Clinical characteristics of refractory mycoplasma pneumoniae pneumonia in children treated with glucocorticoid pulse therapy

Mycoplasma pneumoniae (MP) is the main pathogens of community-acquired pneumonia (CAP) in children [1]. Mycoplasma pneumoniae pneumonia (MPP) is considered as a benign and self-limiting disease. However, it has been found that some children may progress to refractory Mycoplasma pneumoniae pneumonia (RMPP) after being treated with sufficient and long-term macrolide antibiotics in timely [2], which often leads to pulmonary necrosis and pleural effusion, which may not only be difficult to treat and costing, but also leave sequelae such as bronchiectasis, necrotizing pneumonia, bronchiolitis obliteransa and so on [3‐7], thus affect the quality of life. Over-immune response of host plays an important role in the development of RMPP [8, 9]. Studies have confirmed the effectiveness of glucocorticoid (GC) in the treatment of RMPP [2, 10, 11]. GC are effective in the treatment of severe RMPP by down-regulating the cell-mediated immune response associated with lung injury during infection [12‐15]. Therefore, on the basis of adequate anti-infective treatment, GC has attracted more and more attention [16, 17]. It is vital for clinicians to identify severe RMPP as early as possible and give pulse dose of hormone therapy. So, retrospective analysis was performed on 125 children with RMPP hospitalized in our hospital from September 2018 to October 2019. The purpose of this study was to compare the differences of clinical manifestations, laboratory data and imaging findings between two groups and to explore the predictive values of pulse therapy of RMPP.

One of the main pathogens of CAP in children is Mycoplasma pneumoniae. More and more RMPP have been reported [10, 29‐33]recently. Studies [34, 35] have shown that more than 90% of Mycoplasma pneumoniae infections in China are caused by drug-resistant strains. However, the latest research results of Sun et al. [36] have shown that the important cause of MP resistance to macrolide antibiotics was not only related to the irregular use of antibiotics, but also related to the epidemic genotype M4–5–7-2 of Mycoplasma pneumoniae. Through the comparison of genotypes and drug resistance between Chinese, American and Australian strains, it was reasonably explained from a new perspective that the high drug resistance rate in China and even in Asia is not all caused by the abuse of antibiotics, which is closely related to the regional differences in the epidemic genotypes of Mycoplasma pneumoniae [36]. Therefore, macrolides are still used in patients with MP in China. Only when macrolides are ineffective, antibiotics such as tetracyclines or fluoroquinolones can be used according to the condition [37‐41]. Due to the influence of the pathogenesis, most of the RMPP will produce complications. The host’s excessive immune response plays a key role in the development of RMPP disease [8, 9], such as cytokines (including interleukin-2, interleukin-6 and interleukin-8). Over-expression and highly activated cells (including antigen presenting cells and T cells) mediated immune response etc [42]. GC can be used to down-regulate the related cell-mediated immune response and play an effective role in severe cases of MP infection [12‐14]. Early control of lung injury caused by overactive immune response by non-specific adaptive immune cells is essential for reducing the incidence of severe MPP and preventing disease progression. Because the severity of RMPP is related to the immune response, and the effect of GC is dose-dependent, higher doses may be needed in patients with severe MPP [4, 43, 44].

A number of studies have revealed that humoral and cellular immune responses [45, 46]contribute to the pathogenesis of MP infection, providing a theoretical basis for the application of GC in RMPP. Studies have shown that the addition of GC on the basis of the conventional treatment has a definite effect on RMPP, which contributes to the control of the disease progression, the improvement of the condition and the reduction of sequelae [10, 16]. So, it is very important to study the application of GC in the treatment of RMPP [2, 16, 47].

So, in this retrospective research, 125 patients of RMPP were enrolled. Among them, there were 81 cases in group I, and 44 cases in group II. First of all, this study found that there was a statistical difference in age between group I and group II (6.54 ± 3.03, 7.61 ± 2.49, P < 0.05), which was similar to the previous studies [11, 17]. Children’s immune systems gradually mature with age. The more mature of immune system, it is more likely to have a strong inflammatory response to MP and produce too many inflammatory factors,which may lead to the deterioration of RMPP [17].

Secondly, the incidence of hypoxemia, extra-pulmonary complications and plastic bronchitis were higher in the group II than those in the group I (P < 0.05). Besides, the use rate of oxygen therapy, gamma globulin and bronchoscopy in the group II were higher(P < 0.05). The total fever days, hospital stay, fever days after hormone therapy in group II were significantly higher than in group I (P < 0.05). In addition, the study also found that WBC, CRP, LDH, FER, D-D dimer, APTT, TT, PCT, IL-6, ALT and the percentage of neutrophils in peripheral blood in group II were higher than in group I (P < 0.05). Finally, the incidence of pulmonary consolidation and pleural effusion were higher in group II(P < 0.05). The imaging findings may be related to the severity of the disease. The difference may is correlation to direct damage and immune inflammatory response [19]. So, if RMPP was not treated effectively, the disease maybe aggravated and the clinical process of disease maybe prolonged.

In order to study the clinical characteristics that can predict the severity of RMPP disease and guide the GC pulsed dose treatment, analyze statistically significant indicators by ROC curve. In ROC curve analysis, CRP, LDH, FER and white blood cell classification of neutrophils were helpful for identifying more severe RMPP patients. The optimal cutoff value were 44.45 mg/L,590 IU/L,411 ng/L and 73.75%, respectively. This study found that CRP 44.45 mg/L, LDH 590 IU/L, FER 411 ng/L, leukocyte classification neutrophil 73.75%, lung consolidation and pleural effusion may be important clinical features of use pulsed dose hormones to treat RMPP.

