Clinical Features and Risk Factors for Rhabdomyolysis in Patients with Chlamydia psittaci Pneumonia: A Multicenter Study

Introduction

Chlamydia psittaci pneumonia is a rare zoonotic infectious disease caused by the transmission of Chlamydia psittaci bacterium.^1,2 Recently, because of the extensive application of high-throughput sequencing technologies and increased clinical awareness, the reported incidence of Chlamydia psittaci pneumonia has significantly increased.^3,4 Clinical manifestations of Chlamydia psittaci pneumonia are heterogeneous and range from mild influenza-like symptoms to severe community-acquired pneumonia; additionally, Chlamydia psittaci pneumonia is often accompanied by high fever, dry cough, headache, and prominent extrapulmonary manifestations such as hepatic dysfunction and neurological symptoms.^4,5 Diverse symptoms frequently result in a misdiagnosis and delayed treatment.

Clinical observations have indicated that the occurrence of rhabdomyolysis (RM) in patients with Chlamydia psittaci pneumonia is not only prevalent but also often indicates severe disease and a poor prognosis.⁶ Compared with patients with uncomplicated Chlamydia psittaci pneumonia, those with Chlamydia psittaci pneumonia and concurrent RM tend to experience more severe myalgia and higher levels of inflammatory markers, and they are at an increased risk for multiorgan dysfunction.^6,7 Nevertheless, the current understanding of RM is limited because its clinical epidemiological characteristics, such as its incidence and typical clinical presentation, in large multicenter cohorts have not been systematically described. Additionally, key risk factors that predispose certain patients with Chlamydia psittaci pneumonia to RM are unclear. Whether these factors are related to pathogen virulence, host-specific responses, or other clinical or therapeutic factors requires further elucidation. In-depth analyses of clinical outcomes of this patient population, including the development of acute kidney injury (AKI) and the need for intensive care, have been insufficient, thus limiting assessments of the impact of RM on treatment strategies and prognostic evaluations.

Therefore, systematically characterizing the clinical characteristics of Chlamydia psittaci pneumonia complicated by RM and identifying associated risk factors are of critical importance to early risk stratification, which enables timely intervention and enhances clinical prognosis. Therefore, this multicenter retrospective study aimed to comprehensively describe the clinical characteristics of and risk factors for RM in patients with Chlamydia psittaci pneumonia to provide evidence-based support for clinical decision-making.

Materials and Methods

Study Design and Participants

Clinical data of patients with Chlamydia psittaci pneumonia who were admitted to eight hospitals in Guangdong Province between January 2020 and December 2025 were retrospectively collected. The inclusion criteria were as follows: clinical manifestations and chest imaging findings consistent with the diagnostic criteria for community-acquired pneumonia;⁸ negative results of routine microbiological examinations (including cultures and smears of blood, sputum, and bronchoalveolar lavage fluid); and detection of Chlamydia psittaci nucleic acid sequences in bronchoalveolar lavage fluid or blood samples via high-throughput sequencing techniques (eg., metagenomic next-generation sequencing [mNGS] or targeted next-generation sequencing [tNGS]). The exclusion criteria were age younger than 18 years and incomplete clinical data.

The diagnosis of severe community-acquired pneumonia required meeting⁸ either (1) any one of the major criteria, namely, septic shock requiring vasopressors and respiratory failure requiring mechanical ventilation or (2) at least three of the following minor criteria: respiratory rate ≥ 30/min, PaO₂/FiO₂ ≤ 250 mmHg, multilobar infiltrates, confusion and/or disorientation, blood urea nitrogen ≥ 20 mg/dL, white blood cell count < 4×10⁹/L, platelet count < 100×10⁹/L, temperature < 36 °C, or hypotension requiring rapid fluid resuscitation. RM was diagnosed according to the following established criteria:⁹ presence of clinical symptoms such as myalgia and muscle weakness; elevated creatine kinase (CK) levels exceeding five-times the upper limit of normal (310 U/L for male patients and 200 U/L for female patients); and exclusion of common etiologies, such as trauma, exercise, cerebrovascular or cardiovascular events, and drug use. Participants were categorized into the RM group or non-RM group based on these diagnostic criteria. AKI was defined as an increase in serum creatinine level ≥ 0.3 mg/dL within 48 h; an increase to ≥ 1.5 times the known or presumed baseline value within the previous 7 days; or urine output persistently < 0.5 mL/kg/h for 6 h.¹⁰

