dexamethasone, or placebo, suggesting that the benefit of macrolides on airway hyperresponsiveness may be brief. Our findings of a shorter LOS but no difference in readmissions at 28 days or longer, for macrolide recipients compared with non‐recipients, support the limited benefit of macrolide therapy beyond the initial reduction in bacterial load seen in the first few days of therapy.
M. pneumoniae infection has also been implicated as a cause of chronic pulmonary disease, including asthma.610 In the mouse model, peribronchial and perivascular mononuclear infiltrates, increased airway methacholine reactivity, and increased airway obstruction were observed 530 days after M. pneumoniae inoculation.6 M. pneumoniae has been identified in 26 (50%) of 51 children experiencing their first asthma attack,7 and 23 (42%) of 55 adults with chronic, stable asthma.9 Nevertheless, results of other studies addressing the issue are inconsistent, and the role of M. pneumoniae in the development of asthma remains unclear.56 In order to investigate the impact of macrolide therapy on the development of chronic pulmonary disease requiring hospitalization, we examined the readmission rates in the 15 months following index discharge. The proportion of children hospitalized with asthma following the hospitalization for M. pneumoniae pneumonia was higher for both macrolide recipients and non‐recipients compared with the 24‐months prior to infection. These results support a possible role for M. pneumoniae in chronic pulmonary disease. However, macrolide therapy was not associated with long‐term overall hospital readmission or long‐term asthma readmission, either in the entire cohort or in the subset of patients without prior asthma hospitalizations or medications.
This study had several limitations. First, because the identification of children with M. pneumoniae pneumonia relied on ICD‐9 discharge diagnosis codes, it is possible that there was misclassification of disease. We minimized the inclusion of children without M. pneumoniae by including only children who received antibiotic therapy on the first day of hospitalization and by excluding patients younger than 6 years of age, a group at relatively low‐risk for M. pneumoniae infection. Further, our algorithm for identification of M. pneumoniae pneumonia was validated through review of the medical records at 1 institution and was found to have a high positive predictive value. However, the positive predictive value of these ICD‐9 codes may vary across institutions. Additionally, the sensitivity of ICD‐9 codes for identifying children with M. pneumoniae pneumonia is not known. Also, not all children with pneumonia undergo testing for M. pneumoniae, and different tests have varying sensitivity and specificity.57, 58 Thus, some children with M. pneumoniae pneumonia were not diagnosed and so were not included in our study. It is not known how inclusion of these children would affect our results.
Second, the antibiotic information used in this study was limited to empiric antibiotic therapy. It is possible that some patients received macrolide therapy before admission. It is also likely that identification of M. pneumoniae during the hospitalization prompted the addition or substitution of macrolide therapy for some patients. If this therapy was initiated beyond the first day of hospitalization, these children would be classified as macrolide non‐recipients. Since macrolide administration was associated with a shorter hospital LOS, such misclassification would bias our results towards finding no difference in LOS between macrolide recipients and non‐recipients. It is therefore possible that the benefit of macrolide therapy is even greater than found in our study.
Third, there may be unmeasured confounding or residual confounding by indication for adjunct corticosteroid therapy related to clinical presentation. We expect that corticosteroid recipients would be sicker than non‐recipients. We included variables associated with a greater severity of illness (such as intensive care unit admission) in the multivariable analysis. Additionally, the shorter LOS among macrolide recipients remained when the analysis was stratified by receipt or non‐receipt of systemic corticosteroid therapy.
Fourth, we were only able to record readmissions occurring at the same hospital as the index admission; any readmission presenting to a different hospital following their index admission did not appear in our records, and was therefore not counted. It is thus possible that the true number of readmissions is higher than that represented here. Finally, despite the large number of patients included in this study, the number of short‐term readmissions was relatively small. Thus, we may have been underpowered to detect small but significant differences in short‐term readmission rates.
In conclusion, macrolide therapy was associated with shorter hospital LOS, but not with short‐term or longer‐term readmission in children presenting with M. pneumoniae pneumonia.
Appendix
| Variable | Beta Coefficient | Confidence Interval | P Value |
|---|---|---|---|
| Demographics | |||
| Sex | 0.12 | (0.22, 0.02) | 0.022 |
| Race | |||
| Blackreference category | |||
| White | 0.01 | (0.21, 0.23) | 0.933 |
| Other | 0.13 | (0.39, 0.13) | 0.323 |
| Missing | 0.46 | (0.81, 0.11) | 0.012 |
| Presentation during viral respiratory season | 0.05 | (0.19, 0.09) | 0.462 |
| Prior asthma hospitalization | 0.36 | (0.64, 0.08) | 0.015 |
| Intensive care unit admission | 1.05 | (0.87, 1.23) | <0.001 |
| Labs and procedures performed | |||
| Additional radiologic imaging | 0.23 | (0.20, 0.67) | 0.287 |
| Arterial blood gas | 0.69 | (0.50, 0.87) | <0.001 |
| Complete blood count | 0.34 | (0.24, 0.45) | <0.001 |
| Blood culture | 0.17 | (0.98, 0.44) | 0.204 |
| Mechanical ventilation | 1.15 | (0.68, 1.63) | <0.001 |
| Therapies received | |||
| Empiric macrolide therapy | 0.49 | (0.72, 0.25) | <0.001 |
| Systemic steroids | 0.26 | (0.38, 0.14) | <0.001 |
| Chronic asthma medications | 0.20 | (0.38, 0.013) | 0.037 |
| Beta‐agonist therapy | 0.07 | (0.21, 0.08) | 0.357 |
| Vasoactive infusion | 1.08 | (0.727, 1.45) | <0.001 |
| Clindamycin or vancomycin | 0.55 | (0.34, 0.75) | <0.001 |
| Variable | Odds Ratio* | Confidence Interval | P Value |
|---|---|---|---|
| |||
| Demographics | |||
| Sex | 0.56 | (0.23, 1.33) | 0.190 |
| Race | |||
| Blackreference category | |||
| White | 0.46 | (0.19, 1.14) | 0.093 |
| Other | |||
| Missing | |||
| Presentation during viral respiratory season | 0.64 | (0.09, 4.75) | 0.662 |
| Prior asthma hospitalization | |||
| Intensive care unit admission | 4.54 | (1.21, 17.03) | 0.025 |
| Laboratory tests and procedures | |||
| Additional radiologic imaging | 10.00 | (2.25, 44.47) | 0.002 |
| Arterial blood gas | |||
| Complete blood count | 0.92 | (0.24, 3.48) | 0.901 |
| Blood culture | 0.85 | (0.30, 2.36) | 0.738 |
| Mechanical ventilation | |||
| Medications | |||
| Macrolide therapy | 1.18 | (0.25, 5.45) | 0.837 |
| Systemic corticosteroids | 1.04 | (0.276, 4.09) | 0.951 |
| Chronic asthma medication | 1.66 | (0.71, 3.88) | 0.242 |
| Beta‐agonist therapy | 0.66 | (0.16, 2.65) | 0.557 |
| Vasoactive infusions | |||
| Clindamycin or vancomycin | 1.00 | (0.10, 9.90) | 0.998 |
| Variable | Coefficient | Confidence Interval | P Value | % Change | Confidence Interval for % Change |
|---|---|---|---|---|---|
| Demographics | |||||
| Age | 0.287 | (0.012, 0.045) | 0.001 | 2.9 | (1.2, 4.6) |
| Prior asthma hospitalization | 0.272 | (0.094, 0.45) | 0.004 | 31.3 | (9.9, 56.8) |
| Intensive care unit admission | 1.015 | (0.802, 1.23) | <0.001 | 175.9 | (123.0, 241.3) |
| Therapies received | |||||
| Macrolide therapy | 0.379 | (0.59, 0.166) | 0.001 | 31.6 | (44.6, 15.3) |
| Systemic corticosteroids | 0.264 | (0.391, 0.138) | <0.001 | 23.2 | (32.3, 12.9) |
| Chronic asthma medications | 0.056 | (0.255, 0.142) | 0.568 | 5.5 | (22.5, 15.2) |
| Albuterol | 0.07 | (0.059, 0.199) | 0.281 | 7.2 | (5.8, 22.0) |
| Clindamycin or vancomycin | 0.311 | (0.063, 0.559) | 0.015 | 36.5 | (6.5, 74.9) |
| Variable | Adjusted Odds Ratio | Confidence Interval | P Value |
|---|---|---|---|
| Demographics | |||
| Age | 0.91 | 0.72, 1.15 | 0.423 |
| Prior asthma hospitalization | 1.94 | 0.42, 8.90 | 0.394 |
| Intensive care unit admission | 5.73 | 2.03, 16.20 | 0.001 |
| Therapies received | |||
| Macrolide therapy | 1.12 | 0.22, 5.78 | 0.890 |
| Systemic corticosteroids | 0.696 | 0.10, 4.70 | 0.710 |
| Chronic asthma medications | 1.98 | 0.32, 12.20 | 0.460 |
| Albuterol | 0.519 | 0.081, 3.31 | 0.488 |
| Clindamycin or vancomycin | 0.904 | 0.07, 11.13 | 0.937 |
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Mycoplasma pneumoniae is a common cause of community‐acquired pneumonia (CAP), among school‐age children and adolescents.14 Though pneumonia caused by M. pneumoniae is typically self‐limited, severe illness may occur.5 M. pneumoniae has also been implicated in airway inflammation, which may lead to the onset and development of chronic pulmonary disease.610 Few studies have directly addressed appropriate treatment strategies for M. pneumoniae pneumonia,11 and, despite its high prevalence and potential for causing severe complications, treatment recommendations remain inconsistent.
The efficacy of macrolide therapy in particular for M. pneumoniae remains unclear. In vitro susceptibility studies have shown bacteriostatic activity of erythromycin, clarithromycin, and azithromycin against M. pneumoniae.1218 Additionally, several small retrospective studies have shown that among children with atypical CAP (including M. pneumoniae pneumonia), those treated with macrolides were less likely to have persistence or progression of signs and symptoms after 3 days of therapy.19, 20 Lu et al21 found a shorter duration of fever among macrolide recipients compared with non‐recipients. In adults, Shames et al22 found a shorter duration of fever and hospitalization among erythromycin recipients compared with controls. Other randomized controlled trials have also addressed the use of macrolides in treatment of M. pneumoniae, but the ability to draw meaningful conclusions is limited by small samples sizes and by lack of details about the number of patients with M. pneumoniae.11
In addition to their antimicrobial effect, macrolides also have anti‐inflammatory properties.2327 The importance of these anti‐inflammatory properties is supported by studies showing clinical cure in patients treated with macrolides despite persistence of M. pneumoniae organisms,2831 clinical improvement despite the administration of doses that provide tissue levels below the minimum inhibitory concentration of the organism,3234 and clinical cure in patients with macrolide‐resistant M. pneumoniae.18, 35
The objectives of the current study were to examine the impact of macrolide therapy on the length of stay (LOS) and short‐ and longer‐term readmissions, including longer‐term asthma‐related readmissions, in children hospitalized with M. pneumoniae pneumonia.
