Accurate etiological diagnosis of Mycoplasma hominis mediastinitis in immunocompetent patients using metagenomic next-generation sequencing: a case series and literature review
Original Article

Accurate etiological diagnosis of Mycoplasma hominis mediastinitis in immunocompetent patients using metagenomic next-generation sequencing: a case series and literature review

Sishi Cai1, Jue Pan1, Suzhen Wang2, Rong Bao2, Chunmei Zhou2, Xiaodong Gao3, Haruhiko Shiiya4, Bijie Hu1,3

1Department of Infectious Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; 2Department of Microbiology, Zhongshan Hospital, Fudan University, Shanghai, China; 3Department of Hospital Infection Management, Zhongshan Hospital, Fudan University, Shanghai, China; 4Department of Thoracic Surgery, Hokkaido University Hospital, Sapporo, Japan

Contributions: (I) Conception and design: S Cai; (II) Administrative support: J Pan, X Gao, B Hu; (III) Provision of study materials or patients: S Wang, R Bao, C Zhou; (IV) Collection and assembly of data: S Cai; (V) Data analysis and interpretation: S Cai; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Bijie Hu, MD. Department of Infectious Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China; Department of Hospital Infection Management, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Email: Doctorhbj@126.com.

Background: As a culture-independent method, metagenomic next-generation sequencing (mNGS) is widely used in microbiological diagnosis with advantages in identifying potential pathogens, guiding antibiotic therapy, and improving clinical prognosis, especially in culture-negative cases. Mycoplasma hominis (M. hominis) mediastinitis is a rare and severe disease for which etiological diagnosis is important but challenging. The application of mNGS in the etiological diagnosis of mediastinitis has seldom been studied.

Methods: By searching the electronic medical history retrieval system with “Mycoplasma hominis” and “mediastinitis”, seven patients diagnosed with M. hominis mediastinitis were reviewed in Zhongshan Hospital, Fudan University, Shanghai from 9 December 2020 to 14 February 2023. Microbiological cultures and mNGS were conducted for blood, abscess, and/or mediastinal fluid. Adjustment of the antibiotic therapy due to mNGS was assessed. A literature review was conducted in the PubMed database beginning in 1970 for M. hominis infection and mediastinitis.

Results: For the seven patients, cultures of blood, abscess, and mediastinal fluid were negative whereas mNGS identified M. hominis in serum, abscess, and/or mediastinal fluid and was used to guide specific antibiotic therapy. The stringent mapped reads number of genera (SMRNG), stringent mapped reads number of species (SMRN), and coverage rate of M. hominis detection by mNGS were significantly higher in body fluid (abscess or mediastinal fluid) than in serum. All seven patients had underlying heart diseases and underwent previous cardiac surgery. The most common symptoms were fever and sternal pain. After detection of M. hominis, antibiotics were adjusted to quinolones or doxycycline except for one patient, whose diagnosis was clarified after death. Two patients died. Literature review since 1970 identified 30 cases of extra-genital infection caused by M. hominis. Including our seven new cases, 2 (5.4%) were neonates and 35 (94.6%) were adults. Thirty (81.1%) cases were postoperative infection and 15 (40.5%) had implanted devices. Five patients (13.5%) died.

Conclusions: mNGS might be a promising technology in the detection of fastidious pathogens such as M. hominis. Accurate etiological diagnosis by mNGS could guide antibiotic therapy and facilitate clinical management.

Keywords: Metagenomic next-generation sequencing (mNGS); Mycoplasma hominis (M. hominis); mediastinitis; diagnosis; case series

Submitted Feb 22, 2024. Accepted for publication Apr 07, 2024. Published online Apr 12, 2024.

doi: 10.21037/jtd-24-286

Highlight box

Key findings

• Metagenomic next-generation sequencing (mNGS) may be a promising tool for detecting pathogens in patients with Mycoplasma hominis (M. hominis) mediastinitis.

What is known and what is new?

• M. hominis mediastinitis is rare but life-threatening. Culture of M. hominis is challenging and delay of diagnosis is common.

• mNGS is more sensitive and time saving than culture in detecting M. hominis.

What is the implication, and what should change now?

• The application of mNGS for the etiological diagnosis of M. hominis mediastinitis could guide antibiotic treatment strategies and improve clinical outcomes.