Next-Generation Sequencing

In accordance with standard clinical procedures, 5–10 mL of bronchoalveolar lavage fluid or venous blood was collected from each patient and submitted to designated laboratories for mNGS or tNGS. Specifically, mNGS was performed by Daan Gene Co., Ltd. (Guangzhou, China), Vision Medicals Co., Ltd. (Guangzhou, China), BGI Genomics Co., Ltd. (Shenzhen, China), and Seegene Biotech Co., Ltd. (Guangzhou, China). tNGS was conducted by Daan Gene Co., Ltd. (Guangzhou, China), KingMed Diagnostics Group Co., Ltd. (Guangzhou, China), and Huayin Medical Laboratory (Guangzhou, China). All procedures, including nucleic acid extraction and purification, library construction, high-throughput sequencing, and bioinformatics analysis, followed standardized laboratory workflows, and formal pathogen detection reports were issued.

Data Collection

A standardized case report form was developed to record data. This form included the following: baseline characteristics such as age, sex, interval from symptom onset to hospital admission, length of hospital stay, and history of underlying diseases; clinical manifestations and vital signs at admission; laboratory findings upon admission; and treatment regimens and clinical outcomes. Additionally, the Pneumonia Severity Index (PSI) was calculated based on clinical parameters obtained on the day of admission.

Statistical Analysis

Statistical analyses were performed using SPSS version 25.0. Continuous variables with normal distribution were expressed as mean ± standard deviation (SD) (). For normally distributed data, comparisons between groups were performed using the independent samples t-test, and correlations were assessed using Pearson’s correlation analysis. Continuous variables that were not normally distributed were presented as medians (interquartile range [IQR]). For non-normally distributed data, comparisons between groups were conducted using the Mann–Whitney U-test, and correlations were evaluated using Spearman’s rank correlation analysis. Finally, categorical variables were expressed as frequencies (percentages), and comparisons between groups were performed using the χ² test or Fisher’s exact test.

To identify risk factors associated with RM, variables with P < 0.05 in univariate analysis were included in a multivariable logistic regression model for further analysis. Receiver-operating characteristic (ROC) curves were plotted to evaluate the diagnostic performance of relevant indicators of RM. A two-sided P < 0.05 was considered statistically significant.

Results

General Information of Patients with Chlamydia psittaci Pneumonia

A total of 231 patients with Chlamydia psittaci pneumonia were initially included; after excluding one patient younger than 18 years and 10 patients with incomplete clinical data, 220 patients were finally included. Furthermore, 132 (60.0%) were male and 88 (40.0%) were female. The mean age of the participants was 58.9 years (SD, ±12.1 years). The median interval from symptom onset to hospital admission was 5 days (IQR, 3–7 days). Additionally, 113 patients (51.4%) had underlying comorbidities, including hypertension in 56 (25.5%), diabetes mellitus in 44 (20.0%), coronary heart disease in 21 (9.5%), and chronic liver disease in 15 (6.8%) [Table 1]. Furthermore, of these 220 patients, 103 (46.8%) had elevated CK levels and 45 (20.5%) developed RM. Of the 120 patients with non-severe pneumonia, 34 (28.3%) had elevated CK levels and 7 (5.8%) developed RM. In contrast, among the 100 patients with severe pneumonia, 69 (69.0%) exhibited elevated CK levels and 38 (38.0%) developed RM. The proportions of patients with elevated CK levels and those who developed RM were significantly higher in the severe pneumonia group than in the non-severe pneumonia group (P < 0.001) [Figure 1].

Table 1 Clinical Features of Rhabdomyolysis in Patients with C. psittaci Pneumonia

Table 2 Analysis of Laboratory Test Results for Patients with C. psittaci Pneumonia Accompanied with Rhabdomyolysis

Figure 1 Creatine kinase abnormality at admission in patients with Chlamydia psittaci pneumonia by severity of disease. ***Comparison between severe and non-severe pneumonia, P<0.001. Bars represent the number of patients.

Among the 45 patients with RM, CK levels ranged from 1,000 to 4,999 U/L in 28 patients and from 5,000 to 14,999 U/L in 10 patients. Additionally, CK levels were higher than 15,000 U/L in seven patients (Figure 2).

Figure 2 Distribution of creatine kinase levels in 45 patients with rhabdomyolysis. Bars represent the number of patients.

