Okazaki, a Japanese scholar, first discovered MRMP in 2000. The antibiotic resistance was found to be related to a point mutation in the 23S rRNA gene (Okazaki N, 2001). Since then, investigation of MRMP has intensified. Zhao Fei et al. (Zhao F, 2013, Zhao F, 2019, Zhao F, 2019) monitored MRMP in six Chinese cities from 2008 to 2018 and found the macrolide-resistance rate to be as high as 65%–98%. The MRMP rate in Japan was 81.6% in 2008 and 43.6% in 2015. Examples of resistance rates are, 80% in Korea in 2015, 13.2% in the United States in 2013, 8.3% in France in 2011, and 3.1% (Takaaki Tanaka,2017, Lee, E, 2017, Zheng X, 2015, Pereyre S, 2013, Dumke R, 2015) in Germany in 2011-2012. Overall, the macrolide-resistance rate in Asian countries is much higher than that in European and American countries. Analysis of the clinical data for MPP children hospitalized in the Second Pediatric Respiratory Ward of Shengjing Hospital, Affiliated to China Medical University from November 2016 to February 2017 found the resistance rate of MP to be as high as 95.9%. Only one case had the A2064G mutation, with the remainder the classic mutation site, A2063G. These data demonstrate the prevalence of MRMP in hospitalized Chinese children.
For the 47 hospitalized children with MRMP pneumonia, the average fever duration was more than 9 days, which is longer than that of non-macrolide-resistant MPP. Fever was approximately 8.0 ± 6.0 days (n = 12) (Eun Lee，Korean J Pediatr 2017) and 6.0 ± 3.5 days (n = 96) (Kim YJ，J Korean Med Sci 2017) for non-macrolide-resistant MPP. These observations demonstrate MRMP pneumonia to have longer fever duration, which is consistent with this study. The incidence of leukocytosis was approximately 30%, which is consistent with previous reports (Stevens, D. 1978, Medjo B, 2014). Those reports found approximately 27.6% of cases to involve bilateral lungs, which was higher than the 20% of cases in a previous report (Ferwerda, A, 2001). Extra-pulmonary complications were as high as 38.3%, which was higher than the 17% reported previously (Yang TI, 2019). Herein, CRP and NLR during the acute phase were significantly higher than those in the recovery stage. CRP is an acute phase protein secreted by the liver in response to a variety of inflammatory cytokines. NLR can accurately predict the severity of and prognosis for CAP, as well as assist in risk determination for severe pneumonia patients with complications (Che-Morales JL, 2019). Increases in CRP and NLR reflect aggravation of the inflammatory response, suggesting a more serious disease. Approximately half of the cases within the macrolide-resistant group had severe pneumonia. For more than half of the cases, LDH and D-dimer levels were higher than the normal value, suggesting that MRMP likely involves not just the lungs but also other organs. Myocardial, liver, pancreas, and other injuries result in elevated LDH. Hypoxia and endotoxin stimulate inflammatory cells to release a variety of inflammatory mediators that result in vascular endothelial cell damage and coagulation events that significantly increase plasma D-dimer (Yuan SJ, 2017). D-dimer levels can be used as one of the critical markers for monitoring inflammation and severe infection (Wu HB, 2017). Chen Yu (Chen Yu, 2018) found that LDH was higher in patients with MRMP compared with patients with non-drug resistant MPP. Ryou Kawamata concluded that the higher the LDH, the more severe the MPP (Kawamata R, 2015). These results suggest that LDH and D-dimer levels are high in more than half of the cases with MRMP pneumonia cases, indicating that the pneumonia caused by MRMP is more serious clinically.
The duration of fever induced by MRMP is longer than that induced by non- macrolide-resistant MP (Suzuki S, 2006, Zhou YL, 2014, Yao HS, 2016, Yang TI, 2019). Further, fever duration is longer after administration of macrolides, hospitalization time is longer, and extra-pulmonary complications are more serious. MRMP infections are more common in immune suppressed individuals and in cancer patients. The predominant clinical difference between MRMP and non- macrolide-resistant MP is the duration of fever, with no significant difference in lung imaging, laboratory measures, or extra-pulmonary complications (Deng H, 2018, Wu HM, 2013, KB Waites, 2019). According to Jae Hong Choi, MRMP involves the lobes of the lungs without other clinical or laboratory signs of infection (Choi JH, 2019). AE Yoon et al. (Yoon IA, 2017) showed that the duration of fever was related to the severity of lung imaging, but not to drug resistance. These inconsistent reports may be due to differences in sample size or treatment methods.
In this study, the macrolide-resistance rate of MPP inpatients was as high as 95.9%, which was significantly higher than the concomitant rate of 65.4% for outpatients (Zhao F, 2019). We infer that MRMP infection is more likely to cause refractory/severe MPP that results in a higher treatment failure rate for outpatients, such that the macrolide-resistance rate for hospitalized patients is significantly increased. The results of this study identify the total fever duration of drug-resistant MPP patients is 9 days, which is significantly longer than the 5–6 days for patients infected with non-macrolide-resistant MP (Medjo B, 2014). These patients were treated with glucocorticoid (n = 13) and immunoglobulin (n = 5) to shorten the course of fever. Approximately half of macrolide-resistant MPP develops into severe MP. The rate of extra-pulmonary complications is high, with lungs seriously affected as judged by imaging. Therefore, MRMP is more likely to develop into a severe case. We also found severe MPP cases in patients with non-macrolide-resistant MP. Severe MPP is not only related to the macrolide-resistance of the pathogen but also to bacterial load, bacterial virulence, and the immune status of the patient. Future investigations need to consider the influence of these other factors on severe MPP outcomes.
Limitations of this study: This study summarizes the drug resistance and case characteristics of hospitalized patients, but does not include analysis of outpatients with mycoplasma pneumonia. This short term study was performed at a single center and only assessed drug resistant MPP in the Pediatric Department of Shengjing Hospital in the winter of 2016. Further, there were few non-drug resistant cases in this study and comparisons between groups is therefore limited. The results of this study need to be confirmed with a larger sample size and a more in-depth study.
Conclusions: The majority of MPP patients were found to be infected with macrolide-resistant MP (95.9%). The children with MRMP pneumonia were mainly school-aged with a mean age of 6.9 years. Average total fever duration was more than 9 days. Leukocyte count during the acute phase was slightly increased in approximately 30% of cases. CRP and NLR during the acute phase were significantly higher than during the recovery period. LDH and D-dimer levels were increased in more than half of the patients with MRMP. The overall incidence of extra-pulmonary complications was 38.2%. Therefore, MRMP patients exhibited longer fever duration, higher inflammatory index, higher levels of LDH and D-dimer, increased incidence of extra-pulmonary complications, and were likely to develop severe pneumonia. MP resistance requires strict attention, with appropriate administration of antibiotics, and early identification of severe cases. Early glucocorticoid intervention can prevent and/or reduce complications and improve prognosis.