Infective endocarditis caused by Streptococcus sinensis diagnosed with next-generation sequencing: a case report and literature review

Abstract

Background

Infective endocarditis (IE) caused by Streptococcus sinensis is rare and challenging to diagnose due to the irregular use of antibiotics and the limitations of conventional diagnostic methods. Metagenomaic next-generation sequencing (mNGS) has emerged as a valuable diagnostic tool, offering significantly enhanced accuracy in identifying elusive pathogens, particularly in blood culture-negative endocarditis (BCNE).

Case presentation

We reported the case of a 33-year-old male who presented with recurrent intermittent fever lasting over six months. Despite multiple diagnostic attempts, including blood cultures, no causative pathogen was identified. Blood mNGS revealed the presence of S. sinensis, a rare pathogen associated with IE. Echocardiography confirmed vegetation on the mitral and aortic valves, leading to a possible diagnosis of IE. The patient underwent successful surgical valve replacement, and subsequent mNGS of excised valve tissue confirmed the presence of S. sinensis. We administered a tailored antibiotic regimen, and the patient achieved a favorable recovery with no significant complications during follow-up.

Results

We identified 11 additional cases of S. sinensis-induced IE through a literature review, including patients from diverse geographic regions and age groups. Most cases were associated with prior dental procedures or poor oral health. Common diagnostic methods included blood culture and 16 S rRNA sequencing, while recent cases utilized mNGS. Treatment typically involved penicillin-based antibiotics combined with gentamicin, with surgical intervention in most cases leading to favorable outcomes.

Conclusions

This case highlights the diagnostic value of mNGS in identifying pathogens in IE, particularly when traditional methods fail due to prior antibiotic use. While mNGS has significant advantages in pathogen detection, it cannot replace standard microbiological techniques and should be considered a complementary approach. Integrating mNGS into clinical workflows can improve diagnostic accuracy, especially in BCNE cases, and guide effective treatment strategies.

Clinical trial number

Not applicable.

Background

Streptococcus sinensis is a newly identified pathogen, first reported in 2002 in a patient with infective endocarditis (IE) in Hong Kong, and was thus named S. sinensis [1]. As a member of the Streptococcus mitis group, S. sinensis is a facultatively anaerobic, non-spore-forming, gram-positive coccus that arranges in chains [2]. In recent years, this bacterium has gradually gained global attention due to its emerging role as a potential cause of IE [2, 3]. Since 2002, cases of IE caused by S. sinensis have been reported in Switzerland, France, the United Kingdom, the Netherlands, mainland China, and India, totaling 11 cases [2–6].

IE is an infection of the heart’s endocardial surface, primarily involving the heart valve, mural endocardium, septal defects, or indwelling cardiac devices. It manifests with a diverse range of clinical symptoms, including fever, heart murmur, and embolic phenomena. Despite advances in diagnostic methods and treatment, IE still has a high mortality rate of about 30% [7]. The most prevalent microorganisms responsible for IE include Staphylococcus, Streptococcus, and Enterococcus, accounting for about 80% of cases. However, IE caused by S. sinensis remains rare [7].

Most previously reported cases were diagnosed through blood culture, while approximately 10% of IE patients have blood culture-negative endocarditis (BCNE) [8]. The reasons for blood culture negativity include the inability of certain microorganisms to be isolated by conventional culture techniques, with antibiotic use before testing being the most common cause of bacterial growth inhibition [9, 10]. In recent years, metagenomic next-generation sequencing (mNGS) has significantly improved detection rates for these challenging cases [11, 12].

mNGS directly extracts DNA/RNA from clinical samples to construct a metagenomic library. This approach allows pathogen identification through PCR amplification and sequencing, followed by bioinformatic analysis that compares sequences against comprehensive databases [13]. mNGS amplifies all nucleic acid sequences in a sample, allowing unbiased detection of all potential pathogens. It has advantages such as comprehensive coverage, rapid detection, and high sensitivity and specificity in diagnosing various pathogens, leading to its increasingly widespread use in clinical practice [14].

This report presents a case of IE caused by S. sinensis, diagnosed using blood-derived mNGS. In addition, a literature review is provided, aiming to enhance clinical understanding and inform the management of this emerging pathogen.