Clinical Characteristics of RM in Patients with Chlamydia psittaci Pneumonia

Compared with patients without RM, those with RM were predominantly male (Tables 1–3). Furthermore, those with RM exhibited significantly higher frequencies of myalgia, dyspnea, and altered consciousness and had a higher PSI. Patients with RM were also more likely to develop AKI, require prolonged hospital stays, and require invasive mechanical ventilation. Additionally, compared with patients without RM, those with RM had significantly elevated neutrophil-to-lymphocyte ratios (NLRs), C-reactive protein (CRP)-to-albumin ratios (CARs), and levels of CRP, procalcitonin (PCT), CK, lactate dehydrogenase, D-dimer, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, serum creatinine, N-terminal pro-B-type natriuretic peptide, and cardiac troponin T. In contrast, platelet counts and serum sodium and albumin levels were significantly lower in patients with RM (P < 0.05).

Table 3 Treatment and Prognosis for Patients with C. psittaci Pneumonia Accompanied with Rhabdomyolysis

A correlation heatmap analysis demonstrated that CK and lactate dehydrogenase levels were significantly positively correlated with the PSI (r = 0.467, P < 0.001; r = 0.587, P < 0.001), NLR (r = 0.359, P < 0.001; r = 0.363, P < 0.001), CAR (r = 0.393, P < 0.001; r = 0.468, P < 0.001), and levels of PCT (r = 0.559, P < 0.001; r = 0.606, P < 0.001), alanine aminotransferase (r = 0.382, P < 0.001; r = 0.533, P < 0.001), aspartate aminotransferase (r = 0.549, P < 0.001; r = 0.743, P < 0.001), and D-dimer (r = 0.429, P < 0.001; r = 0.628, P < 0.001). Conversely, CK and lactate dehydrogenase levels were significantly negatively correlated with the platelet count (r = −0.393, P < 0.001; r = −0.380, P < 0.001) [Table 4].

Table 4 Correlation of Muscle Enzyme-Related Indicators

Risk Factors for RM in Patients with Chlamydia psittaci Pneumonia

Based on previous literature on RM, both the number of events (ie., number of patients with concurrent RM) and potential collinearity among variables were analyzed to identify factors associated with RM. A multivariable logistic regression analysis of the identified factors was subsequently conducted. RM development was included as the dependent variable, and the PSI, NLR, CRP level, dyspnea, and hyponatremia were included as independent variables. The results demonstrated that a higher PSI (odds ratio [OR], 1.182; 95% confidence interval [CI], 1.029–1.316; P = 0.022), dyspnea (OR, 6.002; 95% CI, 1.212–29.717; P = 0.028), elevated CRP levels (OR, 1.217; 95% CI, 1.182–1.475; P = 0.007), and hyponatremia (OR, 2.249; 95% CI, 1.063–4.762; P = 0.034) were independent risk factors for RM in patients with Chlamydia psittaci pneumonia (Table 5).

Table 5 Risk Factors for Rhabdomyolysis in Multivariate Logistic Regression Model

To evaluate the predictive values of the PSI and CRP levels for RM in Chlamydia psittaci pneumonia, a ROC curve analysis was performed. The area under the ROC curve values for both the PSI and CRP levels were significantly greater than 0.7 (P < 0.001), indicating good diagnostic performance (Table 6 and Figure 3). Using a cutoff value of 107, the sensitivity and specificity of the PSI for predicting RM were 77.1% and 72.0%, respectively. Alternatively, using a cutoff value of 196 mg/L, the sensitivity and specificity of the CRP level were 75.6% and 64.6%, respectively.

Table 6 Predictive Efficacy of PSI Score and CRP for Rhabdomyolysis

Figure 3 ROC curve of PSI and CRP in predicting Chlamydia psittaci Pneumonia complicated with rhabdomyolysis. Abbreviations: CRP, C-reactive protein; PSI, pneumonia severity index.

Discussion

To our knowledge, this is the first study to systematically investigate the clinical characteristics of and risk factors for RM in patients with Chlamydia psittaci pneumonia. This multicenter retrospective analysis indicated that RM is an important complication of Chlamydia psittaci pneumonia that is closely associated with aggravated disease severity and adverse clinical outcomes. Additionally, several independent risk factors with early warning potential were identified in this study.

