Refractory Mycoplasma pneumoniae Pneumonia in Children: Comparison
Please note this is a comparison between Version 3 by Conner Chen and Version 2 by Conner Chen.

Mycoplasma pneumoniae (M. pneumoniae) is one of the most important pathogens for community-acquired pneumonia (CAP) in children. M. pneumoniae pneumonia (MPP) is typically mild and even presents as a self-limited disease. Refractory Mycoplasma pneumoniae pneumonia (RMPP) is a severe state of M. pneumoniae infection. The pathogenesis of RMPP remains unknown, but the excessive host immune responses as well as macrolide resistance of M. pneumoniae might play important roles in the development of RMPP. To improve the prognosis of RMPP, it is mandatory to recognize RMPP in early stage, and detection of macrolide-resistant MP, clinical unresponsiveness to macrolides and elevated proinflammatory cytokines might be the clues. Timely and effective anti-mycoplasmal therapy and immunomodulating therapy are the main strategies for RMPP.

  • Mycoplasma pneumoniae
  • pneumonia
  • prediction

1. Pathogenesis

1.1. Pathogeny and Host Defense

M. pneumoniae can be transmitted through air droplets via coughing, sneezing and close contact. Vertical transmission has occasionally been stated in recent years [1][2]. The incubation period varies from 1 to 3 weeks, and the survival of M. pneumoniae in aerosols is thought to be related to meteorological conditions, especially humidity and temperature, but controversy still remains [3][4][5]. Once infected with the host, M. pneumoniae mainly adheres to ciliary cells of the mucosal epithelium, and close contact and material exchange between the bacterial membrane and the host cell provide an important material basis for its growth and proliferation. Bacterial cellular components such as glycolipids and capsular polysaccharides [6], virulence factors such as community-acquired respiratory distress syndrome (CARDS) toxin [7] and hydrogen sulfide, alanine, and pyruvate producing enzyme (HapE) [8], toxic metabolites such as hydrogen peroxide [9] and H2S [10], and nuclease [11], among others, are the main mechanisms for tissue damage. They also inhibit host clearance and promote immune escape [12].
CARDS toxin was first demonstrated in 2005 [13]. With a high sequence homology to the pertussis toxin S1 subunit, which performs ADP ribosylation and causes vacuolation, choristosis and spallation of mucosal cells. This toxin brings out the typical clinical symptoms of M. pneumoniae infection, for instance, dry cough or even spasmodic cough [14][15][16]. By other means, expressed CARDS toxin can also enhance the induction of the proinflammatory cytokines and stimulate lymphocyte activation in a dose- and activity-dependent manner [7][17][18][19] and is also capable of changing asthma-associated immunological parameters or inducing an allergic-type inflammation [12][20][21], potentially inducing or worsening asthma [22][23].
Hemolytic activity was also one of the identified pathogenicity determinants of M. pneumoniae where both hydrogen peroxide (H2O2) [24] and hydrogen sulfide (H2S) [25] contribute. Hydrogen peroxide is a metabolite of the process of glycerol utilization by Mycoplasma pneumoniae, and glycerol-3-phosphate oxidase (GlpO) is the key enzyme [26]. H2O2 is responsible for the oxidation of heme molecules and is also associated with oxidative stress and cell death [27][28]. H2S, as a by-product of the reaction to desulfurization of the cys by the enzyme HapE, can cause the modification of the heme and is responsible for the lysis of erythrocytes. By other means, H2S can also induce phagocytes to secrete pro-inflammatory factors, aggravating inflammatory reactions and leading to tissue damage [8].
Although the mechanism of RMPP is largely unknown, it has long been believed that the excessive host immune response plays a pivotal role in the disease progression [29][30]. Three mainstream hypotheses to explain the hyperimmune response for MP are summarized below [31]: (i) repeated or recurrent MP infections; (ii) loss of capacity to clear M. pneumoniae from the lungs in primary infection such as macrolide-resistance, which will be discussed later, resulting in a persistent MP infection; and (iii) an overactive innate immune response, such as macrophage activation through heterodimerization of Toll-like receptors [32][33]. The overall result of the above factors is an excessive and overactive immune response, which will be explained in detail in later parts.

