Mycoplasma pneumoniae pneumonia in children

Abstract

Mycoplasma pneumoniae (M. pneumoniae) is a common pathogen that causes community-acquired pneumonia in children. The clinical presentation of this pathogen can range from mild self-limiting illness to severe and refractory cases. Complications may occur, such as necrotizing pneumonia and respiratory failure. Extrapulmonary complications, including encephalitis, myocarditis, nephritis, hepatitis, or even multiple organ failure, can also arise. In this editorial, we discuss the clinical implications of the significant findings from the article "Serum inflammatory markers in children with M. pneumoniae pneumonia and their predictive value for mycoplasma severity" published by Wang et al. They reported that measuring lactic dehydrogenase, interleukin-6 levels, and D-dimer effectively predicts refractory M. pneumoniae pneumonia cases.

Key Words: Cytokine; Mycoplasma pneumoniae pneumonia; Children, Community-acquired pneumonia; Lactic dehydrogenase; Interleukin-6

Core Tip: Children with Mycoplasma pneumoniae pneumonia who have severe imaging abnormalities, respiratory failure, or extrapulmonary complications or do not improve after macrolide treatment should be monitored for inflammatory markers such as lactic dehydrogenase, C-reactive protein, and interleukin-6. These markers help predict severe and refractory cases. Clinicians should identify the cause of macrolide non-responsiveness, such as resistant strains or co-infection, and consider starting glucocorticoid treatment for refractory cases.

TO THE EDITOR

Mycoplasma pneumoniae (M. pneumoniae) is a leading cause of respiratory infections in children, especially community-acquired pneumonia (CAP). It is transmitted via respiratory droplets via coughing, sneezing, and close contact. It usually causes mild illness, though severe complications can occur. CAP in children is a rapidly developing lung infection caused by pathogens contracted outside medical facilities, especially in non-hospital settings[1]. In a prospective, multicenter study on the incidence and causes of CAP among hospitalized US patients, M. pneumoniae was identified as the most common bacterial pathogen (8%) in children under 18. The estimated annual incidence was 1.4 cases per 10000 children, determined using real-time polymerase chain reaction (PCR)[2]. It was most prevalent in school-aged children five and older. Recently, there has been a notable rise in M. pneumoniae pneumonia (MPP) cases among Chinese children, especially after the COVID-19 pandemic[3]. Moreover, nearly 40% of cases progress to severe pneumonia despite appropriate antibiotic treatment[4].

Clinical presentation

Children with MPP often show symptoms such as fever, cough, sore throat, coryza, and occasionally headache[5]. It has also been linked to acute exacerbation of asthma. This infection can occur in any season, usually with a subacute onset. Clinically, children exhibit nonspecific symptoms that do not clearly differentiate it from other causes of CAP. Diagnosing MPP is challenging due to its diverse presentation. Symptoms can range from mild respiratory issues to severe necrotizing pneumonia, pleural effusion, pulmonary embolism, and extrapulmonary manifestations such as encephalitis, myocarditis, nephritis, hepatitis, or even multiple organ failure[6]. These severe or extrapulmonary presentations may result from an excessive immune response or abundant bacterial load[5,7].

Diagnostic test

Nucleic acid amplification: PCR is the gold standard for diagnosing M. pneumoniae infection due to its higher specificity than serology[8-12]. It is a quick and accurate method for diagnosing mycoplasma infections in children, commonly using oropharyngeal or nasopharyngeal samples. Its high sensitivity, specificity, and availability have made it the preferred diagnostic method over slower, less sensitive culture-based techniques, which are often too delayed to help manage acute illness[5]. However, since M. pneumoniae can persist in the respiratory tract after treatment, interpreting PCR results should always involve considering the patient’s clinical condition, as a positive result may not necessarily reflect an active infection[13].