METHODS
Data Source
Data for this retrospective cohort study were obtained from the Pediatric Health Information System (PHIS), which contains administrative data from 38 freestanding children's hospitals. Data quality and reliability are assured through a joint effort by the Child Health Corporation of America (Shawnee Mission, KS) and PHIS‐participating hospitals as described previously.36, 37 Encrypted medical record numbers allow for tracking of individual patients across hospitalizations. This study was reviewed and approved by the Committees for the Protection of Human Subjects at The Children's Hospital of Philadelphia (Philadelphia, PA).
Patients
Children 6‐18 years of age with CAP were eligible if they were discharged from a participating hospital between January 1, 2006 and December 31, 2008. Subjects were included if they received antibiotic therapy on the first day of hospitalization and if they satisfied one of the following International Classification of Diseases, 9th revision (ICD‐9) discharge diagnosis code criteria: 1) Principal diagnosis of M. pneumoniae pneumonia (483.0); 2) Principal diagnosis of a pneumonia‐related symptom (eg, fever, cough) (780.6 or 786.00‐786.52 [except 786.1]) and a secondary diagnosis of M. pneumoniae pneumonia; or 3) Principal diagnosis of pneumonia (481‐483.8 [except 483.0], 485‐486) and a secondary diagnosis of Mycoplasma (041.81).
Children younger than 6 years of age were excluded due to the low prevalence of M. pneumoniae infection.2, 38 Patients with comorbid conditions predisposing to severe or recurrent pneumonia (eg, cystic fibrosis, malignancy) were excluded using a previously reported classification scheme.39 In addition, we excluded patient data from 2 hospitals due to incomplete reporting of discharge information; thus data from 36 hospitals were included in this study.
Validation of Discharge Diagnosis Codes for Mycoplasma pneumoniae
To assess for misclassification of the diagnosis of M. pneumoniae, we reviewed records of a randomly selected subset of subjects from The Children's Hospital of Philadelphia; 14 of 15 patients had signs of lower respiratory tract infection in conjunction with a positive M. pneumoniae polymerase chain reaction test from nasopharyngeal washings to confirm the diagnosis of M. pneumoniae pneumonia. Hence, the positive predictive value of our algorithm for diagnosing M. pneumoniae pneumonia was 93.3%.
Study Definitions
We identified children with asthma in 2 ways. Asthma‐related hospitalizations were identified by an ICD‐9 code for asthma (493.0‐493.92) in any discharge diagnosis field during any hospitalization in the 24 months prior to the current hospitalization. Baseline controller medications were identified by receipt of inhaled corticosteroids (eg, fluticasone) or leukotriene receptor antagonists on the first day of hospitalization.
Systemic corticosteroids (either oral or intravenous) included dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Measures of disease severity included admission to the intensive care unit within 48 hours of hospitalization, and administration of vancomycin or clindamycin, vasoactive infusions (epinephrine, norepinephrine, dopamine, and dobutamine), and invasive (endotracheal intubation) and noninvasive (continuous positive airway pressure) mechanical ventilation within 24 hours of hospitalization, as previously described.40, 41 Viral respiratory season was defined as October through March.
Measured Outcomes
The primary outcomes of interest were hospital LOS and all‐cause readmission within 28 days and 15 months after index discharge. We examined readmissions for asthma 15 months after index discharge as a secondary outcome measure because of the potential role for M. pneumoniae infection in long‐term lung dysfunction, including asthma.42 The 15‐month time frame was selected based on longitudinal data available in PHIS for the entire study cohort.
Measured Exposures
The main exposure was early initiation of macrolide therapy, defined as receipt of erythromycin, clarithromycin, or azithromycin on the first day of hospitalization.
Data Analysis
Continuous variables were described using median and interquartile range (IQR) or range values, and compared using the Wilcoxon rank‐sum test. Categorical variables were described using counts and frequencies, and compared using the chi‐square test. Multivariable linear (for LOS) and logistic (for readmission) regression analyses were performed to assess the independent association of macrolide therapy with the primary outcomes. Because the LOS data had a skewed distribution, our analyses were performed using logarithmically transformed LOS values as the dependent variable. The resulting beta‐coefficients were transformed to reflect the percent difference in LOS between subjects receiving and not receiving macrolide therapy.
Building of the multivariable models began with the inclusion of macrolide therapy. Variables associated with primary outcomes on univariate analysis (P < 0.20) were also considered for inclusion as potential confounders.43 These variables were included in the final multivariable model if they remained significant after adjusting for other factors, or if their inclusion in the model resulted in a 15% or greater change in the effect size of the primary association of interest (ie, macrolide therapy).44 Because corticosteroids also have anti‐inflammatory properties, we assessed for interactions with macrolide therapy. There was no interaction between macrolide and systemic corticosteroid therapy (P = 0.26, Likelihood ratio test), therefore our primary model adjusted for systemic corticosteroids.
Despite adjusting for systemic corticosteroid therapy in our primary analysis, residual confounding by indication for corticosteroid therapy might exist. We therefore repeated the analysis after stratifying by receipt or non‐receipt of systemic corticosteroid therapy. Because the benefit of macrolides in preventing long‐term dysfunction may be limited to those without a prior diagnosis of asthma, we repeated the analysis of readmissions within 15 months of index discharge (any readmission and asthma‐related readmissions) while limiting the cohort to those without evidence of asthma (ie, no prior asthma‐related hospitalizations and no chronic asthma medications). Because children with underlying conditions or circumstances that would predispose to prolonged hospitalizations may have been included, despite our restriction of the cohort to those without an identified chronic complex condition, we also repeated the analysis while limiting the cohort to those with a LOS 7 days. Finally, all analyses were clustered on hospital using the robust standard errors of Huber and White to account for the correlation of exposures and outcomes among children within centers.
Data were analyzed using Stata version 11 (Stata Corporation, College Station, TX). Statistical significance was determined a priori as a two‐tailed P value <0.05.
RESULTS
Patient Characteristics
During the study, 690 children ages 6 to 18 years met inclusion criteria. Characteristics of these patients are shown in Table 1. The median age was 10 years (IQR, 7‐13 years). Ten patients (1.4%) also had a concomitant discharge diagnosis of pneumococcal pneumonia, while 19 patients (2.7%) had a concomitant discharge diagnosis of viral pneumonia; 1 of these patients had discharge diagnoses of both viral and pneumococcal pneumonia.
| Empiric Macrolide Therapy | ||||
|---|---|---|---|---|
| Variable | All Subjects | Yes | No | P |
| ||||
| Demographics | ||||
| Male sex | 356 (51.6) | 200 (49.4) | 156 (54.7) | 0.166 |
| Race | ||||
| Black | 135 (19.6) | 81 (20.0) | 54 (19.0) | 0.506 |
| White | 484 (70.1) | 287 (70.9) | 197 (69.1) | |
| Other | 62 (9.0) | 31 (7.7) | 31 (10.9) | |
| Missing | 9 (1.3) | 6 (1.5) | 3 (1.1) | |
| Presentation during viral respiratory season | 420 (60.9) | 242 (59.8) | 178 (62.5) | |
| Prior asthma hospitalization | 41 (5.9) | 31 (7.7) | 10 (3.5) | 0.023 |
| Intensive care unit admission | 127 (18.4) | 74 (18.3) | 53 (18.6) | 0.914 |
| Laboratory tests and procedures | ||||
| Additional radiologic imaging* | 24 (3.5) | 13 (3.2) | 11 (3.9) | 0.646 |
| Arterial blood gas | 116 (17.3) | 72 (18.5) | 44 (15.6) | 0.316 |
| Complete blood count | 433 (64.4) | 249 (64.0) | 184 (65.0) | 0.788 |
| Blood culture | 280 (41.7) | 167 (42.9) | 113 (39.9) | 0.436 |
| Mechanical ventilation | 16 (2.3) | 5 (1.2) | 11 (3.86) | 0.024 |
| Medications | ||||
| Chronic asthma medication | 116 (16.8) | 72 (17.8) | 44 (15.4) | 0.419 |
| Beta‐agonist therapy | 328 (47.5) | 215 (53.1) | 113 (39.7) | 0.001 |
| Vasoactive infusions | 22 (3.2) | 13 (3.2) | 9 (3.2) | 0.969 |
| Systemic corticosteroids | 252 (36.5) | 191 (47.2) | 61 (21.4) | <0.001 |
| Clindamycin or vancomycin | 86 (12.5) | 24 (5.9) | 62 (21.8) | <0.001 |
Macrolide therapy was administered to 405 (58.7%) patients. Systemic corticosteroid therapy was administered to 252 (36.5%) patients. Overall, 191 (27.7%) of the 690 patients received both macrolides and systemic corticosteroids empirically, while 224 (32.5%) received neither; 61 (8.8%) received corticosteroids but not macrolides, while 214 (31.0%) received macrolides but not corticosteroids. Asthma hospitalization within the 24 months prior to admission was more common among those receiving macrolides (N = 60/405, 14.8%) than among those not receiving macrolides (N = 30/285, 10.5%) (P = 0.023). Macrolide recipients also more commonly received concomitant systemic corticosteroids (N = 191/405, 47.2%) than macrolide non‐recipients (N = 61/285, 21.4%) (P < 0.001) and more commonly received beta‐agonist therapy (N = 215/405, 53.1%) than macrolide non‐recipients (N = 113/285, 39.7%) (P = 0.001).
Length of Stay
The overall median LOS was 3 days (IQR, 2‐6 days); the median LOS was 3 days (IQR, 2‐5 days) for empiric macrolide recipients and 4 days (IQR, 2‐9 days) for non‐recipients (P < 0.001). Overall, 22.9% (N = 158) of children had an LOS 7 days and 8.8% (N = 61) of children had an LOS 14 days. The LOS was 7 days for 15.3% (N = 62) of macrolide recipients and 33.7% (N = 96) of non‐recipients. LOS was 7 days for 17.5% (N = 44) of systemic steroid recipients and 26% (N = 114) of non‐recipients. In unadjusted analysis, macrolide therapy (beta‐coefficient, 0.49; 95% confidence interval [CI]: 0.72 to 0.25; P < 0.001) and systemic corticosteroid administration (beta‐coefficient, 0.26; CI: 0.37 to 0.14; P < 0.001) were associated with shorter hospital LOS (Appendix 1).
