Tropheryma whipplei is a rod-shaped, Gram-positive bacterium that belongs to the family Tropherymataceae, order Micrococcales, class Actinomycetes. It is primarily recognized as the causative agent of Whipple disease, a rare chronic condition characterized by symptoms such as diarrhea, weight loss, arthritis, spondylodiscitis, endocarditis, and lymphadenopathy [1]. Acute infections caused by T. whipplei have also been reported, leading to gastroenteritis and bacteremia [2]. Additionally, T. whipplei has been found in various human samples, including blood, urine, heart valves, myocardium, and skeletal muscle [3]. Its presence in human saliva and stool ranges from approximately 0.2% to 2.3% [4], indicating that asymptomatic carriers may commonly harbor the bacterium. Since 2007, an increasing number of studies have detected the DNA of T. whipplei in bronchoalveolar lavage (BAL) and other respiratory samples from patients with pneumonia, asthma, or interstitial lung disease, suggesting a potential link between the bacterium and respiratory illnesses. A case-control study conducted in 2016 established the causative role of T. whipplei in pneumonia [5]. Despite this evidence, pulmonary infections caused by T. whipplei are still regarded as rare.
From January 2024 to July 2025, a total of 1,308 BAL samples from patients diagnosed or suspected of having pulmonary infections were analyzed using metagenomic next-generation sequencing (NGS) at Jining First People's Hospital in Shandong Province, China. After retrospective analysis, 52 cases (3.98%) were tested positive for T. whipplei . The average age of the patients was 52.23 years, with 78.85% being over 40 years old (Table 1), indicating that older individuals are more susceptible to T. whipplei . Analysis of the monthly incidence rates showed no obvious patterns; however, April and May appeared to be low-incidence months for T. whipplei infection (Supplementary Figure S1).
In most cases, T. whipplei was found alongside various other pathogens, including bacteria, viruses, and fungi. It was identified as the sole pathogen in only three patients: a 58-year-old woman with community-acquired pneumonia, a 60-yearold man with a suspected lung infection, and another 60-year-old man with severe pneumonia. Among the remaining 49 patients, T. whipplei was most frequently co-detected with Herpesvirus (44.90%, 22/49), Aspergillus spp. (32.65%, 16/49), Mycoplasma pneumoniae (24.49%, 12/49), and Mycobacterium spp. (18.37%, 9/49). Other co-detected agents included Streptococcus pneumoniae (10.20%, 5/49), Klebsiella pneumoniae (8.16%, 4/49), Staphylococcus aureus (8.16%, 4/49), Acinetobacter baumannii (6.12%, 3/49), Rhizomucor spp. (6.12%, 3/49), and Candida spp. (6.12%, 3/49) (Supplementary Table S1). Differentiating whether these microorganisms were the etiological agents of pulmonary infections, members of the normal microbiota, or mere contaminants during sampling can be challenging. Notably, in 15 cases (30.61%, 15/49), the number of sequenced reads for T. whipplei was 10 times higher than that of any other co-detected agents. In eight cases (16.33%, 8/49), the reads for T. whipplei were 50 times higher than those of other agents. While the number of reads alone is not a definitive indicator, we suggest that T. whipplei may often be the predominant etiological agent of pulmonary infections.
The clinical diagnoses of the patients were analyzed, revealing that most had more than one diagnosis. The most common diagnoses included severe pneumonia (23.08%, 12/52), pulmonary space-occupying lesions (23.08%, 12/52), community-acquired pneumonia (19.23%, 10/52), and pulmonary nodules (17.31%, 9/52). Additionally, pneumonia/lung infection (11.54%, 6/52), respiratory failure (9.62%, 5/52), and interstitial pneumonia (9.62%, 5/52) were frequently observed. Notably, some patients positive for T. whipplei also exhibited lymphadenopathy, arthritis, and osteoarthritis, with incidence rates of 3.85%, 1.92%, and 1.92%, respectively. These symptoms have been reported in cases of Whipple disease, suggesting the potential for overlooked cases of this disease in China.
NGS is a powerful tool for pathogen identification, offering a rapid and unbiased method to detect a wide variety of pathogens. With economic development and technological advancements, NGS has been widely adopted for clinical diagnosis in numerous hospitals across China. Its extensive use has resulted in an increased detection of T. whipplei in clinical samples. In this study, BAL samples from 52 patients tested positive for T. whipplei DNA, representing 3.98% of all patients with pulmonary infections, such as community- acquired pneumonia and pulmonary nodules. This proportion aligns with findings from other studies in China [3], suggesting a potential link between T. whipplei and pulmonary infections. Additionally, some symptoms observed in T. whipplei -positive patients may indicate the presence of Whipple disease, which is considered extremely rare in China.
This study has several limitations. Like previous research, it remains uncertain whether T. whipplei is the predominant pathogen in most patients. Although the number of reads is significantly higher than that of other agents in many cases, it is still possible that T. whipplei could be an innocent bystander. Histopathological examinations and clinical verifications are necessary to confirm its role. Additionally, there is a lack of control data from healthy populations, which could provide a more rigorous conclusion. Therefore, further investigations are needed to clarify the true prevalence of T. whipplei -associated pulmonary diseases.
No ethics approval was required for this study, as it did not involve the collection or use of human samples or personal data.
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