Case presentation

A 33-year-old Chinese male presented to our hospital with a primary complaint of intermittent fever that had persisted for six months, reaching a maximum temperature of 39.0 °C, along with dry cough and shoulder stiffness. He had been self-administering azithromycin dispersible tablets and levofloxacin irregularly, which provided temporary relief, but the fever recurred within 2–3 days.

The patient had previously been hospitalized at another facility, where laboratory tests revealed a leukocyte count of 10.76 × 10^9/L (normal range: 3.5–9.5 × 10^9/L), with neutrophils at 6.52 × 10^9/L (normal range: 1.8–6.3 × 10^9/L). The erythrocyte sedimentation rate (ESR) was 16 mm/h (normal range: 0–20 mm/h), C-reactive protein (CRP) was 22 mg/L (normal range: 0–6 mg/L), and procalcitonin was 0.134 ng/mL (normal range: 0–0.15 ng/mL). Aerobic and anaerobic blood cultures, along with chest CT scans, were performed, but all results were negative, with no abnormalities detected in the heart or lungs. Lymph node ultrasound showed enlargement of the right neck VI region lymph nodes, which were interpreted as reactive. An electrocardiogram (ECG) revealed mild left ventricular hypertrophy (LVH) and early repolarization. The patient was treated with intravenous moxifloxacin and compound methoxyphenamine capsules before being discharged.

After discharge, the fever recurred, reaching a peak of 39.4 °C and lasting 3–7 days per episode, with symptoms being most pronounced in the afternoon. The patient frequently sought outpatient care at other hospitals and used medications such as ibuprofen, Lianhua Qingwen granules, cephalosporins, clarithromycin, and moxifloxacin irregularly, which provided only temporary relief. During this time, he also experienced occasional palpitations and chest tightness, which resolved as the fever subsided, in addition to a weight loss of approximately 15 kg. For further diagnostic evaluation and management, the patient visited our hospital’s outpatient clinic.

Physical examination: Height, 175 cm; weight, 55 kg; temperature, 37.1 °C; heart rate, 78 bpm; respiratory rate, 21 bpm; blood pressure, 126/77 mmHg. Lung auscultation revealed clear breath sounds, and the heart rhythm was regular; however, pathological murmurs weren’t present. Upon admission, the leukocyte count, neutrophils, and procalcitonin levels were within normal ranges, but CRP was elevated to 43 mg/L (normal range: 0–6 mg/L). The patient had intermittently taken oral antibiotics throughout the illness, which may explain the negative results of the initial blood cultures at the previous hospital. Given the inconclusive results of multiple diagnostic examinations, blood mNGS was performed.

Sequencing on the MGISEQ-2000 platform identified S. sinensis. A total of 77 sequences were detected, with a sequencing depth of 1 and a Shannon index of 0.99. The read distribution of S. sinensis was relatively uniform, with the X-axis representing nucleotide positions and the Y-axis indicating the number of reads at each position. The coverage rate of 0.2713% reflects the proportion of the genome covered by the sequencing reads (Fig. 1). Further BLAST homology analysis showed 100% homology with S. sinensis. Sequencing depth refers to the number of reads covering a specific genomic position or target region. Greater depth typically improves mutation detection accuracy and sensitivity, reducing the likelihood of missing low-frequency variants. The Shannon index, a measure of biodiversity or species diversity in the sample, quantifies the uncertainty or variability in species distribution. A higher Shannon index indicates greater diversity and a more even distribution of species. The sequencing depth and Shannon index of the NGS results suggest that the detection of S. sinensis in this patient is robust and reliable.

Fig. 1.

Reads Distribution of S. sinensis

After the mNGS findings, a thorough inquiry into the patient’s medical history was conducted. The patient reported having undergone multiple root canal treatments over the past decade, with the most recent procedure performed a few years ago. Recently, he experienced gingival swelling after eating hot pot, accompanied by a toothache. The ECG still showed mild LVH and early repolarization. A cardiac echocardiogram was strongly recommended, revealing vegetation on the mitral and aortic valves, possible prolapse of the anterior mitral leaflet with partial chordae rupture, bicuspid mitral function, mild to moderate aortic regurgitation, moderate to severe mitral regurgitation, and left atrial and ventricular enlargement (Fig. 2).