In multivariable analysis, macrolide therapy remained associated with a shorter LOS (Table 2; Appendix 2). Systemic corticosteroid administration was associated with a 23% shorter LOS (adjusted beta‐coefficient, 0.26; 95% CI: 0.39 to 0.14; P < 0.001). In contrast, previous hospitalization for asthma was associated with a 31% longer LOS (adjusted beta‐coefficient, 0.27; 95% CI: 0.09‐0.045; P = 0.004). Receipt of beta‐agonist therapy or chronic asthma medications were not associated with significant differences in LOS. In analysis stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy, empiric macrolide therapy remained associated with a significantly shorter LOS in both systemic corticosteroid recipients and non‐recipient (Table 4). When the cohort was restricted to subjects with a LOS 7 days, macrolide therapy remained significantly associated with a shorter LOS (adjusted percent change, 20%; 95% CI: 32% to 5%; P = 0.015).
| Association of Empiric Macrolide Therapy With Outcomes* | |
|---|---|
| |
| Length of stay (days) | |
| Adjusted beta‐coefficient (95 % CI) | 0.38 (0.59 to 0.17) |
| Adjusted percent change (95% CI) | 32% (45% to 15%) |
| P value | 0.001 |
| Any readmission within 28 days | |
| Adjusted odds ratio (95% CI) | 1.12 (0.22 to 5.78) |
| P value | 0.890 |
| Any readmission within 15 mo | |
| Adjusted odds ratio (95% CI) | 1.00 (0.59 to 1.70) |
| P value | 0.991 |
| Asthma hospitalization within 15 mo | |
| Adjusted odds ratio (95% CI) | 1.09 (0.54 to 2.17) |
| P value | 0.820 |
Readmission
Overall, 8 children (1.2%) were readmitted for pneumonia‐associated conditions within 28 days of index discharge. Readmission occurred in 1.2% of macrolide recipients and 1.1% of non‐recipients (P = 0.83) (Table 4). In unadjusted analysis, neither macrolide therapy (odds ratio [OR], 1.18; 95% CI: 0.25‐5.45; P = 0.84) nor systemic corticosteroid administration (OR, 1.04; 95% CI: 0.27‐4.10; P = 0.95) was associated with 28‐day readmission (Appendix 3). In multivariable analysis, empiric macrolide therapy was not associated with 28‐day readmission in the overall cohort (Table 2; Appendix 4)), or when the analysis was stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy (Table 3).
| Concomitant Systemic Corticosteroid Therapy* | ||
|---|---|---|
| Yes | No | |
| ||
| Length of stay | ||
| Adjusted beta‐coefficient (95% CI) | 0.40 (0.74 to 0.07) | 0.37 (0.58 to 0.16) |
| Adjusted percent change (95% CI) | 33% (52% to 7%) | 31% (44% to 15%) |
| P value | 0.020 | 0.001 |
| Readmission within 28 days | ||
| Adjusted odds ratio (95% CI) | 1.09 (0.05 to 26.7) | 1.50 (0.21 to 10.8) |
| P value | 0.960 | 0.687 |
| Readmission within 15 mo | ||
| Adjusted odds ratio (95% CI) | 1.57 (0.65 to 3.82) | 0.81 (0.45 to 1.46) |
| P value | 0.32 | 0.49 |
| Asthma hospitalization within 15 mo | ||
| Adjusted odds ratio (95% CI) | 1.51 (0.58 to 3.93) | 0.85 (0.36 to 1.97) |
| P value | 0.395 | 0.700 |
| Empiric Macrolide Therapy | ||
|---|---|---|
| N/Total (%) | ||
| Readmission | Yes | No |
| Any readmission within 28 days | ||
| Overall | 5/405 (1.2) | 3/285 (1.1) |
| Systemic corticosteroid therapy | 2/186 (1.1) | 1/66 (1.5) |
| No systemic corticosteroid therapy | 3/177 (1.7) | 2/261 (0.8) |
| Any readmission within 15 mo | ||
| Overall | 96/405 (23.7) | 64/285 (22.5) |
| Systemic corticosteroid therapy | 52/186 (28.0) | 17/66 (25.8) |
| No systemic corticosteroid therapy | 32/177 (18.1) | 59/261 (22.6) |
| Asthma hospitalization within 15 mo | ||
| Overall | 61/405 (15.1) | 34/285 (11.9) |
| Systemic corticosteroid therapy | 39/186 (21.0) | 13/66 (19.7) |
| No systemic corticosteroid therapy | 14/177 (7.9) | 29/261 (11.1) |
Overall, 160 children (23.2%) were readmitted within 15 months of index discharge; 95 were readmitted for asthma during this time (Table 3). Overall readmission occurred in 23.7% of macrolide recipients and 22.5% of macrolide non‐recipients (P = 0.702). Asthma readmission occurred in 15.1% of macrolide recipients and 11.9% of macrolide non‐recipients (P = 0.240). In unadjusted analysis, empiric macrolide therapy was not significantly associated with any readmission within 15 months (OR, 1.07; 95% CI: 0.69‐1.68; P = 0.759) or with asthma‐related readmission within 15 months (OR, 1.31; 95% CI: 0.73‐ 2.36; P = 0.369). In multivariable analysis, neither any readmission nor asthma readmission within 15 months was associated with empiric macrolide therapy overall (Table 2) or when stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy (Table 3).
The analyses for readmissions within 15 months of index discharge were repeated while limiting the cohort to those without prior asthma hospitalizations or chronic asthma medications. In this subset of patients, readmissions for any reason occurred in 55 (18.6%) of 295 macrolide recipients and 50 (22.0%) of 227 non‐recipients. The difference was not statistically significant in multivariable analysis (adjusted odds ratio, 0.79; 95% CI: 0.41‐1.51; P = 0.47). Readmissions for asthma occurred in 30 (10.2%) of 295 macrolide recipients and 26 (11.5%) of 227 non‐recipients; this difference was also not significant in multivariable analysis (adjusted odds ratio, 0.83; 95% CI: 0.36‐1.93; P = 0.83). The magnitude of the estimate of effect for 28‐day and 15‐month readmissions, and 15‐month asthma hospitalizations, was similar to the primary analysis when the cohort was restricted to subjects with a LOS 7 days.
DISCUSSION
This multicenter study examined the role of macrolide therapy in children hospitalized with M. pneumoniae pneumonia. Empiric macrolide therapy was associated with an approximately 30% shorter hospital LOS and, in stratified analysis, remained associated with a significantly shorter hospital LOS in both systemic corticosteroid recipients and non‐recipients. Empiric macrolide therapy was not associated with short‐ or longer‐term hospital readmission.
Previous small randomized trials have been inconclusive regarding the potential benefit of macrolide therapy in M. pneumoniae pneumonia.11 Our study, which demonstrated a shorter LOS among macrolides recipients compared with non‐recipients, has several advantages over prior studies including a substantively larger sample size and multicenter design. Animal models support our observations regarding the potential beneficial antimicrobial role of macrolides. M. pneumoniae concentrations in bronchoalveolar lavage specimens were significantly lower among experimentally infected mice treated with clarithromycin, a macolide‐class antibiotic, compared with either placebo or dexamethasone.45 Combination therapy with clarithromycin and dexamethasone reduced histopathologic inflammation to a greater degree than dexamethasone alone.45
While the relative importance of the antimicrobial and anti‐inflammatory properties of macrolides is not known, observational studies of children infected with macrolide‐resistant M. pneumoniae suggest that the antimicrobial properties of macrolides may provide disproportionate clinical benefit. The duration of fever in macrolide recipients with macrolide‐resistant M. pneumoniae (median duration, 9 days) reported by Suzuki et al46 was significantly longer than those with macrolide‐susceptible infections (median duration, 5 days), and similar to the duration of fever in patients with M. pneumoniae infection treated with placebo (median duration, 8 days) reported by Kingston et al.47 Additionally, macrolide therapy was associated with significant improvements in lung function in patients with asthma and concomitant M. pneumoniae infection, but not in patients with asthma without documented M. pneumoniae infection.9 As corticosteroids also have anti‐inflammatory properties, we expect that any anti‐inflammatory benefit of macrolide therapy would be mitigated by the concomitant administration of corticosteroids. The shorter LOS associated with empiric macrolide therapy in our study was comparable among corticosteroid recipients and non‐recipients.
Atypical bacterial pathogens, including M. pneumoniae, are associated with diffuse lower airway inflammation6, 48 and airway hyperresponsiveness,6 and have been implicated as a cause of acute asthma exacerbations.7, 4954 Among patients with previously diagnosed asthma, acute M. pneumoniae infection was identified in up to 20% of those having acute exacerbations.7, 54 Macrolide therapy has a beneficial effect on lung function and airway hyperresponsiveness in adults with asthma.9, 55 Among mice infected with M. pneumoniae, 3 days of macrolide therapy resulted in a significant reduction in airway hyperresponsiveness compared with placebo or dexamethasone; however, after 6 days of therapy, there was no significant difference in airway hyperresponsiveness between those receiving macrolides, dexamethasone, or placebo, suggesting that the benefit of macrolides on airway hyperresponsiveness may be brief. Our findings of a shorter LOS but no difference in readmissions at 28 days or longer, for macrolide recipients compared with non‐recipients, support the limited benefit of macrolide therapy beyond the initial reduction in bacterial load seen in the first few days of therapy.
M. pneumoniae infection has also been implicated as a cause of chronic pulmonary disease, including asthma.610 In the mouse model, peribronchial and perivascular mononuclear infiltrates, increased airway methacholine reactivity, and increased airway obstruction were observed 530 days after M. pneumoniae inoculation.6 M. pneumoniae has been identified in 26 (50%) of 51 children experiencing their first asthma attack,7 and 23 (42%) of 55 adults with chronic, stable asthma.9 Nevertheless, results of other studies addressing the issue are inconsistent, and the role of M. pneumoniae in the development of asthma remains unclear.56 In order to investigate the impact of macrolide therapy on the development of chronic pulmonary disease requiring hospitalization, we examined the readmission rates in the 15 months following index discharge. The proportion of children hospitalized with asthma following the hospitalization for M. pneumoniae pneumonia was higher for both macrolide recipients and non‐recipients compared with the 24‐months prior to infection. These results support a possible role for M. pneumoniae in chronic pulmonary disease. However, macrolide therapy was not associated with long‐term overall hospital readmission or long‐term asthma readmission, either in the entire cohort or in the subset of patients without prior asthma hospitalizations or medications.
This study had several limitations. First, because the identification of children with M. pneumoniae pneumonia relied on ICD‐9 discharge diagnosis codes, it is possible that there was misclassification of disease. We minimized the inclusion of children without M. pneumoniae by including only children who received antibiotic therapy on the first day of hospitalization and by excluding patients younger than 6 years of age, a group at relatively low‐risk for M. pneumoniae infection. Further, our algorithm for identification of M. pneumoniae pneumonia was validated through review of the medical records at 1 institution and was found to have a high positive predictive value. However, the positive predictive value of these ICD‐9 codes may vary across institutions. Additionally, the sensitivity of ICD‐9 codes for identifying children with M. pneumoniae pneumonia is not known. Also, not all children with pneumonia undergo testing for M. pneumoniae, and different tests have varying sensitivity and specificity.57, 58 Thus, some children with M. pneumoniae pneumonia were not diagnosed and so were not included in our study. It is not known how inclusion of these children would affect our results.
