Corynebacterium striatum Endocarditis After Renal Transplantation Confirmed by Metagenomic Next-Generation Sequencing: Case Report and Literature Review.

Background: Potent immune-suppressive therapy has been demonstrated to increase the risk of infective endocarditis (IE) in renal recipients. Reports of Corynebacterium striatum (C. striatum) endocarditis in renal recipients are scarce, thus limiting understanding of the disease. Case Presentation: We describe a case of native valve endocarditis caused by C. striatum in a 35-year-old male patient. The young man with end-stage renal failure underwent kidney transplantation because of autosomal dominant polycystic kidney disease. Ceftazidime was administered after the surgery according to routine procedures, and the patient was discharged on the 14th day after the surgery without any evidence of infection. The patient experienced fever on the 56th day, and Corynebacterium was cultured from the patient's blood, in agreement with the results of testing of the donor kidney preservation solution. On the 64th day, multiple thromboses were found in the right external iliac artery, particularly around the anastomotic orifice of the transplanted renal artery. Vegetation was found in the posterior mitral valve tip on the 65th day. The patient had symptoms of persistent angina pectoris and chest tightness and underwent mitral valve replacement and vegetative resection. The patient eventually died. C. striatum was detected in the mitral valve and vegetation tissue with metagenomic next-generation sequencing.
Conclusion: C. striatum may cause endocarditis and endanger patients' lives and thus warrants greater attention. Genotypic assays such as metagenomic next-generation sequencing are demonstrated to be effective in confirming species identity. Adequate anti-infection therapy and early surgery are required after IE is discovered.

Background

Infective endocarditis (IE) refers to inflammation of the heart valve or ventricular wall caused by various pathogens. IE may result in valve disease, heart failure and possibly thromboembolic disease, thus endangering patients’ lives. Renal transplant recipients receive life-long immunosuppressive therapy, which may result in a greater risk of severe infections than that in the immunocompetent population. When IE occurs in renal recipients, the infection usually presents specific clinical features and is more difficult to control. The frequency of Corynebacterium striatum (C. striatum) infections appears to have increased in recent years, possibly because of improved simplicity and accuracy in its identification through molecular genetic assays.1 Case reports of C. striatum endocarditis in renal transplant recipients are rare. Here, we report the first case of native valve endocarditis caused by C. striatum, which was accurately identified through metagenomic next-generation sequencing (mNGS).

Case Presentation

A 35-year-old male patient with autosomal dominant polycystic kidney disease underwent kidney transplantation because of end-stage renal failure, without removal of the original bilateral polycystic kidneys. The donor was a 57-year-old man with a confirmed diagnosis of brain death caused by hypertensive intracerebral hemorrhage, and no confirmed infection was reported in the donor. The patient was administered a total of 21.15 mg × kg−1 of methylprednisolone, 0.24 mg × kg−1 of basiliximab and 1.83 mg × kg−1 of rabbit anti-human thymocyte immunoglobulin (ATG) for immune induction therapy. Methylprednisolone (1000 mg) and basiliximab (20 mg) were administered during the operation, and methylprednisolone (500, 240, 120, 80 and 40 mg from the 1st to the 5th day after surgery, respectively) and ATG (50, 25, 25, 25 and 25 mg from the 1st to the 5th day, respectively) were administered postoperatively because of delayed graft function. The maintenance immunosuppressive regimen comprised tacrolimus, mycophenolate mofetil and prednisone. The valley value of tacrolimus concentration was maintained at 6–8 ng/mL. The patient underwent hemodialysis before renal transplantation, had a urine output of more than 3000 mL per day and did not require dialysis after surgery. Corynebacterium was detected in the donor kidney preservation solution (without the drug sensitivity test) on the 4th day, but no evidence of subsequent Corynebacterium-related infection was observed, including an absence of symptoms of infection, or pathogens cultured from subsequent blood, urine and surgical site samples on the 3rd, 7th and 11th day. The antibiotic regimen of 2 g ceftazidime q12 h was prophylactically administered for 2 weeks after surgery, and the patient routinely took oral trimethoprim/sulfamethoxazole for PJP prophylaxis. The patient was discharged on the 14th day with a serum creatinine (Scr) level of 160–170 µmol/L. On the 56th day, the patient had a low fever of 37.9°C with light hematuria, as well as mild frequent, urgent and painful urination. The patient had a white blood cell count of 17.46×109/L, hemoglobin level of 95 g/L, C-reactive protein level of 231.06 mg/L, Scr level of 196.1 µmol/L, prothrombin time of 15.40 s and blood pressure of 87/64 mmHg. Partial intracapsular hemorrhage in the primary bilateral polycystic kidneys was detected by CT. The patient was diagnosed with septic shock and disseminated intravascular coagulation due to severe infection. The possibility of intracapsular hemorrhage with infection of cysts in bilateral polycystic kidney disease could not be ruled out. We carried out supportive treatment after the patient was readmitted to our hospital, and the patient’s vital signs remained stable due to our treatment. The maintenance immunosuppressive regimen was then tapered with withdrawal of mycophenolate, tacrolimus was replaced by cyclosporin, and meropenem was administered to eliminate infection. Corynebacterium was found in the patient’s blood, and Enterococcus faecium and Pseudomonas putida were found in the patient’s urine on the 59th day. Linezolid was additionally administered. Ultrasound examination was performed on the 63rd day, and no special finding was noticed. Tacrolimus was used again on the 63rd day to replace cyclosporin (used for 3 days) due to patient intolerance.

