Excellent Prognosis of Culture Negative Endocarditis in Hemodialysis Patients: A Case Series

Abstract

Despite improved diagnostic methods, antimicrobial agents and more sophisticated echocardiographic studies, the incidence of infective endocarditis remains high, especially in a uremic and end stage renal disease (ESRD) population. Culture negative endocarditis (CNE) patients with normal renal function have increased morbidity and mortality, but clinical features and outcome in hemodialysis patients remains unclear. This study reported five survival cases of CNE in hemodialysis patients. The prognosis of all dialysis-related CNE patients enrolled in this study was excellent.

Keywords:

• bacteremia
• infective endocarditis
• culture negative endocarditis
• hemodialysis

INTRODUCTION

Culture-negative infective endocarditis (CNE) is a diagnostic challenge despite improved echocardiography and blood culture techniques. Cases of CNE constitute 5% of all endocarditis cases, with a reported range of 2.5–31%.[1],[2] Patients with CNE demonstrate increased morbidity and mortality compared to those with culture-positive infective endocarditis.[3],[4] The uremia and end stage renal disease (ESRD) population is a high risk patient group in CNE,[5–7] but the clinical course and outcome of CNE in these patients is unclear. This clinical study of five chronic hemodialysis patients with CNE revealed an excellent outcome in all patients.

CASE REPORTS

Case 1

A sixty-three-year-old female uremic patient with a history of rheumatic heart disease had been on maintenance hemodialysis for three months. The patient had a persistent fever above 38°C and dyspnea for one month prior to admission. The fever persisted despite one month of antibiotics treatment for pneumonia. Other than pansystolic murmur of mitral and aortic insufficiency, the results of physical examination were normal. Native arterio-venous fistula of the left arm showed good bruit and thrill but no local erythema or heat. White blood cell (WBC) was 3500 × 10³/μL, C-reactive protein (CRP) was 30 mg/dL, and erythrocyte sedimentation rate was (ESR) 70 mm/h. All four sets of blood culture specimens were negative, but transthoracic and transesophageal echocardiography revealed vegetation on both leaflets of the mitral valve and an oscillating mass on the anterior leaflet of the aortic valve. Culture-negative infective endocarditis was diagnosed. The patient experienced a sudden onset of right upper limb weakness lasting 24 hours indicating transient ischemic attack due to central nervous system emboli. The patient underwent aortic and mitral valve replacement after five weeks of antibiotic treatment with vancomycin and gentamicin. Fibrosis, acute and chronic inflammation, and granulation tissue formation were observed on both excised valves. Culture of excised vegetation and valve were negative. The patient developed a dramatic recovery after surgery and remained afebrile at outpatient department.

Case 2

A 52-year-old male with history of end stage renal disease, 44 months of previous chronic hemodialysis, congestive heart failure and chronic hepatitis C, was admitted after a persistent fever, worsening dyspnea, and orthopnea for one week. Physical examination showed crackle at right lower lung and systolic murmur at apex. The native arterio-venous fistula of the right forearm was patent without evidence of infective sign. The WBC was 14600 × 10³/μL, CRP was 196 mg/dL and ESR was 134 mm/h. All six sets of blood culture specimens were negative for bacterial growth, but transthoracic echocardiography revealed vegetation on anterior leaflet of mitral valve. Chest roentagraphy disclosed nodular lesion of right lower lung and blunted right costophrenic angle. Culture-negative infective endocarditis with pulmonary emboli was diagnosed. The patient received a six-week course of antibiotic therapy with teicoplanin and gentamicin. The follow-up transthoracic echocardiography showed no vegetation. The hospital course was uneventful, and patient was discharged.

Case 3

A 50-year-old male with end stage renal disease had been undergoing chronic hemodialysis for 66 months. The patient was admitted after two weeks of fever and progressive dyspnea. Vascular access for hemodialysis was a cuffed dual-lumen catheter due to an episode of arteriovenous graft infection and methicillin resistance staphylococcus aureus (MRSA) sepsis two months before admission. The patient had received a two-week course of antibiotics treatment for the sepsis. Temperature was 39°C on arrival. Diastolic murmur indicated aortic insufficiency. The exit site of cuffed dual-lumen catheter was clear. The WBC was 5400 × 10³/μL, CRP was 431 mg/dL, and ESR was 51 mm/h. Two sets of blood culture specimens were both negative. Peripheral vascular duplex scan from silent arteriovenous graft showed no evidence of abscess. Transthoracic echocardiography revealed vegetation on aortic valve, suggesting culture-negative infective endocarditis. Due to progressive dyspnea and intermittent fever, the patient underwent aortic valve replacement after four weeks of vancomycin treatment. The excised valve displayed tissue degeneration, fibrotic necrosis, and acute and chronic inflammation. Culture of the excised valve was negative for bacterial or fungal growth. The fever subsided after operation, and the patient was discharged.