Second, the antibiotic information used in this study was limited to empiric antibiotic therapy. It is possible that some patients received macrolide therapy before admission. It is also likely that identification of M. pneumoniae during the hospitalization prompted the addition or substitution of macrolide therapy for some patients. If this therapy was initiated beyond the first day of hospitalization, these children would be classified as macrolide non‐recipients. Since macrolide administration was associated with a shorter hospital LOS, such misclassification would bias our results towards finding no difference in LOS between macrolide recipients and non‐recipients. It is therefore possible that the benefit of macrolide therapy is even greater than found in our study.
Third, there may be unmeasured confounding or residual confounding by indication for adjunct corticosteroid therapy related to clinical presentation. We expect that corticosteroid recipients would be sicker than non‐recipients. We included variables associated with a greater severity of illness (such as intensive care unit admission) in the multivariable analysis. Additionally, the shorter LOS among macrolide recipients remained when the analysis was stratified by receipt or non‐receipt of systemic corticosteroid therapy.
Fourth, we were only able to record readmissions occurring at the same hospital as the index admission; any readmission presenting to a different hospital following their index admission did not appear in our records, and was therefore not counted. It is thus possible that the true number of readmissions is higher than that represented here. Finally, despite the large number of patients included in this study, the number of short‐term readmissions was relatively small. Thus, we may have been underpowered to detect small but significant differences in short‐term readmission rates.
In conclusion, macrolide therapy was associated with shorter hospital LOS, but not with short‐term or longer‐term readmission in children presenting with M. pneumoniae pneumonia.
Appendix
| Variable | Beta Coefficient | Confidence Interval | P Value |
|---|---|---|---|
| Demographics | |||
| Sex | 0.12 | (0.22, 0.02) | 0.022 |
| Race | |||
| Blackreference category | |||
| White | 0.01 | (0.21, 0.23) | 0.933 |
| Other | 0.13 | (0.39, 0.13) | 0.323 |
| Missing | 0.46 | (0.81, 0.11) | 0.012 |
| Presentation during viral respiratory season | 0.05 | (0.19, 0.09) | 0.462 |
| Prior asthma hospitalization | 0.36 | (0.64, 0.08) | 0.015 |
| Intensive care unit admission | 1.05 | (0.87, 1.23) | <0.001 |
| Labs and procedures performed | |||
| Additional radiologic imaging | 0.23 | (0.20, 0.67) | 0.287 |
| Arterial blood gas | 0.69 | (0.50, 0.87) | <0.001 |
| Complete blood count | 0.34 | (0.24, 0.45) | <0.001 |
| Blood culture | 0.17 | (0.98, 0.44) | 0.204 |
| Mechanical ventilation | 1.15 | (0.68, 1.63) | <0.001 |
| Therapies received | |||
| Empiric macrolide therapy | 0.49 | (0.72, 0.25) | <0.001 |
| Systemic steroids | 0.26 | (0.38, 0.14) | <0.001 |
| Chronic asthma medications | 0.20 | (0.38, 0.013) | 0.037 |
| Beta‐agonist therapy | 0.07 | (0.21, 0.08) | 0.357 |
| Vasoactive infusion | 1.08 | (0.727, 1.45) | <0.001 |
| Clindamycin or vancomycin | 0.55 | (0.34, 0.75) | <0.001 |
| Variable | Odds Ratio* | Confidence Interval | P Value |
|---|---|---|---|
| |||
| Demographics | |||
| Sex | 0.56 | (0.23, 1.33) | 0.190 |
| Race | |||
| Blackreference category | |||
| White | 0.46 | (0.19, 1.14) | 0.093 |
| Other | |||
| Missing | |||
| Presentation during viral respiratory season | 0.64 | (0.09, 4.75) | 0.662 |
| Prior asthma hospitalization | |||
| Intensive care unit admission | 4.54 | (1.21, 17.03) | 0.025 |
| Laboratory tests and procedures | |||
| Additional radiologic imaging | 10.00 | (2.25, 44.47) | 0.002 |
| Arterial blood gas | |||
| Complete blood count | 0.92 | (0.24, 3.48) | 0.901 |
| Blood culture | 0.85 | (0.30, 2.36) | 0.738 |
| Mechanical ventilation | |||
| Medications | |||
| Macrolide therapy | 1.18 | (0.25, 5.45) | 0.837 |
| Systemic corticosteroids | 1.04 | (0.276, 4.09) | 0.951 |
| Chronic asthma medication | 1.66 | (0.71, 3.88) | 0.242 |
| Beta‐agonist therapy | 0.66 | (0.16, 2.65) | 0.557 |
| Vasoactive infusions | |||
| Clindamycin or vancomycin | 1.00 | (0.10, 9.90) | 0.998 |
| Variable | Coefficient | Confidence Interval | P Value | % Change | Confidence Interval for % Change |
|---|---|---|---|---|---|
| Demographics | |||||
| Age | 0.287 | (0.012, 0.045) | 0.001 | 2.9 | (1.2, 4.6) |
| Prior asthma hospitalization | 0.272 | (0.094, 0.45) | 0.004 | 31.3 | (9.9, 56.8) |
| Intensive care unit admission | 1.015 | (0.802, 1.23) | <0.001 | 175.9 | (123.0, 241.3) |
| Therapies received | |||||
| Macrolide therapy | 0.379 | (0.59, 0.166) | 0.001 | 31.6 | (44.6, 15.3) |
| Systemic corticosteroids | 0.264 | (0.391, 0.138) | <0.001 | 23.2 | (32.3, 12.9) |
| Chronic asthma medications | 0.056 | (0.255, 0.142) | 0.568 | 5.5 | (22.5, 15.2) |
| Albuterol | 0.07 | (0.059, 0.199) | 0.281 | 7.2 | (5.8, 22.0) |
| Clindamycin or vancomycin | 0.311 | (0.063, 0.559) | 0.015 | 36.5 | (6.5, 74.9) |
| Variable | Adjusted Odds Ratio | Confidence Interval | P Value |
|---|---|---|---|
| Demographics | |||
| Age | 0.91 | 0.72, 1.15 | 0.423 |
| Prior asthma hospitalization | 1.94 | 0.42, 8.90 | 0.394 |
| Intensive care unit admission | 5.73 | 2.03, 16.20 | 0.001 |
| Therapies received | |||
| Macrolide therapy | 1.12 | 0.22, 5.78 | 0.890 |
| Systemic corticosteroids | 0.696 | 0.10, 4.70 | 0.710 |
| Chronic asthma medications | 1.98 | 0.32, 12.20 | 0.460 |
| Albuterol | 0.519 | 0.081, 3.31 | 0.488 |
| Clindamycin or vancomycin | 0.904 | 0.07, 11.13 | 0.937 |
Mycoplasma pneumoniae is a common cause of community‐acquired pneumonia (CAP), among school‐age children and adolescents.14 Though pneumonia caused by M. pneumoniae is typically self‐limited, severe illness may occur.5 M. pneumoniae has also been implicated in airway inflammation, which may lead to the onset and development of chronic pulmonary disease.610 Few studies have directly addressed appropriate treatment strategies for M. pneumoniae pneumonia,11 and, despite its high prevalence and potential for causing severe complications, treatment recommendations remain inconsistent.
The efficacy of macrolide therapy in particular for M. pneumoniae remains unclear. In vitro susceptibility studies have shown bacteriostatic activity of erythromycin, clarithromycin, and azithromycin against M. pneumoniae.1218 Additionally, several small retrospective studies have shown that among children with atypical CAP (including M. pneumoniae pneumonia), those treated with macrolides were less likely to have persistence or progression of signs and symptoms after 3 days of therapy.19, 20 Lu et al21 found a shorter duration of fever among macrolide recipients compared with non‐recipients. In adults, Shames et al22 found a shorter duration of fever and hospitalization among erythromycin recipients compared with controls. Other randomized controlled trials have also addressed the use of macrolides in treatment of M. pneumoniae, but the ability to draw meaningful conclusions is limited by small samples sizes and by lack of details about the number of patients with M. pneumoniae.11
In addition to their antimicrobial effect, macrolides also have anti‐inflammatory properties.2327 The importance of these anti‐inflammatory properties is supported by studies showing clinical cure in patients treated with macrolides despite persistence of M. pneumoniae organisms,2831 clinical improvement despite the administration of doses that provide tissue levels below the minimum inhibitory concentration of the organism,3234 and clinical cure in patients with macrolide‐resistant M. pneumoniae.18, 35
The objectives of the current study were to examine the impact of macrolide therapy on the length of stay (LOS) and short‐ and longer‐term readmissions, including longer‐term asthma‐related readmissions, in children hospitalized with M. pneumoniae pneumonia.
METHODS
Data Source
Data for this retrospective cohort study were obtained from the Pediatric Health Information System (PHIS), which contains administrative data from 38 freestanding children's hospitals. Data quality and reliability are assured through a joint effort by the Child Health Corporation of America (Shawnee Mission, KS) and PHIS‐participating hospitals as described previously.36, 37 Encrypted medical record numbers allow for tracking of individual patients across hospitalizations. This study was reviewed and approved by the Committees for the Protection of Human Subjects at The Children's Hospital of Philadelphia (Philadelphia, PA).
Patients
Children 6‐18 years of age with CAP were eligible if they were discharged from a participating hospital between January 1, 2006 and December 31, 2008. Subjects were included if they received antibiotic therapy on the first day of hospitalization and if they satisfied one of the following International Classification of Diseases, 9th revision (ICD‐9) discharge diagnosis code criteria: 1) Principal diagnosis of M. pneumoniae pneumonia (483.0); 2) Principal diagnosis of a pneumonia‐related symptom (eg, fever, cough) (780.6 or 786.00‐786.52 [except 786.1]) and a secondary diagnosis of M. pneumoniae pneumonia; or 3) Principal diagnosis of pneumonia (481‐483.8 [except 483.0], 485‐486) and a secondary diagnosis of Mycoplasma (041.81).
Children younger than 6 years of age were excluded due to the low prevalence of M. pneumoniae infection.2, 38 Patients with comorbid conditions predisposing to severe or recurrent pneumonia (eg, cystic fibrosis, malignancy) were excluded using a previously reported classification scheme.39 In addition, we excluded patient data from 2 hospitals due to incomplete reporting of discharge information; thus data from 36 hospitals were included in this study.
Validation of Discharge Diagnosis Codes for Mycoplasma pneumoniae
To assess for misclassification of the diagnosis of M. pneumoniae, we reviewed records of a randomly selected subset of subjects from The Children's Hospital of Philadelphia; 14 of 15 patients had signs of lower respiratory tract infection in conjunction with a positive M. pneumoniae polymerase chain reaction test from nasopharyngeal washings to confirm the diagnosis of M. pneumoniae pneumonia. Hence, the positive predictive value of our algorithm for diagnosing M. pneumoniae pneumonia was 93.3%.
