Clinical significance of D-dimer levels in refractory Mycoplasma pneumoniae pneumonia

Mycoplasma pneumoniae pneumonia (MPP) is a common etiology of childhood community-acquired pneumonia (CAP), accounting for 10–40% of cases, of which, nearly 20% require hospitalization [1‐3]. The clinical manifestations of MPP are complex and varied. In addition to pulmonary involvement, MPP is frequently accompanied by intrapulmonary and extrapulmonary multisystem damage. Refractory M. pneumoniae pneumonia (RMPP) has become increasingly common in recent years. RMPP frequently shows no improvement in clinical and radiological findings despite appropriate macrolide treatment and even present with necrotizing pneumonia, airway occlusion, or thrombosis [4]. The specific pathogenesis of RMPP remains unclear, and pathogenic substances or other host factors may be the cause of lung injury associated with an excessively strong immune response [5‐8]. In practice, it often appears as higher levels of clinical indicators such as CRP, ESR, LDH, and other biomarkers [6‐10]. Therefore, early use of immune modulators such as corticosteroid medications, is recommended in RMPP rather than waiting for antibiotic treatment to exert an effect, which could reduce M. pneumoniae (MP) -mediated immune injury and improve treatment efficacy [11‐13]. However, despite the use of corticosteroids, some patients with RMPP still have persisting fever and radiological deterioration because of the formation of mucus plugs, which requires investigation using bronchoscopy [14]. There is no specificity in early clinical manifestations of RMPP, and early diagnosis is difficult; therefore, early predictors need to be identified. Several cases of MPP complicated with thrombus have recently been reported [4, 15], indicating that children with MPP have abnormal coagulation. The serum D-dimer (D-D) level can be used as a molecular marker for hypercoagulability [4], as well as an indicator for monitoring inflammation and severe infection, such as coronavirus disease 2019(Covid-19) [16]. The present study further explored the role of hypercoagulability in the pathogenesis of RMPP by evaluating D-D levels and changes in D-D levels in children with MPP.

MPP is a common respiratory disease in children, and macrolides are the first choice antibiotics. In recent years, the prevalence of RMPP has been increasing, particularly in Asian countries [2, 6]. Clinical cases of MPP complicated with thrombosis are not unusual, and MPP complicated with deep vein thrombosis is frequently reported [4, 15]. At present, the mechanism by which MPP causes vascular embolization is not fully understood, and it is primarily considered to be related to immune mediation after vascular injury [17]. Under normal circumstances, the coagulation and fibrinolytic systems are in a dynamic equilibrium state. When coagulation occurs in vivo, thrombin acts on fibrin to activate the fibrinolytic system, and D-D can be formed [18]. D-D is primarily used in clinical settings for the initial diagnosis of pulmonary embolism, and shows diagnostic accuracy in the diagnosis of acute pulmonary embolism. Recently, D-D has been shown not only to be a special marker of the fibrinolytic system but also to be an indicator for monitoring inflammation and severe infection [16]. Levels of D-D are also closely related to the inflammatory response and may reflect the effects of infection on coagulation in infectious diseases. Some studies have reported that the levels of D-D are closely related to the severity of CAP [19].

Previous studies [20, 21] have reported that levels of D-D in children with MPP were higher than those in healthy children and were also higher in severe cases of MPP compared with mild cases, especially in severe MPP with extrapulmonary complications [21]. Few studies have reported on D-D levels in RMPP or on the monitoring of D-D levels after treatment. Consistent with previous reports, we found that the levels of D-D in the GMPP and RMPP groups were all above the normal ranges and that the levels in the RMPP group were significantly higher than those in the GMPP group. Elevated D-D levels may imply that hypercoagulability is prevalent in children with MPP and is more severe in children with RMPP and that vascular endothelial cell injury caused by an excessive inflammatory response may be involved in the mechanism of lung injury in RMPP. In a previous study, the levels of D-D were found to have decreased significantly after a period of treatment, and the final levels after treatment were higher in a group with severe pneumonia than in a group with mild pneumonia [21]. Our study found that one week of treatment was associated with a significant decrease in D-D levels, although levels remained abnormal in most cases, indicative of a prolonged state of high coagulation and endothelial injury in RMPP.

