ORIGINAL RESEARCH article

Front. Cell. Infect. Microbiol., 11 July 2024

Sec. Clinical and Diagnostic Microbiology and Immunology

Volume 14 - 2024 | https://doi.org/10.3389/fcimb.2024.1416884

Target next-generation sequencing for the accurate diagnosis of Parvimonas micra lung abscess: a case series and literature review

  • 1. Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

  • 2. Department of Respiratory, Beijing Huairou Hospital, Beijing, China

  • 3. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Beijing, China

Abstract

Background:

Parvimonas micra (P. micra) has been identified as a pathogen capable of causing lung abscesses; however, its identification poses challenges due to the specialized culture conditions for anaerobic bacterial isolation. Only a few cases of lung abscesses caused by P. micra infection have been reported. Therefore, we describe the clinical characteristics of lung abscesses due to P. micra based on our case series.

Methods:

A retrospective analysis was conducted on eight patients who were diagnosed with lung abscesses attributed to P. micra. Detection of P. micra was accomplished through target next-generation sequencing (tNGS). A systematic search of the PubMed database using keywords “lung abscess” and “Parvimonas micra/Peptostreptococcus micros” was performed to review published literature pertaining to similar cases.

Results:

Among the eight patients reviewed, all exhibited poor oral hygiene, with four presenting with comorbid diabetes. Chest computed tomography (CT) showed high-density mass shadows with necrosis and small cavities in the middle. Bronchoscopic examination revealed purulent sputum and bronchial mucosal inflammation. Thick secretions obstructed the airway, leading to the poor drainage of pus, and the formation of local abscesses leading to irresponsive to antibiotic therapy, which finally protracted recovery time. P. micra was successfully identified in bronchoalveolar lavage fluid (BALF) samples from all eight patients using tNGS; in contrast, sputum and BALF bacterial cultures yielded negative results, with P. micra cultured from only one empyema sample. Following appropriate antibiotic therapy, seven patients recovered. In previously documented cases, favorable outcomes were observed in 77.8% of individuals treated with antibiotics and 22.2% were cured after surgical interventions for P. micra lung abscesses.

Conclusions:

This study enriches our understanding of the clinical characteristics associated with lung abscesses attributed to P. micra. Importantly, tNGS has emerged as a rapid and effective diagnostic test in scenarios where traditional sputum cultures are negative. Encouragingly, patients with lung abscesses caused by P. micra infection exhibit a favorable prognosis with effective airway clearance and judicious anti-infective management.

Introduction

Primary lung abscesses typically result from infections leading to necrosis and cavitation of the lung tissue. Aspiration of oral-derived anaerobic bacteria represents the predominant etiology of primary lung abscesses (). Individuals with periodontal disease are at an elevated risk of developing anaerobic lung abscesses. Since anaerobic organisms necessitate specific culture conditions, conventional sputum culture often yields negative results in the detection of anaerobic bacteria. Anaerobic organisms were isolated only in a limited number of lung abscess cases ().

Parvimonas micra (P. micra) is a gram-positive anaerobic coccus prevalent in the oral cavity, particularly in the gingival crevices. P. micra has been associated with aspiration pneumonia (), lung abscesses (), and empyema (). Nevertheless, clinical insights into P. micra-related lung abscesses remain rare.

Given the challenges in culturing and identifying anaerobic bacteria due to their vulnerability to atmospheric exposure, innovative approaches utilizing next-generation sequencing of metagenomes (NGS) have shown promise in enhancing the positive detection rate of anaerobic bacteria ().

In this study, we present findings from eight cases of lung abscess caused by P. micra, with the pathogenic bacterium identified through genomic sequencing. Additionally, a systematic review of prior cases detailed in the published literature was conducted to delineate the clinical features of lung abbesses attributed to this pathogen, which may be unfamiliar to pulmonary healthcare providers.

