JOURNAL OF TROPICAL PEDIATRICS, VOL. 60, NO. 5, 2014
Early Treatment with Corticosteroids in Patients with Mycoplasma pneumoniae pneumonia: A Randomized Clinical Trial by Lizhen Huang, Xiang Gao, and Meiyuan Chen Department of Pediatrics, The First People’s Hospital of Wujiang, Wujiang 215200, Jiangsu, China Correspondence: Meiyuan Chen, Department of Pediatrics, The First People’s Hospital of Wujiang, No. 169, Gongyuan Road, Wujiang 215200, Jiangsu, China. Tel: þ86051263000710. E-mail .
Background: Corticosteroids have been evaluated for management of severe Mycoplasma pneumoniae pneumonia (MP) in children. However, it is unclear whether the timing of treatment with corticosteroids affects the patients’ clinical outcome. Methods: We did a prospective randomized clinical trial to evaluate the effect of early use of corticosteroids. Fifty-three patients were randomly assigned to treatment with corticosteroids within 24 h after admission (cases), and 53 patients were treated 72 h after admission (control patients). Results: Cases had a shorter fever duration [6 days (range 5–11) vs. 10 days (range 8–23), p < 0.001] and length of hospital stay [8 days (range 5–15) vs. 10 days (range 5–21), p ¼ 0.001]. Four cases (1.9%) had a complete radiographic resolution time >4 weeks compared with 10 control patients (17.5%; p ¼ 0.038; Table 2). Conclusions: Early treatment with corticosteroids was associated with a better outcome in patients with severe MP. Key words: corticosteroids, Mycoplasma pneumoniae pneumonia.
Introduction Mycoplasma pneumoniae pneumonia (MP) has been reported in 10–40% of community-acquired pneumonia cases [1–3]. MP is usually mild or self-limited. However, pediatricians recently have been faced with the problems that children with MP have clinical deterioration and delayed radiographic resolution despite an appropriate macrolide therapy [4–6]. Additional therapeutic interventions along with macrolide may help to improve outcome in patients with severe MP. Corticosteroids have been evaluated for severe MP in children with promising efficacy, based on the mechanism of cellular immunological responses [4, 5, 7]. All these studies initiated corticosteroids when cases showed clinical and radiological deterioration despite appropriate antibiotic therapy for 7 days or more. However, it is unclear whether the timing of treatment with corticosteroids affects the patients’ clinical outcome. In view of the shortcomings in the data available, the authors sought to investigate whether early use of adjunctive treatment with corticosteroids, along with antibiotic treatment, results in better outcomes for children with severe MP.
Materials and Methods Between January 2010 and December 2012, children who were admitted because of lower respiratory tract infections were prospectively recruited from the First People’s Hospital of Wujiang. The study protocol was approved by the research ethics board of the First People’s Hospital of Wujiang. Patients were eligible for the study if they had symptoms suggestive of lower respiratory tract infection (cough, sputum production, dyspnea and/or pleuritic chest pain) together with a temperature of 38.5 C or higher (per axilla), presence of new chest radiographic lobar infiltrates and/or pleural effusion and positive results for M. pneumoniae IgM antibody or M. pneumoniae polymerase chain reaction in throat swabs within 12 h of admission. Patients who had fever duration more than 7 days were not included because it was considered unethical to treat without corticosteroids. Exclusion criteria included patients who received corticosteroid therapy before admission, immunocompromised patients and patients whose diagnostic evaluation revealed an etiology other than pneumonia or underlying disease. Patients were randomly assigned to receive corticosteroids within 12 h or 72 h after admission. The
ß The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] doi:10.1093/tropej/fmu022 Advance Access published on 7 April 2014