1.2. Macrolide-Resistant M. pneumoniae (MRMP)

The lack of a cell wall renders M. pneumoniae intrinsically resistant to some antimicrobials, such as beta-lactams, glycopeptides and fosfomycin antimicrobials, which lays a trap for the identification of this atypical pathogen and also results in difficulties in treating pediatric M. pneumoniae infection. Historically, the main efficient drugs against M. pneumoniae include agents targeting the bacterial ribosome for inhibiting protein synthesis, such as macrolides, and others inhibiting DNA replication, such as fluoroquinolones [34]. Macrolides are the first and nearly the only choice for pediatric patients due to toxicity and side effects of other drugs for young children. Unsurprisingly, under the long-term pressure of antibiotic selection, macrolide-resistance emerged.
Thus far, the vast majority of reports correlating with macrolide-resistant infections were from children, due to a high incidence of M. pneumoniae infections and also the wide use of macrolides in pediatric age groups, but macrolide-resistance can also occur in adults [32][33]. Up to now, no difference has been found in disease manifestations between pediatric patients and adults infected by MRMP. Resistance of M. pneumoniae to macrolides was first described in 2001 in Japan [35] and quickly swept across East Asia, wherein the resistance rates were found to be higher than 90% in some countries during the epidemic years [36][37]. Since that time, a progressive increase in incidence rates of MRMP strains was reported worldwide, although with a significant difference among countries [31][38][39]. It is also a common and disturbing problem in China, both in adults and in children [40][41].
Temporal studies suggest that the emergence of significant resistance to macrolides by M. pneumoniae takes precedence over the peak of M. pneumonia episodes [42]. Therefore, the activation of resistant strains may be one of the important causes of the MP outbreak. Additionally, some studies have illustrated that macrolide-resistance of M. pneumoniae may play an essential role in RMPP development and progression, given the limited sensitivity of MRMP to macrolides may result in higher bacterial load and excessive immune response [43][44][45][46]. The opposite point of view also exists, demonstrating that macrolide resistance may not be associated with the development of RMPP [47][48]. Therefore, the association between RMPP and increased macrolide-resistance requires further investigation.

1.3. Co-Infection

Co-infection in CAP is clinically common. Likewise, the dual existence of M. pneumoniae with other organisms is not rare in patients with respiratory syndromes, especially in children [49]. The rates of viral (human bocavirus, rhinovirus, respiratory syncytial virus, among others, respectively) or bacterial (Streptococcus pneumoniae, Hemophilus influenzae, Staphylococcus, among others, respectively) coinfection with M. pneumoniae in children were reported ranging from 8 to 60% [50][51][52][53][54]. Some reports revealed simultaneous laboratory-proven infections with both bacteria and viruses in addition to M. pneumoniae [50][53].
Although the contribution of these coexistent agents remains unclear, since healthy individuals may carry these opportunistic pathogens as well [55][56][57], coinfection with viruses and bacteria causes more severe diseases in pediatric patients, according to previous research [58][59]. In children with RMPP, Zhang et al., demonstrated that coinfection with viruses and bacteria resulted in more severe processes [53]. Zhou recently reported that adenovirus coinfection with MRMP was shown to be more prevalent in RMPP patients [45]. However, Chiu et al., found no significant difference in clinical features, complications, or outcomes between the patients infected with M. pneumoniae alone or with virus coinfection, despite the latter having prolonged fever and hospital stay [52].

2. Prediction and Early Recognition

Almost all previous reports indicated that delayed appropriate treatment was associated with the development of more severe and/or extended illnesses [60]. Thus, clinical awareness, prompt detection of M. pneumoniae and its macrolide resistance and early recognition of RMPP enable effective therapy to begin sooner, potentially improving clinical outcomes [48].

2.1. Clinical Awareness and Confirmation of Macrolide Resistance

The gold standard for diagnosing MRMP is culture and drug sensitivity. However, culture is much too time-consuming, thus the identification of MRMP strains is usually made with molecular biology methods nowadays. M. pneumoniae carry a total of 816,394 bp base pairs with 687 genes on the circulating double strands of DNA function to maintain their viability and reproduction [61]. Molecular epidemiology investigations of M. pneumoniae and macrolide susceptibility have been conducted in a wide range of geographical and temporal contexts [38][62][63][64][65]. Most investigations showed that MRMP usually had specific point mutations in the peptidyl transferase loop of 23S rRNA, as well as insertions or deletions in ribosomal proteins L4 and L22 [60]. Genotyping analysis from Japan suggested that epidemics arise due to variants of P1 sequences [12] and was further verified and refined in subsequent studies [13]. In China, variants in domain V of the 23S rRNA gene are also the major cause of MRMP, with most strains harboring an A2063G mutation, in which P1 type 1 and type 2 lineages co-circulate [40][47][66][67][68]. At present, commercial PCR kits for the rapid detection of both MP gene or antigen and drug resistance mutations simultaneously are available on the market [69][70][71], and makes it possible to rapidly diagnose MRMP.
Some clinical phenomena may also serve as early indicators of macrolide resistance MPP (MRMPP), especially macrolide unresponsiveness. Patients with MRMPP usually have an extended period of fever in spite of macrolide therapy. They are also more susceptible to more severe phenotype, and more complications [72][73]. For the early recognition and confirmation of MRMPP, pediatricians should pay more attention to the initial response to macrolide. If a child with confirmed or suspected MPP does not respond to macrolide therapy in the first three days (macrolide unresponsive MPP), MRMPP should be suspected and further management should be adopted, especially in countries and regions with high MRMP rates [74][75]. Coinfection with bacteria or virus and complications should also be excluded.