Patients and methods

Patients

A retrospective analysis was conducted on patients who were diagnosed with lung abscesses and admitted to Beijing Chao-Yang Hospital between July 2022 and December 2023. The results from bronchoalveolar lavage fluid (BALF) pathogen testing using target next-generation sequencing (tNGS) indicated P. Micra as the predominant bacterium, consistent with the clinical presentation. Two physicians independently confirmed the association of lung abscess with P. micra. Comprehensive patient medical records, laboratory tests, examinations, and treatment modalities were compiled for review.

tNGS testing

Bronchoscopies were performed within 5 days of hospital admission, with BALF samples obtained from the segmental bronchus corresponding to the identified lesions. Immediately following collection, 5 ml of BALF was aseptically preserved at −20°C and transported to Beijing KingMed Diagnostics Laboratory within 4 h. Cellular material within the samples was enriched, lysed, and subjected to DNA extraction from 500 μl of fluid as per established protocols. Subsequent to polymerase chain reaction amplification and purification, sequencing was performed utilizing a genetic sequencing platform (KM MiniSeqDx-CN) and an automatic nucleic acid-protein analyzer (Qsep100, BiOptic, Taiwan). Sequence data interpretation was facilitated by the Pathogenic Microbial Data Analysis and Management System 1.0 (KingMed Diagnostics, Co., Ltd., China), which comprises a bacterial minimal genome database consisting of 198 respiratory pathogens.

Literature review

A systematic search of the PubMed database was conducted to identify journal articles, employing the search terms “lung abscess” and “Parvimonas micra/Peptostreptococcus micros”. The inclusion criteria included papers published from 01/01/1980, to 31/12/2023. Five articles documenting pulmonary abscesses associated with P. micra, with a collective total of nine patients, were contained in the review.

Results

Characteristics

The general characteristics of the eight patients are outlined in Table 1. Their ages ranged from 28 to 83 years, with four patients having diabetes and none presenting HIV infection or receiving immunosuppressive treatment. The median duration from symptom onset to definitive diagnosis was approximately 40 days. Notably, all eight patients exhibited poor oral hygiene, with manifestations including periodontal disease and dental disease.

Table 1

CaseAgeGenderBMIUnderlying diseaseSmoking/drinkingOral hygieneSymptomsTime*WBC 109/LNEU 109/LHgb g/LPCT
ng/ml
CRP
mg/dl
172M20.28DMN/NPeriodontal disease, dental calculus, false toothCough sputum,30 days8.576.1116<0.054.06
267F21.30N/Ndental calculus, teeth lossFever, cough, and sputum50 days5.33.41117<0.050.34
383M27.22DM, HPTY/YDental calculus, decayed teeth, teeth lossFever, cough and sputum, sore throat2 months10.567.61090.0611.5
454F24.43N/NDecayed toothFever, cough, and sputum2 months6.994.8594<0.050.39
549M27.68DM, HPTY/NAbscess tooth, dental calculusFever, cough and sputum, chest pain15 days16.6113.861160.3435.8
657F26.03DM, HPT, CVDN/NPeriodontal disease, false tooth, tooth lossFever, cough, and sputum20 days15.2313.381070.3912.7
759M24.2N/YPeriodontal disease, dental calculusCough and sputum, chest pain, hemoptysis70 days6.564.32127<0.055.55
828M25.25N/YDecayed toothCough, dyspnea14 days17.6115.541060.464.21

Clinical information of patients with P. micra lung abscess.

M, male; F, female; DM, diabetes mellitus; HPT, hypertension; CVD, cerebrovascular disease; N, no; Y, yes.

*Time from clinical onset to diagnosis.

Primary symptoms were non-specific, yet common manifestations included fever (n = 5), cough (n = 8), and sputum production (n = 7). Additional complaints included sore throat, dyspnea, chest pain, and hemoptysis.

Laboratory tests, chest CT, and bronchoscopy

Upon admission, routine blood tests revealed a median white blood cell count of 9.57 × 109/L, with half of the patients exhibiting normal procalcitonin (PCT) levels.

Chest CT findings demonstrated large-scale consolidation with necrosis and small cavities (Figure 1), devoid of classical air-fluid levels. The boundaries of the focusing area were unclear and blurred. The lesions were located in the right upper lobe (n = 2), left upper lobe (n = 2), right middle lobe (n = 1), and inferior lobe of the right lung (n = 3). One patient was complicated with liver abscesses and empyema.