RM developed in 20.5% of patients with Chlamydia psittaci pneumonia in the study cohort, and nearly half exhibited elevated CK levels. This proportion was considerably higher than that reported for pneumococcal pneumonia and coronavirus disease 2019 (COVID-19).^11–13 These findings suggest that Chlamydia psittaci infection may have a stronger propensity for direct skeletal muscle involvement or triggering an intense systemic inflammatory response, thus leading to myocyte injury. The results of this study further revealed that patients with Chlamydia psittaci pneumonia complicated by RM generally experienced more severe disease, as reflected by the increased incidences of dyspnea and altered consciousness, higher PSI, increased need for invasive mechanical ventilation, and prolonged hospital stays. These observations are largely consistent with the findings in cases of RM associated with Legionella infection and COVID-19.^14,15 Additionally, the incidence of AKI in patients with RM was significantly higher than that in patients without RM, suggesting that nephrotoxic substances released during RM, such as myoglobin, may contribute to renal injury.^16,17 This mechanism may play an important role in exacerbating disease severity and poor prognoses. Therefore, RM should be regarded as a clinically significant complication of Chlamydia psittaci pneumonia that warrants heightened attention and proactive management.

The precise mechanisms underlying RM in Chlamydia psittaci pneumonia are unclear. However, based on the findings of this study and the previous literature,^18–22 the following potential mechanisms have been indicated: direct invasion of skeletal muscle cells by the pathogen, immune-mediated injury driven by proinflammatory mediators and cytokines, damage caused by microvascular obstruction, and hypoxia and metabolic disturbances.

Chlamydia psittaci, which is characterized by high pathogenicity, may cause widespread damage to host cells, including myocytes, thereby leading to systemic infection.²³ Participants with RM exhibited significantly elevated inflammatory markers, including the NLR, CAR, and levels of CRP and PCT. Chlamydia psittaci infection can trigger a robust immune response with the release of large amounts of inflammatory cytokines.¹⁹ These inflammatory cytokines may directly injure muscle cells or facilitate the release of reactive oxygen species and proteolytic enzymes through the activation of immune cells (eg., neutrophils and macrophages), further disrupting muscle cell membranes and intracellular structures. Substantially elevated D-dimer levels observed in our cohort suggest a hypercoagulable state and possible endothelial injury.^24,25 Severe Chlamydia psittaci pneumonia can impair pulmonary gas exchange, resulting in systemic hypoxia. Under hypoxic conditions, skeletal muscle cells may develop energy metabolism dysfunction and membrane instability. Notably, although previous studies have reported cases of quinolone-induced RM,²⁶ no such cases were identified in this study.

Infection is a relatively uncommon cause of RM.²² No studies have specifically addressed risk factors for RM in Chlamydia psittaci pneumonia. In this study, based on the results of multivariable logistic regression analysis, several independent risk factors for RM in patients with Chlamydia psittaci pneumonia were identified, including a high PSI, elevated CRP levels, dyspnea, and hyponatremia. These findings indicate that RM development is not driven by a single mechanism; instead, RM development reflects the combined effects of disease severity, systemic inflammation, and internal homeostatic disturbances. Further analysis showed that PSI ≥ 107 or CRP level ≥ 196 mg/L can serve as risk thresholds for predicting concurrent rhabdomyolysis, and they can be used for early clinical warning.

This study investigated the association between a specific pathogen, Chlamydia psittaci, and RM in a large, multicenter cohort. This study systematically characterized the clinical features of RM in Chlamydia psittaci pneumonia and its associated risk factors, thus addressing a significant knowledge gap in this field. Nevertheless, because of its retrospective observational design, this study had certain inherent limitations. The effects of confounding factors (eg., concomitant medications and pre-existing muscle disorders) could not be eliminated. Documentation of clinical symptoms, such as myalgia, relied on medical records and may have been subject to information bias. In addition, the small number of patients in the case group may affect the stability of the prediction model. All data were derived from hospitals within a single province, which may have limited the generalizability of the findings to other populations, and there was no a priori sample size calculation. Future prospective multicenter studies across different regions are warranted to confirm the risk factors identified in this study and further elucidate the molecular mechanisms underlying muscle injury induced by Chlamydia psittaci.

Conclusion

RM is a common and serious complication of Chlamydia psittaci pneumonia that is associated with adverse clinical outcomes. During the treatment of patients with Chlamydia psittaci pneumonia, particularly those with critical illness, physicians should maintain a high level of vigilance. For patients with a high PSI, significantly elevated CRP levels, prominent dyspnea, or hyponatremia, routine and dynamic monitoring of muscle enzyme profiles is recommended to facilitate the early detection of RM.