2.2. Early Identification of RMPP Cued by Cytokine Profiles

The host immune response is a “double-edged sword”. On the one hand, an adequate immune response including cytokine secretion and lymphocyte activation is essential for the elimination of M. pneumoniae, helping alleviate disease [76]. Children with hypogammaglobulinemia appeared to be more vulnerable to invasive and prolonged bacterial infections [77]. On the other hand, an improper immune response to M. pneumoniae generates excessive inflammation, and can exacerbate the disease clinically, even leading to the development of RMPP. Evidence revealed pulmonary lesions were generally mild in immunodeficient children [78]. This theory may also partially explain the selectivity of RMPP in terms of children’s ages. Children over the age of 5 years old have a relatively better developed immune system than younger children; coincidentally, the former group happens to be more susceptible to disease and exhibits more severe phenotypes of disease [43].
Although the direct correlation between the host immune response and RMPP is inconclusive, a growing body of evidence points to it. The course and outcome of mycoplasmal infection seem to be highly dependent on host responses. The stronger the immunological response and activation of cytokine, the more severe the clinical disease and organ damage. Herein, wa que wonderstion is whether cytokine profiling may predict the severity and subtype of illness in advance, allowing for reasonable and individualized therapy adjustments to be made as early as possible.
Numerous literatures have reported the correlation between cytokines, chemokines or other inflammatory biomarkers and RMPP. Lactate dehydrogenase (LDH), for example, has long been regarded as a reliable evaluation index of RMPP. The cut-off value of LDH for considering RMPP ranged from 379 to 480 IU/L among adolescents and adults [75][79][80][81][82]. OurSome previous study suggested LDH ≥ 417 IU/L to be significant predictors in regard to RMPP [79]. Some other inflammatory biomarkers, such as CRP ≥ 16.5 mg/L [79], ESR ≥ 32.5 IU/L [80] and 35 α-hydroxybutyrate dehydrogenase (HBDH) ≥ 259.5 IU/L [80] also have indicative significance for RMPP in children.
To combat MP infection, neutrophils, CD8+ T cells, as well as Th1 biased CD4+ T cells, are recruited followed by enhanced humoral immunity. In recent years, more attention has been paid to proinflammatory cytokines. In sourme previous study, the percentage of neutrophils and CD8+ T cells, as well as the levels of IL-6, IL-10 and IFN-γ, were shown to be beneficial for distinguishing patients with RMPP from those with general MPP [79][83], serum chemokines such as CXCL10/IP-10 may also be potential biomarkers [84]. This phenomenon has been confirmed by other studies in recent years. Therefore, wpeople should be alert to the possibility of RMPP when cytokines such as IFN-γ [43][64][83], TNF-α [43], IL-6 [64][79], IL-10 [83], IL-18 [85][86][87], among others, are obviously elevated. Further confirmation of these candidates is needed.