Serological tests: M. pneumoniae-specific IgM antibodies often remain undetectable during the first week after symptom onset. Despite this early absence, these antibodies can persist in the bloodstream for months following infection[14]. Consequently, a single antibody titer test in the acute phase may not reliably confirm an active M. pneumoniae infection. Supporting this, a previous study found that only 63.6% of patients tested positive for M. pneumoniae IgM upon hospital admission, though this rate increased to 97.5% after one week[15]. Paired serum samples showing a shift from negative to positive or increased antibody titers can significantly enhance diagnostic accuracy. A two-fold increase in M. pneumoniae IgM or a four-fold increase in IgG between the acute and recovery phases offers a reliable diagnosis[5]. However, in patients with weakened immune systems, including infants, the immune response may be too weak to produce detectable antibody levels, complicating diagnosis[5]. A 2004 U.S. study on pediatric patients found a 14% prevalence of M. pneumoniae in 154 children hospitalized with CAP based on serology results. Infection was defined as positive if enzyme-linked immunosorbent assay IgM was ≥ 1: 160 or if there was a ≥ 4-fold rise in IgG titer[4]. However, of the 21 seropositive children who had a nasopharyngeal/oropharyngeal swab collected within 24 hours of admission, only 12 (57%) tested positive for M. pneumoniae using PCR, highlighting the limitations of PCR in detection[11].

In the early stage of infection, when IgM antibodies have not yet developed, a positive PCR result may appear with a negative serological test. On the other hand, during the convalescent phase, a positive serological result may accompany a negative PCR test[5]. As a result, relying on a single test is insufficient for accurately diagnosing M. pneumoniae infection. For patients with suspected symptoms, especially pediatric cases, the combination of PCR and IgM tests provides the most effective strategy for early diagnosis[16]. A diagnosis of acute mycoplasma infection can be confirmed if patients meet any of the following criteria: (1) Seroconversion from negative to positive M. pneumoniae IgM; (2) A two-fold increase in M. pneumoniae IgM or a four-fold increase in specific IgG within two weeks; or (3) Positive PCR results.

Leukocyte count

Choi et al[17] discovered that the leukocyte count was within the normal range across all M. pneumoniae pneumonia cases. Fan et al[6] also observed that the leukocyte count was higher in refractory cases than in general M. pneumoniae pneumonia cases, indicating a more severe inflammatory response.

Imaging findings

M. pneumoniae can infect the entire airway, including the interstitial lung and alveoli, causing varying imaging findings based on the infection site. Despite these variations, chest imaging often shows little difference between MPP and CAP from other pathogens, challenging radiological differentiation. However, Fan et al[6] found a higher incidence of pulmonary consolidation in children with MPP compared to those with CAP from other pathogens. A previous study of 393 hospitalized children with MPP reported lobar or segmental consolidation as the most common radiological finding (37%)[18]. Chest radiography and CT scans at admission showed a higher incidence of lung consolidation in refractory MPP cases than in general cases, indicating more severe lung involvement. The proportion of pleural effusion cases was also higher in the refractory MPP group[6,17,19].

Treatment

Antibiotics: Macrolides, including azithromycin, clarithromycin, and erythromycin, are the first-choice treatment for MPP in children. These antibiotics are effective not only in bacterial eradication but also in providing anti-inflammatory effects by modulating cytokine production, including interleukin (IL)-8[20]. Macrolides are highly effective against macrolide-sensitive M. pneumoniae due to their low minimal inhibitory concentrations (MICs)[5]. Furthermore, the pathogen elimination rate after macrolide treatment is higher than other commonly used antibiotics. In macrolide-sensitive M. pneumoniae, the MIC of azithromycin is less than 0.0005 mg/mL, significantly lower than that of doxycycline (0.25 mg/mL) and levofloxacin (0.5 mg/mL)[21]. The most common adverse event after macrolide treatment is gastrointestinal upset, with azithromycin having the lowest rate of side effects and the longest half-life. Some patients may still respond to macrolide therapy, even when the strain is resistant.

If fever persists, symptoms remain unchanged, or radiological findings worsen within 72 hours of starting macrolide treatment, macrolide-resistant MPP should be considered. Once other causes and coinfections have been excluded, second-line antibiotics, such as doxycycline or fluoroquinolones, should be prescribed to manage macrolide-resistant MPP.