Case 4

A 67-year-old female diabetic patient with end stage renal disease had been on hemodialysis for seven years. The patient was admitted after a persistent one-month fever. Intermittent low grade fever, chills and a non-productive cough had developed after beginning hemodialysis. The patient had undergone two weeks of antibiotics therapy before admission for suspected pneumonia.

Temperature was 40.2°C upon admission. The patient had no heart murmur. Both bruit and thrill were observed on the left arm arterio-venous fistula but no local erythema or heat.

Laboratory tests revealed WBC 12600 × 10³/μL, CRP 126 mg/dL, and ESR 45 mm/h. Serum electrolyte and liver function were normal. No pyuria was noted. Chest film and electrocardiogram were normal. Computed tomography of chest and abdomen disclosed several small enlarged lymph nodes in the mediastinum but no definite mass lesion. Gallium 67 inflammatory scan was negative. Transthoracic echocardiography revealed no vegetation. No bacteria were recovered from blood and urine cultures. The fever relapsed during hospitalization. Rifater was administered for apparent tuberculous lymphadenitis of mediastinum. The fever improved, and the patient was discharged with Rifater. Mycobacterial culture of sputum was negative.

The patient was readmitted 10 days later due to fever despite Rifater treatment. Leukocytosis and high CRP level were noted. Again, all six blood cultures revealed no bacteria. Histological, bacteriologic, and mycobacterial bone marrow studies were all normal. Anti-nuclear antibody and anti-neutrophils cytoplasmic antibody were negative. Vancomycin was given for possible endovascular infection. The patient became afebrile. Follow-up transthoracic echocardiography one week later showed vegetation 0.68 cm at mitral valve. Vancomycin was given instead of Rifater. The patient remained afebrile at outpatient department. The final diagnosis was culture negative endocarditis with delayed appearance of vegetation.

Case 5

A sixty-year-old female with diabetes mellitus and end stage renal disease had undergone chronic hemodialysis for three months prior to admission. The patient was admitted with a 40°C fever, chest pain, seizure, and drowsiness for one day. The patient had an episode of urinary tract infection one month previous and received a three-day course of antibiotics. Physical examination showed systolic murmur at apex. The native arterio-venous fistula of the left arm was patent without evidence of infection. The WBC was 14600 × 10³/μL, CRP was 196 mg/dL, and ESR was 134 mm/h. Cardiac enzymes were within normal limit. Four sets of blood culture specimens were negative, but transthoracic echocardiography revealed calcified mitral valve annular and chaotic motion with small nodule over anterior mitral valve cordae. Thallium scan revealed no myocardial infarction. Right limb hemiparesis developed during admission. Brain tomography disclosed middle cerebral artery territory infarction. Culture-negative infective endocarditis with central nervous system emboli was diagnosed. The patient became afebrile after four weeks of vancomycin treatment. The patient was discharged and followed-up at outpatient department.

DISCUSSION

Culture-negative endocarditis is a diagnostic dilemma and clinical challenge, as blood culture positivity is the major criterion of infective endocarditis (IE). The main causes of increased CNE mortality are postponement of echocardiography establishing the diagnosis and delayed antibiotics therapy.[3],[7],[8] The five above cases were diagnosed by modified Duke criteria.[6] A diagnosis of definite IE required two major criteria, one major and three minor criteria, or five minor criteria. A diagnosis of probable IE required one major criterion and one minor criterion or three minor criteria. Culture-negative endocarditis was defined as either negative blood culture in four culture sets drawn > 12 hours apart after one month of incubation time or as those cultures remaining negative by the time of hospital discharge or demise.

Fever and cardiac murmur is unusual in dialysis patients with IE, but leukocytosis is noted in 50–75% of patients.[9–11] Fever occurred in 100% and a new heart murmur occurred in four of five cases in this series (see Table 1). This is in accord with clinical features reported by other authors.[7],[12],[13] Although non-specific or diagnostic, new onset heart murmur with fever and leukocytosis may be indications of IE, especially in the absence of a positive blood culture. A physical examination and a leukocyte count are necessary for early diagnosis and timely treatment.