Figure 1

Bronchoscopy revealed purulent sputum (Figure 1) and inflammatory changes in the bronchial mucosa at the affected sites.

CT-guided pulmonary biopsy was performed on three patients to differentiate from lung cancer. Pathology indicated inflammation of the lung tissue.

Microbiological examinations

Although gram-positive cocci were identified in five cases via sputum or BALF smears, bacterial cultures yielded negative results for all eight patients. However, tNGS analysis of BALF samples confirmed P. micra as the predominant bacterium. Anaerobic culture of the pleural effusion identified P. micra in one patient complicated with concomitant empyema. Additionally, tNGS reports indicated the presence of other bacteria including Fusbacterium nucleatum (n = 5), Klebsiella pneumoniae (n = 2), Escherichia coli (n = 1), Streptococcus pneumoniae (n = 1), and Acinetobacter baumannii (n = 1).

Treatment and outcomes

Following diagnosis, patients received tailored anti-infection therapies such as piperacillin–tazobactam (n = 3), ampicillin–sulbactam (n = 2), moxifloxacin (n = 1), meropenem (n = 1), and imipenem–cilastatin (n = 1). Mucolytic drugs and airway clearance techniques were also employed to facilitate sputum expectoration.

Their symptoms improved, and chest CT scans indicated resolution of the lung abscesses. Subsequent to initial therapy, oral antibiotics were administered for 2 to 5 months. Seven patients achieved satisfactory outcomes, with almost no symptoms and almost completely absorbed lesions on chest CT. Two months later, one patient developed massive hemoptysis attributed to secondary Enterococcus faecium infection, leading to fatal pneumonia and sepsis.

Literature review

A review of the literature identified other nine reported cases (Table 2), revealing cough (77.8%) and expectoration (77.8%) as the most common symptoms. Additional data indicated smoking history, alcohol consumption, periodontal conditions, and dental issues. The median time taken from clinical onset to make a diagnosis was 2 months. CT scan showed irregular mass shadows which had no obvious improvement after short-term initial empirical treatment. It is difficult to distinguish from malignant lesions. Thus, CT-guided percutaneous lung biopsies were performed in 55.6% of these patients. In published cases, metagenomics next-generation sequencing (mNGS) facilitated pathogen identification in more than half of the cases. The details of coinfections and treatment are shown in Table 3. A majority of P. micra lung abscess cases reported in the literature also displayed favorable outcomes, with 77.8% of patients cured via medication and 22.2% benefitting from surgical intervention.

Table 2

CharacteristicOur case series (n = 8)Literature cases (n = 9)
AgeYear median (range)55.5 (28-82)61.5 (46-82)
GenderMale/female5/38/1
Time from clinical onset to diagnosis (days)40 (14-70)60 (4-260)
Symptom
No. (%)
Fever5 (62.5)3 (33.3)
Cough8 (100)7 (77.8)
Expectoration7 (87.5)7 (77.8)
Chest pain2 (25)3 (33.3)
Dyspnea1 (12.5)2 (22.2)
Hemoptysis1 (12.5)3 (33.3)
Sore throat1 (12.5)0
Circulatory failure01 (11.1)
Method pathogen detectionBALF NGS8 (100)3 (33.3)
Lung tissue NGS02 (22.2)
BALF culture01 (11.1)
Blood culture02 (22.2)
Abscess culture1 (12.5)1 (11.1)
Underlying health statusDiabetes4 (50)1 (11.1)
Hypertension3 (37.5)3 (33.3)
Cerebrovascular disease1 (12.5)0
Bipolar disorder01 (11.1)
Atrial fibrillation01 (11.1)
Heart valve replacement01 (11.1)
Healthy4 (50)3 (33.3)
Location of infectionRight upper lung lobe2 (25)3 (33.3)
Right middle lung lobe1 (12.5)2 (22.2)
Right lower lung lobe3 (37.5)0
Left upper lung lobe2 (25)3 (33.3)
Left lower lung lobe02 (22.2)
Bronchoscopy8 (100)7 (77.8)
CT-guided percutaneous lung puncture3 (37.5)5 (55.6)
PrognosisCured with medicines7 (87.5)7 (77.8)
Surgical resection02 (22.2)
All-cause mortality1 (12.5)0

Clinical characteristics of P. micra in case series and in the literature.