338
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
Summary
L. HUANG ET AL.
Illness in Children with Community-Acquired Pneumonia [8]. Serial posteroanterior and lateral chest roentgenograms were obtained every 4 weeks from the date of admission until radiographic abnormalities had resolved. A pulmonologist and a radiologist who were blinded to the patient’s clinical condition independently evaluated all chest roentgenograms. Interobserver agreement was assessed using the kappa statistic. The kappa value was 0.6. Differences between the two examiners were resolved by consensus. We used n (%) for categorical variables and median (range) for continuous variables with nonnormal distribution or mean (standard deviation, SD) for those with normal distribution. We assessed differences in categorical variables with the 2-test. We calculated 95% confidence interval for differences in medians with an exact test [9]. We analyzed differences in fever duration and length of stay until hospital discharge with the Mann–Whitney U-test. We also performed a Kaplan–Meier method for analysis of length of hospitalization. Results From January 2010 to December 2012, we enrolled 106 patients. Fifty-three patients were randomly
TABLE 1 Baseline characteristics of study patients Day corticosteroids given after fever onset Age (years) Male (number) Criteria for severity of illness Respiratory rate higher than World Health Organization classification for agea Apnea Increased work of breathing (e.g. retractions, dyspnea, nasal flaring and grunting) PaO2/FiO2 ratio 60 breaths/min, age 2–12 months >50 breaths/min, age 1–5 years >40 breaths/min, age >5 years >20 breaths/min. b Defined as a state of awareness that differed from the normal awareness of a conscious person, including sudden confusion, disorientation or stupor, and scored by the treating doctor. c Data are n (%), mean (SD) or median (range).
Journal of Tropical Pediatrics
Vol. 60, No. 5
339
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
randomization schedule had a blocked design and was generated by a statistician who used random numbers. The individual assignments were made by the use of opaque sealed envelopes. All patients received azithromycin (10 mg/kg/day) and a third-generation cephalosporin (80 mg/kg/day) within 4 h after admission. Corticosteroids (methylprednisolone 1 mg/kg every 12 h daily for three consecutive days, then oral prednisolone weaned over 1 week) were administered along with antibiotics. Oxygen therapy was administered at 1.5 l/min by nasal cannula if oxygen saturation (recorded by pulse oximetry) was less than 92%. The decision of hospital discharge was established by our pediatric team. A general rule for hospital discharge was that patients have documented overall clinical improvement, including level of activity, appetite and decreased fever for 72 h, absence of hyperthermia or hypothermia and consistent decrease of C-reactive protein (CRP) concentrations. Laboratory assessment was performed on presentation and included blood cell counts, CRP renal and liver functions, electrolytes and cell immunity. Arterial blood gas analysis was performed as clinically indicated. Subsequently, we measured blood cell counts and CRP on day 4 and day 7. We also measured cell immunity on day 7. We calculated severity of illness based on the Criteria for CAP Severity of
L. HUANG ET AL.
Patients admitted to hospital (100%)
1.0
Cases Controls
0.8 0.6 0.4 0.2 0.0 5.00
10.00 15.00 20.00 Length of stay (days)
25.00
FIG. 2. Kaplan–Meier analysis of the effect of corticosteroids on length of hospital stay in all study patients.
FIG. 1. Defervescence in cases or control patients with MP. Data are presented as mean SD.
TABLE 2 Summary of clinical outcomes Cases (n ¼ 53)a Total fever duration (days) Fever duration after corticosteroids (days) Length of hospitalization (days) Readmission within 7 days from hospital discharge Number of cases that had radiographic resolution time >4 weeks Number of cases that had radiographic resolution time >8 weeks
6 0 8 1
(5–11) (0–5) (5–15) (1.9)
3 (5.6) 0
Control patients (n ¼ 53)a 10 2 10 1
p value
(8–23) (0–8) (5–21) (1.9)
8 weeks, but four control patients (7.0%) had a complete radiographic resolution time of >8 weeks (Table 2). One patient in each group was readmitted within 7 days of hospital discharge. They were readmitted because of abrupt cessation of corticosteroids without tapering, which led to recurrence of fever and new pulmonary infiltration on chest radiograph.
