Tropheryma whipplei detection by metagenomic next-generation sequencing in bronchoalveolar lavage fluid: A retrospective study

doi:10.21203/rs.3.rs-4705443/v1

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Tropheryma whipplei detection by metagenomic next-generation sequencing in bronchoalveolar lavage fluid: A retrospective study

https://doi.org/10.21203/rs.3.rs-4705443/v1

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Whipple’s disease(WD) is a rare chronic and systemic disease caused by the rod-shaped, Gram-positive bacterium Tropheryma whipplei (T. whipplei) that primarily affects the gastrointestinal tract, however, the involvement of the lung is rare, and few study have explored the significance of the detection of TW in bronchoalveolar lavage fluid (BALF). So, we performed a retrospective study in patients with T. whipplei positive in 848 BALF samples which detected by metagenomic next-generation sequencing (mNGS) from 21 September 2022 to 1 March 2024 in The First Hospital of Changsha. Forty-three BALF samples from forty-four (44/848, 5.2%) patients were positive for T. whipplei (one patient was excluded due to incomplete data). Twenty-nine patients were male with an average age of 46.9 years. The main symptoms included cough (36/43), expectoration (22/43), dyspnea/shortness of breath (14/43), fever (13/43), hemoptysis/bloody sputum (5/43), vomiting (2/43), abdominal pain (1/43), and only one patient complained about neurological symptoms. Chronic liver disease (including fatty liver, chronic hepatitis C and chronic hepatitis B) were the most common comorbidity (n = 11, 25.6%), followed by chronic lung disease (n = 8, 18.6%). Only 11 patients (25.6%) were immunocompromised. One patient was finally diagnosed with reactivation tuberculosis and two patients were diagnosed with lung tumors (including one primary lung adenocarcinoma and one primary lung squamous carcinoma), and twenty-two patients (53.5%) had pneumonia. T. whipplei was the sole agent in 6 samples, and Epstein-Barr virus was the most common detected pathogens, followed by Haemophilus influenzae. The most common chest CT imaging manifestation is lung nodules (18/43, 41.9%), including fourteen solid nodules and five ground-glass nodules (three cases of calcified nodules caused by pulmonary tuberculosis were excluded). Our study indicates that T. whipplei is a causative pathogen in various lung diseases, and clinicians should be wary of this. The mNGS technology improves the detection and attention of rare pathogens and provide guidance for treatment in clinical practice. In the future, the natural history of T. whipplei infections and the possible pathogenesis still need to be studied.

Tropheryma whipplei (T. whipplei)

Whipple’s disease (WD)

metagenomic Next-Generation Sequencing(mNGS)

bronchoalveolar lavage fluid (BALF)

Tropheryma whipplei is the causative bacterium of Whipple's disease, which was first described by George Hoyt Whipple in 1907[1]. Whipple’s disease is a rare systemic infection disease mainly affects middle-aged Caucasian men, but extremely rare in the native Asian and African populations[2, 3], but carriage is common in these latter two continents[4, 5]. The gastrointestinal tract is the main target organs for its invasion. T. whipplei can be manifested as local infectious diseases, such as infective endocarditis, encephalitis, skin infection, etc. It has also been associated with acute infections, including gastroenteritis, bacteraemia, and pneumonia [6, 7]. The T. whipplei related pneumonia was rarely reported and first detected from a BALF of a child in 2007[8].

Traditional culture methods are time consuming and have low rates of positive detection. In recent years, diagnosis has become more accessible due to the use of mNGS, this new technology has improved the detection of rare pathogens and provide guidance for treatment in clinical practice.

In this study, we analyzed the demographic characteristics, the symptoms, the co-infection pathogens, laboratory data and the CT images in a population of patients according to the presence of T. whipplei detected by mNGS in BALF.

Patients and Detection procedure

A retrospective analysis was conducted on all T. whipplei positive samples from 848 BALF samples collected between 21 September 2022 and 1 March 2024 at The Affiliated Changsha Hospital of XiangyaSchool of Medicine, Central South University, China. The BALF collection process adhered strictly to clinical operating standards and maintained sterility principles. 3-5mL BALF samples obtained from the involved sub-segments placed in sterile sputum containers, stored in -20°C, and then sent to KingMed Diagnostics (Changsha KingMed Center For Clinical Laboratory, China) for detection(the mNGS procedure for BALF samples including nucleic acid extraction, library construction, sequencing, and bioinformation analysis, as this operation was performed by KingMed Diagnostics, the specific steps were not be described here).

Collecting relevant data on T. whipplei positive patients, including age, gender, laboratory data, clinical symptoms, Comorbidity, imaging examination results, diagnosis, pathological results, and treatment history.