LDH and CRP, which are elevated in several pulmonary diseases, have previously been associated with RMPP and the formation of bronchial mucus plugs, and can be used as early predictors of the condition [6‐8, 14]. In the present study, D-D level was positively correlated with WBC, CRP, and ESR. The increased levels of these indexes may represent a stronger systemic inflammatory response in RMPP, and possibly DD, as we found in the present study, while the positive correlation of D-D with these inflammatory indicators, which suggests that the D-D level may be used to evaluate the inflammatory response and jointly evaluate the severity of the disease. The average age of patients in the RMPP group was 5.7 years, which was older than that in the GMPP group and was consistent with previous studies [6, 7], indicating that older children have a stronger immune inflammatory response that can more readily lead to refractory conditions. A previous study showed that CRP≧50 mg/L and LDH≧480 U/L were associated with longer time to radiographic clearance [22], while ROC curve analysis revealed that the percentage of neutrophils, CRP, and LDH were useful in differentiating patients with RMPP from those with GMPP [6]. In this study, we found that CRP, LDH, and D-D levels were independent risk factors for RMPP, and after comparing the predictive value of CRP, LDH, and D-D for RMPP by ROC analysis, we found that D-D was better able to predict RMPP compared with the other indexes and may therefore be used in the early detection of refractory cases.

Regarding complications, previous studies have reported that the D-D level was positively correlated with extrapulmonary complications in pediatric patients with MPP [21]; however, extensive research on the D-D level and complications has not been reported to date. In a previous study, a higher D-D level was associated with more extensive and serious thrombosis [4]. Our results show that elevated levels of D-D had a good predictive ability for pleural effusion and liver injury and that the incidence of pleural effusion increased with increasing levels of D-D, but there was no significant difference between the moderately elevated group and the severely elevated group. The incidence of atelectasis was only significantly different between the normal D-D level group and the mildly elevated group and the incidence of rash and myocardial damage did not differ significantly between the four groups, which suggested that severely elevated D-D might not be associated with more complications. Moreover, D-D has no obvious correlation with mucus plug formation, which may be related to the hypersecretion of mucus. Therefore, further research including case studies is needed to verify this hypothesis and to avoid overtreatment.

Most of the MPP patients had higher D-D levels, but the incidence of embolic disease was lower in our and previous research [4]. It is more closely related to pleural effusion and liver function damage but not atelectasis and mucus plug formation. Therefore, elevation of D-D may be associated with other inflammatory reactions from insults of MP infection, and further research is needed. Since MPP is a self-limited disease and the host excessive inflammatory response against insults from MP infection is believed to be responsible for lung cell injury, endothelial injury and other cells, the intensity of systemic inflammation during this process is reflected in laboratory parameters such as CRP, LDH, other cytokines and chemokines, and possibly D-D. The immunopathogenesis mechanisms of acute lung injury, skin rashes, and other organ involvement in MP infection are not fully understood. The protein-homeostasis-system hypothesis in MP infection has been proposed [23]. During the incubation period of MP infection, substances including pathogenic proteins are produced in a focus. The substances spread and reach lung cells as main target cells, and various tissues for extrapulmonary manifestations via systemic circulation. Immune cells start to control these substances, not only those originating from pathogens, but also those originating from injured infected-host cells including pathogenic proteins and pathogenic peptides. Then clinical symptoms and signs such as fever, pneumonia, and occasional extrapulmonary manifestations such as skin rash, encephalopathy begin to appear, along with the involvement of other organ cells and associated elevations of AST, ALT, LDH, CRP, D-D and other biomarkers Therefore, early systemic immune modulators (dose-adjusted corticosteroids and/or high-dose intravenous immunoglobulin), may prevent rapid progression of pneumonia and induce rapid recovery of pulmonary lesions in M. pneumoniae pneumonia [11, 24].

Our study had some limitations. First, as this was a retrospective study, selection bias might exist, and further prospective studies are potentially needed. Second, normal control group was not established. Third, only once IgM serologic test was performed and diagnostic error may have occurred. Fourth, our study was based on a single center for data, which might have potential biases.

Children with RMPP were shown to have significantly increased serum levels of D-D, indicating that severe hypercoagulability, excessive inflammatory response and vascular endothelial injury with prolonged duration may exist in this patient population. Elevated serum D-D levels may be an early predictor of RMPP, pleural effusion and liver injury. D-D detection is conducive to the early diagnosis of RMPP, early intervention of hypercoagulability and excessive inflammatory response.