Table 1 Summary of five chronic hemodialysis patients with culture negative infective endocarditis

Case	Sex	Age (y)	Presentation	New murmur	Culture set, positive/total	Echocardiography	Valve	Emboli	Previous antibiotics	Comorbidity	Access	Surgical	Treatment	30-day survival	Outcome
1	F	63	Fever, dyspnea	Pansystolic	0/4	TEE + TTE	Mi + Ao	CNS	Yes	VHD	AVF	Yes	Van+GM	Yes	Alive
2	M	52	Fever, dyspnea	Systolic	0/6	TTE	Mi	Lung	No	CHF, HCV	AVF	No	Teico+GM	Yes	Alive
3	M	50	Fever, dyspnea	Diastolic	0/2	TTE	Ao	No	No	No	DL	Yes	Van	Yes	Alive
4	F	67	Fever, dyspnea	Negative	0/6	TTE	Ao	No	Yes	DM	AVF	No	Van	Yes	Alive
5	F	60	Fever, seizure	Systolic	0/4	TTE	Mi	CNS	Yes	No	AVF	No	Van	Yes	Alive

Abbreviations: y = years, F = female, M = male, TEE = transesophageal echocardiography, TTE = transthoracic echocardiography, Mi = mitral, Ao = aortic, CNS = central nervous system, VHD = valvular heart disease, CHF = congestive heart failure, HCV = Hepatitis C infection, UGIB = Upper gastrointestinal bleeding, DM = diabetes mellitus, AVF = arteriovenous fistula, DL = dual lumen, Van = vancomycin, GM = gentamycin, Teico = teicoplanine.

The incidence of CNE is higher among chronic hemodialysis patients than in the general population.[4],[5] Repeated puncture, defective vessel wall, and immune dysregulation all contribute to the increased incidence of bacteremia in dialysis patients.[14],[15] The high risk of CNE in chronic hemodialysis patients may be due to exposure to prior antibiotics, short and transient bacteremia, slow and fastidious growing microorganisms, inadequate or insufficient microbiologic diagnostic techniques, or the lack of consensus of case definition in dialysis population.[4],[5],[8]

Most authors recommend penicillin or ampicillin combined with gentamicin for treating CNE patients. This regimen is effective against enterococci and most HACEK organisms, but the optimal regimen in a dialysis population is still unknown.[1],[2] However, vancomycin was the initial empirical therapy in four of five patients of our series. Vancomycin should be chosen as the initial regimen for several reasons. First, early and broad-spectrum antibiotics are warranted for definite IE, which is confirmed by vegetation indicated by echocardiography in spite of negative blood culture. Second, S. aureus is the most frequently isolated pathogen in dialysis patients with IE, and the mortality rate secondary to S. aureus IE is high.[9],[14],[16],[17] Third, according to microbiology patterns observed in our own institution, 62% of all S. aureus isolated are methicillin-resistant, and these patients require a thrice-weekly dialysis in a hospital facility; thus, the occurrence of MRSA bacteremia may represent a true nosocomial infection carrying a devastating virulence in an immune dysregulated uremic host.[18–20]

The mortality rate of CNE in the general population ranges from 7–32%[12],[13]; the outcome is even less optimistic in endocarditis patients with true negative blood culture than in patients with previous antibiotics treatment.[21] Furthermore, mortality is increased in patients receiving delayed treatment and in those still febrile after one week of therapy.[5],[12],[22] The outcome of CNE in a dialysis population is unknown. All five patients in our series survived. The mortality rate of CNE in a hemodialysis population is presumed low. However, the early echocardiographic findings and the prompt broad-spectrum antibiotics maximized the survival rate in this study population.

One limitation of this study is that the subjects were patients in a tertiary referral center. Therefore, the results may not be directly extrapolated to other patient populations. Serology tests for Coxiella burnetii, Bartonella species, Chlamydia species, Legionella species and Aspergillus species were not performed. Blood culture for shell vial[8],[23] and direct PCR amplification[24–26] were also not performed. However, the tissue specimens of two patients who had undergone surgical replacement of infective valves were evaluated by an experienced pathologist who found no evidence of bacterial or fungal pathogen.

To conclude, fever, new murmurs and leukocytosis remain the primary clinical features of CNE in chronic hemodialysis patients. Echocardiographic demonstration of endocardial lesion is the sine qua non for defining CNE. The outcome of CNE in a hemodialysis population is good, and survival can be enhanced with prompt echocardiographic study and timely use of broad-spectrum antibiotics.