BALF, bronchoalveolar lavage fluid; NGS, next-generation sequencing.

Table 3

CaseAgeGenderLesion siteBiopsy methodDiagnostic methodCoinfectionTreatmentPrognosis
172MRight middle lung lobeNBALF tNGSK. pneumoniaeAmpicillin sulbactam for 10 days, and amoxicillin clavulanate 500/125 mg every 8 h for 3 monthsCured with medicines
267FLeft upper lung lobeNBALF tNGSNMeropenem 1.0 g every 8 h for 11 days, piperacillin tazobactam 4.5 g every 8 h for 14 days, moxifloxacin 400 mg once a day for 4 monthsCured with medicines
383MRight upper lung lobeCT-GPLPBALF tNGSF. nucleatumMeropenem 1.0 g every 12 h for 8 days, piperacillin tazobactam 4.5 g every 8 h for 6 days, moxifloxacin 400 mg once a day for over 5 monthsCured with medicines
454FRight lower lung lobeCT-GPLPBALF tNGS
Lung tissue NGS
A. baumanniiPiperacillin tazobactam 4.5 g every 8 h for 15 days, moxifloxacin 400 mg once a day for 15 days, amoxicillin and metronidazole for 4 monthsCured with medicines
549MRight lower lung lobeNBALF tNGSP. endodontalisAmpicillin intravenous for 12 days and amoxicillin clavulanate for 2.5 monthsCured with medicines
657FLeft upper lung lobeCT-GPLP
EBUS-TBNA
BALF tNGSNCeftazidime 2.0 g every 8 h for 17 days, moxifloxacin 400 mg once a day for 5 monthsCured with medicines
759MRight upper lung lobeTBLBBALF tNGSP. endodontalis
F. nucleatum
Meropenem 1.0 g every 8 h for 17 days,
moxifloxacin 400 mg once a day for 1.5 months,
Imipenem cilastatin 1.0 g every 8 h for 8 days.
Death from Enterococcus fecal sepsis
828MRight lower lung lobeNBALF tNGS, culture of pleural effusionF. nucleatumMeropenem 1.0 g every 8 h for 12 days, Piperacillin tazobactam 4.5 g every 8 h for 20 days, moxifloxacin for 3 monthsCured with medicines
9 ()57FRight upper lung lobeSurgical resectionBlood cultureNCeftriaxone, vancomycin, and azithromycin for 10 daysCured with resection
10 ()49MLeft lower lung lobeNBlood cultureA. odontolyticusCeftriaxone and clindamycin
Ampicillin sulbactam
Amoxicillin/clavulanate 6 months
Cured with medicines
11 ()61MLeft upper lung lobeCT-GPLPLung tissue NGSNMetronidazole 200 mg every 8 h for 3 monthsCured with
medicines
12 ()81MRight middle lung lobeEBUS-TBNABALF NGSF. nucleatumAmoxicillin clavulanate 375 mg every 8 h for 2 monthsCured with
medicines
13 ()46MLeft lower lung lobeCT-GPLPBALF NGSF. nucleatum, S. constellatusMoxifloxacin 400 mg once a day for 4 monthsCured with
medicines
14 ()82MRight upper lung lobeCT-GPLPLung tissue NGSP. intermedia,
S. constellatus
Metronidazole 200 mg every 8 h for 5 monthsCured with medicines
15 ()62MLeft upper lung lobeCT-GPLPBALF NGSF. nucleatumAmoxicillin–clavulanate 375 mg every 8 h for 4 monthsCured with resection
16 ()62MLeft upper lobeNBALF cultureNPiperacillin–tazobactam 4.5 g every 6 h for 7 days, amoxicillin–clavulanic 875/125mg every 12 h for several weeksCured with medicines
17 ()67MRight upper lobe and middle lobeCT-GPLPChest wall abscess cultureNLevofloxacin for 7 days
Clindamycin 600 mg every 8 h for 8 weeks
Cured with medicines

Diagnosis, treatment, and prognosis of patients with P. micra lung abscess.