The patient’s troponin T and atrial natriuretic peptide levels continually increased during hospitalization. The patient began to complain of chest pain and dyspnea and became unable to lie in the supine position on the 64th day. The patient’s electrocardiogram revealed sinus tachycardia with premature ventricular beats. On the same day, the patient developed acute anuria, and a gradual increase in Scr to 346 µmol/l was detected. Multiple thromboses were found in the right external iliac artery by ultrasound, the largest of which was positioned around the anastomotic orifice of the transplanted renal artery, with a range of approximately 3.8×1.0 cm. The patient was then transferred to the intensive care unit for bedside continuous renal replacement therapy, and an adjusted scheme of meropenem and vancomycin was used for anti-infection treatment.

Sudden persistent angina pectoris in the precordial region, accompanied by chest tightness and no sweating, appeared on the 65th day, and an increase in myocardial enzymes was detected. A cardiac murmur in each valve of the heart was found, particularly in the apical region, with a grade 3/6 diastolic murmur. Echocardiography revealed a medium echoic mass (2.7×1.4 cm in diameter and approximately 3.2 cm2 in area) at the posterior mitral valve tip, which swung with the cardiac cycle (Figure 1). Moderate-to-severe mitral regurgitation and mild-to-moderate tricuspid regurgitation were detected. Chest tightness accompanied by a significant increase in myocardial enzymes occurred on the 66th day. Thus, non-ST segment elevation myocardial infarction was diagnosed, and fraxiparin (0.2 mL, q12 h) was given. The patient had a cough with bloody sputum on the 69th day, and fraxiparin was stopped because of the possibility of pulmonary hemorrhage.

Figure 1

A medium echoic mass revealed by echocardiography.

The operation was scheduled on the 71st day. Allograft nephrectomy was planned to be performed after mitral valve replacement and vegetative resection on the same operation day. The patient experienced cardiac arrest and ventricular fibrillation before entering the operating room. Emergency external chest compression, electric defibrillation, and endotracheal intubation were performed. Mitral valve replacement surgery and vegetative resection were performed after vital signs stabilized. Considering the large operative trauma and patient tolerance, we did not perform allograft nephrectomy. Large polypoid vegetation was found attached to the posterior leaflet of the mitral valve in the resected specimen (Figure 2A). The patient died on the 73rd day after being unable to maintain vital signs after surgery. No pathogens were cultured from the mitral valve or vegetation tissue.

Figure 2

Morphological, pathological and microbiological data of valve tissue and vegetation after mitral valve and vegetation resection.

