Clinical Significance of D-dimer Level in Refractory Mycoplasma Pneumoniae Pneumonia

Abstract

Background

Levels of serum D-dimer (D-D) in children with mycoplasma pneumoniae pneumonia (MPP) were assessed to explore the clinical significance of D-D level in refractory MPP(RMPP).

Method:

A total of 430 patients with MPP were enrolled between January 2015 and December 2015, and divided into a genera MPP (GMPP) group (n = 306) and a RMPP group (n = 124). Clinical data, D-D level, white blood cell (WBC) count, C-reactive protein (CRP), blood sedimentation (ESR), and lactate dehydrogenase (LDH) were compared between the two groups.

Results

(1) Hospitalization time, fever duration, WBC, CRP, LDH, ESR, and D-D were significantly higher in the RMPP group than in the GMPP group, (all P < 0.05). (2) Correlation analysis showed that D-D was positively correlated with WBC, CRP, ESR, and LDH, and could be used to jointly evaluate the severity of the disease. (3) The predictive values of WBC, CRP, ESR, LDH, and D-D for RMPP were further compared using area under the receiver operating characteristic curve(AUC) analysis. D-D had the highest predictive power for RMPP (AUC = 0.923, P < 0.01). When the D-D level was > 738 ng/ml, the predicted sensitivity of RMPP occurrence was 79.8% and the specificity was 93.5%. D-D level also had a good ability to predict pleural effusion and liver injury (AUC = 0.740, P < 0.01 and AUC = 0.812, P < 0.01, respectively). (4) After 1 week of treatment, the levels of D-D in both groups were lower than those before treatment (p < 0.01), but remained outside the normal range in 91.4% of participants, and were moderately or severely increased in 27.1% of the participants, all of whom were in the RMPP group.

Conclusion

Serum D-D levels were significantly increased in patients with RMPP, indicating that severe hypercoagulability and vascular endothelial injury with prolonged duration existed in this patient population. Increased levels of serum D-D may be used as an early predictor of RMPP and the occurrence of complications. Our findings provide a theoretical basis for the early diagnosis of RMPP, early intervention of hypercoagulability, and improvement of microcirculation therapy.

Background

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 multi-system damage. Refractory Mycoplasma 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 may present with necrotizing pneumonia, airway occlusion, or thrombosis [4]. Therefore, early identification and active treatment are needed. Several cases of MPP complicated with thrombus have recently been reported [4–5], indicating that children with MPP have abnormal coagulation. 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 [6]. 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.

Methods

Data Collection

All children were admitted to hospital within 24 h after routine screening for infection, including peripheral white blood cell (WBC) count, C-reactive protein (CRP), blood sedimentation (ESR), sputum culture, M. pneumoniae DNA, phlegm and blood respiratory etiology examination, levels of serum D-D, liver and kidney function, X-ray chest radiograph (or chest CT), and electrocardiogram (ECG).General information including sex, age, history, medical history, physical examination, and complications were documented, as well as an assessment of the patient’s condition. Patients with significantly increased levels of D-D (≥ 1400 ng/ml) were reviewed after treatment for 1 week, and WBC and CRP were also reviewed at this time point.

Diagnostic criteria for myocardial injury were as follows: (1) clinical manifestations of cardiac insufficiency; (2) cardiac enlargement; (3) ECG changes such as ST-T changes and arrhythmias; increased levels of CK-MB or positive cardiac troponin, excluding children with previous underlying heart disease. Diagnostic criteria for liver injury were ALT ≥ 3 times normal value upper limit (ULN) and ratio of ALT measured value/ALT normal value upper limit and ALP measured value/ALP normal value upper limit ≥ 5. Viral hepatitis, metabolic diseases, and other diseases involving the liver were excluded.

The levels of serum D-D were determined by immunoturbidimetry using an ACLTOP700 automatic blood coagulation analyzer (Wofen Inc., USA) in accordance with the manufacturer’s instructions. The normal range of serum D-D was ≤ 280 ng/ml. In the present study, the degree of D-D elevation was defined as follows: mild increase: < 5-fold increase (> 280 to < 1400 ng/ml), moderate increase: < 10-fold increase (≥ 1400 to < 2800 ng/ml), and severe increase: >10-fold increase (≥ 2800 ng/ml).