Macrolide-resistant M. pneumoniae isolates have been reported at 3%-10% rates in the United States. However, these rates are much higher in Asian countries, ranging from 60%-90% in places like China, Japan, and South Korea[5,22-25]. Macrolides inhibit protein synthesis by binding to domains II and/or V of the 23S rRNA in the bacterial 50S ribosomal subunit[5]. Mutations in domain V of the 23S rRNA are the main cause of macrolide resistance in M. pneumoniae[9]. Although PCR testing for macrolide-resistant M. pneumoniae can guide more effective antibiotic selection, it is not widely used in clinical practice due to its high cost. Additionally, some patients with macrolide-resistant MPP still improve with macrolide therapy alone, further limiting the use of this test[26,27].

Patients with macrolide-resistant MPP often experience prolonged fevers, primarily due to delayed initiation of effective antibiotic treatment[28,29]. Nonetheless, it is uncertain whether macrolide-resistant strains result in more severe disease compared to sensitive strains. Some studies have shown that during hospitalization, inflammatory markers and radiological findings in patients with macrolide-resistant MPP are not more severe than those in patients with macrolide-sensitive MPP[26,28]. In contrast, Zhou et al[30] found that patients with macrolide-resistant MPP had more extrapulmonary complications and more severe radiological findings than those with macrolide-sensitive MPP.

Steroids and intravenous immunoglobulin: Refractory MPP is diagnosed when a patient continues to have fever or worsening clinical and radiological signs for seven or more days despite appropriate antibiotics, such as three days of azithromycin followed by at least four days of doxycycline[7,31,32]. Before confirming this diagnosis, other infections, co-infections with other pathogens, and inflammatory markers should be assessed. Most patients improve with corticosteroids, though optimal dosing and duration remain uncertain[32,33]. Meta-analyses suggest that early corticosteroid use after antibiotics improves outcomes in refractory cases[4]. If fever persists beyond 72 hours while on methylprednisolone, increasing the dose or adding intravenous immunoglobulin may be considered[34].

Patients with refractory MPP often experience longer fevers, prolonged hospital stays, and more frequent extra-pulmonary complications than those with non-refractory MPP[35]. Evidence suggests that macrolide-resistant strains may not directly contribute to refractory MPP, as studies show similar resistance rates in both refractory and general cases[29,30]. Although the exact cause of refractory MPP remains unknown, most studies indicate that immunological mechanisms play a major role.

The pathogenesis of MPP is linked to the activation of macrophages through toll-like receptors, which trigger the release of inflammatory cytokines and chemokines, such as IL-8 and IL-18[36]. In some instances, the host immune response becomes dysregulated, resulting in severe inflammation despite the use of effective antimicrobial treatments. This dysregulation involves the overactivation of immune cells, including antigen-presenting cells and T cells, and excessive production of cytokines like IL-2, IL-5, IL-6, IL-8, and IL-18, contributing to disease progression[37]. In severe or refractory MPP cases, lung damage is primarily caused by the excessive immune response rather than direct damage from the pathogen.

Severity and complications

MPP is generally a mild and self-limiting illness, but in some cases, children may experience a worsening of symptoms. Severe MPP can manifest as necrotizing pneumonia, respiratory failure, encephalitis, myocarditis, nephritis, hepatitis, or multiple organ failure. The exact mechanisms of these severe forms remain unclear, but several hypotheses have been suggested. One proposes that repeated M. pneumoniae infections trigger a hyperimmune response in the lungs. Another suggests that an ineffective initial immune response prolongs the infection, leading to hyperimmunity. The final hypothesis points to overactivation of the innate immune system, particularly macrophage stimulation through Toll-like receptors, as the primary cause of inflammation[38,39].

Predictors of refractory cases

M. pneumoniae proliferates within respiratory epithelial cells by binding its P1 protein to cilia. This P1 protein facilitates binding and exhibits high immunogenicity and antigenic specificity, distinguishing its epitopes from other bacterial species. The binding of the P1 protein stimulates the production of proinflammatory cytokines in the airway mucosa, triggering cellular inflammatory responses, tissue damage, and alterations in host immune function[40-42]. In addition to its role in immune response, M. pneumoniae also triggers both the exogenous and endogenous coagulation systems through various mechanisms, leading to clotting abnormalities and thrombosis and further contributing to inflammation and tissue damage[43].