Introduction

Mycoplasma hominis (M. hominis) is a small fastidious bacterium, 0.3–0.4 µm in diameter, that lacks a typical bacterial peptidoglycan cell wall, belonging to the Mycoplasmataceae family within the Mollicutes class (1). It is part of the urogenital and respiratory tract commensal flora of healthy individuals, colonizing in the urogenital tract among 21–54% of women and 4–13% of men. Its colonization rate in the upper respiratory tract ranges from 1% to 3% among healthy adults (2). M. hominis predominantly causes genitourinary tract infections such as pyelonephritis, pelvic inflammatory diseases, chorioamnionitis, and cesarean section wound infections. These infections particularly occur during the peripartum period and might be associated with potential adverse neonatal outcomes such as bronchopulmonary dysplasia (3,4). Extra-genitourinary infections are relatively rare but have also been documented, including mediastinitis (2,5-8), wound infections (1,9), arthritis (10-14), meningitis (4,15-18), endocarditis (19-21), and abscess (22,23), a large portion of which are postoperative infection. Among them, M. hominis mediastinitis especially tends to be severe with high mortality. In previous literatures, these infections usually occur in immunocompromised patients. However, extra-genitourinary infections of M. hominis are rare and the number of reported cases is limited. Patients with extra-genitourinary infections of M. hominis have significant heterogeneity and this disease lacks sufficient study.

The lack of a rigid cell wall renders M. hominis unable to be visualized on bacterial gram stains and osmotically fragile, requiring an M. hominis-specific culture, which is not widely available. Growth on standard aerobic or anaerobic bacterial culture plates is slow and insensitive (8). Difficulty in culturing and identifying M. hominis leads to a dilemma in early diagnosis and intervention. Delayed diagnosis is common and might be associated with inappropriate antibiotic application and poor outcomes. Culture-independent techniques such as polymerase chain reaction (PCR) and M. hominis antigen tests might be more sensitive, but a prior suspicion of M. hominis infection is required for their implementation, which is often overlooked clinically.

Metagenomic next-generation sequencing (mNGS) is an advanced technique with high sensitivity for the etiological diagnosis of infectious diseases. The comprehensive and unbiased nature of mNGS has especially facilitated identification of relatively rare pathogens (24). However, its application in diagnosing M. hominis mediastinitis has been less studied, mainly due to the status that this disease is very rare. As a culture-independent diagnostic method, mNGS has advantages in the identification of fastidious pathogens such as M. hominis. Here, we report seven cases of M. hominis mediastinitis identified by mNGS and review them along with previously reported cases of extra-genitourinary M. hominis infections. In our study, the seven reported cases of M. hominis mediastinitis were not immunocompromised, expanding our understanding of this disease. We present this article in accordance with the STROBE and AME Case Series reporting checklists (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-286/rc).

Methods

Patients

The research design of this study was a retrospective case series. Searching our electronic medical history retrieval system, we retrospectively reviewed seven patients diagnosed with M. hominis mediastinitis who were admitted to Zhongshan Hospital, Fudan University, Shanghai from 9 December 2020 to 14 February 2023. Routine microbiological cultures for blood, abscess, mediastinal fluid, and sputum were conducted after admission. mNGS was applied when conventional culture turned negative and atypical pathogens were suspected. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethical Review Committee of Zhongshan Hospital, Fudan University, Shanghai, China (No. B2017-193R) and informed consent was taken from all the patients or the relatives.

Literature review

We searched in PubMed articles published in English beginning in 1970 with the terms “M. hominis infection” or “mediastinitis”. Demographic, clinical, and microbiological data were collected in a specifically developed case report form.

Culture

All seven patients underwent blood culture by peripheral venous puncture at least once during fever after admission. 8–10 mL of blood samples were injected into aerobic, anaerobic, and fungal blood culture bottles [BD BACTECTM, Becton, Dickinson, and Co. (BD), Franklin Lakes, NJ, USA] and then loaded into an automated continuous monitoring system (BD BACTECTM, BD) for 1 week. Abscess, mediastinal fluid, and sputum were cultured onto blood agar, chocolate agar, and fungal chromogenic plates for 1 week. If the culture had bacterial or fungal growth, strain identification was performed by VITEK MALDI-TOF mass spectrometry (bioMérieux, Craponne, France). Antimicrobial susceptibility tests were conducted using Vitek 2 (bioMérieux).