We retrospectively analysed this case 1 year after the operation. Large polypoid excrescences of fibrin and platelets along the disrupted endocardial surface were seen in the pathological sections of valve tissue and vegetation (Figure 2B). Gram staining of the pathological sections revealed that the vegetations were acutely inflamed, with areas of valvular and leukocyte necrosis containing colonies of bacteria (Figure 2C). mNGS was retrospectively performed to detect pathogens in the mitral valve and vegetation wax tissue, using the following steps: DNA was extracted using the Generic Rapid Genomic DNA Extraction Kit (Lifefeng: DK806-02), quantified by Qubit (Thermo Fisher Scientific) and qualified by NanoDrop (Thermo Fisher Scientific); KAPA Hyper Prep kit (KAPA Biosystems) was used for the preparation of DNA libraries according to the manufacturer’s protocols. Quality control was performed using Agilent 2100 and DNA libraries were 75 bp single-end sequenced on Illumina NextSeq 550Dx (Illumina); High-quality sequencing data were collected by removing low-quality reads, adapter contamination, duplicated and shot (length <36 bp) reads. Human host sequences were identified by mapping to the human reference genome (hs37d5) using Bowtie2 software. Pathogen identification was performed by retaining nonhuman sequences and aligning them with the microorganism genome database, which contained bacterial, fungal, viral and parasite genomic sequences (download from ); the result was considered positive if a species detected by mNGS had a species-specific read number ≥1 with sequences of Mycobacterium, Nocardia and Legionella pneumophila, and the result was considered positive if species had at least 3 nonoverlapping reads with sequences of bacteria (excluding Mycobacterium, Nocardia and Legionella pneumophila), fungi, viruses and parasites. The identified gene sequences were found to be identical to those of C. striatum, thus confirming C. striatum endocarditis. The raw sequencing data were submitted and deposited at the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) with the accession number SAMN30015192.

Literature Review

We reviewed 30 previously reported cases of C. striatum endocarditis through an English language literature search in PubMed with the following keywords: “Corynebacterium striatum” and “Endocarditis” (Table 1). The mean age of the patients was 62.1 years (range 24–83), 19 patients (63.3%) were male, and 17 (56.7%) patients had heart disease. Most of the cases exhibited native valve endocarditis (80%, 24/30), most of which were associated with the mitral valve (43.3%, 13/30), followed by the aortic valve (30%, 9/30). Several cases were associated with medical devices (including one case with an artificial valve and five cases with a pacemaker lead). Among all cases, four cases of C. striatum endocarditis were identified through molecular genetic assays, and other cases were identified through traditional culture tests. All patients, except for two with unknown status, accepted antibiotic treatment, and 15 (50%) patients underwent surgery in addition to antibiotic treatment. Four patients (13.3%) eventually died, and 21 (70%) survived. The outcomes of the remaining patients are unknown. The mortality rate in patients who underwent surgery was 20% and that among all patients was 23.3%.

Table 1

30 Reported Cases of Infective Endocarditis Caused by Corynebacterium striatum

Year	Sex	Age	Trans	ESRD	Heart Disease	Artificial Valve/Heart Surgery	Pacemaker	Position	Vegetation	Antibiotic	Drug Resistance	Surgery	Survival
2016	M	55	N	N	N	N	N	MV	Y	Vancomycin	N	Y	A
2012	M	56	N	Y	N	N	N	MV	Y	Telavancin	Y	Y	D
2021	M	55	N	Y	Y	N	Y	AV	Y	Daptomycin, rifampin	N	Y	D
2021	M	82	N	N	Y	N	N	AV	Y	Vancomycin	N	N	D
2018	M	54	N	Y	N	N	N	MV, AV, TV	Y	N/A	N/A	Y	N/A
2008	F	73	N	N	Y	N	N	MV	Y	Vancomycin	N	N	A
2014	F	53	N	N	N	N	N	AV	Y	Ampicillin/sulbactam, gentamycin	N	Y	A
2022	F	73	N	N	N	N	Y	Pacemaker	N	Vancomycin	N	Y	A
2010	F	71	N	N	Y	N	Y	Pacemaker	Y	Daptomycin	Y	Y	A
2002	F	62	N	N	Y	Y	N	Artificial valve	N	Vancomycin	N	N	A
2005	F	72	N	N	Y	Y	N	N/A	Y	Vancomycin, rifampin	N	N	A
2005	F	61	N	N	Y	N	N	MV	Y	Vancomycin, gentamicin	N	N	A
1996	M	24	N	N	Y	Y	N	Pulmonary valve	Y	Moxicillin, netilmicin, teicoplanin	N	Y	A
1996	M	68	N	N	Y	N	N	MV	Y	Vancomycin, penicillin	N	N	N/A
2017	M	63	N	N	Y	N	N	Left atrium	Y	Linezolid, daptomycin	Y	Y	A
1990	M	76	N	N	N	N	N	AV	Y	Ampicillin, gentamicin	N	Y	D
2021	M	48	N	N	Y	N	Y	TV, pacemaker	Y	Vancomycin, daptomycin	Y	Y	A
2005	F	46	N	Y	N	N	N	TV	Y	Linezolid, vancomycin, daptomycin, rifampin	N	N	A
1994	M	54	N	N	N	N	N	AV	N	Vancomycin, ampicillin, gentamicin	N	Y	A
2018	M	69	N	N	Y	Y	N	AV	Y	Vancomycin	N	N	D
2006	M	68	N	N	Y	Y	N	Prosthetic MV	Y	Vancomycin	Y	N	A
2008	M	83	N	N	N	N	N	MV	Y	Penicillin, gentamicin, daptomycin	N	N	D
2020	M	54	N	Y	N	N	N	MV, AV, TV	Y	Vancomycin, ceftriaxone	N/A	Y	A
2002	F	72	N	N	Y	Y	N	MV	Y	Vancomycin, gentamicin, benzyl pencillin	N/A	N	D
2015	M	27	N	N	Y	N	N	MV	Y	Penicillin, cefuroxime	N/A	N	A
2012	M	78	N	Y	Y	N	Y	TV	Y	Daptomycin	Y	N	A
1996	M	72	N	N	Y	N	Y	MV, pacemaker	Y	Vancomycin, rifampin	Y	N	A
2002	M	50	N	N	N	N	N	AV	Y	Vancomycin, netilmicin	Y	Y	A
2006	F	77	N	N	N	N	N	MV	Y	Unknown	N/A	N	A
2006	F	69	N	N	N	N	N	MV	N	Vancomycin, cefepime	N	Y	A