  1. Srinivasjois, R.M.; Kohan, R.; Keil, A.D.; Smith, N.M. Congenital Mycoplasma pneumoniae pneumonia in a neonate. Pediatr. Infect. Dis. J. 2008, 27, 474–475.
  2. Huber, B.M.; Meyer Sauteur, P.M.; Unger, W.W.J.; Hasters, P.; Eugster, M.R.; Brandt, S.; Bloemberg, G.V.; Natalucci, G.; Berger, C. Vertical Transmission of Mycoplasma pneumoniae Infection. Neonatology 2018, 114, 332–336.
  3. Xu, Y.C.; Zhu, L.J.; Xu, D.; Tao, X.F.; Li, S.X.; Tang, L.F.; Chen, Z.M. Epidemiological characteristics and meteorological factors of childhood Mycoplasma pneumoniae pneumonia in Hangzhou. World J. Pediatr. 2011, 7, 240–244.
  4. Wright, D.N.; Bailey, G.D.; Goldberg, L.J. Effect of temperature on survival of airborne Mycoplasma pneumoniae. J. Bacteriol. 1969, 99, 491–495.
  5. Onozuka, D.; Hashizume, M.; Hagihara, A. Impact of weather factors on Mycoplasma pneumoniae pneumonia. Thorax 2009, 64, 507–511.
  6. Jiang, Z.; Li, S.; Zhu, C.; Zhou, R.; Leung, P.H.M. Mycoplasma pneumoniae Infections: Pathogenesis and Vaccine Development. Pathogens 2021, 10, 119.
  7. Bose, S.; Segovia, J.A.; Somarajan, S.R.; Chang, T.H.; Kannan, T.R.; Baseman, J.B. ADP-ribosylation of NLRP3 by Mycoplasma pneumoniae CARDS toxin regulates inflammasome activity. mBio 2014, 5, e02186-14.
  8. Bazhanov, N.; Escaffre, O.; Freiberg, A.N.; Garofalo, R.P.; Casola, A. Broad-Range Antiviral Activity of Hydrogen Sulfide Against Highly Pathogenic RNA Viruses. Sci. Rep. 2017, 7, 41029.
  9. Yamamoto, T.; Kida, Y.; Kuwano, K. Mycoplasma pneumoniae protects infected epithelial cells from hydrogen peroxide-induced cell detachment. Cell. Microbiol. 2019, 21, e13015.
  10. Li, S.; Xue, G.; Zhao, H.; Feng, Y.; Yan, C.; Cui, J.; Sun, H. The Mycoplasma pneumoniae HapE alters the cytokine profile and growth of human bronchial epithelial cells. Biosci. Rep. 2019, 39, BSR20182201.
  11. Yamamoto, T.; Kida, Y.; Sakamoto, Y.; Kuwano, K. Mpn491, a secreted nuclease of Mycoplasma pneumoniae, plays a critical role in evading killing by neutrophil extracellular traps. Cell. Microbiol. 2017, 19, e12666.
  12. Maselli, D.J.; Medina, J.L.; Brooks, E.G.; Coalson, J.J.; Kannan, T.R.; Winter, V.T.; Principe, M.; Cagle, M.P.; Baseman, J.B.; Dube, P.H.; et al. The Immunopathologic Effects of Mycoplasma pneumoniae and Community-acquired Respiratory Distress Syndrome Toxin. A Primate Model. Am. J. Respir. Cell Mol. Biol. 2018, 58, 253–260.
  13. Kannan, T.R.; Provenzano, D.; Wright, J.R.; Baseman, J.B. Identification and characterization of human surfactant protein A binding protein of Mycoplasma pneumoniae. Infect. Immun. 2005, 73, 2828–2834.
  14. Waites, K.B. What’s new in diagnostic testing and treatment approaches for Mycoplasma pneumoniae infections in children? Adv. Exp. Med. Biol. 2011, 719, 47–57.
  15. Waites, K.B.; Balish, M.F.; Atkinson, T.P. New insights into the pathogenesis and detection of Mycoplasma pneumoniae infections. Future Microbiol. 2008, 3, 635–648.
  16. Kannan, T.R.; Baseman, J.B. ADP-ribosylating and vacuolating cytotoxin of Mycoplasma pneumoniae represents unique virulence determinant among bacterial pathogens. Proc. Natl. Acad. Sci. USA 2006, 103, 6724–6729.
  17. Hardy, R.D.; Coalson, J.J.; Peters, J.; Chaparro, A.; Techasaensiri, C.; Cantwell, A.M.; Kannan, T.R.; Baseman, J.B.; Dube, P.H. Analysis of pulmonary inflammation and function in the mouse and baboon after exposure to Mycoplasma pneumoniae CARDS toxin. PLoS ONE 2009, 4, e7562.
  18. Saber, S.; Ghanim, A.M.H.; El-Ahwany, E.; El-Kader, E.M.A. Novel complementary antitumour effects of celastrol and metformin by targeting IkappaBkappaB, apoptosis and NLRP3 inflammasome activation in diethylnitrosamine-induced murine hepatocarcinogenesis. Cancer Chemother. Pharm. 2020, 85, 331–343.
  19. Yin, H.; Guo, Q.; Li, X.; Tang, T.; Li, C.; Wang, H.; Sun, Y.; Feng, Q.; Ma, C.; Gao, C.; et al. Curcumin Suppresses IL-1beta Secretion and Prevents Inflammation through Inhibition of the NLRP3 Inflammasome. J. Immunol. 2018, 200, 2835–2846.
