KL-6 emerges as a strong biomarker for severe Chlamydia pneumoniae infection in children

Chlamydia pneumoniae is an obligate intracellular bacterium that infects the ciliated epithelium of the human respiratory tract. First isolated in 1965 from a conjunctival specimen collected during a trachoma vaccine trial in Taiwan, the pathogen is now recognized as one of the common causes of community-acquired pneumonia, and humans remain its only known natural reservoir. Transmission occurs through respiratory droplets, and the incubation period stretches three to four weeks, long enough that most infections present as mild to moderate symptoms such as a runny nose and cough and are easily overlooked. A minority of patients, however, progress to severe pneumonia or even extrapulmonary complications, and clinicians have long lacked a laboratory indicator that reliably reflects the degree of pulmonary parenchymal injury in these cases.

Routine inflammatory markers used to gauge pneumonia severity have limited specificity for the lung damage caused by C. pneumoniae. White blood cell counts, high-sensitivity C-reactive protein, and procalcitonin are commonly measured, but they reflect systemic inflammation rather than local alveolar epithelial injury. Because C. pneumoniae triggers a chronic, monocyte-macrophage-predominant non-necrotic inflammation localized mainly to the airway mucosa, many of these markers remain normal even when the infection is severe. A team of clinical laboratory researchers in Suzhou, China, led by Lei Ding of the Children’s Hospital of Wujiang District and collaborating with colleagues at The Fifth People’s Hospital of Suzhou, Nanjing Medical University, and Suzhou Municipal Hospital, set out to determine whether a different kind of biomarker could fill this gap.

The marker they investigated is Krebs von den Lungen-6, or KL-6, a large molecular weight glycoprotein antigen mainly secreted by proliferating or damaged type II alveolar epithelial cells. KL-6 corresponds to the shed ectodomain of mucin 1, a transmembrane glycoprotein constitutively expressed on the apical surface of type II alveolar epithelial cells. Under both physiological and pathological conditions, circulating KL-6 concentrations are determined by basal and stress-induced MUC1 synthesis coupled with tightly regulated ectodomain shedding. During pulmonary inflammation or fibrotic remodeling, matrix metalloproteinase-mediated proteolytic cleavage of MUC1 releases the soluble KL-6 ectodomain into the alveolar space, and subsequent spillover into the systemic circulation produces measurable elevations in serum levels. The Japanese scholar Kohno and colleagues first used KL-6 in 1989 to evaluate disease activity in interstitial lung disease, and in 1999 the Japanese National Health Insurance System officially included it as a biomarker for assessing ILD disease activity. Since then, KL-6 has been shown to predict the risk of severe COVID-19 pneumonia, correlate with in-hospital mortality in community-acquired pneumonia, and monitor disease progression in immune checkpoint inhibitor-induced pneumonitis. Its expression pattern in acute C. pneumoniae infection in children, however, remained unclear.

To address this, the researchers enrolled 68 hospitalized children with acute lower respiratory tract infection caused by C. pneumoniae at the Children’s Hospital of Wujiang District between May 2024 and April 2025. The cohort comprised 48 mild cases and 20 severe cases, with 19 healthy children serving as controls. Inclusion required a clinical diagnosis based on the Zhu Futang practice of pediatrics, positive serum C. pneumoniae-IgM, and imaging findings of segmental pneumonia or extensive unilateral or bilateral lesions. Severe cases were defined by poor general condition, refusal to eat or dehydration, consciousness disturbance, rapid respiratory rate, cyanosis, dyspnea, pulmonary infiltration involving multiple lobes or at least two-thirds of the lung, pleural effusion, pulse oxygen saturation at or below 0.92, or extrapulmonary complications. Children with allergies, tumors, immunodeficiency, or other congenital diseases were excluded, as were those with mixed infections involving Mycoplasma pneumoniae, influenza A or B virus, respiratory syncytial virus, human rhinovirus, or adenovirus, confirmed by multiplex PCR on throat swabs.

Serum KL-6 levels were measured using a Fujifilm LUMIPULSE G1200 chemiluminescent immunoassay system with a lower limit of detection of 1 U/mL and an intra-assay coefficient of variation of at most 4.4 percent. C. pneumoniae-IgM was quantified on an iFlash 3000 chemiluminescent immunoassay system, and routine blood tests, biochemical parameters, coagulation, and infection markers were performed on automated analyzers from Mindray, Sysmex, and Roche. Imaging examinations used a GE Optima 640 whole-body CT scanner, and the number of infected lung segments was collected retrospectively. Statistical analyses were carried out with GraphPad Prism 8.0 and IBM SPSS Statistics 22, with normally distributed data compared using the t test and non-normally distributed data analyzed with the Wilcoxon rank-sum test. Diagnostic performance was assessed using ROC curves, and the 95 percent confidence interval of the area under the curve was calculated with the Percentile Bootstrap method, generating 1000 ROC curves through repeated sampling with replacement to avoid the limitation of the traditional normal approximation when the AUC is close to 1 and the sample size is small.