mNGS

Sample processing, mNGS, and analysis were performed as described previously. Blood samples were stored at room temperature whereas all other specimens were stored at −80 °C before testing. A total of 5 mL of blood was drawn from patients. After centrifugation, the plasma sample was transferred to a new sterile tube. Samples of 3 mL of abscess or mediastinal fluid were collected from patients according to standard procedures. DNA was extracted using a TIANamp Micro DNA Kit (DP316; TIANGEN Biotech, Beijing, China), followed by DNA library generation, PCR amplification, and analysis by an Ion Torrent Proton Sequencer (Life Technologies, Carlsbad, CA, USA). Before sequencing, an Agilent 2100 Bioanalyzer (Agilent Technologies, Santa Clara, CA, USA) and quantitative PCR (qPCR) were used to evaluate the quality of the DNA libraries. Qualified DNA libraries were sequenced on the Ion Torrent Proton (Life Technologies, South San Francisco, CA, USA) sequencing platform. High-quality sequencing data were produced by removal of low-quality and short (length <35 bp) reads. Human host sequences mapped to the human reference genome (hg19) were removed via Burrows-Wheeler Alignment. The remaining nonhuman data were aligned to four microbial genome databases consisting of viruses, bacteria, fungi, and parasites which can be downloaded from the National Center for Biotechnology Information (NCBI; ftp://ftp.ncbi.nlm.nih.gov/genomes/). The RefSeq contains 4,189 virus, 2,328 bacteria, 199 fungi, and 135 parasites related to human infectious diseases.

Criteria for a positive mNGS result

The measurement parameters of mNGS results in this study consisted of coverage rate, relative abundance of species, stringent mapped reads number of species (SMRN), relative abundance of genera, and stringent mapped reads number of genera (SMRNG).

For bacteria, viruses, and parasites, a positive mNGS result must meet the following conditions: on the species level, mNGS identified a bacterium, virus, or parasite whose coverage rate scored 10-fold greater than that of any other bacteria, viruses, or parasites according to a previous study (24).

For fungi, the criteria for a positive mNGS result were as follows: on the species level, mNGS identified a fungus whose coverage rate scored 5-fold greater than that of any other fungi (24).

Statistical analysis

Continuous variables were expressed as median (interquartile range) if they followed a non-normal distribution. Comparative analysis between the two groups was conducted by the Mann-Whitney U test. Data analysis was performed with the statistical software SPSS version 21.0 (IBM Corp., Armonk, NY, USA). All tests were two-tailed, and statistical significance was considered at P<0.05.

Results

Patient evaluation

The clinical features of the seven patients are summarized in Table 1. All seven patients had underlying heart diseases and underwent previous cardiac surgery, five at our hospital and two at the local hospital before onset of infection. None of them were receiving glucocorticoids or immunosuppressive therapy.