  20. Medina, J.L.; Coalson, J.J.; Brooks, E.G.; Winter, V.T.; Chaparro, A.; Principe, M.F.; Kannan, T.R.; Baseman, J.B.; Dube, P.H. Mycoplasma pneumoniae CARDS toxin induces pulmonary eosinophilic and lymphocytic inflammation. Am. J. Respir. Cell Mol. Biol. 2012, 46, 815–822.
  21. Tang, L.F.; Shi, Y.C.; Xu, Y.C.; Wang, C.F.; Yu, Z.S.; Chen, Z.M. The change of asthma-associated immunological parameters in children with Mycoplasma pneumoniae infection. J. Asthma 2009, 46, 265–269.
  22. Wood, P.R.; Hill, V.L.; Burks, M.L.; Peters, J.I.; Singh, H.; Kannan, T.R.; Vale, S.; Cagle, M.P.; Principe, M.F.; Baseman, J.B.; et al. Mycoplasma pneumoniae in children with acute and refractory asthma. Ann. Allergy Asthma Immunol. 2013, 110, 328–334.e1.
  23. Yano, T.; Ichikawa, Y.; Komatu, S.; Arai, S.; Oizumi, K. Association of Mycoplasma pneumoniae antigen with initial onset of bronchial asthma. Am. J. Respir. Crit. Care Med. 1994, 149, 1348–1353.
  24. Somerson, N.L.; Walls, B.E.; Chanock, R.M. Hemolysin of Mycoplasma pneumoniae: Tentative identification as a peroxide. Science 1965, 150, 226–228.
  25. Grosshennig, S.; Ischebeck, T.; Gibhardt, J.; Busse, J.; Feussner, I.; Stulke, J. Hydrogen sulfide is a novel potential virulence factor of Mycoplasma pneumoniae: Characterization of the unusual cysteine desulfurase/desulfhydrase HapE. Mol. Microbiol. 2016, 100, 42–54.
  26. Hames, C.; Halbedel, S.; Hoppert, M.; Frey, J.; Stulke, J. Glycerol metabolism is important for cytotoxicity of Mycoplasma pneumoniae. J. Bacteriol. 2009, 191, 747–753.
  27. Blotz, C.; Stulke, J. Glycerol metabolism and its implication in virulence in Mycoplasma. FEMS Microbiol. Rev. 2017, 41, 640–652.
  28. Hobbins, J.C.; Romero, R.; Grannum, P.; Berkowitz, R.L.; Cullen, M.; Mahoney, M. Antenatal diagnosis of renal anomalies with ultrasound. I. Obstructive uropathy. Am. J. Obs. Gynecol. 1984, 148, 868–877.
  29. Moynihan, K.M.; Barlow, A.; Nourse, C.; Heney, C.; Schlebusch, S.; Schlapbach, L.J. Severe Mycoplasma pneumoniae Infection in Children Admitted to Pediatric Intensive Care. Pediatr. Infect. Dis. J. 2018, 37, e336–e338.
  30. Zhang, B.; Chen, Z.M. Changes in clinical manifestations of Mycoplasma pneumoniae pneumonia in children older than 3 years during 2000–2006 in Hangzhou. Zhonghua Er Ke Za Zhi 2010, 48, 531–534.
  31. Pereyre, S.; Goret, J.; Bebear, C. Mycoplasma pneumoniae: Current Knowledge on Macrolide Resistance and Treatment. Front. Microbiol. 2016, 7, 974.
  32. Miyashita, N.; Oka, M.; Atypical Pathogen Study Group; Kawai, Y.; Yamaguchi, T.; Ouchi, K. Macrolide-resistant Mycoplasma pneumoniae in adults with community-acquired pneumonia. Int. J. Antimicrob. Agents 2010, 36, 384–385.
  33. Miyashita, N.; Kawai, Y.; Akaike, H.; Ouchi, K.; Hayashi, T.; Kurihara, T.; Okimoto, N.; Atypical Pathogen Study Group. Macrolide-resistant Mycoplasma pneumoniae in adolescents with community-acquired pneumonia. BMC Infect. Dis. 2012, 12, 126.
  34. Tamura, A.; Matsubara, K.; Tanaka, T.; Nigami, H.; Yura, K.; Fukaya, T. Methylprednisolone pulse therapy for refractory Mycoplasma pneumoniae pneumonia in children. J. Infect. 2008, 57, 223–228.
  35. Okazaki, N.; Narita, M.; Yamada, S.; Izumikawa, K.; Umetsu, M.; Kenri, T.; Sasaki, Y.; Arakawa, Y.; Sasaki, T. Characteristics of macrolide-resistant Mycoplasma pneumoniae strains isolated from patients and induced with erythromycin in vitro. Microbiol. Immunol. 2001, 45, 617–620.
  36. Lee, J.K.; Lee, J.H.; Lee, H.; Ahn, Y.M.; Eun, B.W.; Cho, E.Y.; Cho, H.J.; Yun, K.W.; Lee, H.J.; Choi, E.H. Clonal Expansion of Macrolide-Resistant Sequence Type 3 Mycoplasma pneumoniae, South Korea. Emerg. Infect. Dis. 2018, 24, 1465–1471.
  37. Zhao, F.; Li, J.; Liu, J.; Guan, X.; Gong, J.; Liu, L.; He, L.; Meng, F.; Zhang, J. Antimicrobial susceptibility and molecular characteristics of Mycoplasma pneumoniae isolates across different regions of China. Antimicrob. Resist. Infect. Control 2019, 8, 143.