Statistical Analyses

All statistical analyses were conducted using IBM SPSS Statistics for Windows, version. 22.0 (IBM Corp., Armonk,NY, USA). For continuous variables, comparison of means was conducted using a t-test. For categorical variables, χ2 or Fisher’s exact test was used. For ordinally scaled data, the Wilcoxon rank-sum test was used. Skewed distribution data were expressed as median values (25th-75th interquartile ranges) and comparisons between two groups were conducted using the Mann-Whitney U rank sum test. The Wilcoxon rank sum test was used to compare serum D-D levels before and after treatment. Multi-scale logistic regression analysis was used to analyze the relationship between D-D level and complications. Values of P < 0.05 were considered statistically significant. The critical value of the diagnostic value of each predictor was obtained using receiver operating characteristic (ROC) curve analysis.

Results

Predictive Value Of D-d Level For Rmpp

The predictive value of WBC, CRP, ESR, LDH, and D-D for RMPP werer compared using area under the ROC curve (AUC) analysis. D-D was found to have the highest predictive power for RMPP (AUC = 0.923, P = 0.000). When the D-D level was > 738 ng/ml, the predicted sensitivity of RMPP occurrence was 79.8% and the specificity was 93.5% (Fig. 2).

Predictive Value Of D-d Level For Mpp With Complications

AUC analysis was used to further evaluate the value of D-D level in predicting complications such as atelectasis, pleural effusion, liver injury, erythema, myocardial damage, and pulmonary embolism. The results showed that the serum D-D level could robustly predict pleural effusion and liver injury (AUC = 0.740, P = 0.000 and AUC = 0.812, P = 0.000, respectively) (Fig. 3). For D-D level > 930 ng/ml, the sensitivity and specificity of the prediction for pleural effusion were 80.6% and 60.5%, respectively.For D-D level > 2100.5 ng/ml, the sensitivity and specificity of the prediction for liver injury were 93.3% and 72.7%, respectively.

Degree Of D-d Elevation And Complications

Levels of D-D were classified as normal, mildly increased, moderately increased, and severely increased. Pleural effusion was the most prevalent complication across the four classifications, The incidence of pleural effusion increased with increasing D - D level and differed significantly among the normal, mild increase, and moderate increase groups (P < 0.01); however, the difference between the moderate increase group and the severe increase group was not statistically significant (P > 0.05; Fig. 4). The incidence of atelectasis was significantly higher in the group with mildly elevated D-D level compared with in the normal group (P < 0.01), but did not further increase with increasing D-D level (moderately elevated group, P = 0.622; severely elevated group, P = 0.421).

Serum D-d Level After Treatment For 1 Week

A total of 74 children were reviewed for D-D level, WBC, and CRP after treatment for 1 week, including 5 patients with GMPP and 69 patients with RMPP. After treatment, the levels of WBC and CRP in most children were reduced to normal (63.0% and 81.5%, respectively). In both the GMPP and RMPP groups, D-D level decreased significantly with treatment (P < 0.05, Table 3), although 91.4% of children had D-D levels that remained above the upper limit of normal (> 280 ng/ml) and 27.1% of children had a moderate-to-severe increase in D-D, all of which were within the RMPP group (Fig. 5). According to the D-D level after a further 1-week interval, patients were divided into a normal group and an abnormal group. More pleural effusions were observed in the abnormal group than in the normal group (28.6% and 67.2%, respectively, P = 0.04; Fig. 6).

Discussion

MPP is a common respiratory disease in children. In recent years, the prevalence of RMPP has been increasing, particularly in Asian countries [7, 8]. The specific pathogenesis of RMPP remains unclear, however, pathogenic substances or other host factors may be the cause of lung injury associated with an excessively strong immune response [9–11]. Previous studies have reported that RMPP is associated with more serious lung injury and higher levels of clinical indicators such as CRP, ESR, and LDH, as well as longer recovery time [8, 10, 12]. Therefore, early use of immune modulators is recommended in RMPP rather than waiting for antibiotic treatment to exert an effect; this approach can reduce MP-mediated immune injury and improve treatment efficacy [13–15]. However, there is no specificity in early clinical manifestations of RMPP and early diagnosis is difficult, meaning that early predictors need to be identified.