Table 1

Summary of the seven newly reported cases of M. hominis mediastinitis

Patient: age (years), gender Associated conditions Initial operation(s) Onset of symptoms Image findings Specimen(s) positive for M. hominis identified by mNGS Concurrent infection(s) Antimicrobial therapy Revision operation(s) or procedure(s) Outcomes
A: 54, M CKD, congenital bicuspid aortic valve malformation, severe aortic and mitral regurgitation, LVEF 55% Bentall procedure, mechanical mitral valve replacement, tricuspid valve plasty POD 2, fever, purulent mediastinal fluid,
CRP 304.3 mg/L		 POD 3, X-ray, bilateral lung exudation, left pleural effusion, POD 26, CT scan, slight inflammation in both lungs POD 7, serum POD 14, A. baumannii in sputum identified by culture POD 2, Vm, Mem, POD 7, Dox, Lev for 3 weeks, POD 14, Scf added for 1 week Mediastinum drainage Defervescence and improvement of mediastinal fluid after application of specific medication against M. hominis, POD 27, discharge, recovery
B: 56, M Rheumatic heart disease, severe mitral stenosis and regurgitation, LVEF 49%, AF Mechanical mitral valve replacement, tricuspid valve plasty, radiofrequency ablation of AF POD 6, fever, purulent sternal wound fluid,
CRP 217.9 mg/L,
PCT 2.33 ng/mL		 POD 7, CT scan, mediastinal, pericardial and pleural effusion, improved on CT scan POD 12 POD 12, serum and surgical debridement abscess POD 12, Ureaplasma parvum in serum and surgical debridement abscess, identified by mNGS POD 6, Vm, Mem, POD 12, Lev added POD 10, resternotomy, debridement, drainage Defervescence and improvement of general conditions after application of specific medication against M. hominis, POD 20, discharge, recovery
C: 55, M Severe aortic regurgitation, aortic valve prolapse, LVEF 64% Mechanical aortic valve replacement, ascending aortoplasty, CABG POD 7, purulent sternal wound fluid POD 7, CT scan, mediastinal, pericardial and pleural effusion, POD 48, TTE, aortic valve perivalvular abscess and vegetations POD 58, serum and surgical debridement abscess POD 58, Ureaplasma urealyticum in surgical debridement abscess identified by mNGS POD 7, Vm, Cxm, POD 44, Lzd, Ctrx, POD 49, Dap, Tzp Mediastinum drainage, POD 56, resternotomy, debridement, Bentall procedure Infection worsening, MODS, POD 57, death
D: 73, M AF, bilateral atrial enlargement, moderate mitral regurgitation, severe tricuspid regurgitation, LVEF 63% Mitral and tricuspid valve plasty, radiofrequency ablation of AF POD 12, fever, purulent mediastinal fluid, PCT
6.76 ng/mL		 POD 13, X-ray, bilateral lung exudation POD 17, mediastinal fluid POD 15, multidrug-resistant A. baumannii in sputum identified by culture, POD 17, A. baumannii in mediastinal fluid identified by mNGS POD 2, Tzp, POD 10, Vm, Mem, POD 16, Lzd, Mem, Pb, POD 17, Lev added Mediastinum drainage POD 3, CRRT, POD 10, tracheal intubation, assisted ventilation, infection worsening, MODS, POD 22, death
E: 54, M Stanford type A aortic dissection 3 years before admission Ascending aortic arch replacement, descending aortic stent implantation and Bentall procedure at the local hospital 3 years before admission Recurrent fever for 6 months, CRP 34.2 mg/L, PCT
0.1 ng/mL on admission		 18F-FDG PET/CT on admission, inflammation of the artificial aorta and mediastinum, TTE, artificial aortic perivalvular abscess and rupture, LVEF 64% Serum on admission None Dox, Mxf for 3 months since detection of M. hominis Resternotomy and debridement after 1-month treatment of Dox, Mxf Defervescence 5 days after usage of Dox and Mxf, improvement of general conditions, recovery
F: 70, M Congenital bicuspid aortic valve malformation Aortic valve replacement at the local hospital 8 years before admission, PVE, resternotomy and aortic valve replacement 2 years before admission, blood and valve culture negative Fever for 2 weeks, CRP
57.9 mg/L, PCT 0.13 ng/mL on admission		 18F-FDG PET/CT on admission, aortic perivalvular, pericardial and mediastinal inflammation, TTE, artificial aortic perivalvular abscess, vegetations and leak, LVEF 50% Serum on admission None Lev for 3.5 months since detection of M. hominis Resternotomy, debridement, Bentall procedure after 6-week treatment of Lev Defervescence 7 days after usage of Lev, improvement of general conditions, recovery
G: 56, M Hypertension, Stanford type A aortic dissection Aortic valve, ascending aorta and half aortic arch replacement POD 40, febrile, sternal wound split and pus discharge, CRP 112.4 mg/L, PCT 0.88 ng/mL POD 40, CT scan, mediastinal, pericardial and pleural effusion POD 65, mediastinal fluid POD 65, Ureaplasma urealyticum in mediastinal fluid identified by mNGS POD 40, Dap, Ctrx, POD 65, Dox for 3 months POD 50, resternotomy and debridement, mediastinum drainage Defervescence 6 days after usage of Dox, improvement of general conditions, recovery

M. hominis, Mycoplasma hominis; mNGS, metagenomic next-generation sequencing; M, male; CKD, chronic kidney disease; LVEF, left ventricular ejection fraction; POD, postoperative day; CRP, C-reactive protein; CT, computed tomography; A. baumannii, Acinetobacter baumannii; Vm, vancomycin; Mem, meropenem; Dox, doxycycline; Lev, levofloxacin; Scf, cefoperazone sulbactam; AF, atrial fibrillation; PCT, procalcitonin; CABG, coronary artery bypass grafting; TTE, transthoracic echocardiography; Cxm, cefuroxime; Lzd, linezolid; Ctrx, ceftriaxone; Dap, daptomycin; Tzp, piperacillin tazobactam; MODS, multiple organ dysfunction syndrome; Pb, polymyxin B; CRRT, continuous renal replacement therapy; 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography; Mxf, moxifloxacin; PVE, prosthetic valve endocarditis.

Infection occurred 2 days, 6 days, 7 days, 12 days, 2.5 years, and 40 days after the initial cardiac surgery in patient A, B, C, D, E, and G, respectively. For patient F, infection occurred 5 years after the first cardiac surgery and 2 years after the second surgery, presumably caused by the same pathogen. All seven patients had fever and sternal pain, which were the first signs of infection. Patients with acute or subacute courses (A, B, C, D, and G) had purulent mediastinal or sternal wound fluids.