Study Definitions
We identified children with asthma in 2 ways. Asthma‐related hospitalizations were identified by an ICD‐9 code for asthma (493.0‐493.92) in any discharge diagnosis field during any hospitalization in the 24 months prior to the current hospitalization. Baseline controller medications were identified by receipt of inhaled corticosteroids (eg, fluticasone) or leukotriene receptor antagonists on the first day of hospitalization.
Systemic corticosteroids (either oral or intravenous) included dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone. Measures of disease severity included admission to the intensive care unit within 48 hours of hospitalization, and administration of vancomycin or clindamycin, vasoactive infusions (epinephrine, norepinephrine, dopamine, and dobutamine), and invasive (endotracheal intubation) and noninvasive (continuous positive airway pressure) mechanical ventilation within 24 hours of hospitalization, as previously described.40, 41 Viral respiratory season was defined as October through March.
Measured Outcomes
The primary outcomes of interest were hospital LOS and all‐cause readmission within 28 days and 15 months after index discharge. We examined readmissions for asthma 15 months after index discharge as a secondary outcome measure because of the potential role for M. pneumoniae infection in long‐term lung dysfunction, including asthma.42 The 15‐month time frame was selected based on longitudinal data available in PHIS for the entire study cohort.
Measured Exposures
The main exposure was early initiation of macrolide therapy, defined as receipt of erythromycin, clarithromycin, or azithromycin on the first day of hospitalization.
Data Analysis
Continuous variables were described using median and interquartile range (IQR) or range values, and compared using the Wilcoxon rank‐sum test. Categorical variables were described using counts and frequencies, and compared using the chi‐square test. Multivariable linear (for LOS) and logistic (for readmission) regression analyses were performed to assess the independent association of macrolide therapy with the primary outcomes. Because the LOS data had a skewed distribution, our analyses were performed using logarithmically transformed LOS values as the dependent variable. The resulting beta‐coefficients were transformed to reflect the percent difference in LOS between subjects receiving and not receiving macrolide therapy.
Building of the multivariable models began with the inclusion of macrolide therapy. Variables associated with primary outcomes on univariate analysis (P < 0.20) were also considered for inclusion as potential confounders.43 These variables were included in the final multivariable model if they remained significant after adjusting for other factors, or if their inclusion in the model resulted in a 15% or greater change in the effect size of the primary association of interest (ie, macrolide therapy).44 Because corticosteroids also have anti‐inflammatory properties, we assessed for interactions with macrolide therapy. There was no interaction between macrolide and systemic corticosteroid therapy (P = 0.26, Likelihood ratio test), therefore our primary model adjusted for systemic corticosteroids.
Despite adjusting for systemic corticosteroid therapy in our primary analysis, residual confounding by indication for corticosteroid therapy might exist. We therefore repeated the analysis after stratifying by receipt or non‐receipt of systemic corticosteroid therapy. Because the benefit of macrolides in preventing long‐term dysfunction may be limited to those without a prior diagnosis of asthma, we repeated the analysis of readmissions within 15 months of index discharge (any readmission and asthma‐related readmissions) while limiting the cohort to those without evidence of asthma (ie, no prior asthma‐related hospitalizations and no chronic asthma medications). Because children with underlying conditions or circumstances that would predispose to prolonged hospitalizations may have been included, despite our restriction of the cohort to those without an identified chronic complex condition, we also repeated the analysis while limiting the cohort to those with a LOS 7 days. Finally, all analyses were clustered on hospital using the robust standard errors of Huber and White to account for the correlation of exposures and outcomes among children within centers.
Data were analyzed using Stata version 11 (Stata Corporation, College Station, TX). Statistical significance was determined a priori as a two‐tailed P value <0.05.
RESULTS
Patient Characteristics
During the study, 690 children ages 6 to 18 years met inclusion criteria. Characteristics of these patients are shown in Table 1. The median age was 10 years (IQR, 7‐13 years). Ten patients (1.4%) also had a concomitant discharge diagnosis of pneumococcal pneumonia, while 19 patients (2.7%) had a concomitant discharge diagnosis of viral pneumonia; 1 of these patients had discharge diagnoses of both viral and pneumococcal pneumonia.
| Empiric Macrolide Therapy | ||||
|---|---|---|---|---|
| Variable | All Subjects | Yes | No | P |
| ||||
| Demographics | ||||
| Male sex | 356 (51.6) | 200 (49.4) | 156 (54.7) | 0.166 |
| Race | ||||
| Black | 135 (19.6) | 81 (20.0) | 54 (19.0) | 0.506 |
| White | 484 (70.1) | 287 (70.9) | 197 (69.1) | |
| Other | 62 (9.0) | 31 (7.7) | 31 (10.9) | |
| Missing | 9 (1.3) | 6 (1.5) | 3 (1.1) | |
| Presentation during viral respiratory season | 420 (60.9) | 242 (59.8) | 178 (62.5) | |
| Prior asthma hospitalization | 41 (5.9) | 31 (7.7) | 10 (3.5) | 0.023 |
| Intensive care unit admission | 127 (18.4) | 74 (18.3) | 53 (18.6) | 0.914 |
| Laboratory tests and procedures | ||||
| Additional radiologic imaging* | 24 (3.5) | 13 (3.2) | 11 (3.9) | 0.646 |
| Arterial blood gas | 116 (17.3) | 72 (18.5) | 44 (15.6) | 0.316 |
| Complete blood count | 433 (64.4) | 249 (64.0) | 184 (65.0) | 0.788 |
| Blood culture | 280 (41.7) | 167 (42.9) | 113 (39.9) | 0.436 |
| Mechanical ventilation | 16 (2.3) | 5 (1.2) | 11 (3.86) | 0.024 |
| Medications | ||||
| Chronic asthma medication | 116 (16.8) | 72 (17.8) | 44 (15.4) | 0.419 |
| Beta‐agonist therapy | 328 (47.5) | 215 (53.1) | 113 (39.7) | 0.001 |
| Vasoactive infusions | 22 (3.2) | 13 (3.2) | 9 (3.2) | 0.969 |
| Systemic corticosteroids | 252 (36.5) | 191 (47.2) | 61 (21.4) | <0.001 |
| Clindamycin or vancomycin | 86 (12.5) | 24 (5.9) | 62 (21.8) | <0.001 |
Macrolide therapy was administered to 405 (58.7%) patients. Systemic corticosteroid therapy was administered to 252 (36.5%) patients. Overall, 191 (27.7%) of the 690 patients received both macrolides and systemic corticosteroids empirically, while 224 (32.5%) received neither; 61 (8.8%) received corticosteroids but not macrolides, while 214 (31.0%) received macrolides but not corticosteroids. Asthma hospitalization within the 24 months prior to admission was more common among those receiving macrolides (N = 60/405, 14.8%) than among those not receiving macrolides (N = 30/285, 10.5%) (P = 0.023). Macrolide recipients also more commonly received concomitant systemic corticosteroids (N = 191/405, 47.2%) than macrolide non‐recipients (N = 61/285, 21.4%) (P < 0.001) and more commonly received beta‐agonist therapy (N = 215/405, 53.1%) than macrolide non‐recipients (N = 113/285, 39.7%) (P = 0.001).
Length of Stay
The overall median LOS was 3 days (IQR, 2‐6 days); the median LOS was 3 days (IQR, 2‐5 days) for empiric macrolide recipients and 4 days (IQR, 2‐9 days) for non‐recipients (P < 0.001). Overall, 22.9% (N = 158) of children had an LOS 7 days and 8.8% (N = 61) of children had an LOS 14 days. The LOS was 7 days for 15.3% (N = 62) of macrolide recipients and 33.7% (N = 96) of non‐recipients. LOS was 7 days for 17.5% (N = 44) of systemic steroid recipients and 26% (N = 114) of non‐recipients. In unadjusted analysis, macrolide therapy (beta‐coefficient, 0.49; 95% confidence interval [CI]: 0.72 to 0.25; P < 0.001) and systemic corticosteroid administration (beta‐coefficient, 0.26; CI: 0.37 to 0.14; P < 0.001) were associated with shorter hospital LOS (Appendix 1).
In multivariable analysis, macrolide therapy remained associated with a shorter LOS (Table 2; Appendix 2). Systemic corticosteroid administration was associated with a 23% shorter LOS (adjusted beta‐coefficient, 0.26; 95% CI: 0.39 to 0.14; P < 0.001). In contrast, previous hospitalization for asthma was associated with a 31% longer LOS (adjusted beta‐coefficient, 0.27; 95% CI: 0.09‐0.045; P = 0.004). Receipt of beta‐agonist therapy or chronic asthma medications were not associated with significant differences in LOS. In analysis stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy, empiric macrolide therapy remained associated with a significantly shorter LOS in both systemic corticosteroid recipients and non‐recipient (Table 4). When the cohort was restricted to subjects with a LOS 7 days, macrolide therapy remained significantly associated with a shorter LOS (adjusted percent change, 20%; 95% CI: 32% to 5%; P = 0.015).
| Association of Empiric Macrolide Therapy With Outcomes* | |
|---|---|
| |
| Length of stay (days) | |
| Adjusted beta‐coefficient (95 % CI) | 0.38 (0.59 to 0.17) |
| Adjusted percent change (95% CI) | 32% (45% to 15%) |
| P value | 0.001 |
| Any readmission within 28 days | |
| Adjusted odds ratio (95% CI) | 1.12 (0.22 to 5.78) |
| P value | 0.890 |
| Any readmission within 15 mo | |
| Adjusted odds ratio (95% CI) | 1.00 (0.59 to 1.70) |
| P value | 0.991 |
| Asthma hospitalization within 15 mo | |
| Adjusted odds ratio (95% CI) | 1.09 (0.54 to 2.17) |
| P value | 0.820 |
Readmission
Overall, 8 children (1.2%) were readmitted for pneumonia‐associated conditions within 28 days of index discharge. Readmission occurred in 1.2% of macrolide recipients and 1.1% of non‐recipients (P = 0.83) (Table 4). In unadjusted analysis, neither macrolide therapy (odds ratio [OR], 1.18; 95% CI: 0.25‐5.45; P = 0.84) nor systemic corticosteroid administration (OR, 1.04; 95% CI: 0.27‐4.10; P = 0.95) was associated with 28‐day readmission (Appendix 3). In multivariable analysis, empiric macrolide therapy was not associated with 28‐day readmission in the overall cohort (Table 2; Appendix 4)), or when the analysis was stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy (Table 3).