assigned to treatment with corticosteroids within 24 h after admission (cases), and 53 patients were treated 72 h after admission (control patients). Baseline patient demographics are summarized in Table 1. The two groups had similar characteristics on admission. Mean age of the two groups was 5.7 2.5 years and 6.1 2.3 years, respectively. The ratio of male to female subjects was 0.9:1 in cases and 1.1:1 in control patients. Severity of illness on the day of admission did not differ between the two groups. The fever duration before admission was 5 (range 2–7) days in cases and 5 (3–7) days in control patients. Duration of antibiotic use before admission was 3 (range 0–6) days and 3 (0–7) days, respectively. Five cases (9.4%) and 6 control patients (11.3%) received oxygen therapy. None of the patients was transferred to the intensive care unit or received mechanical ventilation during their hospital stay. Resolution of fever was faster in the cases (Fig. 1). The total duration of fever and the duration of fever after corticosteroids were both significantly shorter in
L. HUANG ET AL.
Discussion In our study, cases were noted to have a significantly shorter length of hospital stay after corticosteroid administration. We also noted an overall reduction in complete radiographic resolution time in cases.
TABLE 3 Summary of cell immunity on day 7
CD3 þ T cells (%) CD3þCD4þ T cells (%) CD3-CD8þ T cells (%) CD4/CD8 T-cell ratio B cells (%) CD19þCD23þ B cells (%) Natural killer cell (%)
Cases (n ¼ 53)
Control patients (n ¼ 53)
p
63.7 9.3 31.5 7.4 26.4 6.8 1.4 1.0 20.9 7.5 8.2 4.8 11.3 7.3
65.6 10.6 35.7 8.9 26.7 6.3 1.4 0.5 20.2 9.2 6.5 3.9 11.2 8.1
0.32 0.01 0.82 0.66 0.70 0.07 0.94
These findings support our hypothesis that early administration of corticosteroids changes the hyperimmune reaction and thereby reduces fever duration and length of hospital stay in patients with MP. This modulation is shown in the sharp decline in CRP and an increase in lymphocyte differential in cases on day 4 after admission. On day 7, the CD3þCD4þ T cells in cases were significantly lower than those in control patients. T cells are important immune cells involved in the immune reaction to MP [10, 11]. Pathological findings show a large number of lymphocytes, mainly CD3þCD4þ T cell infiltration [12]. The phenomenon of lower CD3þCD4þ T cells in cases also reflects the impact of corticosteroids on the process of the CD3þCD4þ T cell infiltration. Symptom resolution and reduction of length of hospital admission are important clinical goals in the treatment of patients with CAP. Previous clinical and experimental studies have reported that additional corticosteroids are effective, especially in those with MP because they have the ability to downregulate the cell-mediated immune response [4, 5, 7, 13, 14]. Tamura and colleagues [5] reported a rapid improvement of radiological abnormalities in patients with severe MP who were treated with methylprednisolone pulse therapy for 3 days. A retrospective study [4] described 15 children with severe MP who responded to oral prednisolone therapy (1 mg/kg/day for 3–7 days, then weaned over 1 week). Our results are in line with these studies that showed a beneficial effect of corticosteroids in patients with severe MP. Our study was the first study that evaluates whether the timing of treatment with corticosteroids affects the patients’ clinical outcome. In our study, two patients had recurrence of fever and new pulmonary infiltration on chest radiograph because of abrupt cessation of corticosteroids without tapering after discharge. The effect of a delayed
FIG. 3. Serum CRP levels and lymphocyte differential on the day of presentation, day 4 and day 7 for patients in both study groups. Data are presented as mean SEM. Journal of Tropical Pediatrics
Vol. 60, No. 5
341
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
We measured blood cell counts and concentrations of CRP on the day of presentation (day 1), as well on day 4 and day 7. On day 4, we noted a sharp decline in concentrations of CRP and an increase in lymphocyte differential in cases, but an increase in CRP and a decline in lymphocyte differential in control patients (Fig. 3). We also measured cell immunity on day 1 and day 7 in 67 patients (30 in cases and 37 in control patients). On day 1, the differential of CD3þCD4þ T cells, CD3-CD8þ T cells, B cells, CD19þCD23þ B cells and natural killer cells did not differ in cases and control patients. However, on day 7, the CD3þCD4þ T cells in cases were significantly lower than those in control patients (31.5 7.4 vs. 35.7 8.9, p ¼ 0.01), Table 3.