Imaging examination such as X-ray or computed tomography (CT) scan revealed mediastinal, pericardial, pleural effusion, and lung exudation. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT showed glucose metabolism increase in paraaortic, pericardial, and mediastinal areas in patients E and F, as shown in Figure 1. Transthoracic echocardiography (TTE) indicated concurrent infective endocarditis in patients C, E, and F. Detection of M. hominis by mNGS in serum indicated concurrent bloodstream infection in patient A, B, C, E, and F.

Figure 1 18F-FDG PET/CT showed glucose metabolism increase in paraaortic, pericardial, and mediastinal areas in patient E [(A,B) maximal SUV 28.9] and F [(C,D) maximal SUV 8.4]. R, right; A, anterior; 18F-FDG, 18F-fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; SUV, standardized uptake value.

Pathogen detection

For each patient, blood cultures were conducted at least once during fever after admission, all of which returned negative results. Abscess of surgical debridement tissues or sternal wound and mediastinal fluid were cultured repeatedly and also returned sterile results. Sputum samples of patient A and D were culture positive for Acinetobacter baumannii (A. baumannii).

Among the seven patients, mNGS identified M. hominis in nine clinical specimens including five serums, two abscesses, and two mediastinal fluids, as shown in Table 2. mNGS also detected concurrent infections of Ureaplasma parvum in the serum and abscess of patient B, Ureaplasma urealyticum in the abscess of patient C and mediastinal fluid of patient G, and A. baumannii in the mediastinal fluid of patient D. The turn-around time (TAT) of mNGS took 24 hours. Delay in the diagnosis of M. hominis infections mainly resulted from delayed conduction of mNGS.

Table 2

Identification of M. hominis by mNGS in the seven newly reported mediastinitis cases

Patient No. Specimen SMRNG Relative abundance of
genera (%)		 SMRN Relative abundance of
species (%)		 Coverage rate (%)
A Serum 72 40.62 71 40.62 0.57
B Serum 182 31.27 176 30.29 1.14
Abscess 7,036 62.71 6,682 61.6 33.18
C Serum 127 7.91 123 7.78 0.83
Abscess 13,822 96.01 13,099 94.03 52.12
D Mediastinal fluid 70,687 45.65 66,898 44.65 80
E Serum 2,165 88.13 2,095 87.32 12.48
F Serum 8,390 91.7 8,156 91.04 38.52
G Mediastinal fluid 109,706 98.65 105,970 98.11 70.12

M. hominis, Mycoplasma hominis; mNGS, metagenomic next-generation sequencing; SMRNG, stringent mapped reads number of genera; SMRN, stringent mapped reads number of species.

Differences of M. hominis detection results by mNGS between serum and body fluid

The SMRNG, SMRN, and coverage rate of M. hominis detection by mNGS were significantly higher in body fluid (abscess or mediastinal fluid) than in serum (P<0.05), as shown in Table 3. There was no significant difference in relative abundance of genera or species of M. hominis detection between serum and body fluid.

Table 3

Differences of M. hominis detection by mNGS between serum and body fluid

Parameters of mNGS results Serum Body fluid P value
SMRNG 182 (99.5, 5,278) 8,733 (42,255, 99,951) 0.03
Relative abundance of genera (%) 40.62 (19.59, 89.92) 79.36 (49.92, 97.99) 0.19
SMRN 176 (97, 5126) 39,999 (8,286, 96,202) 0.03
Relative abundance of species (%) 40.62 (19.04, 89.18) 77.82 (48.89, 97.09) 0.19
Coverage rate (%) 1.14 (0.7, 25.5) 61.12 (37.92, 77.53) 0.03

Data are presented as median (IQR). M. hominis, Mycoplasma hominis; mNGS, metagenomic next-generation sequencing; SMRNG, stringent mapped reads number of genera; SMRN, stringent mapped reads number of species; IQR, interquartile range.

Antibiotic adjustment, surgical treatment, and outcomes

After detection of M. hominis, antibiotic regimens were adjusted to quinolones or doxycycline except for in patient C, whose diagnosis was clarified after death. Patients A and D received merely antibiotic treatment and mediastinum drainage while the other five patients underwent resternotomy and debridement surgery in addition to conservative treatment. Patients C and D died as a result of infection deterioration whereas the other five patients completely recovered.