| Concomitant Systemic Corticosteroid Therapy* | ||
|---|---|---|
| Yes | No | |
| ||
| Length of stay | ||
| Adjusted beta‐coefficient (95% CI) | 0.40 (0.74 to 0.07) | 0.37 (0.58 to 0.16) |
| Adjusted percent change (95% CI) | 33% (52% to 7%) | 31% (44% to 15%) |
| P value | 0.020 | 0.001 |
| Readmission within 28 days | ||
| Adjusted odds ratio (95% CI) | 1.09 (0.05 to 26.7) | 1.50 (0.21 to 10.8) |
| P value | 0.960 | 0.687 |
| Readmission within 15 mo | ||
| Adjusted odds ratio (95% CI) | 1.57 (0.65 to 3.82) | 0.81 (0.45 to 1.46) |
| P value | 0.32 | 0.49 |
| Asthma hospitalization within 15 mo | ||
| Adjusted odds ratio (95% CI) | 1.51 (0.58 to 3.93) | 0.85 (0.36 to 1.97) |
| P value | 0.395 | 0.700 |
| Empiric Macrolide Therapy | ||
|---|---|---|
| N/Total (%) | ||
| Readmission | Yes | No |
| Any readmission within 28 days | ||
| Overall | 5/405 (1.2) | 3/285 (1.1) |
| Systemic corticosteroid therapy | 2/186 (1.1) | 1/66 (1.5) |
| No systemic corticosteroid therapy | 3/177 (1.7) | 2/261 (0.8) |
| Any readmission within 15 mo | ||
| Overall | 96/405 (23.7) | 64/285 (22.5) |
| Systemic corticosteroid therapy | 52/186 (28.0) | 17/66 (25.8) |
| No systemic corticosteroid therapy | 32/177 (18.1) | 59/261 (22.6) |
| Asthma hospitalization within 15 mo | ||
| Overall | 61/405 (15.1) | 34/285 (11.9) |
| Systemic corticosteroid therapy | 39/186 (21.0) | 13/66 (19.7) |
| No systemic corticosteroid therapy | 14/177 (7.9) | 29/261 (11.1) |
Overall, 160 children (23.2%) were readmitted within 15 months of index discharge; 95 were readmitted for asthma during this time (Table 3). Overall readmission occurred in 23.7% of macrolide recipients and 22.5% of macrolide non‐recipients (P = 0.702). Asthma readmission occurred in 15.1% of macrolide recipients and 11.9% of macrolide non‐recipients (P = 0.240). In unadjusted analysis, empiric macrolide therapy was not significantly associated with any readmission within 15 months (OR, 1.07; 95% CI: 0.69‐1.68; P = 0.759) or with asthma‐related readmission within 15 months (OR, 1.31; 95% CI: 0.73‐ 2.36; P = 0.369). In multivariable analysis, neither any readmission nor asthma readmission within 15 months was associated with empiric macrolide therapy overall (Table 2) or when stratified by receipt or non‐receipt of concomitant systemic corticosteroid therapy (Table 3).
The analyses for readmissions within 15 months of index discharge were repeated while limiting the cohort to those without prior asthma hospitalizations or chronic asthma medications. In this subset of patients, readmissions for any reason occurred in 55 (18.6%) of 295 macrolide recipients and 50 (22.0%) of 227 non‐recipients. The difference was not statistically significant in multivariable analysis (adjusted odds ratio, 0.79; 95% CI: 0.41‐1.51; P = 0.47). Readmissions for asthma occurred in 30 (10.2%) of 295 macrolide recipients and 26 (11.5%) of 227 non‐recipients; this difference was also not significant in multivariable analysis (adjusted odds ratio, 0.83; 95% CI: 0.36‐1.93; P = 0.83). The magnitude of the estimate of effect for 28‐day and 15‐month readmissions, and 15‐month asthma hospitalizations, was similar to the primary analysis when the cohort was restricted to subjects with a LOS 7 days.
DISCUSSION
This multicenter study examined the role of macrolide therapy in children hospitalized with M. pneumoniae pneumonia. Empiric macrolide therapy was associated with an approximately 30% shorter hospital LOS and, in stratified analysis, remained associated with a significantly shorter hospital LOS in both systemic corticosteroid recipients and non‐recipients. Empiric macrolide therapy was not associated with short‐ or longer‐term hospital readmission.
Previous small randomized trials have been inconclusive regarding the potential benefit of macrolide therapy in M. pneumoniae pneumonia.11 Our study, which demonstrated a shorter LOS among macrolides recipients compared with non‐recipients, has several advantages over prior studies including a substantively larger sample size and multicenter design. Animal models support our observations regarding the potential beneficial antimicrobial role of macrolides. M. pneumoniae concentrations in bronchoalveolar lavage specimens were significantly lower among experimentally infected mice treated with clarithromycin, a macolide‐class antibiotic, compared with either placebo or dexamethasone.45 Combination therapy with clarithromycin and dexamethasone reduced histopathologic inflammation to a greater degree than dexamethasone alone.45
While the relative importance of the antimicrobial and anti‐inflammatory properties of macrolides is not known, observational studies of children infected with macrolide‐resistant M. pneumoniae suggest that the antimicrobial properties of macrolides may provide disproportionate clinical benefit. The duration of fever in macrolide recipients with macrolide‐resistant M. pneumoniae (median duration, 9 days) reported by Suzuki et al46 was significantly longer than those with macrolide‐susceptible infections (median duration, 5 days), and similar to the duration of fever in patients with M. pneumoniae infection treated with placebo (median duration, 8 days) reported by Kingston et al.47 Additionally, macrolide therapy was associated with significant improvements in lung function in patients with asthma and concomitant M. pneumoniae infection, but not in patients with asthma without documented M. pneumoniae infection.9 As corticosteroids also have anti‐inflammatory properties, we expect that any anti‐inflammatory benefit of macrolide therapy would be mitigated by the concomitant administration of corticosteroids. The shorter LOS associated with empiric macrolide therapy in our study was comparable among corticosteroid recipients and non‐recipients.
Atypical bacterial pathogens, including M. pneumoniae, are associated with diffuse lower airway inflammation6, 48 and airway hyperresponsiveness,6 and have been implicated as a cause of acute asthma exacerbations.7, 4954 Among patients with previously diagnosed asthma, acute M. pneumoniae infection was identified in up to 20% of those having acute exacerbations.7, 54 Macrolide therapy has a beneficial effect on lung function and airway hyperresponsiveness in adults with asthma.9, 55 Among mice infected with M. pneumoniae, 3 days of macrolide therapy resulted in a significant reduction in airway hyperresponsiveness compared with placebo or dexamethasone; however, after 6 days of therapy, there was no significant difference in airway hyperresponsiveness between those receiving macrolides, dexamethasone, or placebo, suggesting that the benefit of macrolides on airway hyperresponsiveness may be brief. Our findings of a shorter LOS but no difference in readmissions at 28 days or longer, for macrolide recipients compared with non‐recipients, support the limited benefit of macrolide therapy beyond the initial reduction in bacterial load seen in the first few days of therapy.
M. pneumoniae infection has also been implicated as a cause of chronic pulmonary disease, including asthma.610 In the mouse model, peribronchial and perivascular mononuclear infiltrates, increased airway methacholine reactivity, and increased airway obstruction were observed 530 days after M. pneumoniae inoculation.6 M. pneumoniae has been identified in 26 (50%) of 51 children experiencing their first asthma attack,7 and 23 (42%) of 55 adults with chronic, stable asthma.9 Nevertheless, results of other studies addressing the issue are inconsistent, and the role of M. pneumoniae in the development of asthma remains unclear.56 In order to investigate the impact of macrolide therapy on the development of chronic pulmonary disease requiring hospitalization, we examined the readmission rates in the 15 months following index discharge. The proportion of children hospitalized with asthma following the hospitalization for M. pneumoniae pneumonia was higher for both macrolide recipients and non‐recipients compared with the 24‐months prior to infection. These results support a possible role for M. pneumoniae in chronic pulmonary disease. However, macrolide therapy was not associated with long‐term overall hospital readmission or long‐term asthma readmission, either in the entire cohort or in the subset of patients without prior asthma hospitalizations or medications.
This study had several limitations. First, because the identification of children with M. pneumoniae pneumonia relied on ICD‐9 discharge diagnosis codes, it is possible that there was misclassification of disease. We minimized the inclusion of children without M. pneumoniae by including only children who received antibiotic therapy on the first day of hospitalization and by excluding patients younger than 6 years of age, a group at relatively low‐risk for M. pneumoniae infection. Further, our algorithm for identification of M. pneumoniae pneumonia was validated through review of the medical records at 1 institution and was found to have a high positive predictive value. However, the positive predictive value of these ICD‐9 codes may vary across institutions. Additionally, the sensitivity of ICD‐9 codes for identifying children with M. pneumoniae pneumonia is not known. Also, not all children with pneumonia undergo testing for M. pneumoniae, and different tests have varying sensitivity and specificity.57, 58 Thus, some children with M. pneumoniae pneumonia were not diagnosed and so were not included in our study. It is not known how inclusion of these children would affect our results.
Second, the antibiotic information used in this study was limited to empiric antibiotic therapy. It is possible that some patients received macrolide therapy before admission. It is also likely that identification of M. pneumoniae during the hospitalization prompted the addition or substitution of macrolide therapy for some patients. If this therapy was initiated beyond the first day of hospitalization, these children would be classified as macrolide non‐recipients. Since macrolide administration was associated with a shorter hospital LOS, such misclassification would bias our results towards finding no difference in LOS between macrolide recipients and non‐recipients. It is therefore possible that the benefit of macrolide therapy is even greater than found in our study.
Third, there may be unmeasured confounding or residual confounding by indication for adjunct corticosteroid therapy related to clinical presentation. We expect that corticosteroid recipients would be sicker than non‐recipients. We included variables associated with a greater severity of illness (such as intensive care unit admission) in the multivariable analysis. Additionally, the shorter LOS among macrolide recipients remained when the analysis was stratified by receipt or non‐receipt of systemic corticosteroid therapy.
Fourth, we were only able to record readmissions occurring at the same hospital as the index admission; any readmission presenting to a different hospital following their index admission did not appear in our records, and was therefore not counted. It is thus possible that the true number of readmissions is higher than that represented here. Finally, despite the large number of patients included in this study, the number of short‐term readmissions was relatively small. Thus, we may have been underpowered to detect small but significant differences in short‐term readmission rates.
In conclusion, macrolide therapy was associated with shorter hospital LOS, but not with short‐term or longer‐term readmission in children presenting with M. pneumoniae pneumonia.