L. HUANG ET AL.
Conclusions We conclude that early treatment with corticosteroids favored a better outcome in patients with MP. References 1. Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 2004; 113:701–7. 2. Nolevaux G, Bessaci-Kabouya K, Villenet N, et al. Epidemiological and clinical study of Mycoplasma pneumoniae respiratory infections in children hospitalized in a pediatric ward between 1999 and 2005 at the Reims University Hospital [in French]. Arch Pediatr 2008;15:1630–6. 3. Chiang WC, Teoh OH, Chong CY, et al. Epidemiology, clinical characteristics and antimicrobial resistance patterns of community-acquired pneumonia in 1702 hospitalized children in Singapore. Respirology 2007; 12:254–61. 4. Lee KY, Lee HS, Hong JH, et al. Role of prednisolone treatment in severe Mycoplasma pneumoniae pneumonia in children. Pediatr Pulmonol 2006;41:263–8.
342
5. Tamura A, Matsubara K, Tanaka T, et al. Methylprednisolone pulse therapy for refractory Mycoplasma pneumoniae pneumonia in children. J Infect 2008;57:223–8. 6. Liang H, Jiang W, Han Q, et al. Ciliary ultrastructural abnormalities in Mycoplasma pneumoniae pneumonia in 22 pediatric patients. Eur J Pediatr 2012;171:559–63. 7. Lu A, Wang L, Zhang X, et al. Combined treatment for child refractory Mycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Pediatr Pulmonol 2011;46:1093–7. 8. Bradley JS, Byington CL, Shah SS, et al. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis 2011;53:617–30. 9. Campbell MJ, Gardner MJ. Calculating confidence intervals for some non-parametric analyses. Br Med J (Clin Res Ed) 1988;296:1454–6. 10. Yang J, Hooper WC, Phillips DJ, et al. Cytokines in Mycoplasma pneumoniae infections. Cytokine Growth Factor Rev 2004;15:157–68. 11. Hardy RD, Jafri HS, Olsen K, et al. Elevated cytokine and chemokine levels and prolonged pulmonary airflow resistance in a murine Mycoplasma pneumoniae pneumonia model: a microbiologic, histologic, immunologic, and respiratory plethysmographic profile. Infect Immun 2001;69:3869–76. 12. Opitz O, Pietsch K, Ehlers S, et al. Cytokine gene expression in immune mice reinfected with Mycoplasma pneumoniae: the role of T cell subsets in aggravating the inflammatory response. Immunobiology 1996;196: 575–87. 13. Tagliabue C, Salvatore CM, Techasaensiri C, et al. The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection. J Infect Dis 2008;198:1180–8. 14. Hirao S, Wada H, Nakagaki K, et al. Inflammation provoked by Mycoplasma pneumoniae extract: implications for combination treatment with clarithromycin and dexamethasone. FEMS Immunol Med Microbiol 2011;62:182–9. 15. Yende S, D’Angelo G, Kellum JA, et al. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008;177:1242–7.
Journal of Tropical Pediatrics
Vol. 60, No. 5
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
inflammatory response due to withdrawal of corticosteroids can cause rebound of reactions in the clinical and radiographic findings. The assumption of rebound of inflammation is strengthened by the higher CRP levels in patients after being readmitted. Previous study proved that a tapering of corticosteroids might protect patients against the rebound of inflammation [15]. In our study, there were no rebound reactions in the clinical and radiographic findings after tapering of prednisolone and no further infectious complications in the rest of patients. Some limitations may apply to our study. First, evaluation of adverse events of corticosteroids is limited. No assessments of glucose concentration and adrenal function were performed in these patients, so no data regarding the presence of relative hyperglycemia and adrenal insufficiency are known. Second, the duration of hospital stay is a subjective outcome parameter, prone to bias. But in our opinion, this reflects daily clinical practice and the bias is minimized.