Literature review

Our literature review since 1970 identified 30 cases of mediastinitis, wound infections, arthritis, meningitis, endocarditis, and abscess caused by M. hominis, as shown in Table 4. Including our seven new cases, 2 (5.4%) were neonates and 35 (94.6%) were adults. A total of 31 patients (83.8%) were male. Surgery had been previously conducted in 30 patients (81.1%) and 15 (40.5%) had implanted devices. There were 12 patients (32.4%) who were immunocompromised including 7 (18.9%) with organ transplantation and 5 (13.5%) under glucocorticoids or immunosuppressive therapy due to autoimmune diseases. Concurrent infections occurred in 12 patients (32.4%) including three coinfected with Ureaplasma urealyticum, three with Staphylococcus epidermidis, two with A. baumannii, one with Ureaplasma parvum, one with Actinomyces, one with Klebsiella pneumoniae and Serratia marcescens, and one with Pseudomonas aeruginosa. There were 24 cases (64.9%) whose culture returned positive. 16S ribosomal RNA (rRNA) sequencing and PCR assisted the etiological diagnosis in 29 cases (78.4%). Except for our seven patients, only one case was subjected to mNGS in pathogen detection. There were 31 patients (83.8%) who underwent surgical debridement or drainage whereas 35 (94.6%) received specific antibiotic treatment against M. hominis including doxycycline, minocycline, quinolones, and azithromycin. A total of 5 patients (13.5%) died eventually.

Table 4

Summary of previously reported cases of mediastinitis, wound infections, arthritis, meningitis, endocarditis, and abscess caused by M. hominis

Patient No.: age (years), gender Associated conditions Specimen(s) positive for M. hominis Identification technology Concurrent infection(s) Treatment against M. hominis Outcome Ref.
1: –, M Congenital heart disease, lung transplantation Sternal wound swab Culture None Dox, Azm, debridement Resolved (6)
2: –, M CF, lung transplantation Pleural fluid Culture None None Died (6)
3: –, M COPD, lung transplantation Pleural fluid and BAL Culture None Dox, Mxf, debridement Resolved (6)
4: –, M COPD, lung transplantation Pleural fluid and BAL Culture Ureaplasma urealyticum in pleural fluid and BAL Dox, Cm, debridement Resolved (6)
5: –, M ILD, lung transplantation Sternal wound swab and BAL Culture None Dox, Mxf, debridement Resolved (6)
6: 78, M AMI, cardiac failure, CABG Pleural fluid Culture and PCR None Cm, Cpfx, resternotomy, drainage Resolved (2)
7: 68, M OMI, cardiac failure, CABG Sternal wound swab Culture and PCR None Cm, resternotomy, drainage Died (2)
8: 44, M AF, CHD, CABG Sternal wound swab Culture and PCR None Ofx, resternotomy, drainage Resolved (2)
9: 51, M OMI, CABG Sternal wound swab Culture and PCR Staphylococcus epidermidis in trachea Cm, Dox, debridement, drainage Resolved (2)
10: 58, M OMI, CABG Mediastinal fluid Culture and PCR Staphylococcus epidermidis in sternal wound Cm, Cpfx, resternotomy and debridement ×3, drainage Resolved (2)
11: 48, F Submandibular abscess, mediastinitis Pleural fluid Culture and PCR Actinomyces in neck abscess Cm, thoracotomy ×2, drainage Resolved (2)
12: 63, M Lung transplantation, mediastinitis BAL and sputum PCR None Dox, Lev, resternotomy, debridement Resolved (7)
13: 54, M Aortic valve stenosis, PFO, aortic valve replacement and PFO closure Mediastinal abscess and urine Culture and PCR None Lev, Mh, resternotomy, debridement Resolved (5)
14: 21, M Restrictive cardiomyopathy, pulmonary hypertension, heart-lung transplantation Periaortic abscess Culture and PCR Klebsiella pneumoniae and Serratia marcescens in sputum Lev, Mh, resternotomy and debridement, mediastinal lavage Resolved (25)
15: 48, M MS, immunocompromised, right hip arthroplasty Synovial fluid of the hip and blood Culture None Mh, irrigation and debridement Resolved (10)
16: 58, F RA, immunocompromised, bilateral hip arthroplasty Synovial fluid of the knee and hip Culture and PCR None Dox, Mxf, debridement Resolved (13)
17: 59, M Left hip replacement Synovial fluid of the left hip Culture and 16S None Cm, Mxf, debridement Resolved (14)
18: 27, F SLE, immunocompromised Synovial fluid of the left elbow 16S None Dox Resolved (11)
19: 30, M TTP, immunocompromised Abscess of the left hip and iliopsoas Culture and PCR None Dox, Mxf, arthrotomy ×2, irrigation Resolved (12)
20: 52, M Traumatic brain injury, decompressive craniotomy Head incision fluid and CSF Culture and 16S None Mh, continued CSF drainage Resolved (15)
21: 61, M Intracerebral hemorrhage, decompression craniotomy CSF mNGS and PCR None Mxf Resolved (16)
22: 39, M Subarachnoid hemorrhage, external ventricular drainage CSF Culture, 16S, PCR None Mxf, external ventricular drainage Died (18)
23: 0, F Born at term, uncomplicated vaginal delivery CSF 16S None Mxf Resolved (4)
24: 0, M Extremely preterm neonate (25+6 weeks), vaginal delivery, intraventricular hemorrhage CSF 16S None Dox, Mxf Resolved (17)
25: 67, M Ventricular tachycardia and ICD implantation Pericardial fluid, pocket wound exudate, ICD lead Culture and PCR None Dox, Mxf, ICD explantation, debridement of the generator pocket Resolved (19)
26: 28, M Aortic valve and root replacement, PVE, reoperation ×5, aortic homograft Surgically removed valves and aortic tissues 16S None Mxf, debridement, heart transplantation Resolved (20)
27: 74, M Mitral and aortic prosthetic valve replacement, PVE Surgically removed valves Culture and 16S Staphylococcus epidermidis by blood culture Cm, Dox, mitral and aortic valve replacement Resolved (21)
28: 43, M Multiple open traumas caused by a traffic accident Serum and wound swab Culture and 16S Pseudomonas aeruginosa in wound swab Mh Resolved (9)
29: 55, F RA, immunocompromised, perirectal abscess Perirectal abscess Culture None Dox, debridement, resection of the rectum Resolved (22)
30: 38, F Total disc arthroplasty, postoperative retroperitoneal abscess Retroperitoneal abscess Culture None Dox, debridement, drainage Resolved (23)