Fig. 2.

Cardiac Echocardiogram (showing a high-echogenic mass attached near the root of the anterior leaflet of the mitral valve, measuring approximately 9.1 × 4.4 mm)

Based on the 2023 Duke-ISCVID IE criteria, the patient was diagnosed with possible IE caused by S. sinensis, fulfilling one major criterion (imaging) and two minor criteria (fever and microbiological evidence) [15].

Given the large size of the patient’s mass and the high risk associated with it, immediate cardiothoracic consultation was recommended. The patient underwent aortic and mitral valve mechanical valve replacement. Postoperative mNGS of the excised valvular tissue detected both S. sinensis and Streptococcus cristatus. Based on the 2023 Duke-ISCVID IE criteria, the patient fulfilled the pathologic criterion, and the final diagnosis was definite IE [15].

Postoperatively, the patient received intravenous vancomycin (1 g IV every 12 h) for six weeks, in accordance with standard recommendations for IE caused by β-lactam–allergic, streptococcus-associated infections. However, due to hospitalization policy constraints, the patient could not remain admitted for the entire duration of treatment. Consequently, the patient was discharged after four weeks and instructed to continue daily intravenous vancomycin at a local hospital to complete the six-week course. The patient later reported difficulty maintaining daily intravenous therapy at the local hospital. Given the lack of access to intravenous therapy, oral linezolid (600 mg orally twice daily) was proposed as an alternative for the remaining two weeks to ensure treatment completion.

At the two-month follow-up, the patient had discontinued antibiotics, reported no discomfort, and was stable on oral warfarin and metoprolol for anticoagulation.

Results

A search of the PubMed database was conducted using “Infective Endocarditis” and “Streptococcus sinensis” as keywords, covering all studies published up until October 2024. After screening, a total of 11 cases of S. sinensis-induced IE were identified. These cases represent patients from diverse geographic regions, age groups, and underlying conditions, reflecting the complexity and variability of S. sinensis infections. Detailed clinical information on all reported patients is summarized in Table 1.

Table 1.

Literature review of reported infective endocarditis cases caused by S. sinensis

Year	Gender	Age	Region	History of oral surgery	Diagnostic method	Strain	Cardiac echocardiogram	Antibiotics	Duration	Surgical procedure	Outcome	Reference
1998	Male	57	Switzerland	Dental surgery	Blood culture and 16 S rRNA	Geneva	Vegetation + Mitral valve involvement	PCN, GEN	6 weeks	Yes	Three years later, he died due to a cerebral hematoma caused by oral anticoagulant therapy. The autopsy revealed no sequelae from the previous infection	[6]
2000	Female	42	Hong Kong	NA	Blood culture and 16 S rRNA	HKU4	-	AMP, GEN	6 weeks	NA	NA	[1]
2005	Male	55	France	NA	Blood culture and 16 S rRNA	HDP2005-0155	Mitral valve involvement	AMX, GEN	8 weeks	Yes	Survival	[5]
2015	Female	20	France	NA	Mass spectrometry (MALDI-TOF, Vitek MS) and 16 S rRNA	NA	Vegetation + Patent ductus arteriosus	AMX, GEN	4 weeks	Yes	Survival	[30]
2019	Male	63	British	Dental bridge restoration	Blood culture	NA	Vegetation	AMX, GEN	6 weeks	Yes	Survival	[2]
2019	Male	37	France	Dental examination revealed that six teeth need to be extracted	Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS, Bruker Daltonik GmbH, Germany), and 16 S rDNA	11,026,353	Vegetation + Patent ductus arteriosus	AMX, GEN	4 weeks	Yes	NA	[22]
2020	Male	19	Mainland China	NA	Blood culture, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS, Bruker Daltonik GmbH, Germany), and 16 S rRNA	BC1012612	Vegetation + Mitral valve involvement	PCN, GEN, CRO, MEM	6 weeks	Yes	Survival	[9]
2020	Male	57	Netherlands	NA	Blood culture, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS, Bruker Daltonik GmbH, Germany)	NA	Vegetation + Mitral valve involvement	PCN, GEN	1 week	No	Death	[3]
2022	Male	59	China, Guizhou	NA	Blood culture, Autof MS-1000 microbial mass spectrometer and 16 S rDNA	NA	Vegetation + Aortic valve involvement	MEM, VAN, CRO	4 weeks	Yes	Survival	[31]
2024	Female	8	India	NA	Blood culture	NA	Vegetation	CIP, GEN	6 weeks	Yes	Survival	[32]
2024	Female	40	China, Beijing	Dental filling procedure	mNGS, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI Biotyper Microflex LT, Bruker, Germany)	NA	Prosthetic valve	VAN, Pen G, CRO, AMP, TEC, LVX, MEM	10 weeks	Yes	Survival	[30]
2024	Male	33	China, Shanxi	Root canal treatment	mNGS	NA	Vegetation + Mitral and aortic valve involvement	VAN, LNZ	6 weeks	Yes	Survival	This article

