Oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children

Transcription

1 경희의학 : 제 32 권제 1 호 원 저 J Kyung Hee Univ Med Cent : Vol. 32, No. 1, 2017 Oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children Ho Young Song, Soo Yeon Kang, Joon Hyuk Song Department of Pediatrics, Myongji Hospital, Seonam University College of Medicine, Goyang, Korea INTRODUCTION Mycoplasma pneumoniae (M. pneumoniae) is a common cause of pediatric and adult communityacquired pneumonia that accounts for 10-40% of cases. (1-4) Mycoplasma pneumoniae pneumonia (MP) is usually a benign and self-limited disease. However, it may develop into severe life-threatening pneumonia and complications, such as acute respiratory distress syndrome, necrotizing pneumonitis, and fulminant pneumonia in rare cases.(5-8) In Korea, the epidemic incidence of MP have occurred every 3-4 years in the past decade. Especially the age of incidence with MP has lowered in the recent epidemics.(9,10) In 2015, MP was more prevalent throughout the country and caused more severe clinical features than any other time. Especially severe and refractory MP was more prevalent that clinical symptoms were not improved even though using macrolides. Macrolides are first-choice antimicrobials with excellent effectiveness against MP.(3) However, progression to severe pneumonia might develop despite appropriate Corresponding author: Joon Hyuk Song, Department of Pediatrics, Myongji Hospital, Seonam University College of Medicine, Hwajeong-dong, Deokyang-gu, Goyang-si, Gyeonggi-do 10475, Korea Tel: stealawayou@hanmail.net antibiotic including macrolides. Although the exact mechanism of macrolide-nonresponsive and progressive condition remains unclear, the pathogenesis is suggested to be related to cellular immunological responses.(6,8,11,12) For example, patients may show an excessive immune response against pathogens, such as vigorous expression of cytokines and highly activated cell-mediated immune responses.(13) Recent studies have shown that systemic corticosteroid treatment improved the clinical results of MP unresponsive to macrolides.(11,14,15) These are assumed that overreaction of host immune systems are related. However, effects and appropriate methods of systemic corticosteroid treatment, in particular optimal dose and duration of treatment, have not been fully clarified. In this study, we evaluated the efficacy of systemic corticosteroid administration on refractory MP in children by examining clinical signs and symptoms, as well as laboratory and radiological findings. SUBJECTS AND METHODS During the recent MP epidemic in Korea, we treated 367 patients with MP at Seonam University Myongji Hospital (Goyang, Korea) between August 2015 and December The diagnosis of M. pneumoniae

2 Ho Young Song, et al:oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children Fig. 1. Study population. MP, Mycoplasma pneumoniae pneumonia; RT-PCR, reverse transcription polymerase chain reaction; CRP, C-reactive protein. infection was confirmed based on serological test using the indirect microparticle agglutinin method (Serodia- Myo II, Fujirebio Inc., Tokyo, Japan). Positive result of M. pneumoniae infection was defined as an initial microparticle agglutinin titer of 1:640 or a four-fold rising titer in double-checked samples. To exclude other respiratory infections, we performed microbiological testing of blood cultures and reverse transcription polymerase chain reaction (RT-PCR) analysis of common respiratory viruses (influenza viruses, parainfluenzaviruses, respiratory syncytial viruses, coronaviruses, human rhinoviruses, adenoviruses, and human metapneumoviruses) before antibiotic. None of the tests resulted in detection of any other pathogens. Refractory MP was defined as follows: 1) prolonged fever for 7 days or more or 2) persistent pneumonic infiltration of the lung despite appropriate antibiotic treatment, including use of macrolides over 72 hours (Fig. 1). Among them, 12 patients with refractory MP were selected. They had no underlying disease and were previously healthy children. The medical records and chest radiographic findings of 12 patients were retrospectively reviewed. Laboratory tests including complete blood count and differential count, serum aminotransferase, and C-reactive protein (CRP), as well as chest X-ray were examined upon admission and followed up over time. After admission to the hospital, initial