Clinical cases of MPP complicated with thrombosis are not unusual, and MPP complicated with deep vein thrombosis is frequently reported [4–5]. At present, the mechanism by which Mycoplasma pneumoniae pneumonia causes vascular embolization is not fully understood, and it is primarily considered to be related to immune mediation after vascular injury [16]. 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 [17]. 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. However, D-D has been shown not only to be a special marker of fibrinolytic system but also to be an indicator for monitoring inflammation and severe infection [6]. 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 [18].

Previous studies [19, 20] 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 [20]. However, 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 levels of D-D in the GMPP and RMPP groups were all above the normal range, and that 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 compared with a group having mild pneumonia [20]. Our study found 1 week of treatment was associated with a significant decrease in D-D level, 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 can be used as early predictors of the condition [10, 11, 21]. In the present study, D-D level was positively correlated with WBC, CRP, and ESR. The increased levels of these analytes may represent a stronger systemic inflammatory response in RMPP, while the positive correlation of D-D with these inflammatory indicators means that 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 [8], 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 the percentage of neutrophils, CRP, and LDH were found in ROC curve analysis to be useful in differentiating patients with RMPP from those with GMPP [8]. In the present study, we found that D-D levels and LDH were positively correlated, and after comparing the predictive value of WBC, CRP, ESR, LDH, and D-D for RMPP by AUC 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 D-D level was positively correlated with extra-pulmonary complications in pediatric patients with MPP [20]; however, extensive research on D-D level and complications has not been reported to date. In a previous study, a higher level of D-D was associated with more extensive and serious thrombosis [8]. 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 D-D level. However, 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. However, further research including case studies is needed to verify this hypothesis and thus avoid overtreatment.

At present, controversy remains over the use of anticoagulant treatment in pneumonia [23]. Further research on D-D and pneumonia is therefore needed to clarify the relationship between dynamic changes in D-D and the course and progression of disease, thus allowing the appropriate anticoagulant treatment strategy to be selected.

Conclusion

Children with RMPP were shown to have significantly increased serum levels of D-D, indicating that severe hypercoagulability and vascular endothelial injury with prolonged duration may exist in this patient population. Increased serum levels of D-D may therefore represent an early prediction index for RMPP, pleural effusion, and liver injury, thus facilitating the early diagnosis of RMPP, early intervention in hypercoagulability, and improved microcirculation therapy.

Abbreviations

Declarations

Ackowlegements

The authors thank all nursing staff working in our department for keeping extremely detailed patient records, which contributed greatly to the completion of this research. The authors also thank Clare Cox, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Authors’ contributions

XH wrote the main manuscript text; XH and DL collected and analyzed clinical data; XH, FL and DZ contributed to study design and project implementation as well as critically reviewed and edited the manuscript. XH and YZ performed statistical analyses for the study. HT was principal investigators for the study and critically revised the manuscript.All authors reviewed the manuscript. All authors read and approved the final manuscript.

Funding

No funding received.

Availability of data and materials

All the information supporting our conclusions are included in the manuscript. There are no datasets related to this case report.