  38. Esposito, S.; Argentiero, A.; Gramegna, A.; Principi, N. Mycoplasma pneumoniae: A pathogen with unsolved therapeutic problems. Expert Opin. Pharm. 2021, 22, 1193–1202.
  39. Loconsole, D.; De Robertis, A.L.; Sallustio, A.; Centrone, F.; Morcavallo, C.; Campanella, S.; Accogli, M.; Chironna, M. Update on the Epidemiology of Macrolide-Resistant Mycoplasma pneumoniae in Europe: A Systematic Review. Infect. Dis. Rep. 2021, 13, 811–820.
  40. Zhou, Z.; Li, X.; Chen, X.; Luo, F.; Pan, C.; Zheng, X.; Tan, F. Macrolide-resistant Mycoplasma pneumoniae in adults in Zhejiang, China. Antimicrob. Agents Chemother. 2015, 59, 1048–1051.
  41. Cao, B.; Zhao, C.J.; Yin, Y.D.; Zhao, F.; Song, S.F.; Bai, L.; Zhang, J.Z.; Liu, Y.M.; Zhang, Y.Y.; Wang, H.; et al. High prevalence of macrolide resistance in Mycoplasma pneumoniae isolates from adult and adolescent patients with respiratory tract infection in China. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2010, 51, 189–194.
  42. Akashi, Y.; Hayashi, D.; Suzuki, H.; Shiigai, M.; Kanemoto, K.; Notake, S.; Ishiodori, T.; Ishikawa, H.; Imai, H. Clinical features and seasonal variations in the prevalence of macrolide-resistant Mycoplasma pneumoniae. J. Gen. Fam. Med. 2018, 19, 191–197.
  43. Wang, M.; Wang, Y.; Yan, Y.; Zhu, C.; Huang, L.; Shao, X.; Xu, J.; Zhu, H.; Sun, X.; Ji, W.; et al. Clinical and laboratory profiles of refractory Mycoplasma pneumoniae pneumonia in children. Int. J. Infect. Dis. 2014, 29, 18–23.
  44. Song, Q.; Xu, B.P.; Shen, K.L. Effects of bacterial and viral co-infections of Mycoplasma pneumoniae pneumonia in children: Analysis report from Beijing Children’s Hospital between 2010 and 2014. Int. J. Clin. Exp. Med. 2015, 8, 15666–15674.
  45. Zhou, Y.; Wang, J.; Chen, W.; Shen, N.; Tao, Y.; Zhao, R.; Luo, L.; Li, B.; Cao, Q. Impact of viral coinfection and macrolide-resistant mycoplasma infection in children with refractory Mycoplasma pneumoniae pneumonia. BMC Infect. Dis. 2020, 20, 633.
  46. Morozumi, M.; Takahashi, T.; Ubukata, K. Macrolide-resistant Mycoplasma pneumoniae: Characteristics of isolates and clinical aspects of community-acquired pneumonia. J. Infect. Chemother. 2010, 16, 78–86.
  47. Zhou, Y.; Zhang, Y.; Sheng, Y.; Zhang, L.; Shen, Z.; Chen, Z. More complications occur in macrolide-resistant than in macrolide-sensitive Mycoplasma pneumoniae pneumonia. Antimicrob. Agents Chemother. 2014, 58, 1034–1038.
  48. Yang, T.I.; Chang, T.H.; Lu, C.Y.; Chen, J.M.; Lee, P.I.; Huang, L.M.; Chang, L.Y. Mycoplasma pneumoniae in pediatric patients: Do macrolide-resistance and/or delayed treatment matter? J. Microbiol. Immunol. Infect. 2019, 52, 329–335.
  49. Cimolai, N.; Wensley, D.; Seear, M.; Thomas, E.T. Mycoplasma pneumoniae as a cofactor in severe respiratory infections. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 1995, 21, 1182–1185.
  50. Diaz, M.H.; Cross, K.E.; Benitez, A.J.; Hicks, L.A.; Kutty, P.; Bramley, A.M.; Chappell, J.D.; Hymas, W.; Patel, A.; Qi, C.; et al. Identification of Bacterial and Viral Codetections with Mycoplasma pneumoniae Using the TaqMan Array Card in Patients Hospitalized with Community-Acquired Pneumonia. Open Forum Infect. Dis. 2016, 3, ofw071.
  51. Chen, C.J.; Lin, P.Y.; Tsai, M.H.; Huang, C.G.; Tsao, K.C.; Wong, K.S.; Chang, L.Y.; Chiu, C.H.; Lin, T.Y.; Huang, Y.C. Etiology of community-acquired pneumonia in hospitalized children in northern Taiwan. Pediatr. Infect. Dis. J. 2012, 31, e196–e201.
  52. Chiu, C.Y.; Chen, C.J.; Wong, K.S.; Tsai, M.H.; Chiu, C.H.; Huang, Y.C. Impact of bacterial and viral coinfection on mycoplasmal pneumonia in childhood community-acquired pneumonia. J. Microbiol. Immunol. Infect. 2015, 48, 51–56.