3 경희의학제 32 권제 1 호 2017 antibiotic consisted of β-lactam antibiotics (ampicillin with sulbactam) and additionally one of macrolides (clarithromycin, azithromycin or roxithromycin). And sometimes a third-generation cephalosporin (cefotaxime) was added because of a lack of clinical improvement. Fever persisted despite administration of appropriate antibiotics especially use of macrolides over 72 hours. Furthermore, pneumonic infiltrations of chest radiograph and clinical symptoms were aggravated despite antibiotic. In these cases, we administered oral prednisolone at a dose of 1 mg/kg/day for 7 consecutive days. Data were analyzed using the IBM SPSS software, version 20. The body temperatures and CRP concentrations during the follow-up were subjected to repeated-measures analysis of variance (ANOVA). Significance was defined as P<0.05. The study was approved by the Ethical Committee of Seonam University Myongji Hospital. RESULTS 1. Clinical characteristics of the patients Twelve children (seven females and five males) with refractory M. pneumoniae pneumonia were identified. The mean age of 12 children was 8.1±3.6 years (range, 4-16 years). The average febrile duration prior to admission was 6.3±4.7 days (range, 3-13 days). Upon admission, the vital sign was as follows; the mean body temperature was 38.4±1.0 C, heart rate was 113.5±17.4 beats per minute, and respiratory rate was 24.9±5.7 breaths per minute. One patient showed bronchopneumonia on the initial chest X-ray. The other patients showed lobar consolidation in the initial chest radiograph. Four of 12 patients showed the deterioration of chest radiography with pleural effusion. But no one needed thoracentesis. Four of 12 patients were required oxygen via nasal cannula because of tachypnea. No patient was required admission to the intensive care unit at the initial admission or during their inpatient period. Based on serological diagnostic tests, two patients had an initial value of greater M. pneumoniae antibody (Ab.) titer than 1:640 upon admission, while the others had a fourfold or greater increase in M. pneumoniae Ab. titer with a mean interval of 3.1±1.3 days (range, 2-6 days) (Table 1). 2. Clinical and laboratory findings of oral prednisolone All 12 patients had symptoms and signs indicative of lower respiratory tract infection upon admission, including persistent high fever and pneumonic infiltrations on chest radiographs with elevated level of serum CRP. All patients responded well to oral prednisolone. The mean total duration of high fever was 9.9±2.4 days (range, 8-17 days). The mean duration of sustained fever from the administration of prednisolone was 7.0±7.6 hours (range 0-24 hours). In other words, fever subsided within 24 hours after the initiation of oral prednisolone (Fig. 2A, P< 0.001). In addition, it was accompanied by improvement in clinical symptoms such as cough, sputum and respiratory distress. The total duration of hospitalization was 9.5±2.3 days (range, 6-13 days), and the duration of hospitalization after prednisolone was 5.0±2.2 days (range, 3-9 days) (Table 1). Radiologic abnormal findings of pneumonic consolidation and/or pleural effusion also improved at 3.0±0.7 days (range, 2-4 days) after initiation of prednisolone. There were no rebound reactions in the clinical and radiologic findings after discontinuation of corticosteroid. There was an apparent decrease in serum CRP levels after oral prednisolone. The initial mean serum

4 Ho Young Song, et al:oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children Table 1. Clinical Characteristics of Patients with Refractory Mycoplasma pneumoniae Pneumonia Patient Age/ Sex Adm. day of PD Total (days) Duration of fever Before admission (days) After PD (hours) Duration of hospital stay After PD Total (days) (days) WBC (neutrophil/lymphocyte, %) Before PD After PD Laboratory results Before PD CRP (mg/dl) After PD 1 4/F (61.7/29.5) 6600(63.6/27.6) (-) (-) >1: /F (83.1/9.9) 9500(75.3/19.1) :640 >1: /M (69.8/20.3) 15300(56.1/35.8) >1: /M (64.3/23.4) 3900(79.3/14.6) (-) 1:320 >1: /M (59.0/23.8) 10000(66.8/19.8) :80 1: /F (82.0/65.8) 9800(65.8/21.1) :40 1:160 >1: /F (62.2/26.0) 9300(65.0/25.7) :320 >1: /F (80.7/8.9) 10500(83.3/8.5) :640 1:640 >1: /M (77.5/13.9) 6800(77.0/12.3) >1: /F (70.4/19.9) 16800(67.0/20.9) :640 >1: /M (78.8/13.3) 5100(75.2/11.1) (-) 1:320 >1: /F (67.9/18.8) 15800(71.0/22.0) :160 >1: PD, oral prednisolone; Adm., administration; WBC, white blood cell; CRP, C-reactive protein; MA, Mycoplasma antibody titer; M, male; F, female MA (1st) MA (2nd) MA (3rd) Day of improved chest radiograph after PD CRP concentration on admission was 6.3±3.9 mg/dl and increased to 8.1±7.0 mg/dl before prednisolone (3.4±0.6 days after admission). They also decreased to 4.7±4.4 mg/dl in 6.3±0.9 days after admission. (Fig. 2B, P<0.001). The mean white blood cell (WBC) count was 7.2± /μl and the differential was 71.4±8.6% neutrophils and 18.4±6.5% lymphocytes, respectively upon admission. After prednisolone, these values changed to 9.6±3.8x10 3 /μl, 69.9±8.1%, 19.7± 7.7% respectively. However, these differences were not statistically significant. There were no adverse events in any patients during corticosteroid treatment, and all patients were discharged without any complications. DISCUSSION M. pneumoniae infection is common in children. M. pneumoniae infection is usually a benign disease that resolves quickly with appropriate antibiotic such as macrolides.(16) Occasionally, progression to severe and potentially fatal pneumonia could occur despite appropriate antibiotic treatment.(5,16) These conditions are known as refractory MP.(15,17) The immunopathogenesis of MP is not still known perfectly. It has been proposed that excessive cellmediated immunity and cytokine responses against the pathogens play an important role in the pathogenesis of refractory M. pneumoniae infections.(5,13,18) Cytoadherence by M. pneumoniae in the respiratory tract is the initial event of infection. Clinical manifestations of respiratory tract disease occur as a result of cytodherence of the organism on the host's respiratory epithelium followed by the production of a variety of substances that induce local damage and stimulate release of inflammatory mediators by the host. Severity