Wang et al[44] observed that children with severe MPP are more likely to exhibit asthma, extrapulmonary symptoms, lung consolidation, pleural effusion, post-infectious bronchiolitis obliterans, and macrolide-resistant M. pneumonia compared to those with mild cases. The early identification of these extrapulmonary symptoms and potential complications can facilitate prompt clinical intervention. Such early corticosteroid treatment may mitigate severe clinical manifestations and improve patient outcomes.

Early prediction of refractory cases is also crucial for timely intervention, particularly using specific serum markers. Several inflammatory markers, including lactate dehydrogenase (LDH), C-reactive protein (CRP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum ferritin, IL-6, IL-10, TNF-α, interferon-gamma, prothrombin time (PT), and D-dimer, have been investigated as potential indicators for predicting refractory cases. These markers can also help guide decisions regarding the initiation of corticosteroid therapy[6,7,17,45-47].

Wang et al[44] identified LDH, IL-6, IL-10, TNF-α, and D-dimer as significant predictors of severe MPP. However, they didn’t plot the Receiver’s operating characteristic (ROC) curves and calculated the area under the curve (AUC) to evaluate the predictive value of indicators for severe MPP. Previous studies have also identified the cut-off values for these predictors of refractory MPP (RMPP), which vary significantly across studies. Chen et al[48] identified LDH ≥ 379 IU/L, CRP ≥ 39.34 mg/L, and D-dimer ≥ 1.47 ng/mL as independent predictors of RMPP, with AUC values of 0.893, 0.870, and 0.841, respectively, and specificity ranging from 94%-99%. Zhang et al[45] reported that LDH ≥ 417 IU/L, CRP ≥ 16.5 mg/L, and IL-6 ≥ 14.75 pg/mL were significant predictors, with sensitivity between 74-83% and specificity from 63%-77%. Fan et al[6] found that LDH > 378 U/L and IL-6 > 13.2 pg/mL were good predictors of RMPP, both with 70% sensitivity and 80% specificity. Additionally, IL-10 at 5.6 pg/mL was found to be the second most useful biomarker (AUC = 0.735). Similarly, Inamura et al[49] found that LDH ≥ 412 IU/L strongly predicted RMPP, with 80% sensitivity and 100% specificity. Zhang et al[35] also identified IL-10 ≥ 3.65 pg/mL and IFN-γ ≥ 29.05 pg/mL as significant predictors, with strong odds ratios and statistically significant P-values.

LDH is considered a reliable biomarker for refractory MPP due to its upregulation in the disease and commercial availability. The LDH cut-off level for refractory MPP treatment varies from 378 to 480 IU/L across different reports[31,45,50,51]. These findings underscore the need to validate other inflammatory markers as predictors in future clinical studies and highlight the potential clinical implications for initiating early corticosteroid therapy for RMPP.

Clinical implication

Children diagnosed with MPP who fail to improve or worsen after macrolide treatment or have severe chest imaging abnormalities, respiratory failure, or extrapulmonary complications should be monitored for inflammatory markers. Specifically, LDH, CRP, and IL-6 are useful predictors for severity and refractory cases. Based on these markers, clinicians should promptly identify the cause of macrolide non-responsiveness, such as macrolide-resistant strain or co-infection with other pathogens. They should also consider initiating glucocorticoid treatment for RMPP.

Conclusion

M. pneumoniae is a common pathogen of CAP in children. This pathogen can produce proinflammatory cytokines in the airway mucosa, triggering cellular inflammation and altering host immune responses. Monitoring serum inflammatory markers is beneficial in assessing severity, predicting refractory cases, and guiding treatment.

ACKNOWLEDGEMENTS

We gratefully acknowledge the Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University for supporting the manuscript development and Aditya Rana for English editing.