Early Treatment with Corticosteroids in Patients with Mycoplasma pneumoniae pneumonia: A Randomized Clinical Trial by Lizhen Huang, Xiang Gao, and Meiyuan Chen Department of Pediatrics, The First People’s Hospital of Wujiang, Wujiang 215200, Jiangsu, China Correspondence: Meiyuan Chen, Department of Pediatrics, The First People’s Hospital of Wujiang, No. 169, Gongyuan Road, Wujiang 215200, Jiangsu, China. Tel: þ86051263000710. E-mail .
Background: Corticosteroids have been evaluated for management of severe Mycoplasma pneumoniae pneumonia (MP) in children. However, it is unclear whether the timing of treatment with corticosteroids affects the patients’ clinical outcome. Methods: We did a prospective randomized clinical trial to evaluate the effect of early use of corticosteroids. Fifty-three patients were randomly assigned to treatment with corticosteroids within 24 h after admission (cases), and 53 patients were treated 72 h after admission (control patients). Results: Cases had a shorter fever duration [6 days (range 5–11) vs. 10 days (range 8–23), p < 0.001] and length of hospital stay [8 days (range 5–15) vs. 10 days (range 5–21), p ¼ 0.001]. Four cases (1.9%) had a complete radiographic resolution time >4 weeks compared with 10 control patients (17.5%; p ¼ 0.038; Table 2). Conclusions: Early treatment with corticosteroids was associated with a better outcome in patients with severe MP. Key words: corticosteroids, Mycoplasma pneumoniae pneumonia.
Introduction Mycoplasma pneumoniae pneumonia (MP) has been reported in 10–40% of community-acquired pneumonia cases [1–3]. MP is usually mild or self-limited. However, pediatricians recently have been faced with the problems that children with MP have clinical deterioration and delayed radiographic resolution despite an appropriate macrolide therapy [4–6]. Additional therapeutic interventions along with macrolide may help to improve outcome in patients with severe MP. Corticosteroids have been evaluated for severe MP in children with promising efficacy, based on the mechanism of cellular immunological responses [4, 5, 7]. All these studies initiated corticosteroids when cases showed clinical and radiological deterioration despite appropriate antibiotic therapy for 7 days or more. However, it is unclear whether the timing of treatment with corticosteroids affects the patients’ clinical outcome. In view of the shortcomings in the data available, the authors sought to investigate whether early use of adjunctive treatment with corticosteroids, along with antibiotic treatment, results in better outcomes for children with severe MP.
Materials and Methods Between January 2010 and December 2012, children who were admitted because of lower respiratory tract infections were prospectively recruited from the First People’s Hospital of Wujiang. The study protocol was approved by the research ethics board of the First People’s Hospital of Wujiang. Patients were eligible for the study if they had symptoms suggestive of lower respiratory tract infection (cough, sputum production, dyspnea and/or pleuritic chest pain) together with a temperature of 38.5 C or higher (per axilla), presence of new chest radiographic lobar infiltrates and/or pleural effusion and positive results for M. pneumoniae IgM antibody or M. pneumoniae polymerase chain reaction in throat swabs within 12 h of admission. Patients who had fever duration more than 7 days were not included because it was considered unethical to treat without corticosteroids. Exclusion criteria included patients who received corticosteroid therapy before admission, immunocompromised patients and patients whose diagnostic evaluation revealed an etiology other than pneumonia or underlying disease. Patients were randomly assigned to receive corticosteroids within 12 h or 72 h after admission. The
ß The Author [2014]. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] doi:10.1093/tropej/fmu022 Advance Access published on 7 April 2014