M. hominis, Mycoplasma hominis; ref., reference; –, not available; M, male; Dox, doxycycline; Azm, azithromycin; CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; BAL, bronchoalveolar lavage; Mxf, moxifloxacin; Cm, clindamycin; ILD, interstitial lung disease; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; PCR, polymerase chain reaction; Cpfx, ciprofloxacin; OMI, old myocardial infarction; AF, atrial fibrillation; CHD, coronary heart disease; Ofx, ofloxacin; F, female; Lev, levofloxacin; PFO, patent foramen ovale; Mh, minocycline; MS, multiple sclerosis; RA, rheumatoid arthritis; 16S, 16S ribosomal RNA sequencing; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura; CSF, cerebrospinal fluid; mNGS, metagenomic next-generation sequencing; ICD, implantable cardioverter defibrillator; PVE, prosthetic valve endocarditis.

Discussion

Extra-genital infections due to M. hominis including wound infections, abscesses, arthritis, osteitis, meningitis, and endocarditis have been documented. These infections especially occur among patients under immunosuppressive therapy due to organ transplantation or autoimmune diseases (25). M. hominis infection is rare among immunocompetent hosts yet might occur postoperatively. The route of infection has been suspected to be colonization of M. hominis on the skin, the urinary tract, or the respiratory tract via surgical procedures, urethral catheterization, or tracheal intubation. M. hominis infections involving the mediastinum tended to be more severe than infections of other sites. Some cases presented as fulminant infection or sepsis whereas others may be indolent with a chronic course lasting years (2). In our newly reported seven cases, five had concurrent bloodstream infection, and were thus more difficult to manage clinically.

Up to now, M. hominis culture has always been challenging. Cultures of M. hominis usually manifest as pinpoint-sized, transparent, and nonhemolytic colonies on blood-agar plates, requiring experienced technical staff to recognize (15). Sensitivity of conventional culture is low whereas negative gram staining and the slow growth bring more challenges, leading to the underestimation of this pathogen. When regular culture is negative, atypical organisms including M. hominis should be taken into consideration.

M. hominis growth might be facilitated by specific culture media which is not widely available in our hospital, partially explaining the completely negative culture results of all seven patients. Even on specific culture plates, M. hominis growth usually takes 7 days or longer, requiring prolonged incubation, which is easily overlooked clinically. In a previous study, microbiological identification of M. hominis took an average of 9.1 days (range, 5–21 days) after clinical samples were obtained (2). Prompt etiological diagnosis and specific antibiotic therapy is essential in the treatment of M. hominis infections whereas delayed diagnosis and inappropriate antibiotic usage might lead to poor outcomes, as demonstrated in our patients C and D.