Appendix
| Variable | Beta Coefficient | Confidence Interval | P Value |
|---|---|---|---|
| Demographics | |||
| Sex | 0.12 | (0.22, 0.02) | 0.022 |
| Race | |||
| Blackreference category | |||
| White | 0.01 | (0.21, 0.23) | 0.933 |
| Other | 0.13 | (0.39, 0.13) | 0.323 |
| Missing | 0.46 | (0.81, 0.11) | 0.012 |
| Presentation during viral respiratory season | 0.05 | (0.19, 0.09) | 0.462 |
| Prior asthma hospitalization | 0.36 | (0.64, 0.08) | 0.015 |
| Intensive care unit admission | 1.05 | (0.87, 1.23) | <0.001 |
| Labs and procedures performed | |||
| Additional radiologic imaging | 0.23 | (0.20, 0.67) | 0.287 |
| Arterial blood gas | 0.69 | (0.50, 0.87) | <0.001 |
| Complete blood count | 0.34 | (0.24, 0.45) | <0.001 |
| Blood culture | 0.17 | (0.98, 0.44) | 0.204 |
| Mechanical ventilation | 1.15 | (0.68, 1.63) | <0.001 |
| Therapies received | |||
| Empiric macrolide therapy | 0.49 | (0.72, 0.25) | <0.001 |
| Systemic steroids | 0.26 | (0.38, 0.14) | <0.001 |
| Chronic asthma medications | 0.20 | (0.38, 0.013) | 0.037 |
| Beta‐agonist therapy | 0.07 | (0.21, 0.08) | 0.357 |
| Vasoactive infusion | 1.08 | (0.727, 1.45) | <0.001 |
| Clindamycin or vancomycin | 0.55 | (0.34, 0.75) | <0.001 |
| Variable | Odds Ratio* | Confidence Interval | P Value |
|---|---|---|---|
| |||
| Demographics | |||
| Sex | 0.56 | (0.23, 1.33) | 0.190 |
| Race | |||
| Blackreference category | |||
| White | 0.46 | (0.19, 1.14) | 0.093 |
| Other | |||
| Missing | |||
| Presentation during viral respiratory season | 0.64 | (0.09, 4.75) | 0.662 |
| Prior asthma hospitalization | |||
| Intensive care unit admission | 4.54 | (1.21, 17.03) | 0.025 |
| Laboratory tests and procedures | |||
| Additional radiologic imaging | 10.00 | (2.25, 44.47) | 0.002 |
| Arterial blood gas | |||
| Complete blood count | 0.92 | (0.24, 3.48) | 0.901 |
| Blood culture | 0.85 | (0.30, 2.36) | 0.738 |
| Mechanical ventilation | |||
| Medications | |||
| Macrolide therapy | 1.18 | (0.25, 5.45) | 0.837 |
| Systemic corticosteroids | 1.04 | (0.276, 4.09) | 0.951 |
| Chronic asthma medication | 1.66 | (0.71, 3.88) | 0.242 |
| Beta‐agonist therapy | 0.66 | (0.16, 2.65) | 0.557 |
| Vasoactive infusions | |||
| Clindamycin or vancomycin | 1.00 | (0.10, 9.90) | 0.998 |
| Variable | Coefficient | Confidence Interval | P Value | % Change | Confidence Interval for % Change |
|---|---|---|---|---|---|
| Demographics | |||||
| Age | 0.287 | (0.012, 0.045) | 0.001 | 2.9 | (1.2, 4.6) |
| Prior asthma hospitalization | 0.272 | (0.094, 0.45) | 0.004 | 31.3 | (9.9, 56.8) |
| Intensive care unit admission | 1.015 | (0.802, 1.23) | <0.001 | 175.9 | (123.0, 241.3) |
| Therapies received | |||||
| Macrolide therapy | 0.379 | (0.59, 0.166) | 0.001 | 31.6 | (44.6, 15.3) |
| Systemic corticosteroids | 0.264 | (0.391, 0.138) | <0.001 | 23.2 | (32.3, 12.9) |
| Chronic asthma medications | 0.056 | (0.255, 0.142) | 0.568 | 5.5 | (22.5, 15.2) |
| Albuterol | 0.07 | (0.059, 0.199) | 0.281 | 7.2 | (5.8, 22.0) |
| Clindamycin or vancomycin | 0.311 | (0.063, 0.559) | 0.015 | 36.5 | (6.5, 74.9) |
| Variable | Adjusted Odds Ratio | Confidence Interval | P Value |
|---|---|---|---|
| Demographics | |||
| Age | 0.91 | 0.72, 1.15 | 0.423 |
| Prior asthma hospitalization | 1.94 | 0.42, 8.90 | 0.394 |
| Intensive care unit admission | 5.73 | 2.03, 16.20 | 0.001 |
| Therapies received | |||
| Macrolide therapy | 1.12 | 0.22, 5.78 | 0.890 |
| Systemic corticosteroids | 0.696 | 0.10, 4.70 | 0.710 |
| Chronic asthma medications | 1.98 | 0.32, 12.20 | 0.460 |
| Albuterol | 0.519 | 0.081, 3.31 | 0.488 |
| Clindamycin or vancomycin | 0.904 | 0.07, 11.13 | 0.937 |
- ,,, et al.Prospective surveillance for atypical pathogens in children with community‐acquired pneumonia in Japan.J Infect Chemother.2006;12:36–41.
- ,,.Incidence of community‐acquired pneumonia in children caused by Mycoplasma pneumoniae: serological results of a prospective, population‐based study in primary health care.Respirology.2004;9:109–114.
- ,,.Mycoplasma pneumoniae infections in University of Wisconsin students.Am Rev Respir Dis.1967;96:237–244.
- .Infections caused by Mycoplasma pneumoniae and possible carrier state in different populations of patients.Clin Infect Dis.1993;17(suppl 1):S37–S46.
- .Mycoplasma pneumoniae. In: Long SS, Pickering LK, Prober CG, eds.Principles and Practice of Pediatric Infectious Diseases.3rd ed.Philadelphia, PA:Churchill Livingstone;2008:979–985.
- ,,, et al.Mycoplasma pneumoniae induces chronic respiratory infection, airway hyperreactivity, and pulmonary inflammation: a murine model of infection‐associated chronic reactive airway disease.Infect Immun.2002;70:649–654.
- ,,, et al.Mycoplasma pneumoniae and asthma in children.Clin Infect Dis.2004;38:1341–1346.
- ,,,.Isolation of Mycoplasma pneumoniae from asthmatic patients.Ann Allergy.1993;70:23–25.
- ,,,.Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin.Chest.2002;121:1782–1788.
- ,,,,.A link between chronic asthma and chronic infection.J Allergy Clin Immunol.2001;107:595–601.
- ,,.Antibiotics for community‐acquired lower respiratory tract infections secondary to Mycoplasma pneumoniae in children.Cochrane Database Syst Rev.2010;7:CD004875.
- ,,,.In vitro susceptibilities of mycoplasmas and ureaplasmas to new macrolides and aryl‐fluoroquinolones.Antimicrob Agents Chemother.1988;32:1500–1502.
- ,,.Inhibitory and bactericidal activities of gemifloxacin and other antimicrobials against Mycoplasma pneumoniae.Int J Antimicrob Agents.2003;21:574–577.
- ,,,,.The in vitro activity of some 14‐, 15‐ and 16‐ membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum.Drugs Exp Clin Res.1991;17:91–99.
- ,,, et al.In vitro and in vivo activities of macrolides against Mycoplasma pneumoniae.Antimicrob Agents Chemother.1994;38:790–798.
- ,.Comparative in vitro activity of azithromycin, clarithromycin, erythromycin and lomefloxacin against Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum.Eur J Clin Microbiol Infect Dis.1990;9:838–841.
- ,,, et al.Characteristics of macrolide‐resistant Mycoplasma pneumoniae strains isolated from patients and induced with erythromycin in vitro.Microbiol Immunol.2001;45:617–620.
- ,,, et al.Characterization and molecular analysis of macrolide‐resistant Mycoplasma pneumoniae clinical isolates obtained in Japan.Antimicrob Agents Chemother.2004;48:4624–4630.
- ,,,.Role of Mycoplasma pneumoniae and Chlamydia pneumoniae in children with community‐acquired lower respiratory tract infections.Clin Infect Dis.2001;32:1281–1289.
- ,,, et al.Characteristics of Streptococcus pneumoniae and atypical bacterial infections in children 2–5 years of age with community‐acquired pneumonia.Clin Infect Dis.2002;35:1345–1352.
- ,,,,.Macrolide use shortens fever duration in Mycoplasma pneumoniae infection in children: a 2‐year experience.J Microbiol Immunol Infect.2008;41:307–310.
- ,,,,.Comparison of antibiotics in the treatment of mycoplasmal pneumonia.Arch Intern Med.1970;125:680–684.
- ,,, et al.Antimicrobial and immunologic activities of clarithromycin in a murine model of Mycoplasma pneumoniae‐induced pneumonia.Antimicrob Agents Chemother.2003;47:1614–1620.
- ,.Antibiotics in asthma.Curr Allergy Asthma Rep.2004;4:132–138.
- ,.Immunomodulatory activity and effectiveness of macrolides in chronic airway disease.Chest.2004;125:70S–78S.
- ,,, et al.Interleukin‐8 gene repression by clarithromycin is mediated by the activator protein‐1 binding site in human bronchial epithelial cells.Am J Respir Cell Mol Biol.2000;22:51–60.
- ,,, et al.Clarithromycin inhibits NF‐kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells.Antimicrob Agents Chemother.2001;45:44–47.
- ,,,,.Epidemiology of Mycoplasma pneumoniae infection in families.JAMA.1966;197:859–866.
- ,,.Shedding of Mycoplasma pneumoniae after tetracycline and erythromycin therapy.N Engl J Med.1967;276:1172–1175.
- ,,.Mycoplasma pneumoniae disease: clinical spectrum, pathophysiology, epidemiology, and control.J Infect Dis.1971;123:74–92.
- .Is there a role for antibiotics in the treatment of asthma? Involvement of atypical organisms.BioDrugs.2000;14:349–354.
- ,.Diffuse panbronchiolitis: role of macrolides in therapy.Am J Respir Med.2002;1:119–131.
- ,,,,,.Long‐term low‐dose administration of erythromycin to patients with diffuse panbronchiolitis.Respiration.1991;58:145–149.
- ,,,,,.[Long‐term therapeutic effects of erythromycin and newquinolone antibacterial agents on diffuse panbronchiolitis].Nihon Kyobu Shikkan Gakkai Zasshi.1990;28:1305–1313.
- ,,, et al.A comparative clinical study of macrolide‐sensitive and macrolide‐resistant Mycoplasma pneumoniae infections in pediatric patients.J Infect Chemother.2009;15:380–383.
- ,,,.Corticosteroids and mortality in children with bacterial meningitis.JAMA.2008;299:2048–2055.
- ,,,,.Intravenous immunoglobulin in children with streptococcal toxic shock syndrome.Clin Infect Dis.2009;49:1369–1376.
- ,,, et al.Etiology of childhood pneumonia: serologic results of a prospective, population‐based study.Pediatr Infect Dis J.1998;17:986–991.
- ,,,,,.Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services.Pediatrics.2001;107:E99.
- ,,,,,.Adjunct corticosteroids in children hospitalized with community‐acquired pneumonia.Pediatrics.2011;127:e255–e263.
- ,,, et al.Comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood.J Hosp Med.2011;6:256–263.
- ,,, et al.Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma.Am J Respir Crit Care Med.1998;158:998–1001.
- ,.The impact of confounder selection criteria on effect estimation.Am J Epidemiol.1989;129:125–137.
- ,,.The risk of determining risk with multivariable models.Ann Intern Med.1993;118:201–210.