CT-GPLP, computed tomography-guided percutaneous lung puncture; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; BALF, bronchoalveolar lavage fluid; NGS, next generation sequencing. N, no; M, male; F, female

Discussion

The majority of lung abscesses are believed to be caused by the aspiration of anaerobic bacteria from the oral cavity, particularly from gingival crevices. P. micra is one of the most prevalent anaerobic microorganisms in the human oral cavity (). However, due to challenges in laboratory culture, there are limited published data on the clinical characteristics of P. micra lung abscess, mainly in the last 5 years (; ; ; ; ).

Anaerobic lung infections are often associated with poor oral hygiene conditions and inadequate airway protection (). Zhang et al (). reported that patients with a long smoking history and poor oral hygiene are susceptible to P. micra lung abscesses. However, in our study, smoking was not identified as a significant risk factor, as only two male patients had a long history of smoking, whereas the other patients were non-smokers. Lai et al. reported four cases of childhood pneumonia and abscesses caused by oral obligate anaerobes, primarily P. micra, where poor oral hygiene was a crucial risk factor (). Therefore, poor oral health is an important risk factor for P. micra–induced lung abscesses. In addition, alcoholism should also be noted as a common predisposing condition for aspiration (). Among our patients, three male patients had a history of regular alcohol consumption.

The symptoms observed in these patients were non-specific. All patients presented with a productive cough with sputum, and most experienced fever. Radiologically, chest CT scans revealed mass of lung consolidation with liquefactive necrosis and small cavities within the consolidation, without a distinct liquid–gas plane. Given the presence of small cavities with thick walls of consolidations on lung CT scan, along with non-specific symptoms, many patients underwent lung puncture biopsy for the differentiation of lung cancer. The lung biopsy pathology from these lung puncture biopsies revealed chronic inflammation of the lung tissue (). Gorospe et al. reported a case of a chest wall abscess of P. micra following CT-guided needle lung biopsy of the right lung consolidation ().

In our case series, bronchoscopy revealed sticky secretion plugging in the bronchi as a feature of P. micra infection. For patients with lung consolidation and necrosis, bronchoscopy could be performed initially for pathogenic analysis. When empyema secretion plugging in the bronchial region was detected, without neoplasm, P. micra was isolated, and symptoms and radiological findings improved following targeted antibiotic therapy, percutaneous lung biopsy could be avoided.

The mNGS markedly improves pathogenic diagnosis, but it is expensive and involves procedural DNA and RNA sequencing, respectively. Target NGS is a more economical technology with a cost of approximately one-fifth of that of mNGS, with the similar advantages of rapid speed and high accuracy. The target detection of 198 pathogens include 80 bacteria, 79 DNA and RNA viruses, 32 fungi, and 7 mycoplasmas and chlamydia, which account for 95% respiratory infections (). Clinical data have shown that tNGS is effective and economical for diagnosis of respiratory infection (). However, NGS technology cannot achieve antibiotic sensitivity of the pathogen, and anaerobic culture remains important, particularly for determining antibiotic resistance. Additionally, as NGS often detects multiple bacterial species, clinicians must carefully ascertain the true pathogenic bacteria, by integrating patients’ symptoms, laboratory tests, and radiological findings. Compared with traditional culture, tNGS had a shorter turnaround time for positive pathogen detection (1 day vs. 4 days). Finally, for detected pathogens with high NGS sequencing read numbers, especially in RNA sequencing tests, this approach could be helpful for the differentiation of colonization and infection.

tNGS is only a method for detecting microbes rather than a diagnostic method. However, tNGS is designed to target highly suspected microbes when they are commonly recognized as pathogens that cause lower respiratory tract infections. Furthermore, after its routine application in the clinical diagnostic process in clinical practice for pathogen identification in our hospital, its role as an examination for diagnostic purposes becomes increasingly important. Therefore, we could have a positive view of its promising diagnostic usage in the future. Finally, the results from tNGS could not be held as the only diagnostic evidence. To establish a precise diagnosis for an infection, tNGS should be combined with other clinical information such as medical history, symptoms, laboratory, and radiological findings.