CRP is the most widely used acute phase inflammatory protein. CRP rises rapidly after inflammation stimulation, which value can reflect the development of the immune system. CRP levels in patients with acute infection, inflammation or trauma may increase in a short time. Chen et al. [19, 21]. showed that when CRP was 16.5 mg/L or higher, the sensitivity and specificity for diagnosing MPP with hypoxia were 74.7 and 77.2%, respectively. The cutoffs were less than that in our study. In our study, the optimal cutoff point for CRP was 44.45 mg/L, with a sensitivity of 55% and specificity of 85%.

LDH is an inflammatory marker. After cell damage, LDH is released into the serum and can be used to monitor tissue damage in many inflammatory processes. Studies have shown that LDH was related to many lung diseases [48, 49]. Serum LDH was a biomarker of RMPP severity [1, 11, 13, 19]. Lu et al. [50].reported that serum LDH can be used as a biomarker for predicting RMPP and evaluating whether to initiate corticosteroid therapy during the initial hospitalization of patients. Chen et al. [19, 21]. showed that when LDH was 417 IU/L or higher, the sensitivity and specificity for diagnosing MPP with hypoxia were 79.7 and 65.0%, respectively. In this study, the optimal cutoff for LDH was 590 IU/L, with a sensitivity of 76.3% and specificity of 47.5%, which was higher than that of previous studies [13, 19].

Elevated levels of ferritin may be positively correlated with the severity of inflammation, infection, renal failure and metabolic syndrome. In lung diseases, lung inflammation and tissue damage can lead to increased ferritin levels [51]. Kawamata et al. [12] showed that serum ferritin levels were positively correlated with the severity of children’s MPP, and ferritin may be a useful indicator for the initiation of glucocorticoid therapy for MPP. However, there is still no report about the correlation of ferritin in treatment of RMPP with pulse dose of GC. Choi et al. [52] reported that when ferritin was greater than or equal to 230 ng/mL, the sensitivity and specificity for diagnosing RMPP were 67 and 67%. In this study, the area under the curve for ferritin was 0.814 in the ROC curve analysis, which indicates that ferritin has a fair discriminative power in predicting the use of pulse dose to treat RMPP. The optimal cutoff for ferritin was 411 ng/mL, the sensitivity and specificity were 86.4 and 68.2%. The reasons for the difference in the studies are as follows: Firstly, it may be that the research object is RMPP, and the clinical manifestations are more serious; secondly, it may be that the research object contains unrecognized mixed infections.

Systemic GC can be considered for severe MPP with acute onset, rapid progression, especially for RMPP. However, there is no corresponding indicator for the use and timing of hormone dose. There are different opinions on the dosage of hormones in the existing article [11, 16]: You and Lee et al. [42]used intravenous infusion of methylprednisolone 10 mg/kg/day× 3 days for some patients who had failed oral treatment (dose reduction within 1 week). The clinical manifestations of all patients were significantly improved, and there were no related side effects. Lee [11] et al.treated 15 children with RMPP orally with prednisolone 1 mg/kg/day, and the dose was reduced after continuous use for 3–7 days, which has a significant therapeutic effect on children with RMPP. Luo et al. proved that oral prednisone (2 mg/kg/day) was more effective than azithromycin alone in children with RMPP. And Tamura [2] gave 6 patients with RMPP an intravenous drip of 30 mg/kg/day× 3 days methylprednisolone. The body temperature of all patients returned to normal within 14 h, and the clinical symptoms were significantly improved. They think that the combined use of hormone therapy can reduce the length of hospital stay and the occurrence of RMPP, and there is no adverse hormone response. The study implied that elder children are prone to more severe presentations, higher incidence of extra-pulmonary complications and more serious imaging. The study suggested that the severity of RMPP was related to host immune response, and the optimal values of CRP, LDH, FER and leukocyte classification neutrophils (CRP44.45 mg/L, LDH590IU/L, FER411ng/L, leukocyte classification neutrophils 73.75%), lung consolidation, and pleural effusion may be the valuable predictors of using methylprednisolone pulse therapy to treat RMPP.

This study indicated that in the treatment of RMPP, timely use of appropriate doses of GC can reduce the intensity of local inflammation, alleviates the immune reaction, and promote disease recovery. During the treatment of RMPP with GC, blood pressure, blood glucose, blood potassium and liver function should be monitored, notice the adverse reactions such as circulatory system and gastrointestinal bleeding, and pay attention to ECG monitoring during pulse dose treatment. And be sure to: ①the suitable time for treatment; ②exclude whether there are other infections or lesions; ③prevent the occurrence of double infection.

The study has some limitations. Firstly, retrospective research may have selection bias,which may need large sample, further prospective studies. Second, our hospital is a tertiary hospital with many severely ill patients. The uneven distribution of critically ill patients in this study has a certain impact on the experimental results. Thirdly, the source of patients is relatively single, and the research results may not be ideally suited for patients from other sources. To solve this problem, multi-regional research is required in the future. Fourth, some patients may be infected with other pathogens, but this pathogen has not been detected, and it may cause the deterioration of RMPP. Finally, the optimal value of risk factor obtained by ROC curve may have some limitations and only guide judgment to a certain extent. More clinical data should be accumulated and further verified in clinical work to obtain more accurate reference standards.

This research shows that immune inflammatory response may play a vital role in the progression of RMPP. CRP ≥ 44.45 mg/L, LDH ≥ 590 IU/L, FER ≥ 411 ng/L, neutrophil≥73.75%, lung consolidation, and pleural effusion may be meaningful predictors that guide the treatment of RMPP with pulse dose of GC, which can reduce the incidence of severe RMPP and the occurrence of severe sequelae.