  53. Zhang, X.; Chen, Z.; Gu, W.; Ji, W.; Wang, Y.; Hao, C.; He, Y.; Huang, L.; Wang, M.; Shao, X.; et al. Viral and bacterial co-infection in hospitalised children with refractory Mycoplasma pneumoniae pneumonia. Epidemiol. Infect. 2018, 146, 1384–1388.
  54. Zhao, F.; Liu, J.; Xiao, D.; Liu, L.; Gong, J.; Xu, J.; Li, H.; Zhao, S.; Zhang, J. Pathogenic Analysis of the Bronchoalveolar Lavage Fluid Samples with Pediatric Refractory Mycoplasma pneumoniae Pneumonia. Front. Cell. Infect. Microbiol. 2020, 10, 553739.
  55. Tenenbaum, T.; Franz, A.; Neuhausen, N.; Willems, R.; Brade, J.; Schweitzer-Krantz, S.; Adams, O.; Schroten, H.; Henrich, B. Clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 3173–3182.
  56. Skevaki, C.L.; Tsialta, P.; Trochoutsou, A.I.; Logotheti, I.; Makrinioti, H.; Taka, S.; Lebessi, E.; Paraskakis, I.; Papadopoulos, N.G.; Tsolia, M.N. Associations Between Viral and Bacterial Potential Pathogens in the Nasopharynx of Children with and without Respiratory Symptoms. Pediatr. Infect. Dis. J. 2015, 34, 1296–1301.
  57. Self, W.H.; Williams, D.J.; Zhu, Y.; Ampofo, K.; Pavia, A.T.; Chappell, J.D.; Hymas, W.C.; Stockmann, C.; Bramley, A.M.; Schneider, E.; et al. Respiratory Viral Detection in Children and Adults: Comparing Asymptomatic Controls and Patients with Community-Acquired Pneumonia. J. Infect. Dis. 2016, 213, 584–591.
  58. Mandell, L.A. Community-acquired pneumonia: An overview. Postgrad. Med. 2015, 127, 607–615.
  59. Michelow, I.C.; Olsen, K.; Lozano, J.; Rollins, N.K.; Duffy, L.B.; Ziegler, T.; Kauppila, J.; Leinonen, M.; McCracken, G.H., Jr. Epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children. Pediatrics 2004, 113, 701–707.
  60. Waites, K.B.; Xiao, L.; Liu, Y.; Balish, M.F.; Atkinson, T.P. Mycoplasma pneumoniae from the Respiratory Tract and Beyond. Clin. Microbiol. Rev. 2017, 30, 747–809.
  61. Waites, K.B.; Talkington, D.F. Mycoplasma pneumoniae and its role as a human pathogen. Clin. Microbiol. Rev. 2004, 17, 697–728.
  62. Dumke, R.; Luck, P.C.; Noppen, C.; Schaefer, C.; von Baum, H.; Marre, R.; Jacobs, E. Culture-independent molecular subtyping of Mycoplasma pneumoniae in clinical samples. J. Clin. Microbiol. 2006, 44, 2567–2570.
  63. Degrange, S.; Cazanave, C.; Charron, A.; Renaudin, H.; Bebear, C.; Bebear, C.M. Development of multiple-locus variable-number tandem-repeat analysis for molecular typing of Mycoplasma pneumoniae. J. Clin. Microbiol. 2009, 47, 914–923.
  64. Matsuda, K.; Narita, M.; Sera, N.; Maeda, E.; Yoshitomi, H.; Ohya, H.; Araki, Y.; Kakuma, T.; Fukuoh, A.; Matsumoto, K. Gene and cytokine profile analysis of macrolide-resistant Mycoplasma pneumoniae infection in Fukuoka, Japan. BMC Infect. Dis. 2013, 13, 591.
  65. Wu, T.H.; Wang, N.M.; Liu, F.C.; Pan, H.H.; Huang, F.L.; Fang, Y.P.; Chiang, T.W.; Yang, Y.Y.; Song, C.S.; Wu, H.C.; et al. Macrolide Resistance, Clinical Features, and Cytokine Profiles in Taiwanese Children with Mycoplasma pneumoniae Infection. Open Forum Infect. Dis. 2021, 8, ofab416.
  66. Zhao, F.; Lv, M.; Tao, X.; Huang, H.; Zhang, B.; Zhang, Z.; Zhang, J. Antibiotic sensitivity of 40 Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant isolates from Beijing, China. Antimicrob. Agents Chemother. 2012, 56, 1108–1109.
  67. Liu, Y.; Ye, X.; Zhang, H.; Xu, X.; Li, W.; Zhu, D.; Wang, M. Antimicrobial susceptibility of Mycoplasma pneumoniae isolates and molecular analysis of macrolide-resistant strains from Shanghai, China. Antimicrob. Agents Chemother. 2009, 53, 2160–2162.
  68. Qu, J.; Chen, S.; Bao, F.; Gu, L.; Cao, B. Molecular characterization and analysis of Mycoplasma pneumoniae among patients of all ages with community-acquired pneumonia during an epidemic in China. Int. J. Infect. Dis. 2019, 83, 26–31.
  69. Wagner, K.; Imkamp, F.; Pires, V.P.; Keller, P.M. Evaluation of Lightmix Mycoplasma macrolide assay for detection of macrolide-resistant Mycoplasma pneumoniae in pneumonia patients. Clin. Microbiol. Infect. 2019, 25, 383.e5–383.e7.