338
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
Summary
L. HUANG ET AL.
Illness in Children with Community-Acquired Pneumonia [8]. Serial posteroanterior and lateral chest roentgenograms were obtained every 4 weeks from the date of admission until radiographic abnormalities had resolved. A pulmonologist and a radiologist who were blinded to the patient’s clinical condition independently evaluated all chest roentgenograms. Interobserver agreement was assessed using the kappa statistic. The kappa value was 0.6. Differences between the two examiners were resolved by consensus. We used n (%) for categorical variables and median (range) for continuous variables with nonnormal distribution or mean (standard deviation, SD) for those with normal distribution. We assessed differences in categorical variables with the 2-test. We calculated 95% confidence interval for differences in medians with an exact test [9]. We analyzed differences in fever duration and length of stay until hospital discharge with the Mann–Whitney U-test. We also performed a Kaplan–Meier method for analysis of length of hospitalization. Results From January 2010 to December 2012, we enrolled 106 patients. Fifty-three patients were randomly
TABLE 1 Baseline characteristics of study patients Day corticosteroids given after fever onset Age (years) Male (number) Criteria for severity of illness Respiratory rate higher than World Health Organization classification for agea Apnea Increased work of breathing (e.g. retractions, dyspnea, nasal flaring and grunting) PaO2/FiO2 ratio 60 breaths/min, age 2–12 months >50 breaths/min, age 1–5 years >40 breaths/min, age >5 years >20 breaths/min. b Defined as a state of awareness that differed from the normal awareness of a conscious person, including sudden confusion, disorientation or stupor, and scored by the treating doctor. c Data are n (%), mean (SD) or median (range).
Journal of Tropical Pediatrics
Vol. 60, No. 5
339
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
randomization schedule had a blocked design and was generated by a statistician who used random numbers. The individual assignments were made by the use of opaque sealed envelopes. All patients received azithromycin (10 mg/kg/day) and a third-generation cephalosporin (80 mg/kg/day) within 4 h after admission. Corticosteroids (methylprednisolone 1 mg/kg every 12 h daily for three consecutive days, then oral prednisolone weaned over 1 week) were administered along with antibiotics. Oxygen therapy was administered at 1.5 l/min by nasal cannula if oxygen saturation (recorded by pulse oximetry) was less than 92%. The decision of hospital discharge was established by our pediatric team. A general rule for hospital discharge was that patients have documented overall clinical improvement, including level of activity, appetite and decreased fever for 72 h, absence of hyperthermia or hypothermia and consistent decrease of C-reactive protein (CRP) concentrations. Laboratory assessment was performed on presentation and included blood cell counts, CRP renal and liver functions, electrolytes and cell immunity. Arterial blood gas analysis was performed as clinically indicated. Subsequently, we measured blood cell counts and CRP on day 4 and day 7. We also measured cell immunity on day 7. We calculated severity of illness based on the Criteria for CAP Severity of
L. HUANG ET AL.
Patients admitted to hospital (100%)
1.0
Cases Controls
0.8 0.6 0.4 0.2 0.0 5.00
10.00 15.00 20.00 Length of stay (days)
25.00
FIG. 2. Kaplan–Meier analysis of the effect of corticosteroids on length of hospital stay in all study patients.
FIG. 1. Defervescence in cases or control patients with MP. Data are presented as mean SD.
TABLE 2 Summary of clinical outcomes Cases (n ¼ 53)a Total fever duration (days) Fever duration after corticosteroids (days) Length of hospitalization (days) Readmission within 7 days from hospital discharge Number of cases that had radiographic resolution time >4 weeks Number of cases that had radiographic resolution time >8 weeks
6 0 8 1
(5–11) (0–5) (5–15) (1.9)
3 (5.6) 0
Control patients (n ¼ 53)a 10 2 10 1
p value
(8–23) (0–8) (5–21) (1.9)
8 weeks, but four control patients (7.0%) had a complete radiographic resolution time of >8 weeks (Table 2). One patient in each group was readmitted within 7 days of hospital discharge. They were readmitted because of abrupt cessation of corticosteroids without tapering, which led to recurrence of fever and new pulmonary infiltration on chest radiograph.
assigned to treatment with corticosteroids within 24 h after admission (cases), and 53 patients were treated 72 h after admission (control patients). Baseline patient demographics are summarized in Table 1. The two groups had similar characteristics on admission. Mean age of the two groups was 5.7 2.5 years and 6.1 2.3 years, respectively. The ratio of male to female subjects was 0.9:1 in cases and 1.1:1 in control patients. Severity of illness on the day of admission did not differ between the two groups. The fever duration before admission was 5 (range 2–7) days in cases and 5 (3–7) days in control patients. Duration of antibiotic use before admission was 3 (range 0–6) days and 3 (0–7) days, respectively. Five cases (9.4%) and 6 control patients (11.3%) received oxygen therapy. None of the patients was transferred to the intensive care unit or received mechanical ventilation during their hospital stay. Resolution of fever was faster in the cases (Fig. 1). The total duration of fever and the duration of fever after corticosteroids were both significantly shorter in
L. HUANG ET AL.
Discussion In our study, cases were noted to have a significantly shorter length of hospital stay after corticosteroid administration. We also noted an overall reduction in complete radiographic resolution time in cases.