5 경희의학제 32 권제 1 호 2017 A B Fig. 2. Apparent improvement of clinical and laboratory findings was observed in all children after oral prednisolone. (A) The graph of body temperatures of patients. Fever was subsided within 24 hours after prednisolone in all children. The administration of prednisolone was 3.7±0.6 (range, ) days from admission. These data were analyzed by repeated measures ANOVA (P<0.001). HD#1*=the admission day. HD, hospital day. (B) The graph of serum CRP concentrations measured serially. Serum CRP levels decreased in all children after prednisolone. These data were analyzed by repeated measures ANOVA (P<0.001). HD#1*=the admission day. Before prednisolone. After prednisolone. CRP, C-reactive protein; HD, hospital day. of disease appears to be related to the degree to which the host immune response reacts to the infection.(19) M. pneumoniae shows strong cytoadherence to the host respiratory epithelium. The cytoadherence is mediated by P1 adhesin and other additional proteins such as P30 or high molecular weight (HMW) proteins.(20-23) The cytoadherence of M. pneumoniae is important for the induction of cytokines.(24) The cytoadherence of M. pneumoniae is one of the key factors to initiate immune responses leading to MP.(25) Pneumonia by M. pneumoniae may come from local cellular damage by superoxide radicals and innate immune response, including the secretion of proinflammatory cytokines such as interleukin-1β.(13,19) Although cytokine production and lymphocyte activation may minimize disease through the enhancement of host defense mechanisms, these immune responses exacerbate disease through the development of immunologic hypersensitivity. The more excessive cell-mediated immune response and cytokine stimulation can lead to the more severe clinical illness and pulmonary injury.(19,26) In our study, all children were healthy prior to M. pneumoniae infection, and they had no underlying disease. The mean age of infected children was 8.1±7.0. The elevated CRP concentration (6.3±3.9 mg/dl upon admission and 8.1±7.0 mg/dl before administration of steroid) was associated with the acute systemic inflammatory reactions to M. pneumoniae infection. This reflected a well-developed immune system. The host-cellular immune response to M. pneumoniae played a central role in developing a severe pneumonia. Some reports show that fulminant M. pneumoniae infection is associated with an excessive immune response. Previously sensitized lymphocytes from an earlier infection are activated during a subsequent infection and release supranormal levels of mediators that cause local tissue damage.(18) The clinical signs and symptoms of MP were more severe in previously healthy young adults, while the clinical manifestations of a relatively immunocom