  70. Morinaga, Y.; Suzuki, H.; Notake, S.; Mizusaka, T.; Uemura, K.; Otomo, S.; Oi, Y.; Ushiki, A.; Kawabata, N.; Kameyama, K.; et al. Evaluation of GENECUBE Mycoplasma for the detection of macrolide-resistant Mycoplasma pneumoniae. J. Med. Microbiol. 2020, 69, 1346–1350.
  71. Kakiuchi, T.; Miyata, I.; Kimura, R.; Shimomura, G.; Shimomura, K.; Yamaguchi, S.; Yokoyama, T.; Ouchi, K.; Matsuo, M. Clinical Evaluation of a Novel Point-of-Care Assay to Detect Mycoplasma pneumoniae and Associated Macrolide-Resistant Mutations. J. Clin. Microbiol. 2021, 59, e0324520.
  72. Choi, Y.J.; Chung, E.H.; Lee, E.; Kim, C.H.; Lee, Y.J.; Kim, H.B.; Kim, B.S.; Kim, H.Y.; Cho, Y.; Seo, J.H.; et al. Clinical Characteristics of Macrolide-Refractory Mycoplasma pneumoniae Pneumonia in Korean Children: A Multicenter Retrospective Study. J. Clin. Med. 2022, 11, 306.
  73. Chen, Y.C.; Hsu, W.Y.; Chang, T.H. Macrolide-Resistant Mycoplasma pneumoniae Infections in Pediatric Community-Acquired Pneumonia. Emerg. Infect. Dis. 2020, 26, 1382–1391.
  74. Aliberti, S.; Dela Cruz, C.S.; Amati, F.; Sotgiu, G.; Restrepo, M.I. Community-acquired pneumonia. Lancet 2021, 398, 906–919.
  75. Tsai, T.A.; Tsai, C.K.; Kuo, K.C.; Yu, H.R. Rational stepwise approach for Mycoplasma pneumoniae pneumonia in children. J. Microbiol. Immunol. Infect. 2021, 54, 557–565.
  76. Lai, J.F.; Zindl, C.L.; Duffy, L.B.; Atkinson, T.P.; Jung, Y.W.; van Rooijen, N.; Waites, K.B.; Krause, D.C.; Chaplin, D.D. Critical role of macrophages and their activation via MyD88-NFkappaB signaling in lung innate immunity to Mycoplasma pneumoniae. PLoS ONE 2010, 5, e14417.
  77. Roifman, C.M.; Rao, C.P.; Lederman, H.M.; Lavi, S.; Quinn, P.; Gelfand, E.W. Increased susceptibility to Mycoplasma infection in patients with hypogammaglobulinemia. Am. J. Med. 1986, 80, 590–594.
  78. Foy, H.M.; Ochs, H.; Davis, S.D.; Kenny, G.E.; Luce, R.R. Mycoplasma pneumoniae infections in patients with immunodeficiency syndromes: Report of four cases. J. Infect. Dis. 1973, 127, 388–393.
  79. Zhang, Y.; Zhou, Y.; Li, S.; Yang, D.; Wu, X.; Chen, Z. The Clinical Characteristics and Predictors of Refractory Mycoplasma pneumoniae Pneumonia in Children. PLoS ONE 2016, 11, e0156465.
  80. Lu, A.; Wang, C.; Zhang, X.; Wang, L.; Qian, L. Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia in Children. Respir. Care 2015, 60, 1469–1475.
  81. Liu, T.Y.; Lee, W.J.; Tsai, C.M.; Kuo, K.C.; Lee, C.H.; Hsieh, K.S.; Chang, C.H.; Su, Y.T.; Niu, C.K.; Yu, H.R. Serum lactate dehydrogenase isoenzymes 4 plus 5 is a better biomarker than total lactate dehydrogenase for refractory Mycoplasma pneumoniae pneumonia in children. Pediatr. Neonatol. 2018, 59, 501–506.
  82. Inamura, N.; Miyashita, N.; Hasegawa, S.; Kato, A.; Fukuda, Y.; Saitoh, A.; Kondo, E.; Teranishi, H.; Wakabayashi, T.; Akaike, H.; et al. Management of refractory Mycoplasma pneumoniae pneumonia: Utility of measuring serum lactate dehydrogenase level. J. Infect. Chemother. 2014, 20, 270–273.
  83. Zhang, Y.; Mei, S.; Zhou, Y.; Huang, M.; Dong, G.; Chen, Z. Cytokines as the good predictors of refractory Mycoplasma pneumoniae pneumonia in school-aged children. Sci. Rep. 2016, 6, 37037.
  84. Li, M.; Chen, Y.; Li, H.; Yang, D.; Zhou, Y.; Chen, Z.; Zhang, Y. Serum CXCL10/IP-10 may be a potential biomarker for severe Mycoplasma pneumoniae pneumonia in children. BMC Infect. Dis. 2021, 21, 909.
  85. Narita, M. Classification of Extrapulmonary Manifestations Due to Mycoplasma pneumoniae Infection on the Basis of Possible Pathogenesis. Front. Microbiol. 2016, 7, 23.
  86. Tanaka, H.; Narita, M.; Teramoto, S.; Saikai, T.; Oashi, K.; Igarashi, T.; Abe, S. Role of interleukin-18 and T-helper type 1 cytokines in the development of Mycoplasma pneumoniae pneumonia in adults. Chest 2002, 121, 1493–1497.
  87. Izumikawa, K. Clinical Features of Severe or Fatal Mycoplasma pneumoniae Pneumonia. Front. Microbiol. 2016, 7, 800.