Ethics approval and consent to participate

This study was approved by the ethics committee of the Children’s Hospital of Nanjing Medical University. Individual informed consent was waived by the ethics committee listed above because this study used currently existing sample collected during the course of routine medical care and did not pose any additional risks to the patients. All patient data were anonymized prior to the analysis.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1. Oumei H, Xuefeng W, Jianping L, et al. Etiology of Community-Acquired Pneumonia in 1500 Hospitalized Children. J Med Virol. 2018;90(3):421–28.
2. Gao LW, Yin J, Hu YH, et al. The epidemiology of paediatric Mycoplasma pneumoniae pneumonia in North China: 2006 to 2016. Epidemiol Infect. 2019;147:e192:1–5.
3. Ravelomanana L, Bouazza N,Rakotomahefa M,et al. Prevalence of mycoplasma pneumoniae infection in malagasy children. Pediatr Infect Dis J. 2017;36(5):467–71.
4. Liu J, He R, Wu R, et al. Mycoplasma pneumoniae pneumonia associated thrombosis at Beijing Children’s hospital. BMC Infect Dis. 2020;16(1):51. 20(.
5. Kalicki B, Sadecka M, Wawrzyniak A, et al. Absence of inferior vena cava in 14-year old boy associated with deep venous thrombosis and positive Mycoplasma pneumoniae serum antibodies–a case report. BMC Pediatr. 2015;15:40.
6. Wu HB, Ma WG, Zhao HL, et al. Risk factors for continuous renal replacement therapy after surgical repair of type A aortic dissection. J Thorac Dis. 2017;9:1126–32.
7. You SY, Jwa HJ, Yang EA,et al. Effects of methylprednisolone pulse therapy on refractory mycoplasma pneumoniae pneumonia in children. Allergy Asthma Immunol Res. 2014;6(1):22–6.
8. Zhang Y, Zhou Y, Li S, et al. The clinical characteristics and predictors of refractory mycoplasma pneumoniae pneumonia in children. PLoS One. 2016;11(5):e0156465.
9. Yang M, Meng F, Wang K, et al. Interleukin 17A as a good predictor of the severity of Mycoplasma pneumoniae pneumonia in children. Sci Rep. 2017;7(1):12934.
10. Lu A, Wang C, Zhang X, et al. Lactate dehydrogenase as a biomarker for prediction of refractory mycoplasma pneumoniae pneumonia in children. Respir Care. 2015;60(10):1469–75.
11. Choi YJ, Jeon JH, Oh JW. Critical combination of initial markers for predicting refractory Mycoplasma pneumoniae pneumonia in children: a case control study. Respir Res. 2019;20(1):193.
12. Wang L, Lu S, Feng Z, et al. The early examination of combined serum and imaging data under flexible fiberoptic bronchoscopy as a novel predictor for refractory Mycoplasma pneumoniae pneumonia diagnosis. Medicine. 2017;96(50):e9364.
13. Lee KY. Pneumonia,acute spiratory distress syndrome,and early immune-modulator therapy. Int J Mol Sci. 2017;18(2):388.
14. Waites KB, Xiao L, Liu Y, et al. Mycoplasma pneumoniae from the respiratory tract and beyond. Clin Microbiol Rev. 2017;30(3):747–809.
15. Shan LS, Liu X, Kang XY, et al. Effects of Methylprednisolone or Immunoglobulin When Added to Standard Treatment With Intravenous Azithromycin for Refractory Mycoplasma Pneumoniae Pneumonia in Children. World J Pediatr. 2017;13(4):321–7.
16. Van Es N, Kraaijpoel N, Klok FA,et al. The original and simplified Wells rules and age-adjusted D-dimer testing to rule out pulmonary embolism:an individual patient data meta-analysis. J Thromb Haemost. 2017;15(4):678–84.
17. Yin X, Liu P, Liu BY,et al. Preventive effects of low molecular weight heparin on formation of deep vein thrombosis by reducing D dimer values in patients undergoing spinal surgery. Eur Rev Med Pharm Sci. 2018;22(1):229–37.
18. Snijders D, Schoorl M, Schoorl M,et al. D-dimer levels in as sessing severity and clinical outcome in patients with community-acquired pneumonia: a secondary analysis of a randomized clinical trial. Eur J Intern Med. 2012;23(5):436–41.
19. Li T, Yu H, Hou W, et al. Evaluation of variation in coagulation among children with Mycoplasma pneumoniae pneumonia: a case-control study. J Int Med Res. 2017;45(6):2110–8.
20. Jin X, Zhu Y, Zhang Y, et al. Assessment of levels of D-dimer and interferon-γ in pediatric patients with Mycoplasma pneumoniae pneumonia and its clinical implication. Exp Ther Med. 2018;16(6):5025–30.
21. Choi Y-J, Jeon J-H, Oh J-W. Critical combination of initial markers for predicting refractory Mycoplasma pneumoniae pneumonia in children: a case control study. Respir Res. 2019;20(1):193.
22. Huang L, Huang X, Jiang W, et al. Independent predictors for longer radiographic resolution in patients with refractory Mycoplasma pneumoniae pneumonia: a prospective cohort study.BMJ Open. 2018;8(12): e023719.
23. Bandeshe H, Boots ï¼², Dulhunty J, et al. Is inhaled prophylactic heparin useful for prevention and Management of Pneumonia in ventilated ICU patients?: The IPHIVAP investigators of the Australia.