6 Ho Young Song, et al:oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children A B C D Fig. 3. Chest radiographs of patient 6. (A) Chest radiograph on admission showed lobar consolidation on right lower lobe. (B) Chest radiograph showed deteriorated findings of right lower lobe with pleural effusion at hospital day 4 before prednisolone. (C) Chest radiograph showed improving of lobar consolidation on right lower lobe with effusion after initiation of prednisolone at hospital day 8. (D) At hospital day 12, chest radiograph showed almost resolution of abnormal radiologic findings. promised host were not as severe.(5) Pathogenesis of severe M. pneumoniae infection is closely related to an excessive, activated cell-mediated immune response to M. pneumoniae infection. Therefore these hypotheses support immunomodulating effect of corticosteroid for severe M. pneumoniae infections. Steroids can exert immune regulatory and anti-inflammatory effects through several molecular mechanisms, such as inhibition of nuclear factor κb, and also influence natural lung immunity by regulating alveolar macrophages and neutrophils.(27,28) Some reports have shown that steroid in children with severe MP results in clinical improvement. After initiating steroid for children with refractory MP, fever subsided rapidly and accompanied by rapid improvement of radiological and laboratory abnormalities.(11,14,15) Thus corticosteroid treatment appeared to be temporally associated with clinical and radiographic improvement, and may be helpful for reducing morbidity in children with refractory MP. In our study, all children had prolonged high fever and pneumonic consolidation upon admission. Four of 12 patients progressed to the deterioration of respiratory distress symptoms with development of pleural effusion and need of oxygen supplement. The fever was refractory despite appropriate antibiotic treatment. The deteriorated clinical and radiological findings of refractory MP improved rapidly after oral prednisolone at a dose of 1mg/kg/day. In all patients defervescence was achieved within 24 hours and radiological findings was improved on 3.0±0.7 days after initiation of prednisolone. The level of CRP decreased from 8.1±7.0 mg/dl to 4.7±4.4 mg/dl after initiation of prednisolone. Macrolides resistance is mainly due to transition mutations at positions A2063 or A2064 in domain V of the 23S rrna gene, a binding site of macrolide antibiotics.(29) The A2063G transition is the most common mutation, followed by the A2064G transition. (25) Since macrolide resistance of MP was first reported in Japan in 1970,(30) the prevalence of macrolide-resistant M. pneumoniae pneumonia (MRMP) is especially high in East Asian countries, such as China, Japan, and Korea.(25,31,32) The M144V mutation of the L4 protein and mutation at position 2064 of domain V in the 23S rrna gene of M. pneumoniae was reported in 2010 and the appearance of macrolide-resistant strains has also increased in Korea.(33) In Korea, the macrolide resistance rate of M. pneumoniae was rapidly increased from 62.9% in 2011(32) to 87.2% in 2015.(34) This is equivalent to that in China or Japan according to recent reports

7 경희의학제 32 권제 1 호 2017 (35,36) The macrolide-resistant strains are known to cause severe and refractory MP.(25) Although we did not perform an antimicrobial susceptibility test in this study, the unresponsiveness to antibiotics in these patients was likely associated with macrolide resistance. Some investigators have reported that alternative antibiotics such as minocycline, doxycycline or fluoroquinolones for refractory MP showed good outcome. (37,38) But these antibiotics are relatively contraindicated to use in pediatrics because of their side effects like tooth discoloration of tetracyclines under age 8 years and cartilage toxicity of fluoroquinolones under age 18 years. The clinical effects of oral prednisolone and intravenous methylprednisolone on severe and refractory MP have been evaluated. A recent study showed that oral prednisolone of 1 mg/kg/day for more than 1 week for severe MP in children may be helpful to reduce morbidity.(11) And three-day methylprednisolone pulse could be applied to treatment of refractory MP and appeared to be efficacious and well-tolerated treatment.(15,39) Although the clinical effects of corticosteroid on severe and refractory MP have been observed as above, treatment guidelines for corticosteroid have not been established. In conclusion, we report that management of prednisolone in children with refractory MP showed good outcome without any side effects. This study suggests that severe pulmonary injury is related to excessive host immune responses to M. pneumoniae infection and corticosteroid can be used effectively for refractory MP in children. The effects of optimal dose and timing of corticosteroid treatment remain unclear for refractory MP. Therefore, the more studies are required to evaluate further mechanisms and the efficacy of corticosteroid for the treatment of refractory MP in childhood. ABSTRACT Oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children Ho Young Song, Soo Yeon Kang, Joon Hyuk Song Department of Pediatrics, Myongji Hospital, Seonam University College of Medicine, Goyang, Korea Purpose: Mycoplasma pneumoniae (M. pneumoniae) is one of the most common causes of communityacquired pneumonia in children. The progression of M. pneumoniae infection is self-limited and benign. Rarely, progression to severe pneumonia occurs despite appropriate antibiotic. The aim of this study was to investigate the effects of oral prednisolone for refractory M. pneumoniae pneumonia (MP) in children. Methods: M. pneumoniae infection was diagnosed serologically. Refractory MP was defined as follows: clinical symptoms and radiologic findings worsened despite appropriate antibiotic including macrolides. We retrospectively evaluated in 12 children with refractory MP. Results: We administered oral prednisolone (1 mg/kg/day) in addition to antibiotics. All patients responded well to oral prednisolone. Fever persisted in all 12 children until steroid administration. However, all patients who received prednisolone showed rapid defervescence within 24 hours and clinical symptoms improved without adverse events. The high C-reactive protein levels (8.1±7.0 mg/dl) decreased to 4.7±4.4 mg/dl and the abnormal radiologic findings improved within several days after initiating prednisolone. Conclusions: This study showed good outcomes of prednisolone in children with refractory MP. This could be an efficacious and well-tolerated treat