- ,,, et al.The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection.J Infect Dis.2008;198:1180–1188.
- ,,, et al.Clinical evaluation of macrolide‐resistant Mycoplasma pneumoniae.Antimicrob Agents Chemother.2006;50:709–712.
- ,,, et al.Eaton agent pneumonia.JAMA.1961;176:118–123.
- .The role of viral and atypical bacterial pathogens in asthma pathogenesis.Pediatr Pulmonol Suppl.1999;18:141–143.
- ,,.The association of viral and mycoplasma infections with recurrence of wheezing in the asthmatic child.Ann Allergy.1970;28:43–49.
- ,,,.Association of viral and mycoplasma infections with exacerbations of asthma.Ann Allergy.1974;33:145–149.
- ,,, et al.Acute Chlamydia pneumoniae and Mycoplasma pneumoniae infections in community‐acquired pneumonia and exacerbations of COPD or asthma: therapeutic considerations.J Chemother.2004;16:70–76.
- ,,, et al.Mycoplasma pneumoniae is a frequent cause of exacerbation of bronchial asthma in adults.Ann Allergy.1986;57:263–265.
- ,,, et al.Acute exacerbations of asthma in adults: role of Chlamydia pneumoniae infection.Eur Respir J.1994;7:2165–2168.
- ,,, et al.Atypical pathogen infection in adults with acute exacerbation of bronchial asthma.Am J Respir Crit Care Med.2003;167:406–410.
- ,,,,,.Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma.Chest.1991;99:670–673.
- ,,,,.Atypical bacteria and macrolides in asthma.Allergy Asthma Clin Immunol.2008;4:111–116.
- ,,.Acute respiratory infection due to Mycoplasma pneumoniae: current status of diagnostic methods.Eur J Clin Microbiol Infect Dis.2010;29:1055–1069.
- ,,,,,.A multicenter pilot external quality assessment programme to assess the quality of molecular detection of Chlamydophila pneumoniae and Mycoplasma pneumoniae.J Microbiol Methods.2010;82:131–135.
- ,,, et al.Prospective surveillance for atypical pathogens in children with community‐acquired pneumonia in Japan.J Infect Chemother.2006;12:36–41.
- ,,.Incidence of community‐acquired pneumonia in children caused by Mycoplasma pneumoniae: serological results of a prospective, population‐based study in primary health care.Respirology.2004;9:109–114.
- ,,.Mycoplasma pneumoniae infections in University of Wisconsin students.Am Rev Respir Dis.1967;96:237–244.
- .Infections caused by Mycoplasma pneumoniae and possible carrier state in different populations of patients.Clin Infect Dis.1993;17(suppl 1):S37–S46.
- .Mycoplasma pneumoniae. In: Long SS, Pickering LK, Prober CG, eds.Principles and Practice of Pediatric Infectious Diseases.3rd ed.Philadelphia, PA:Churchill Livingstone;2008:979–985.
- ,,, et al.Mycoplasma pneumoniae induces chronic respiratory infection, airway hyperreactivity, and pulmonary inflammation: a murine model of infection‐associated chronic reactive airway disease.Infect Immun.2002;70:649–654.
- ,,, et al.Mycoplasma pneumoniae and asthma in children.Clin Infect Dis.2004;38:1341–1346.
- ,,,.Isolation of Mycoplasma pneumoniae from asthmatic patients.Ann Allergy.1993;70:23–25.
- ,,,.Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin.Chest.2002;121:1782–1788.
- ,,,,.A link between chronic asthma and chronic infection.J Allergy Clin Immunol.2001;107:595–601.
- ,,.Antibiotics for community‐acquired lower respiratory tract infections secondary to Mycoplasma pneumoniae in children.Cochrane Database Syst Rev.2010;7:CD004875.
- ,,,.In vitro susceptibilities of mycoplasmas and ureaplasmas to new macrolides and aryl‐fluoroquinolones.Antimicrob Agents Chemother.1988;32:1500–1502.
- ,,.Inhibitory and bactericidal activities of gemifloxacin and other antimicrobials against Mycoplasma pneumoniae.Int J Antimicrob Agents.2003;21:574–577.
- ,,,,.The in vitro activity of some 14‐, 15‐ and 16‐ membered macrolides against Staphylococcus spp., Legionella spp., Mycoplasma spp. and Ureaplasma urealyticum.Drugs Exp Clin Res.1991;17:91–99.
- ,,, et al.In vitro and in vivo activities of macrolides against Mycoplasma pneumoniae.Antimicrob Agents Chemother.1994;38:790–798.
- ,.Comparative in vitro activity of azithromycin, clarithromycin, erythromycin and lomefloxacin against Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum.Eur J Clin Microbiol Infect Dis.1990;9:838–841.
- ,,, et al.Characteristics of macrolide‐resistant Mycoplasma pneumoniae strains isolated from patients and induced with erythromycin in vitro.Microbiol Immunol.2001;45:617–620.
- ,,, et al.Characterization and molecular analysis of macrolide‐resistant Mycoplasma pneumoniae clinical isolates obtained in Japan.Antimicrob Agents Chemother.2004;48:4624–4630.
- ,,,.Role of Mycoplasma pneumoniae and Chlamydia pneumoniae in children with community‐acquired lower respiratory tract infections.Clin Infect Dis.2001;32:1281–1289.
- ,,, et al.Characteristics of Streptococcus pneumoniae and atypical bacterial infections in children 2–5 years of age with community‐acquired pneumonia.Clin Infect Dis.2002;35:1345–1352.
- ,,,,.Macrolide use shortens fever duration in Mycoplasma pneumoniae infection in children: a 2‐year experience.J Microbiol Immunol Infect.2008;41:307–310.
- ,,,,.Comparison of antibiotics in the treatment of mycoplasmal pneumonia.Arch Intern Med.1970;125:680–684.
- ,,, et al.Antimicrobial and immunologic activities of clarithromycin in a murine model of Mycoplasma pneumoniae‐induced pneumonia.Antimicrob Agents Chemother.2003;47:1614–1620.
- ,.Antibiotics in asthma.Curr Allergy Asthma Rep.2004;4:132–138.
- ,.Immunomodulatory activity and effectiveness of macrolides in chronic airway disease.Chest.2004;125:70S–78S.
- ,,, et al.Interleukin‐8 gene repression by clarithromycin is mediated by the activator protein‐1 binding site in human bronchial epithelial cells.Am J Respir Cell Mol Biol.2000;22:51–60.
- ,,, et al.Clarithromycin inhibits NF‐kappaB activation in human peripheral blood mononuclear cells and pulmonary epithelial cells.Antimicrob Agents Chemother.2001;45:44–47.
- ,,,,.Epidemiology of Mycoplasma pneumoniae infection in families.JAMA.1966;197:859–866.
- ,,.Shedding of Mycoplasma pneumoniae after tetracycline and erythromycin therapy.N Engl J Med.1967;276:1172–1175.
- ,,.Mycoplasma pneumoniae disease: clinical spectrum, pathophysiology, epidemiology, and control.J Infect Dis.1971;123:74–92.
- .Is there a role for antibiotics in the treatment of asthma? Involvement of atypical organisms.BioDrugs.2000;14:349–354.
- ,.Diffuse panbronchiolitis: role of macrolides in therapy.Am J Respir Med.2002;1:119–131.
- ,,,,,.Long‐term low‐dose administration of erythromycin to patients with diffuse panbronchiolitis.Respiration.1991;58:145–149.
- ,,,,,.[Long‐term therapeutic effects of erythromycin and newquinolone antibacterial agents on diffuse panbronchiolitis].Nihon Kyobu Shikkan Gakkai Zasshi.1990;28:1305–1313.
- ,,, et al.A comparative clinical study of macrolide‐sensitive and macrolide‐resistant Mycoplasma pneumoniae infections in pediatric patients.J Infect Chemother.2009;15:380–383.
- ,,,.Corticosteroids and mortality in children with bacterial meningitis.JAMA.2008;299:2048–2055.
- ,,,,.Intravenous immunoglobulin in children with streptococcal toxic shock syndrome.Clin Infect Dis.2009;49:1369–1376.
- ,,, et al.Etiology of childhood pneumonia: serologic results of a prospective, population‐based study.Pediatr Infect Dis J.1998;17:986–991.
- ,,,,,.Deaths attributed to pediatric complex chronic conditions: national trends and implications for supportive care services.Pediatrics.2001;107:E99.
- ,,,,,.Adjunct corticosteroids in children hospitalized with community‐acquired pneumonia.Pediatrics.2011;127:e255–e263.
- ,,, et al.Comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood.J Hosp Med.2011;6:256–263.
- ,,, et al.Detection of Mycoplasma pneumoniae in the airways of adults with chronic asthma.Am J Respir Crit Care Med.1998;158:998–1001.
- ,.The impact of confounder selection criteria on effect estimation.Am J Epidemiol.1989;129:125–137.
- ,,.The risk of determining risk with multivariable models.Ann Intern Med.1993;118:201–210.
- ,,, et al.The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection.J Infect Dis.2008;198:1180–1188.
- ,,, et al.Clinical evaluation of macrolide‐resistant Mycoplasma pneumoniae.Antimicrob Agents Chemother.2006;50:709–712.
- ,,, et al.Eaton agent pneumonia.JAMA.1961;176:118–123.
- .The role of viral and atypical bacterial pathogens in asthma pathogenesis.Pediatr Pulmonol Suppl.1999;18:141–143.
- ,,.The association of viral and mycoplasma infections with recurrence of wheezing in the asthmatic child.Ann Allergy.1970;28:43–49.
- ,,,.Association of viral and mycoplasma infections with exacerbations of asthma.Ann Allergy.1974;33:145–149.
- ,,, et al.Acute Chlamydia pneumoniae and Mycoplasma pneumoniae infections in community‐acquired pneumonia and exacerbations of COPD or asthma: therapeutic considerations.J Chemother.2004;16:70–76.
- ,,, et al.Mycoplasma pneumoniae is a frequent cause of exacerbation of bronchial asthma in adults.Ann Allergy.1986;57:263–265.
- ,,, et al.Acute exacerbations of asthma in adults: role of Chlamydia pneumoniae infection.Eur Respir J.1994;7:2165–2168.
- ,,, et al.Atypical pathogen infection in adults with acute exacerbation of bronchial asthma.Am J Respir Crit Care Med.2003;167:406–410.
- ,,,,,.Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma.Chest.1991;99:670–673.
- ,,,,.Atypical bacteria and macrolides in asthma.Allergy Asthma Clin Immunol.2008;4:111–116.
- ,,.Acute respiratory infection due to Mycoplasma pneumoniae: current status of diagnostic methods.Eur J Clin Microbiol Infect Dis.2010;29:1055–1069.
- ,,,,,.A multicenter pilot external quality assessment programme to assess the quality of molecular detection of Chlamydophila pneumoniae and Mycoplasma pneumoniae.J Microbiol Methods.2010;82:131–135.
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