Immunocompromised patients were considered to be those with malignancy undergoing treatment, organ transplant, AIDS patients, diabetes mellitus patients or long-term therapy with corticosteroid or immunosuppressive agent[9]. Pneumonia was diagnosed by the symptoms and chest CT imaging.

Statistical analysis

Continuous variables are presented as the mean ± standard deviation, otherwise, median and IQR (interquartile range). Comparative analysis was conducted by t’ test. The chi-square test was used to calculate the difference between both groups, or the exact Fisher test as appropriate. Data analysis and mapping were performed with GraphPad Prism10. A p-value < 0.05 was considered to be significant.

Forty-three BALFs were positive for T. whipplei. Twenty-eight patients were male (65.1%) with an average age of 46.9 years, ranged from 4 to 89 years. Fifteen patients were female (34.9%) with an average age of 58.4 years, the age ranged from 11 to 75 years. All patients were hospitalized, with 31(72%) patients in Respiratory and Critical Care Medicine Department, 4(9.3%) in Infection and Immunology Department, 4(9.3%) in Pediatrics Department, 2 (4.7%) in Thoracic surgery and 2 (4.7%) in Intensive-Care Unit at the sampling time of BALF. The main clinical symptoms of patients included cough (36/43), expectoration (22/43), dyspnea/shortness of breath (14/43), fever (13/43), hemoptysis/bloody sputum (5/43), vomiting (2/43), abdominal pain (1/43), and only one patient complained about neurological symptoms (slight headache). (Table 1).

Table 1

The characteristics of patients with T. whipplei positive in BALF
Parameter	T. whipplei positive (n = 43)
Age Male(mean,SD) Female(mean,SD) Smoking history, n (%) Never Current Immunocompromised, n (%) Symptoms, n (%) Cough Expectoration Dypnea/shortness of breath Fever Hemoptysis/bloody sputum Abdominal pain Vomiting Chest tightness Weight loss Neurological Blood test result White blood cell count (×10⁹/L) (mean, SD) Neutrophils Percentage (%) (mean, SD) Lymphocyte Percentage (%) (mean, SD) Haemoglobin (g/L) (mean, SD) CRP (mg/L) (median, IQR) ESR (mm/h) (median, IQR) LDH(U/L) (median, IQR) PCT(normal<0.05ng/mL)(median, IQR) Main CT images, n (%) Ground glass nodules or solid nodules Patchy infiltration Pleural effusion Interstitial changes Mass Cavity	28(46.9, 22.8) 15 (58.4, 17.6) 29(67.4%) 14(32.6%) 11(25.6%) 36(83.7%) 22 (51.2%) 14(32.6%) 13 (30.2%) 5 (11.6%) 4 (9.4%) 3 (7.0%) 2 (4.7%) 2 (4.7%) 1 (2.3%) 6.74 (2.62) 63.2 (11.7) 24.8 (11.0) 124 (19.2) 5.13 (1.9–24.5) 50 (20–93) 199 (167–273) 0.06(0.02–0.11) 18(41.9%) 16(37.2%) 5(11.6%) 2(4.7%) 2(4.7%) 1(2.35%)

ESR, Erythrocyte sedimentation rate LDH, lactic dehydroge PCT, Procalcitonin

Comorbidity, immune status, and laboratory data

Chronic liver disease(including fatty liver, Chronic hepatitis C and Chronic hepatitis B) were the most common comorbidity (n = 11, 25.6%), followed by chronic lung disease(n = 8, 18.6%),including chronic obstructive pulmonary disease and Bronchiectasia. Non-immunocompromised patients accounted for the majority. Immunodeficiency in 11 patients (25.6%) was including taken leflunomide (n = 1), corticosteroids (n = 1), AIDS (n = 4), diabetes mellitus(n = 3) and lung cancer (n = 2). (Fig. 1).

The laboratory tests data of 43 patients was collected before treatment. The mean white blood cell count, neutrophils percentage, and haemoglobin were 6.74×10⁹/L, 63.2% (11.7), and 124g/L, respectively. The median LDH was 199U/L (IQR 167–273), C-reactive protein was 5.13mg/L (IQR 1.9-24.5mg/L), PCT was 0.06ng/mL (IQR 0.02–0.11), and ESR was 50mm/h (IQR 20–93). (Table 1).

Chest CT Images

We simply described the chest CT findings (Fig. 2), the most common chest CT imaging manifestation is pulmonary nodules (18/43, 41.9%), including eleven solid nodules and seven ground-glass nodules(one miliary tuberculosis patient and three cases of fibrocalcific nodules caused by pulmonary tuberculosis were excluded), and followed by patchy infiltration (16/43, 37.2%),the remaining CT findings included pleural effusion (n = 5), mass(n = 2), interstitial fibrosis (n = 2 ) and cavity (n = 1), In summary, the chest imaging manifestations were various.