The results showed that serum KL-6 levels were significantly higher in the severe group than in the mild group, with a median of 303.00 U/mL in severe cases compared with 146.50 U/mL in mild cases, a difference that was highly statistically significant. Binary logistic regression analysis, which entered a maximum of two predictor variables following the ten events per variable rule to mitigate overfitting risk, indicated that KL-6 was independently associated with severe C. pneumoniae infection in children, with an odds ratio of 1.048 per unit increase. The area under the ROC curve for differentiating severe from mild infection was 0.951, with a 95 percent confidence interval of 0.880 to 0.997, indicating a statistically significant capacity to discriminate disease severity. The optimal cut-off value was 196.5 U/mL, which fell below the proposed pediatric benchmarks of 250 U/mL reported by Imai and colleagues and 300 U/mL proposed by Kubota and Haruta.

Further analysis revealed that the KL-6 level was positively correlated with the number of pulmonary lesions, the number of hospitalization days, and C. pneumoniae-IgM levels, but not with other indicators such as CRP, PCT, or IL-6. Children with fewer than three lesions had significantly lower KL-6 levels than those with three or more lesions. When the cohort was split into high and low expression groups based on the median KL-6 level of 159 U/mL, the high KL-6 group exhibited longer hospitalization duration and higher C. pneumoniae-IgM levels, whereas no inter-group differences were observed for other laboratory indicators. This pattern suggests that KL-6 mainly reflects pulmonary parenchymal injury rather than the systemic inflammatory response, compensating for the deficiency of routine indicators in evaluating local lung injury.

Interestingly, serum lactate dehydrogenase was marginally lower in the severe group than in the mild group, but both values fell within the healthy pediatric reference range, and the inter-group difference was smaller than the intrinsic biological variation among healthy children. The researchers attribute this borderline statistical result partly to the small sample size of severe cases and retrospective sampling on admission. The finding fits the pathogenic features of C. pneumoniae, which triggers chronic, non-necrotic inflammation localized mainly to the airway mucosa without widespread acute pulmonary parenchymal necrosis, thereby limiting systemic LDH release. Multiple pediatric cohorts corroborate this view, with most inflammatory markers normal in 145 children with C. pneumoniae pneumonia, and in a 141-patient risk model only wheezing and co-infection were independent predictors of severe disease, whereas necrosis-associated markers such as LDH were excluded.

The study is the first to confirm that serum KL-6 is independently associated with severe acute C. pneumoniae infection in children, and the results are consistent with the role of KL-6 in other lung diseases, including Mycoplasma pneumoniae pneumonia and respiratory syncytial virus bronchiolitis. The average KL-6 expression level in patients with C. pneumoniae infection is lower than that in patients with Mycoplasma pneumoniae pneumonia, possibly because C. pneumoniae infection causes mainly mild to moderate lung injury and the study excluded children with mixed infections, reducing the inflammatory effect. The authors suggest that if KL-6 levels continue to increase, severe infection should be suspected and timely intervention implemented. KL-6 does not need to be a routine screening indicator given that C. pneumoniae infection is mainly mild, but for children with severe symptoms such as persistent cough and rapid breathing, KL-6 detection can improve the accuracy of disease assessment and optimize the allocation of medical resources.

The researchers acknowledge several limitations. The study was single-center and small, with only 20 severe cases among 68 enrolled children, which may have affected statistical power. Changes in KL-6 levels before and after treatment were not tracked, so the value of KL-6 in monitoring treatment effects could not be evaluated. Children with mixed infections or underlying diseases were excluded, so the results may not generalize to complex cases, and no mechanistic experiments were performed to determine how KL-6 is released during alveolar epithelial cell injury, meaning the findings establish associations rather than causal relationships. Future work, the authors suggest, should include multicenter prospective investigations, longitudinal serial monitoring of KL-6 dynamics, inclusion of patients with complex comorbidities or mixed infections, and rigorous mechanistic dissection of MUC1-mediated KL-6 release pathways. Published in Frontiers in Cellular and Infection Microbiology on 16 October 2026, the study provides a basis for the rational selection of clinical detection items and positions KL-6 as an auxiliary biomarker for assessing pulmonary parenchymal injury in suspected severe C. pneumoniae cases.

Subject of Research: Biomarkers

Article Title: Clinical significance and discriminatory performance of the serum KL-6 level as a biomarker for severe Chlamydia pneumoniae infection in children

Article References: Ding, L., Chen, S., Song, H., Cheng, S., Shao, M., Zhang, H., Hua, J., Gao, F., & Xu, J. (2026). Clinical significance and discriminatory performance of the serum KL-6 level as a biomarker for severe Chlamydia pneumoniae infection in children. Frontiers in Cellular and Infection Microbiology, 16, Article 1791097. https://doi.org/10.3389/fcimb.2026.1791097

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1791097

Keywords: Clinical, significance, discriminatory, performance, serum, KL-6, level, biomarker, severe, Chlamydia, pneumoniae, infection