Evaluating the predictive value of procalcitonin, cough duration, and heat peak in severe Mycoplasma pneumoniae pneumonia CURRENT

Objective To investigate the predictive value of risk factors for severe Mycoplasma pneumoniae pneumonia (MPP). Retrospective analyses conducted on 342 children with acute MPP hospitalized between 2018. A total of 342 cases were including in the analyses, with most cases involving infants and preschool-aged children. Patients were categorized as general and severe MPP. Patients in the severe group had increased heat peak, fever duration, cough duration, length of hospitalization, and levels of white blood cell, neutrophils, C-reactive protein, and procalcitonin, as well as reduced levels of lymphocytes and platelets compared to the general group. Logistic regression and receiver operating characteristic curve analyses showed that increased levels of procalcitonin (>0.67 ng/mL), prolonged cough duration (>13.5 days), and heat peak above 38.4°C may be early predictors for severe MPP.

3 value of risk factors for severe MPP were evaluated.

Study subjects
Retrospective analyses were conducted on 342 children with MPP who were hospitalized between December 2015 to December 2018 in the pediatric departments of Tongji Hospital of Huazhong University of Science and Technology and Women and Children's Hospital of Xiamen University. All cases were confirmed according to the guidelines for CAP and MP infections [4][5][6]. Exclusion criteria included disease course > 1 month; mixed infections; congenital lung, chronic, or genetic metabolic disease; antibiotic treatment > 1 week before admission; and insufficient data. After exclusions, a total of 342 children with MPP were included in the analyses. The cases were divided into two groups: general MPP (n = 275) and severe MPP (n = 67). Patients with severe MPP met at least one of the following criteria: severe toxicosis symptom or dyspnea; radiological deterioration observed in more than two lobes of the lung, pleural thickening, adhesion, pleural effusion, atelectasis, or pulmonary abscess; and severe extrapulmonary complications, severe organ damage, or severe disturbance of acid-alkaline balance and electrolyte [5,[7][8][9][10]. Demographic and clinical data including age, sex, season of onset, heat peak(before admission), fever duration(before admission), cough duration(before admission), length of hospitalization (in days), and laboratory results were collected for all participants.
Detection of procalcitonin Procalcitonin (PCT) levels were measured using electrochemiluminescence immunoassays after admission with a detection limit of 0.02 ng/mL. The blood was drawn in vacuum tube filled with separation gel and centrifuged at 3500 rpm for 5 minutes, and PCT levels were analyzed by Roche cobas 8000 automatic biochemistry analyzer within 30 minutes.

Statistical analyses
Categorial data are expressed as frequencies and the differences between the two groups were compared using chi-square and Fisher's exact tests. Continuous data are expressed as mean ± standard deviation and the differences between the two groups were compared using independent samples t-tests. Multivariate logistic regression analyses and receiver operating characteristic (ROC) curves were used to assess the risk factors and their predictive value for severe MPP. All statistical analyses were performed using SPSS version 25.0 (IBM Corp, Armonk, NY, USA). P-values < 0.05 were considered statistically significant.

Population
Among the 342 patients with MPP, the average age was 4.07 ± 2.57 years old (54.4% male). Of all participants, 77.8% were infants or preschool-aged children. The incidence rate by season was 36.5% in spring, 28.4% in summer, 26.6% in autumn, and 8.5% in winter. A total of 208 cases (60.8%) reported a fever.