Pathogens detected in BALF by mNGS

T. whipplei was the sole agent in only 6 BALF samples. The most common detected bacterial pathogen with T. whipplei was Haemophilus influenzae, followed by Staphylococcus aureus, Klebsiella pneumoniae, and Moraxella catarrhalis. The most common detected atypical pathogen was Mycoplasma pneumoniae. The most commonly detected fungi were Pneumocystis jirovecii, followed by Candida albicans. Epstein-Barr virus (EBV) was the most commonly detected virus, as illustrated in Table 2 and Fig. 3. Immunodeficient patients had a higher detection rate of fungi compared to non-immunodeficient patients (9/11, 81% vs 8/32, 28%, p < 0.01), with Talaromyces marneffei only being detected in immunodeficient patients (specifically AIDS patients). There is no correlation between T. whipplei reads and the patient's immune status(p = 0.2245) or the incidence of pneumonia(p = 0.1492), as you can see in Fig. 4 (a, b).

Table 2

Pathogens detected by mNGS
Pathogen	N (n/N, %)
T. whipplei as sole agent Co-infection with two or more pathogens Co-infection with three or more pathogens Epstein-Barr virus Haemophilus influenzae Pneumocystis jirovecii Candida albicans Staphylococcus aureus Mycoplasma pneumoniae Klebsiella pneumoniae Human Herpesvirus- 7 Moraxella catarrhalis Cytomegalovirus Fusobacterium nucleatum Rhinovirus COVID-19 Streptococcus pneumonia Aspergillus fumigatus Influenza A virus Talaromyces marneffei Legionella Chlamydia psittaci Coxsackievirus Other	6 (14.0%) 37 (86.0%) 29 (67.4%) 13 (30.2%) 10 (23.3%) 8 (18.6%) 7 (16.3%) 7 (16.3%) 7 (16.3%) 6 (14.0%) 6 (14.0%) 4 (9.3%) 4 (9.3%) 4 (9.3%) 3 (7.0%) 3 (7.0%) 3 (7.0%) 2 (4.7%) 2 (4.7%) 2 (4.7%) 1 (2.3%) 1 (2.3%) 1 (2.3%) 5 (11.6%)

Diagnosis

Twenty-two patients (51.2%) were diagnosed with pneumonia and all received antimicrobial treatment. Three patients (6.9%) were ultimately diagnosed with reactivation tuberculosis and received anti-tuberculosis treatment. Histopathology results showed that two patients (4.7%) were diagnosed with lung cancer. Additionally, one patient was diagnosed with PCP and another patient was diagnosed with ABPA.

Whipple’s disease (WD) is a rare infectious disease with an incidence of one in a million individuals. It can affect multiple organs, leading to highly heterogeneous clinical manifestations. Although it was first described over a hundred years, but due to the low positive rate of traditional detection methods and a lack of understanding of the disease, a considerable such disease has been overlooked. With the advancement of molecular biological diagnostic technology, it has greatly improved the detection of T. whipplei in various samples and enlarged the spectrum of TW infections[10]. NGS is a new technology that uses High-Throughput Sequencing to sequence all the DNA in samples. This new technology has improved the detection of rare pathogens, a retrospective study reported that the total positive rate detected by NGS method (91.1%) was significantly higher than that detected by the culture method (62.2%) in acute respiratory distress syndrome (ARDS) patients[11]. In recent years, many pneumonia caused by T. whipplei have been diagnosed by the use of NGS in BALF [12, 13, 14, 15, 16], this also confirms that T. whipplei can cause respiratory infections, but few study have explored the significance of the detection of T. whipplei in BALF. So, we performed a retrospective study in 43 patients with T. whipplei positive in 848 BALF samples. To the best of our knowledge, the present study is the first in a Hunan region, the second largest sample size in the epidemiological study of T. whipplei detected in BALF in China followed the study performed by Lin et al[12], and may provide valuable initial data for future epidemiological studies.

Our study showed that the disease was more likely to occur in middle-aged males rather than females, consistent with the study performed by Biagi F et al [17], and some scholars suggested that hormonal or genetic sex chromosome-associated factors influence the course of the infection or susceptibility[18]. However, a newer study in the United States suggested that the prevalence of Whipple’s disease was similar between males and females[19]. We found T. whipplei detected in the BALF is not related to smoking history, and the number of T. whipplei sequences was not related to the patient's immune status(Fig. 4). Besides, most patients in our study were non-immunodeficient status, we did not detect a higher prevalence of T. whipplei infection in immunocompromised patients which unlike the recent study performed by Lozupone et al[20], and a large study has also shown that T. whipplei infection had nothing to do with the patient’s immune status[9]. In our study, there were 22 patients diagnosed with pneumonia, accounting for half of the samples, this also supports that T. whipplei can causes acute lung infections, but the number of T. whipplei sequences was not related to the occurrence of pneumonia, so it indicates that only a limited number of carriers may develop to lung infection, so it supports that the host, bacterial, and environmental factors may all contribute to the pathogenesis[21], and some study suggested the host immunity appears to play a crucial role in developing the disease. Therefore, the mechanism of T. whipplei leading to pulmonary infection still needs further research.