In bronchoscopy, if bronchial blockage by purulent secretions is observed, which leads to local hypoxia and creates conditions for anaerobic bacterial growth, promoting sputum excretion and maintaining airway patency are critical treatment procedures on the base of drug therapy. Chest physiotherapy by respiratory therapists, including the use of devices such as the Acapella valve and high-frequency chest wall oscillation devices, are helpful in clearing airway secretions ()

P. micra is susceptible to many antibiotics, including penicillin G, ampicillin, cefepime, vancomycin, and metronidazole (; ). In the case of lung abscess, intravenous antibiotics were administered for 2 to 4 weeks, followed by oral antibiotic treatment for 2 to 3 months until the chest radiographic lesions resolved. Proper drainage helps with absorption and hastens recovery. Although lung abscesses associated with P. micra have rarely been reported, it has a benign prognosis, as most patients recover after antibiotic treatment.

In patients who do not respond to antibiotic therapy, catheter drainage or surgical resection should still be considered (). Both percutaneous tube drainage () and endoscopic drainage () have been shown to effectively reduce abscess size and improve clinical outcomes. However, catheter placement in P. micra-related lung abscesses with small cavities can be challenging (). Surgical resection may be necessary if antibiotic therapy is ineffective or in cases of life-threatening hemoptysis. In cases reported previously, two patients were cured after surgery.

This study has several limitations. First, this study has a small sample size, which may lead to bias. Furthermore, sputum or BALF cultures were negative for all patients. Finally, tNGS results do not cover all pathogens, which may be inaccurate in finding rare coinfected pathogens. To avoid missing important pathogens, retesting or conversion to mNGS would be considered, if the tNGS results not align with the clinical situation or if patients exhibited a poor response to treatment.

Conclusion

In conclusion, our study systemically reports the characteristics of P. micra–related lung abscesses in adults based on the largest number of cases to date. Imaging features included mass consolidation with necrosis without a clear liquid–gas plane on chest CT, and sticky secretion plugging in the bronchial region on bronchoscopy. tNGS is an effective and cost-efficient tool for rapidly detecting pathogens. The lung abscesses caused by P. micra have a good prognosis with appropriate treatment. Improving oral health, promoting sputum excretion, and following an appropriate extended course of antibiotic treatment are crucial for recovery from P. micra-induced anaerobic lung abscesses.

Statements

Data availability statement

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.

Ethics statement

The studies involving humans were approved by Ethics Review Committee of the Beijing Chao-Yang Hospital, Capital Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Author contributions

DZ: Validation, Writing – original draft, Conceptualization. BF: Data curation, Investigation, Writing – original draft. YY: Data curation, Investigation, Writing – original draft. CJ: Data curation, Investigation, Writing – review & editing. LA: Conceptualization, Supervision, Writing – review & editing. XW: Data curation, Investigation, Writing – review & editing. HH: Project administration, Supervision, Visualization, Writing – review & editing.

Funding

The authors declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Scientific Technology Support Project of the Xizang Autonomous Region (XZ202201ZY0037G).

Conflict of interest

The authors declare that the research was conducted in the absence of commercial or financial relationships and without conflicts of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Summary

Keywords

Parvimonas micra, lung abscess, target next-generation sequencing, TNGS, diagnosis

Citation

Zhang D, Fan B, Yang Y, Jiang C, An L, Wang X and He H (2024) Target next-generation sequencing for the accurate diagnosis of Parvimonas micra lung abscess: a case series and literature review. Front. Cell. Infect. Microbiol. 14:1416884. doi: 10.3389/fcimb.2024.1416884

Received

13 April 2024

Accepted

26 June 2024

Published

11 July 2024

Volume

14 - 2024

Edited by

Jiemin Zhou, Vision Medicals Co, Ltd, China

Reviewed by

Jiajia Zheng, Peking University, China

Yang Jiao, Second Military Medical University, China

Yong Liu, First Affiliated Hospital of Jilin University, China

Updates

Copyright

*Correspondence: Hangyong He,

†These authors have contributed equally to this work

Disclaimer

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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