TABLE 3 Summary of cell immunity on day 7
CD3 þ T cells (%) CD3þCD4þ T cells (%) CD3-CD8þ T cells (%) CD4/CD8 T-cell ratio B cells (%) CD19þCD23þ B cells (%) Natural killer cell (%)
Cases (n ¼ 53)
Control patients (n ¼ 53)
p
63.7 9.3 31.5 7.4 26.4 6.8 1.4 1.0 20.9 7.5 8.2 4.8 11.3 7.3
65.6 10.6 35.7 8.9 26.7 6.3 1.4 0.5 20.2 9.2 6.5 3.9 11.2 8.1
0.32 0.01 0.82 0.66 0.70 0.07 0.94
These findings support our hypothesis that early administration of corticosteroids changes the hyperimmune reaction and thereby reduces fever duration and length of hospital stay in patients with MP. This modulation is shown in the sharp decline in CRP and an increase in lymphocyte differential in cases on day 4 after admission. On day 7, the CD3þCD4þ T cells in cases were significantly lower than those in control patients. T cells are important immune cells involved in the immune reaction to MP [10, 11]. Pathological findings show a large number of lymphocytes, mainly CD3þCD4þ T cell infiltration [12]. The phenomenon of lower CD3þCD4þ T cells in cases also reflects the impact of corticosteroids on the process of the CD3þCD4þ T cell infiltration. Symptom resolution and reduction of length of hospital admission are important clinical goals in the treatment of patients with CAP. Previous clinical and experimental studies have reported that additional corticosteroids are effective, especially in those with MP because they have the ability to downregulate the cell-mediated immune response [4, 5, 7, 13, 14]. Tamura and colleagues [5] reported a rapid improvement of radiological abnormalities in patients with severe MP who were treated with methylprednisolone pulse therapy for 3 days. A retrospective study [4] described 15 children with severe MP who responded to oral prednisolone therapy (1 mg/kg/day for 3–7 days, then weaned over 1 week). Our results are in line with these studies that showed a beneficial effect of corticosteroids in patients with severe MP. Our study was the first study that evaluates whether the timing of treatment with corticosteroids affects the patients’ clinical outcome. In our study, two patients had recurrence of fever and new pulmonary infiltration on chest radiograph because of abrupt cessation of corticosteroids without tapering after discharge. The effect of a delayed
FIG. 3. Serum CRP levels and lymphocyte differential on the day of presentation, day 4 and day 7 for patients in both study groups. Data are presented as mean SEM. Journal of Tropical Pediatrics
Vol. 60, No. 5
341
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
We measured blood cell counts and concentrations of CRP on the day of presentation (day 1), as well on day 4 and day 7. On day 4, we noted a sharp decline in concentrations of CRP and an increase in lymphocyte differential in cases, but an increase in CRP and a decline in lymphocyte differential in control patients (Fig. 3). We also measured cell immunity on day 1 and day 7 in 67 patients (30 in cases and 37 in control patients). On day 1, the differential of CD3þCD4þ T cells, CD3-CD8þ T cells, B cells, CD19þCD23þ B cells and natural killer cells did not differ in cases and control patients. However, on day 7, the CD3þCD4þ T cells in cases were significantly lower than those in control patients (31.5 7.4 vs. 35.7 8.9, p ¼ 0.01), Table 3.