The most common symptoms among these 43 patients were cough, expectoration, shortness of breath, and fever. Digestive and neurological symptoms were rare, this may be related to the fact that the gastrointestinal and nervous systems of these patients are not affected, which suggests that the respiratory tract can be an independent infected system, and if we can conduct pathological examinations on the intestines of these patients, it may better explain this phenomenon.

A previous study shown that routine laboratory tests for WD patients has no specific results, including elevated ESR or CRP levels (84%), and anemia in 50 patients (60%) [22], our study found the white blood cell count(WBC) can be elevated or normal, the PCT often increased slightly, but anemia is uncommon. In a recent study showed T. whipplei infection often led to increased serum lactate dehydrogenase (LDH) levels, and this might be used to predict the prognosis[23]. But, as far as we know, LDH can increased in many cases, the role of LDH in WD requires further research.

Chest CT image of the those patients exhibited a diverse range of findings, the most common imaging manifestation is lung nodules(18/43, 41.9%), including eleven solid nodules and seven ground-glass nodules, which could be solitary or diffuse, this is consistent with some other research findings[24], but the relationship between T. whipplei and lung nodules is not yet clear, and further exploration and research are needed in the future. Patchy infiltration (16/43, 37.2%) was the second most common imaging manifestation. Besides, five cases (5/43, 11.6%) had pleural effusion, two had interstitial changes, and only one case had cavity.

T. whipplei as the sole pathogen only in 6 BALF samples, and more often it co-exists with other pathogens. Among them, the most common co-exists is Epstein-Barr virus EBV(n = 13), followed by Haemophilus influenzae (n = 10), there is no research report on similar results currently. In addition, it is also common to have fungal co-exists, with a total number of 19 cases(including Pneumocystis jirovecii, Candida albicans, Aspergillus fumigatus and Penicillium marneffei), the most common detected fungi was Pneumocystis jirovecii, consistent with the research findings of Ying Li et al[25]. As for why there is such a high probability of co-exists between them, larger prospective studies are needed. However, unlike the results reported by Lin et al[12], none of our patients were found to have Mycobacterium tuberculosis complex, although one case was ultimately diagnosed with pulmonary tuberculosis and improved after anti-tuberculosis treatment.

In conclusion, we summary analyzed the clinical characteristics of patients with positive T. whipplei detected by mNGS in BALF, further enhanced the understanding of this pathogen. The use of mNGS technology has enhanced the detection of rare and slow-growing pathogens, providing significant benefits in pinpointing the causative pathogen and facilitating targeted antimicrobial treatment. However, our study has some limitations. Primarily, our sample size is not sufficiently large; perhaps collaborating with other centers to conduct a multi-center study on this disease would yield more representative results; Secondly, most patients seek medical attention due to respiratory symptoms and are hospitalized in the Respiratory and Critical Care Medicine department, no relevant examinations were conducted on their digestive system; Thirdly, we did not set up a control group for comparison. However, we believe the study is informative, and may provide valuable data for future comparative and epidemiological studies. In the future, the design of an animal model of pneumonia induced by T. whipplei are needed to improve our understanding of the natural history of T whipplei infections and of the possible predisposing immune factors that permit development of infection.

Competing Interests

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Zhixiong He and Hui Li. The first draft of the manuscript was written by Zhixiong He and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Consent to Publish

All authors agree to publish.

Data Availability

The datasets analysed during the current study are not publicly available due to individual privacy could be compromised but are available from the corresponding author on reasonable request.

Ethics statement

This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee of The Affiliated Changsha Hospital of XiangyaSchool of Medicine (The First Hospital of Changsha 2024 (5) V 1.0).

Acknowledgements

We thank Changsha KingMed Center For Clinical Laboratory for their technical assistance.

Funding

This work was funded by the Changsha Science and Technology Program(kq1907013), Youth Fund of the Hunan Natural Science Foundation(2023JJ4006) and Hunan Provincial Health Commission (202103020384).

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No competing interests reported.

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Tropheryma whipplei detection by metagenomic next-generation sequencing in bronchoalveolar lavage fluid: A retrospective study

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Abstract

Figures

Introduction

Material and methods

Patients and Detection procedure

Statistical analysis

Results

Comorbidity, immune status, and laboratory data

Chest CT Images

Pathogens detected in BALF by mNGS

Diagnosis

Discussion

Conclusion

Declarations

References

Additional Declarations

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