Clinical characteristics and laboratory detection
There were no differences in age, sex, season of onset, and prevalence of fever between the two groups. However, heat peak, fever duration, cough duration, and length of hospitalization were increased in patients with severe MPP compared to those with general MPP (Table 1). Moreover, patients with severe MPP had increased levels of white blood cell(WBC), neutrophils, C-reactive protein (CRP), and PCT, and reduced levels of lymphocytes and platelets ( Table 2).   Table 3). The analyses found that the optimal cutoff value for PCT was 0.67 ng/mL, with an area under the curve (AUC) of 0.835, sensitivity of 64.2%, and specificity of 89.8%. The optimal cutoff value for cough duration was 13.5 days, with an AUC of 0.805, sensitivity of 62.7%, and specificity of 85.5%. The optimal cutoff value for heat peak was 38.4 °C, with an AUC of 0.761, sensitivity of 71.6%, and specificity of 83.3% (Fig. 1). Lymphocytes were excluded from the analyses, as the ROC curve was below the diagonal line.  [11]. However, in our study, the majority of patients with MPP were infants or preschool-aged children. This finding is consistent with a study based in Thailand [12]. Regional differences in the season of onset have been demonstrated, with increased incidence in the fall and winter in North China, and increased incidence in the summer and fall in South China [11]. Moreover, previous studies have reported an association between MPP and elevated atmospheric temperatures and humidity, with a 17% increase in MPP cases for every 1 °C increase, and a 4% increase in MPP cases for every 1% humidity increase [6,13]. In the present study, patients lived in Central and South China, and most MPP cases occurred in the spring, summer, and fall, similar to previous studies [6,13]. Nevertheless, no significant differences in age, sex, and seasonal onset between patients with general MPP and severe MPP were observed in this study. Further large-scale, multicenter studies are needed to validate these findings.
The most common symptoms of MPP were fever and cough. Fever was reported in 73.1% of patient with severe MPP and 57.8% of patients with general MPP. While not statistically significant, fevers tended to be higher in patients with severe MPP. Most children with severe MPP had moderate or high fevers, whereas most children with general MPP had moderate or low fever. The majority of the patients with severe MPP had a fever lasting more than 7 days, a cough lasting more than 2 weeks, and most required hospitalization for more than 7 days. Patients with general MPP had significantly shorter fever durations, cough durations, and hospitalizations compared to those with severe MPP, consistent with previous reports [8,14,15]. The Japanese Respiratory Society's scoring system provides guidance for recognizing MPP, with white blood cell (WBC) count < 10 × 10 9 /L being one of six standard parameters [3]. In our study, patients with MPP had WBC counts below this threshold.
Patients with severe MPP had significantly increased levels of neutrophils, CRP and PCT, as well as reduced levels of lymphocytes and platelets compared to patients with general MPP. These findings are consistent Yan et al. [8,16,17]. Previous studies have suggested that thrombocytopenia is an extrapulmonary manifestation of MPP [3,18]. Therefore, acute-phase thrombocytopenia may have predictive value for severe MPP. In general, the presence of pyrogenic products of inflammation and excessive inflammatory response can cause lung damage or even lead to necrotizing pneumonia [19][20][21][22].
In recent years, several studies have investigated the risk factors for MPP, but few have assessed their predictive value. Our ROC curve analyses showed that increased PCT levels (> 0.67 ng/mL), prolonged cough duration (> 13.5 days), and heat peak above 38.4 °C may be early predictors for severe MPP in children. The analyses revealed that PCT offers slightly greater predictive value than cough duration and heat peak. Therefore, a detailed history of cough duration and heat peak may be required when assessing the risk for severe MPP [17]. In addition, PCT had greater specificity compared to the other two risk factors. PCT is a 116 amino acid protein encoded by the CALC-1 gene, which typically exists in low concentrations in parafollicular cells of the thyroid gland in healthy individuals. In the presence of an infection, CALC-1 gene expression is induced in non-neuroendocrine cells, resulting in increased PCT levels [23]. As a clinical biomarker of bacterial infections, PCT levels are measured to assess the severity and prognosis of CAP, acute respiratory distress syndrome, and sepsis, and guide antibiotic and glucocorticoid treatment [23][24][25][26][27]. While several studies have investigated the relationship between PCT and Streptococcus pneumoniae, Haemophilus influenzae, and other common bacterial pathogens in patients with CAP, few clinical studies have assessed this relationship in patients with MPP [28]. PCT levels increase within 2-4 h after infection and peak within 24-48 h [29]. The PCT assessment has several advantages including its availability, ease of use, low cost, universality, and reliability. Moreover, in this study, the threshold value for PCT was 0.67 ng/mL, which is much lower than the threshold for severe bacterial infections and sepsis (≥ 2 ng/mL). These findings are consistent with those of previous study that suggested that PCT levels may be used to predict severe MPP in patients with acute MPP [16]. In addition, PCT levels at admission were associated with longer fever duration and hospitalization, indicating that PCT may be a risk factor for prolonged fever in MPP [30].

Conclusion
This study found increased intrapulmonary and extrapulmonary complications as well as worse outcomes in patients with severe MPP compared to those with MPP. Moreover, the severity of disease was closely linked to clinical manifestations and the inflammatory response. Our findings suggest that in children with MPP, increased levels of procalcitonin (> 0.67 ng/mL), prolonged cough duration (> 13.5 days), and heat peak above 38.4 °C can be used as a reference index for the assessment of disease severity.

Limitations
There were some limitations in this study. First, it was a retrospective observational study and the enrolled patients were only from two tertiary centers. Second,some patients received antibiotic treatment before admission and it might affect the results of heat peak cough duration and PCT levels. However, our evaluation had been done in a large study population even excluded the patients who received more than a week of antibiotic treatment and those with mixed infections.
Furthermore cases received antibiotic were the true status for most hospitalized MPP children.

Ethical declarations
This study was approved by the Ethics Committee of Tongji Hospital and all participants provided written informed consent from parents/guardians.

Consent for publication
Not applicable.

Availability of data and materials
All data generated or analyzed during the current study are available from the corresponding author Yan Liu on reasonable request. Data are not publicly available due to concerns regarding research participant privacy.

Competing interests
The authors declare no conflicts of interest relevant to this study.

Funding
Not applicable.

Authors'contributions
Liqing Chen and Ying Yang contributed to designing the study and interpreting data. Ying Yang contributed to drafting the manuscript. Yan Liu contributed to designing the study, acquisition of and interpreting data and approving the final version of the manuscript. All authors read and approved the final manuscript.