8 Ho Young Song, et al:oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children ment for refractory MP. Further studies may be needed to make the guideline of steroid treatment. Key Words: Children, Prednisolone, Macrolides, Mycoplasma pneumoniae, Pneumonia REFERENCES 1. Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human pathogen. Clin Microbiol Rev 2004;17: Atkinson TP, Balish MF, Waites KB. Epidemiology, clinical manifestations, pathogenesis and laboratory detection of Mycoplasma pneumoniae infections. FEMS Microbiol Rev 2008;32: Heiskanen-Kosma T, Korppi M, Jokinen C, Kurki S, Heiskanen L, Juvonen H, et al. Etiology of childhood pneumonia: serologic results of a prospective, population-based study. Pediatr Infect Dis J 1998;17: Sinaniotis CA, Sinaniotis AC. Community-acquired pneumonia in children. Curr Opin Pulmon Med 2005;11: Chan ED, Welsh CH. Fulminant Mycoplasma pneumoniae pneumonia. West J Med 1995;162: Radisic M, Torn A, Gutierrez P, Defranchi HA, Pardo P. Severe acute lung injury caused by Mycoplasma pneumoniae: potential role for steroid pulses in treatment. Clin Infect Dis 2000;31: Wang RS, Wang SY, Hsieh KS, Chiou YH, Huang IF, Cheng MF, et al. Necrotizing pneumonitis caused by Mycoplasma pneumoniae in pediatric patients. Pediatr Infect Dis J 2004;23: Takiguchi Y, Shikama N, Aotsuka N, Koseki H, Terano T, Hirai A. Fulminant Mycoplasma pneumoniae pneumonia. Intern Med 2001;40: Lee KY. Pediatric respiratory infections by Mycoplasma pneumoniae. Expert Rev Anti Infect Ther 2008;6: Lee SH, Noh SM, Lee KY, Lee HS, Hong JH, Lee MH, et al. Clinico-epidemiologic study of Mycoplasma pneumoniae pneumonia (1993 through 2003). Korean J Pediatr 2005;48: Lee KY, Lee HS, Hong JH, Lee MH, Lee JS, Burgner D, et al. Role of prednisolone treatment in severe Mycoplasma pneumoniae pneumonia in children. Pediatr Pulmonol 2006;41: Miyashita N, Obase Y, Ouchi K, Kawasaki K, Kawai Y, Kobashi Y, et al. Clinical features of severe Mycoplasma pneumoniae pneumonia in adults admitted to an intensive care unit. J Med Microbiol 2007;56: Shimizu T, Kida Y, Kuwano K. Cytoadherencedependent induction of inflammatory responses by Mycoplasma pneumoniae. Immunology 2011;133: Lu A, Wang L, Zhang X, Zhang M. Combined treatment for child refractory Mycoplasma pneumoniae pneumonia with ciprofloxacin and glucocorticoid. Pediatr Pulmonol 2011;46: Tamura A, Matsubara K, Tanaka T, Nigami H, Yura K, Fukaya T. Methylprednisolone pulse for refractory Mycoplasma pneumoniae pneumonia in children. J Infect 2008;57: Ferwerda A, Moll HA, de Groot R. Respiratory tract infections by Mycoplasma pneumoniae in children: a review of diagnostic and therapeutic measures. Eur J Pediatr 2001;160: Radisic M, Torn A, Gutierrez P, Defranchi HA, Pardo P. Severe acute lung injury caused by Mycoplasma pneumoniae: potential role for steroid pulses in treatment. Clin Infect Dis 2000;31: Noriega ER, Simberkoff MS, Gilroy FJ, Rahal JJ