L. HUANG ET AL.
Conclusions We conclude that early treatment with corticosteroids favored a better outcome in patients with MP. References 1. Michelow IC, Olsen K, Lozano J, et al. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 2004; 113:701–7. 2. Nolevaux G, Bessaci-Kabouya K, Villenet N, et al. Epidemiological and clinical study of Mycoplasma pneumoniae respiratory infections in children hospitalized in a pediatric ward between 1999 and 2005 at the Reims University Hospital [in French]. Arch Pediatr 2008;15:1630–6. 3. Chiang WC, Teoh OH, Chong CY, et al. Epidemiology, clinical characteristics and antimicrobial resistance patterns of community-acquired pneumonia in 1702 hospitalized children in Singapore. Respirology 2007; 12:254–61. 4. Lee KY, Lee HS, Hong JH, et al. Role of prednisolone treatment in severe Mycoplasma pneumoniae pneumonia in children. Pediatr Pulmonol 2006;41:263–8.
342
5. Tamura A, Matsubara K, Tanaka T, et al. Methylprednisolone pulse therapy for refractory Mycoplasma pneumoniae pneumonia in children. J Infect 2008;57:223–8. 6. Liang H, Jiang W, Han Q, et al. Ciliary ultrastructural abnormalities in Mycoplasma pneumoniae pneumonia in 22 pediatric patients. Eur J Pediatr 2012;171:559–63. 7. Lu A, Wang L, Zhang X, et al. Combined treatment for child refractory Mycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Pediatr Pulmonol 2011;46:1093–7. 8. Bradley JS, Byington CL, Shah SS, et al. Executive summary: the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the Pediatric Infectious Diseases Society and the Infectious Diseases Society of America. Clin Infect Dis 2011;53:617–30. 9. Campbell MJ, Gardner MJ. Calculating confidence intervals for some non-parametric analyses. Br Med J (Clin Res Ed) 1988;296:1454–6. 10. Yang J, Hooper WC, Phillips DJ, et al. Cytokines in Mycoplasma pneumoniae infections. Cytokine Growth Factor Rev 2004;15:157–68. 11. Hardy RD, Jafri HS, Olsen K, et al. Elevated cytokine and chemokine levels and prolonged pulmonary airflow resistance in a murine Mycoplasma pneumoniae pneumonia model: a microbiologic, histologic, immunologic, and respiratory plethysmographic profile. Infect Immun 2001;69:3869–76. 12. Opitz O, Pietsch K, Ehlers S, et al. Cytokine gene expression in immune mice reinfected with Mycoplasma pneumoniae: the role of T cell subsets in aggravating the inflammatory response. Immunobiology 1996;196: 575–87. 13. Tagliabue C, Salvatore CM, Techasaensiri C, et al. The impact of steroids given with macrolide therapy on experimental Mycoplasma pneumoniae respiratory infection. J Infect Dis 2008;198:1180–8. 14. Hirao S, Wada H, Nakagaki K, et al. Inflammation provoked by Mycoplasma pneumoniae extract: implications for combination treatment with clarithromycin and dexamethasone. FEMS Immunol Med Microbiol 2011;62:182–9. 15. Yende S, D’Angelo G, Kellum JA, et al. Inflammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis. Am J Respir Crit Care Med 2008;177:1242–7.
Journal of Tropical Pediatrics
Vol. 60, No. 5
Downloaded from http://tropej.oxfordjournals.org/ at University of Cambridge on August 8, 2015
inflammatory response due to withdrawal of corticosteroids can cause rebound of reactions in the clinical and radiographic findings. The assumption of rebound of inflammation is strengthened by the higher CRP levels in patients after being readmitted. Previous study proved that a tapering of corticosteroids might protect patients against the rebound of inflammation [15]. In our study, there were no rebound reactions in the clinical and radiographic findings after tapering of prednisolone and no further infectious complications in the rest of patients. Some limitations may apply to our study. First, evaluation of adverse events of corticosteroids is limited. No assessments of glucose concentration and adrenal function were performed in these patients, so no data regarding the presence of relative hyperglycemia and adrenal insufficiency are known. Second, the duration of hospital stay is a subjective outcome parameter, prone to bias. But in our opinion, this reflects daily clinical practice and the bias is minimized.