Abbreviations: AV, aortic valve; TV, tricuspid valve; MV, mitral valve; N/A, no mention.

C. striatum is a commonly isolated Corynebacterium in clinical microbiology laboratories, but confirmed C. striatum infections are relatively rare. In the diagnosis of C. striatum endocarditis, traditional diagnostic methods based on microbiology laboratory findings are mature and relatively inexpensive; however, most are time-consuming and have low positivity,2 and may even lead to misidentification.1,3 mNGS has higher sensitivity than the traditional method and thus has been recommended for early pathogen diagnosis.2 A combination of pathology and etiology has also been suggested to diagnose IE.4 Appropriate antibiotic therapy along with strict source control (eg, removal of prosthetic devices) are usually considered effective methods for the treatment of C. striatum endocarditis.5 Among all cases reviewed, seven received daptomycin as an antibiotic treatment, which has been demonstrated to be a useful option for patients whose infections are refractory to traditional antibiotics.6–8 During the course of conservative management, surgical intervention should always be considered to prevent fatal cardiovascular events.9–11

Discussion and Conclusions

Clinical features of Corynebacterium infection have been described as subacute because of its low virulence, and its tendency to occur in older patients with comorbidities or prosthetic devices.12 The incidence is rare, but the mortality rate is substantial. A previous study13 has reported 4246 IE cases caused by various pathogens over a 10-year period, only 30 of which were caused by Corynebacterium. The incidence rate during that period was as low as 0.032 IE/105 annually. Compared with the immunocompetent population, the population receiving long-term immunosuppressive therapy may have a greater risk of infection after solid organ transplantation. When IE occurs in renal transplant recipients, it usually exhibits unique characteristics and is more difficult to control. According to a previous retrospective study14 analysing the clinical characteristics of 73 cases of IE in renal transplant recipients, the average age of the affected recipients was 45 years, which was younger than that of the general population, which had a mean age of >60 years. Unlike immunocompetent patients with IE, immunocompromised recipients remain at high risk of IE even without cardiac structural abnormalities. C. striatum is a Gram-positive, rod-shaped, nonspore-forming bacillus from the nondiphtherial Corynebacterium species. Reports of C. striatum endocarditis in renal transplant recipients are scarce, thus limiting the understanding of the clinical manifestations.