In recent years, mNGS for pathogen detection has become widely available for a variety of sample types and patient indications. The excellent sensitivity similar to specific PCR assays, the ability to identify more potential pathogens than conventional methods, and the unbiased nature have made mNGS favored in different clinical situations (26). Previous studies most frequently elaborated on clinical application of mNGS in pulmonary infections (27), central nervous system infections (28), osteoarticular infections (29), and bloodstream infections (30) both in immunocompromised and immunocompetent patients. However, the clinical value of mNGS in the etiological diagnosis of mediastinitis has seldom been interpreted. To our knowledge, this is the first case series applying mNGS in the etiological diagnosis of M. hominis mediastinitis. mNGS identified the causative pathogen in seven culture-negative patients and guided specific antibiotic therapy. Clinical outcomes of patient A, B, E, F, and G had been improved and benefited by mNGS. Conduction of mNGS was significantly delayed in patients C and D and partly associated with their poor outcomes.

On the other hand, the high cost of mNGS has limited its clinical application in China to some extent. Not all patients are financially capable of payment of mNGS testing fees. For patient C and D, at the beginning of the worsening of their conditions, clinicians had already recommended mNGS to their family. Their family hesitated for financial reasons. By the time they decided to undergo mNGS testing, infection had worsened, and the patients subsequently died. For patient D, mNGS was recommended POD12. Although the patient died of multiple organ failure, partly due to surgical trauma, infection is still the most important reason for his condition worsening. A. baumannii seems to be less virulent than M. hominis and might not be the main cause of death.

In our hospital, the TAT of mNGS is 24 hours, much shorter than that of conventional culture. mNGS is more sensitive and time saving than culture in the detection of fastidious pathogens.

mNGS detected M. hominis with higher SMRNG, SMRN, and coverage rate in body fluid specimens (abscess or mediastinal fluid) than in serum, probably indicating more biomass and priority of body fluid if there was a choice of specimen type.

In previously reported cases, treatment for M. hominis infections included drainage, debridement, lavage, and specific antibiotics such as doxycycline, minocycline, quinolones, and azithromycin. Surgical debridement is crucial as demonstrated in many cases, especially our patient G. His general conditions had already significantly improved since resternotomy and debridement postoperative day (POD) 50 before identification of M. hominis infection and specific antibiotic treatment, which were delayed until POD 65. As for our patient F, after 6-week treatment of levofloxacin before debridement surgery, his serum mNGS was still positive for M. hominis although biomass amount had reduced (SMRNG: 8,390→2,538; SMRN: 8,156→2,462). After debridement surgery, he was prescribed levofloxacin for another 2 months after which serum mNGS turned negative. For patient C, resternotomy and debridement were delayed until POD 56 and M. hominis was identified after death. For patient D, debridement surgery was infeasible because of their severely ill condition and identification of M. hominis was delayed until POD 17. Lack of prompt debridement and specific antibiotics partly led to the deaths of patients C and D.

Conclusions

Extra-genital infection caused by M. hominis is extremely rare among immunocompetent hosts and could be life-threatening. Identification of M. hominis is challenging through conventional microbiological culture and delay of diagnosis is common. mNGS is more sensitive and time saving than culture in the detection of M. hominis. If conventional microbiological findings are negative or the patient responds poorly to standard therapy, the clinicians should consider the possibility of M. hominis involvement and apply culture-independent methods such as mNGS. Early diagnosis, specific antibiotics, drainage, and debridement are crucial to the treatment of M. hominis infection.

Acknowledgments

The authors extend their thanks to all the clinicians and microbiologists who assisted in this study.

Funding: This work was funded by the Zhongshan Hospital of Fudan University (No. 2021ZSFZ06).

Footnote

Reporting Checklist: The authors have completed the STROBE and AME Case Series reporting checklists. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-286/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-286/dss

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-286/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethical Review Committee of Zhongshan Hospital, Fudan University, Shanghai, China (No. B2017-193R) and informed consent was taken from all the patients or the relatives.

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Cite this article as: Cai S, Pan J, Wang S, Bao R, Zhou C, Gao X, Shiiya H, Hu B. Accurate etiological diagnosis of Mycoplasma hominis mediastinitis in immunocompetent patients using metagenomic next-generation sequencing: a case series and literature review. J Thorac Dis 2024;16(4):2499-2509. doi: 10.21037/jtd-24-286

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