Note: “-” indicates no result; NA: not available; PCN: penicillin; GEN: gentamicin; CRO: ceftriaxone; MEM: meropenem; AMP: ampicillin; AMX: amoxicillin; VAN: vancomycin; CIP: ciprofloxacin; LNZ: linezolid; Pen G: Penicillin G; TEC: teicoplanin; LVX: levofloxacin

Among the 12 cases (including the current case), there were 4 females and 8 males, with ages ranging from 8 to 63 years. The median age was 40 years, illustrating the broad demographic impact of this infection. Geographically, the cases were distributed across multiple regions, including Europe (Switzerland, France, United Kingdom, Netherlands), Asia (China, India, Hong Kong), and North America. Most patients had significant underlying health conditions, such as congenital heart disease, chronic rheumatic heart disease, or a history of dental procedures, highlighting the increased susceptibility of individuals with pre-existing cardiovascular or dental issues.

Common presenting symptoms included fever (9/12), fatigue (5/12), and weight loss (4/12). In some cases, specific findings such as Janeway lesions (2/12) or Roth spots (1/12) were observed, indicating embolic complications. Cardiac murmurs were reported in all cases where auscultation findings were available, with holosystolic murmurs being the most common.

The diagnosis of S. sinensis-induced IE was made using various microbiological techniques, including traditional blood culture combined with 16 S rRNA sequencing, matrix-assisted laser desorption/ionization time-of-flight mass spectrometr, and, in recent cases, mNGS. The increasing use of mNGS has significantly enhanced the detection of S. sinensis, particularly in cases with prior antibiotic use, where conventional diagnostic methods often fail.

Echocardiography revealed vegetations in all patients, with valve involvement distributed as follows: 5 cases involved the mitral valve, 2 cases involved the aortic valve, 2 cases involved patent ductus arteriosus, and 1 case involved a prosthetic valve. Notably, one case showed no vegetations on echocardiography but presented with severe cardiac dysfunction, highlighting the complexity of S. sinensis IE.

The majority of patients received combination antibiotic therapy, typically involving β-lactams (penicillin or ampicillin) combined with gentamicin. In cases where the infection involved prosthetic valves or resistance was suspected, vancomycin or meropenem was administered. Patients were treated for durations ranging from 4 to 10 weeks. Surgical valve replacement was performed in 10 cases, with excellent outcomes in most patients. However, two cases resulted in mortality, one due to complications unrelated to the infection and the other due to delayed diagnosis and treatment.

Discussion

In this case, we presented a young male patient with a prolonged history of intermittent fever. The fever’s responsiveness to antibiotic treatment suggested an infectious etiology as the primary differential diagnosis, while the patient’s history of prior oral surgery raised suspicion for IE. However, due to the non-standard and irregular use of antibiotics, blood cultures consistently returned negative results, delaying both diagnosis and treatment. The use of peripheral blood mNGS enabled the identification of Streptococcus sinensis, a rare causative agent of IE. Timely and comprehensive imaging confirmed the presence of vegetations. The patient underwent surgical intervention followed by a standardized course of oral antibiotics. At follow-up, the patient demonstrated a good prognosis with no recurrence of symptoms.

IE is most commonly caused by staphylococcus aureus and streptococcal species; however, a variety of less common pathogens, often challenging to diagnose, have also been implicated. These include Serratia marcescens, Coxiella burnetii, Bartonella species, and Brucella species, all of which have been reported in cases of IE. Such pathogens should be considered as part of the differential diagnosis, particularly in patients with atypical clinical presentations or in cases where conventional microbiological methods fail to identify the causative agent [16–19].

Woo et al. amplified S. sinensis 16 S rRNA and groEL fragments from saliva, suggesting that the oral cavity may be the natural reservoir of S. sinensis [20]. In previously reported cases, four patients had dental problems, which may be related to the oral origin of S. sinensis. The patient in this case had undergone multiple root canal treatments, and the current dental examination indicated dental defects, suggesting a possible persistent oral source of infection [21].

To date, there have been no reports of Streptococcus sinensis causing human infections other than IE. Goret et al. proposed that this bacterium may possess virulence factors that enable it to adhere to and colonize heart valves, resulting in endocardial damage [22]. However, similar to other viridans group streptococci, S. sinensis may also cause various types of infections. Since commercial diagnostic tools often misidentify S. sinensis as Streptococcus intermedius or Streptococcus anginosus, and viridans group streptococci are not typically identified to the species level in routine testing, the number of cases of IE or other infections caused by S. sinensis may be underestimated. The patient in this case had previously sought medical attention multiple times without a clear infection diagnosis, and S. sinensis was detected using mNGS. This case illustrates the importance of re-evaluating prior diagnoses and actively seeking pathogen evidence when routine treatment fails to improve the patient’s condition. The clinical manifestations of IE are diverse, and its diagnosis remains challenging.

Generally, heart murmurs are a characteristic sign of IE, and such signs are commonly reported in previous case studies. However, in this case, despite multiple hospital visits and examinations by various physicians, no murmurs were detected. This may be attributed to the following reasons: The patient presented with severe mitral regurgitation, which was eccentric in nature. Eccentric regurgitation can direct blood flow toward the left atrial wall, reducing turbulence at the central atrial level, resulting in softer or even absent murmurs upon auscultation. Additionally, the patient had left atrial enlargement, which can suppress regurgitation turbulence, further contributing to the subtle or undetectable nature of the murmur.

Most patients with S. sinensis infection have been reported to receive a six-week course of penicillin combined with gentamicin, while some patients were treated with antibiotics such as meropenem, vancomycin, and linezolid. In this case, the patient’s history of β-lactam allergy and prior antibiotic exposure necessitated the use of vancomycin as the most appropriate treatment option. However, due to special circumstances, the patient was unable to continue intravenous vancomycin treatment. As a result, oral therapy was chosen to complete the remaining course of treatment. After considering the microbial characteristics, the antibiotic spectrum of activity, and previously published literature, oral linezolid was ultimately selected for continued treatment. Studies have shown that linezolid is highly effective in the treatment of streptococcal infections. For streptococci, the probabilities of target attainment (PTAs) were significantly higher, with 67%/84% for oral treatment in relation to clinical breakpoint on day 1/day 5. For minimal inhibitory concentrations, the PTA for streptococci is 100%/92% on day 1/day 5 for oral treatment, indicating the strong efficacy of linezolid against streptococcal infections [23, 24].

In recent years, mNGS has rapidly expanded in infectious disease diagnosis, demonstrating significant advantages. It is particularly suitable for the detection of acute and severe infections, complex and mixed infections, and difficult-to-culture pathogens [25, 26]. In this case, mNGS was successfully used to diagnose IE caused by Streptococcus sinensis, highlighting its significant advantage in detecting low-abundance pathogens following irregular antibiotic use (with 77 reads of S. sinensis detected). mNGS enables rapid and comprehensive identification of pathogens, avoiding the false-negative results commonly seen in blood cultures. The application of this technology in challenging and chronic infection cases has broad prospects, significantly improving diagnostic accuracy and efficiency [26, 27].

Approximately 10% of IE cases are classified as BCNE, often caused by prior antibiotic use, including self-medication and antibiotic overuse in clinical settings. These practices inhibit bacterial growth, rendering conventional culture methods ineffective and underscoring the need for advanced diagnostic techniques. In contrast, mNGS offers a significant advantage by directly detecting microbial DNA or RNA, bypassing the need for live organisms. Unlike traditional methods, mNGS is unaffected by prior antibiotic use, enabling the identification of fastidious, slow-growing, or non-culturable pathogens. This makes mNGS particularly valuable in BCNE cases, as it bridges a critical diagnostic gap and provides clinicians with actionable insights for therapy.

Building on this, recent studies have demonstrated the transformative role of mNGS in diagnosing IE. For example, Zeng et al. highlighted the superiority of mNGS in perioperative IE diagnostics, with a sensitivity of 85.9% for valve mNGS compared to 29.3% for blood cultures and 16.2% for valve cultures. Notably, mNGS identified fastidious organisms such as Bartonella quintana and Coxiella burnetii, which were missed by conventional methods [28]. This finding is consistent with the work of Jun Cheng et al., who reported a sensitivity of 97.6% for NGS in resected heart valves, far surpassing the sensitivity of blood and valve cultures (46.2% and 17.1%, respectively) [29]. These studies collectively highlight the diagnostic power of mNGS and NGS, particularly in cases of blood culture-negative IE or difficult-to-culture pathogens.

mNGS is a promising diagnostic tool; however, it has certain limitations that warrant careful consideration. The technology is expensive, requires sophisticated laboratory facilities, and remains unavailable in many clinical settings. Additionally, due to its high sensitivity, mNGS may detect non-pathogenic microorganisms, potentially leading to overdiagnosis or misinterpretation of results. Crucially, mNGS identifies microorganisms using relatively short sequences, typically not exceeding 50 base pairs. As demonstrated in this case, misidentification of pathogens—such as the erroneous identification of S. sinensis as Streptococcus cristatus—can occur during mNGS analysis due to sequence mismatches. This highlights the need for careful interpretation of mNGS results in clinical practice. When possible, confirmatory analysis using BLAST sequence comparison and the construction of custom databases may help mitigate these issues.

It is important to note that mNGS cannot yet replace standard microbiological methods and should be viewed as a complementary approach within the diagnostic framework. While mNGS can aid in pathogen identification, it does not directly dictate treatment decisions, especially in the absence of antibiotic susceptibility test results.

In this case, we were faced with a complex clinical situation in which the patient presented with multisystem, nonspecific symptoms, including recurrent fever, cough, and joint pain. mNGS demonstrated its advantage by offering unbiased and comprehensive pathogen detection, rapidly identifying the infection source that blood cultures had failed to reveal. Furthermore, the risk of S. sinensis bacteremia is elevated in patients with poor dental health, as seen in this case. This reinforces the importance of raising awareness about the potential risk of endocarditis in patients with dental issues, and the need to take preventive measures for individuals with similar backgrounds.

Thus, in managing cases with complex medical histories and diverse symptoms, attention should be paid to potential pathogen sources, with treatment strategies adjusted accordingly. These insights offer important guidance for managing similar cases in the future.

Conclusion

In conclusion, S. sinensis is a newly identified pathogen causing IE, but it is often underdiagnosed due to the limitations of conventional detection methods. mNGS provides a high-throughput, unbiased diagnostic approach, significantly improving the accuracy of pathogen identification, especially in cases where traditional methods fail. Clinicians should remain vigilant for S. sinensis infection in patients with a history of dental issues or underlying cardiac conditions, as these factors may increase the risk of IE.

Abbreviations

IE

Infective endocarditis

BCNE

Blood culture-negative endocarditis

mNGS

Metagenomic next-generation sequencing

ECG

Electrocardiogram

CRP

C-reactive protein

ESR

Erythrocyte sedimentation rate

LVH

Left ventricular hypertrophy

PTA

Probabilities of target attainment

Author contributions

All authors contributed to the study conception and design. WR collected patient data and drafted the manuscript. NB and RJ performed experiments (mNGS). ZL provided comments on the manuscript. All authors read and approved the final manuscript.

Funding

Not applicable.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The present study was conducted in line with the Declaration of Helsinki. Informed written and signed consent for participation from the patient was acquired prior to the submission.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent will be provided to the Editor-in-Chief of this journal upon request.

Competing interests

The authors declare no competing interests.