Corynebacterium was cultured from both the donor kidney preservation solution and the patient’s blood after the patient experienced fever, but no confirmed Corynebacterium infection was reported in the donor. The case we reported cannot be classified as a proven or possible DDI, but transmission of infection from the donor kidney to the recipient cannot be formally excluded; similarities were observed in a previous report.15 Here, we propose the possibility of donor kidney-derived Corynebacterium sp infection, which is also the first case of C. striatum endocarditis in a renal recipient confirmed by mNGS to date. The patient was discharged with no evidence of C. striatum infection, and the antibiotic regimen of ceftazidime was not adjusted because of the lack of drug sensitivity testing. The infection occurred 2 months postoperatively. One possibility was that the original ceftazidime antibiotic administered was not active against this particular strain of Corynebacterium, and the use of high-dose methylprednisolone and ATG might also have been associated with the delayed onset of C. striatum infection. The patient was initially admitted with symptoms of low fever and mild urinary tract infection, followed by signs of septic shock. The manifestation of intracapsular hemorrhage in polycystic kidneys detected on CT scans brought our attention to the possibility of infection secondary to intracapsular hemorrhage of the primary bilateral polycystic kidneys. The patient was 35 years old—younger than the average age of 64 years in the general population with IE in our literature review. The patient’s condition developed so rapidly that we did not realize the occurrence of IE until the patient had experienced an acute renal transplant artery embolism event. All these findings highlight the challenges in the management of Corynebacterium infections among immunosuppressed renal recipients. Clinical detection of IE is critical, and echocardiography is the primary tool used. In our experience, in cases of unexplained fever, cardiac murmur, anemia and other conditions in renal transplant recipients, even if no structural heart lesions are present and the patient is young, the possibility of IE should be considered, and echocardiography should be performed early and repeatedly throughout the diagnosis and treatment process.

Descriptions of native valve C. striatum endocarditis in previous case reports are rare and were usually confirmed from only blood cultures. Only four cases of C. striatum endocarditis identified by genotypic assays were found in our literature review.1,3,16,17 Interestingly, except for only one positive blood culture result of Corynebacterium after fever, Corynebacterium was not cultured again from the patient’s blood specimens or from resected endocardial specimens, possibly because of the slow growth rate of Corynebacterium and potential bactericidal effects due to the antibiotic treatment. We also note that Corynebacterium has usually been considered contamination when cultured from clinical specimens, and thus drug sensitivity testing for Corynebacterium may be ignored. The findings underscore the low detection rate of this bacterium through laboratory blood culture. Recently developed genotypic assays, such as mNGS, 16S ribosomal RNA sequencing and rpoB gene sequencing, have been used to improve pathogen identification in recent years. In this case report, we highly suspected that the endocarditis in our patient was caused by Corynebacterium; however, no pathogens were cultured from the mitral valve and vegetation tissue according to our microbiology laboratory results. We retrospectively performed mNGS on the valve tissue 1 year later and finally identified C. striatum endocarditis; therefore, we believe that mNGS has good application prospects for the management of IE. mNGS was recommended for early infection diagnosis on the basis of clinical suspicion of rare infection (eg, there is evidence of infection, but no pathogen cultured from clinical specimens based on our clinical microbiology laboratory results; infection caused by pathogens detected by our clinical microbiology laboratory tests cannot explain the clinical symptoms of the patient). To our knowledge, this is the first case of native mitral valve C. striatum endocarditis confirmed in valve and vegetation tissue using mNGS.

Most C. striatum strains have been reported to be resistant to erythromycin, clindamycin and tetracycline, whereas penicillin, gentamicin, erythromycin and vancomycin have been reported to be most effective against C. striatum.18,19 In our case, antimicrobial therapy (linezolid, meropenem and vancomycin) was used empirically in the absence of bacterial sensitivity test results. Nonetheless, the patient’s condition deteriorated so rapidly that we needed to perform valve replacement and vegetation resection to prevent the occurrence of cardiovascular events threatening the patient’s life. We recognize that even with surgical treatment, the mortality rate of IE patients remains high. Half the patients in our literature review underwent valve replacement surgery, and the total mortality rate was approximately 23.3%. The resistome of C. striatum has been highlighted as dynamic and in evident expansion, which emphasizes the importance of implementing genomic surveillance programs and studies on the mechanisms of antimicrobial resistance should be further carried out.20

The following experience can be summarized from this case. Adequate anti-infection treatment should be administered to renal transplant recipients at high risk of IE, and intermittent monitoring of bacterial culture and sensitivity testing should be performed during hospitalization and follow-up after discharge. Molecular methods are recommended for monitoring infection based on a clinical suspicion of rare infection. Requirements for anti-infection treatment may include sufficient long-term and combined application of antibiotics according to drug sensitivity testing. The risk of IE should be considered in cases of unexplained low fever and nonspecific clinical symptoms, and echocardiography should be performed promptly. Renal transplant recipients may have an extremely high risk of death and poor prognosis when they develop IE with valve vegetation. Early surgical intervention can improve the survival rate and decrease the mortality rate of IE, according to previous reports.21,22 Thus, such intervention is recommended concurrently with anti-infection treatment.