9 경희의학제 32 권제 1 호 2017 Jr. Life-threatening Mycoplasma pneumoniae pneumonia. JAMA 1974;229: Waites KB, Balish MF, Atkinson TP. New insights into the pathogenesis and detection of Mycoplasma pneumoniae infections. Future Microbiol 2008;3: Krause DC, Balish MF. Structure, function, and assembly of the terminal organelle of Mycoplasma pneumoniae. FEMS MicrobiolLett 2001;198: Razin S, Herrmann R. Molecular Biology and Pathogenicity of Mycoplasmas. New York: Kluwer Academic/Plenum Publishers; p Miyata M. Centipede and inchworm models to explain Mycoplasma gliding. Trends Microbiol 2008;16: Lenz P. Cell Motility. New York: Springer Science; p Yang J, Hooper WC, Phillips DJ, Talkington DF. Regulation of proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae. Infect Immun 2002;70: Morozumi M, Takahashi T, Ubukata K. Macrolideresistant Mycoplasma pneumoniae: characteristics of isolates and clinical aspects of community-acquired pneumonia. J Infect Chemother 2010;16: Yang J, Hooper WC, Phillips DJ, Talkington DF. Cytokines in Mycoplasma pneumoniae infections. Cytokine Growth Factor Rev 2004;15: De Pascale G, Bello G, Antonelli M. Steroids in severe pneumonia: a literature review. Minerva Anestesiol 2011;77: Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids-new mechanisms for old drugs. N Engl J Med 2005;353: Lucier TS, Heitzman K, Liu SK, Hu PC. Transition mutations in the 23S rrna of erythromycinresistant isolates of Mycoplasma pneumoniae. Antimicrob Agents Chemother 1995;39: Niitu Y, Hasegawa S, Suetake T, Kubota H, Komatsu S, Horikawa M. Resistance of Mycoplasma pneumoniae to erythromycin and other antibiotics. J Pediatr 1970;76: Zhao F, Lv M, Tao X, Huang H, Zhang B, Zhang Z, et al. Antibiotic sensitivity of 40 Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant isolates from Beijing, China. Antimicrob Agents Chemother 2012;56: Hong KB, Choi EH, Lee HJ, Lee SY, Cho EY, Choi JH, et al. Macrolide resistance of Mycoplasma pneumoniae, South Korea, Emerg Infect Dis 2013;19: Oh CE, Choi EH, Lee HJ. Detection of genetic mutations associated with macrolide resistance of Mycoplasma pneumoniae. Korean J Pediatr 2010; 53: Kim JH, Kim JY, Yoo CH, Seo WH, Yoo Y, Song DJ, et al. Macrolide Resistance and its impacts on Mycoplasma pneumoniae pneumonia in children: comparison of two recent epidemics in Korea. Allergy Asthma Immunol Res. 2017;9: Xin D, Mi Z, Han X, Qin L, Li J, Wei T, et al. Molecular mechanisms of macrolide resistance in clinical isolates of Mycoplasma pneumoniae from China. Antimicrob Agents Chemother 2009;53: Kawai Y, Miyashita N, Kubo M, Akaike H, Kato A, Nishizawa Y, et al. Nationwide surveillance of macrolide-resistant Mycoplasma pneumoniae infection in pediatric patients. Antimicrob Agents Chemother 2013;57: Okada T, Morozumi M, Tajima T, Hasegawa M, Sakata H, Ohnari S, et al. Rapid effectiveness of minocycline or doxycycline against macrolideresistant Mycoplasma pneumoniae infection in a 2011 outbreak among Japanese children. Clin

10 Ho Young Song, et al:oral Prednisolone Therapy for Refractory Mycoplasma pneumoniae Pneumonia in Children Infect Dis 2012;55: Kawai Y, Miyashita N, Kubo M, Akaike H, Kato A, Nishizawa Y, et al. Therapeutic efficacy of macrolides, minocycline, and tosufloxacin against macrolide-resistant Mycoplasma pneumoniae pneumonia in pediatric patients. Antimicrob Agents Chemother 2013;57: You SY, Jwa HJ, Yang EA, Kil HR, Lee JH. Effects of methylprednisolone pulse on refractory Mycoplasma pneumoniae pneumonia in children Allergy Asthma Immunol Res 2014; 6: