Neisseria subflava endocarditis

Neisseria subflava Endocarditis Case Report and Review of the Literature

STEVEN POLLACK, M.D.

Neisseria subflava is a rare cause of bacterial endocarditis. Only seven cases have been identified in the world literature if strict criteria as to organism classification and of endocarditis are applied to individual case reports. The first reported case in an intravenous drug user is described. In addition, findings on serial two-dimensional and M-mode echocardiography performed during and after the treatment period are presented. This patient’s recovery with antlmicrobial therapy alone despite evidence of aortic and significant mitral valve involvement is in accord with results of other antlbiotic-treated cases.

ALLEN MOGTADER, M.D. MICHAEL LANGE, M.D. New York, New York

Neisseria subflava, a species of bacteria within the genus Neisseria of the family Neisseriaceae, is a chromogenic gram-negative diplococcus identified by specific growth, biochemical, and morphologic criteria [ 11. In contrast to N. gonorrhoeae and N. meningitidis, it is considered a member of the nonpathogenic Neisseria along with N. flavescens, N. lactamica, N. mucosa, and N. sicca. The organism is known to constitute part of the normal oropharyngeal flora of humans and has only rarely been reported as a pathogen. There has not been a comprehensive analysis of N. subflava endocarditis applying strict criteria of organism classification and endocarditis case definition as well as detailing the host characteristics and clinical course. The case presented is the first reported N. subflava endocarditis occurring in an intravenous drug user. Of particular interest was the absence of a known predisposing cardiac lesion, a feature that is usually considered a necessary prerequisite in the pathogenesis of subacute bacterial endocarditis with nonvirulent bacteria. CASE REPORT A 43-year-old parenteral heroin user was admitted

From the Division of Cardiology and the Division of Infectious Diseases, Medical Service, St. Luke’sRoosevelt Hospital Center, and the Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York. Requests for reprints should be addressed to Dr. Allen Mogtader, Division of Cardiology, St. Luke’s Hospital, Amsterdam Avenue at 114th Street, New York, New York 10025. Manuscript accepted May 17, 1983.

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to St. Luke’s-Roosevelt

for evaluation of septicemia. Three weeks preceding admission, he began experiencing intermittent fevers, chills, myalgias, and persistent anorexia. After one week of these symptoms, he was evaluated by a private physician who noted unremarkable findings on physical examination and normal complete blood count. A tentative diagnosis of upper respiratory tract infection was made, and the patient was treated with decongestants. Two blood cultures were also obtained at this time. One week prior to admission, the patient noted intermittent, sharp, nonpleuritic right upper quadrant abdominal discomfort. When findings on both blood cultures were reported as positive for N. subflava, the patient was advised by his physician to seek hospitalization. This he eventually did following several days’ delay. He had no medical history of cardiovascular disease, but it was significant Hospital

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for alcoholic liver disease with biopsy-proved Laennec’s cirrhosis and multiple admissions for alcoholic hepatitis. A mesocaval shunt with a Dacron graft prosthesis had been placed seven years earlier for bleeding esophageal varices. He denied recent alcohol consumption. Additionally, there was a history of cholelithiasis, recurrent urinary tract infections, and positive results of a PPD test. On admission, he was found to be a delirious, diaphoretic, thin man with an oral temperature of 100.4’F, a blood pressure of 11O/80 mm Hg, and a pulse rate of 110 beats per minute. The sclerae were icteric. Results of funduscopic examination were unremarkable. The neck was supple with shoddy cervical lymphadenopathy. There was no jugular venous distention. The lungs were clear to percussion and auscultation. The heart was not enlarged on cardiac examination. First and second heart sounds were normal. A blowing grade II/VI early systolic murmur, which did not change with Valsalva or inspiratory maneuvers, was present at the apex. No gallop, rub, or diastolic murmur was noted. The liver span was 12 cm by percussion with overlying tenderness. The spleen tip was palpable. There was no evidence of ascites. There were no rashes, petechiae, joint swellings, or edema. Neurologic examination demonstrated an abnormal mental status with asterixis. Urinalysis showed 0 to two red blood cells per high-power field, 0 to two white blood cells per high-power field, and no casts. Hematocrit was 36.5 percent. The white blood cell count was 32,000/mm3 with 70 percent neutrophils, 5 percent lymphocytes, 2 percent monocytes, and 23 percent nonsegmented neutrophils. The platelet count was 84,000/mm3. The prothrombin time was three seconds over control with a normal partial thromboplastin time. Findings on stool examination were faintly positive for occult blood. Blood urea nitrogen level was 7 mg/dl, calcium level 7.8 mg/dl, albumin level 2.3 g/dl, and total bilirubin level 4.3 mg/dl with a direct bilirubin level of 3.2 mg/dl. The serum glutamic oxaloacetic transaminase level was 63 IU/liter, serum glutamic pyruvic transaminase level 55 Ill/liter, gamma-glutamyl transpeptidase level 87 It-j/liter, alkaline phosphatase level 237 IU/liter, serum amylase level 225 Somogyi units/liter, and serum creatinine level 0.8 mg/dl. Results of chest films were normal. X-ray films of the abdomen disclosed a right upper quadrant calcification. Electrocardiography revealed sinus tachycardia but findings were otherwise within normal limits. The patient refused to undergo lumbar puncture. The initial diagnostic impression was sepsis secondary to endocarditis or to hepatobiliary tract disease. The patient was treated initially with ampicillin 1 g intravenously every four hours, cefoxitin 2 g intravenously every four hours, and gentamicin 70 mg intravenously every eight hours. Further diagnostic evaluation included technetium sulfur colloid liver-spleen scanning, which demonstrated hepatosplenomegaly with portal hypertension, ultrasound examination of the gallbladder, which demonstrated cholelithiasis, and renal ultrasonography, which demonstrated normal findings. A painful erythematous nodule was noted on the patient’s left fourth digit on the third hospital day. Subsequent M-mode echocardiography performed the following day (Figure 1A)

SUBFLAVA

ENDOCARDITIS-

POLLAGK

ET AL

Figure 1. Serial M-mode echocardiograms taken during the treatment period (A) and five months after hospital discharge (6). demonstrating virtual disappearance of the vegetation attached to the anterior mitral valve leaflet. AML = anterior mitral leaflet; IVS = interventricular septum; PML = posterior mitral leaflet; PW = left ventricular posterior wall; RV = right ventricle; Veg = vegetation.

disclosed on echo density attached to the anterior mitral leaflet consistent with a valvular vegetation. Results of blood cultures obtained on the day of admission were positive in three of three sets for N. subflava, which was sensitive to ampicillin. Urine culture findings were positive for Acinetobacter, which was sensitive only to gentamicin among the initial antibiotics chosen. Following initiation of antimicrobial therapy, there was resolution of the abdominal tenderness by Day 2 and of leukocytosis by Day 8. During the first week of hospitalization, there was improvement in liver function as well as in the general clinical status. Serum bactericidal levels were therapeutic. Concern persisted over continued spiking fevers to 102”F, and all three antibiotics were temporarily discontinued on the 1 lth hospital day to rule out the possibility of drug fever. Further diagnostic studies at this point included bone scanning, gallium scanning of the abdomen, and abdominal ultrasonography, all of which showed negative findings. Surveillance blood cultures were obtained, results of which were subsequently reported as negative. Findings on repeat chest roentgenography and electrocardiography remained unremarkable. Results of a test for hepatitis B surface antigen were negative. Parenteral ampicillin alone was resumed on the 14th hospital day. Two-dimensional echocardiography performed three days later demonstrated a mobile, pedunculated echo density attached to the atrial surface of the anterior mitral leaflet (Figure 2). A small nodular echo density

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was also noted on the noncoronary cusp of the aortic valve. The spiking fever pattern subsided between the fourth and fifth week of hospitalization, although the magnitude of the fever spikes and the baseline temperature had been slowly decreasing up to this point. An immune competence evaluation included a normal quantitative C3 level, and findings on serum protein electrophoresis were notable only for a polyclonal gammopathy. M-mode echocardiography performed after completion of a six-week course of antibiotics just prior to patient discharge demonstrated no significant change from previous studies. Follow-up M-mode (Figure IB) and two-dimensional (Figure 3) echocardiography five months after discharge showed virtual disappearance of the pedunculated mass attached to the anterior mitral leaflet with no significant change in the echo density involving the aortic valve. There was no clinical event compatible with embolization. Follow-up examination at 14 months revealed only a grade II/VI apical

Figure 2. Two-dimensional echocardiogram from the parasternal long-axis view, during the treatment period, demonstrating a pedunculated echo density within the mitral orifice and attached to the atrial surface of the anterior mitral leaflet. AML = anterior mitral leaflet; Ao = aorta; A V = aortic valve closure; IVS = interventricular septum; LA = leftatriurn; L V = left ventricle; PML = posterior mitral leaflet; PW = left ventricular posterior wall; RV = right ventricle; Veg. = vegetation.

systolic murmur. LITERATURE REVIEW Seven cases of well-documented N. subflava endocarditis have been identified in the world literature [2-81. The majority of authors of these reports applied classification schemes detailed in older texts [9] in which N. subflava, N. perflava, and N. flava are distinguished as separate species differentiated by fermentative properties. For purposes of this review, they will be collectively referred to as N. subflava in accordance with current convention. Excluded in our series are case reports involving presumed nonpathogenic Neisseria in which precise organism classification was not possible due to either lack of reproducibility of biochemical and culture characteristics [ 10,l l] or identification of the pathogen only as N. pharyngis [ 12,131. This label was frequently used to represent collectively a number of nonpathogenic Neisseria in the older literature [ 141. Fermentative and culture data were not furnished in these case reports [ 12,131. Furthermore, to lend uniformity to the diagnosis of endocarditis, the cases are labeled as “definite,” “probable,” or “possible,” applying the criteria of Von Reyn et al [ 151, reflecting in decreasing order the relative certainty of the diagnosis of endocarditis. All seven cases analyzed meet these definitions and can be given one of these three labels. Table I summarizes the clinical characteristics of these seven individual case studies of N. subflava endocarditis and includes our patient. Precipitating events providing potential portals of entry for bacteria were identified in four patients (Patients 1, 2, 4, and 5). Predisposing heart disease was found in five patients (Patients 1,2, 4, 5, and 6), including one (Patient 6) in whom the medical history was unavailable; this patient presented with clinical evidence of mitral regurgitation and atrial fibrillation without congestive heart failure, and

xis view, obtain discharge, demonstrating the disappearance of the mitral vegetation with mild residual increased thickness of the anterior mitral leaflet. AML = anterior mitral leaflet; Ao = aorta; A V = aortic valve closure; IVS = interventricular septum; LA = left atrium: L V = left ventricle; PML = posterior mitral leaflet; PW = left ventricular posterior wall; RV = right ventricle.

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Breslin et al [4], 1967

Clark and Patton [5], 1968

Scott [6], 1971

Chong et al [7], 1975 Moonetal [8], 1975

Pollack et al, 1983 (present patient)

3

4

5

6

8

None

None

43, M Drug addiction

ND

?MV dysfunction 36, M None

59, F

Dental abscess

5, F

CHD, VSD, and Al

?Intraoperative infection

47, M Prosthetic AV

Dental extraction

None

History of rheumatic fever

22, F

Cardiac Complications*

None Cerebral and popliteal mycotic aneurysms ?

None Acute Al and CHF

None

Hematuria

Glomerulonephritis

ND

(4

(a) Splenic and renal infarcts

Fever Response to Antibiotics

(4

AV; MV; preexisting AV disease (a) MS with vegetation and aortic valvulitis

Valve Affected and Method of Localization

Spiking fevers for MV and ?AV 35 days by echocardiography

MV by auscultation Spiking fevers for AV (a) 38 days

?

Afebrile after two ? days

Temperature AV (s) decline after 24 hours; subsequent low-grade fever Afebrile after 24 AV (s) hours

NA

Hepatic and NA renal necrosis

Noncardiac Complications*

Cardiac tamponade from suture line tear not endocarditisrelated None

Acute Al and CHF

(a)

Cardiomegafy

URI; status after CHF (a) tonsillectomy

Precipitating Events or Factors*

44, M None

Al

M

l

Predisposing Cardiac Disease

Possible

Possible Definite

Well at one-year follow-up No follow-up Died

Probable

Definite Died

Well at 14-month follow-up

Definite

Definite

Definite

AV replacement at four months; well at 10 months

Died

Died

Clinical Course

l

Endocarditis Classification’

* Valvular or congenital heart disease or valve prosthesis. + Events or factors predisposing to bacteremia. ? New congestive heart failure occurring during or after the endocarditis episode or pre-existing congestive failure worsened by it. 9 Suppurative or nonsuppurative embolic events or major immunologic phenomena. * * Categorization in accordance with criteria proposed by Von Reyn et al [ 151. (a) = confirmed at autopsy; Al = aortic insufficiency; AV = aortic valve; CHD = congenital heart disease; CHF = congestive heart failure; MS = mitral stenosis; MV = mitral valve; NA = not applicable; ND = not described; (s) = confirmed at surgery: URI = upper respiratory tract infection; VSD = ventricular septal defect.

7

2

Kammerer and Wegner [ 21, 1914 Connaughton and Rountree [ 31, 1939

Reference

and Sex

Age (years)

Clinical Characteristics of N. Subflava Endocarditis

1

Patient Number

TABLE I

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ET AL

had a rapid response to antibiotic therapy. In this instance, the clinical course was believed to be more compatible with pre-existing valve dysfunction rather than acute mitral insufficiency secondary to endocarditis. When we refer only to the five antibiotic-treated patients (Patients 3 to 7) excluding the two case reports (Patients 1 and 2) published in the preantibiotic era in which both patients ultimately died, cardiac complications (acute aortic insufficiency) occurred in two instances (Patients 3 and 7). Noncardiac complications were identified in three patients and consisted of glomerulonephritis (Patient 4), hematuria (Patient 5), and multiple mycotic aneurysms of the cerebral vessels and right popliteal artery (Patient 7). The temperature normalized or decreased in three patients (Patients 3 to 5) within 48 hours of antibiotic institution. In a fourth instance (Patient 6), the patient was described as generally improved, with defervescence after 15 days of hospitalization, although the precise fever response to antibiotic administration was not indicated. A fifth patient (Patient 7) had persistent intermittent spiking fevers until his death on the 38th hospital day. There were two deaths in the antibiotic-treated group. Only one of these was directly related to an endocarditis complication-intracranial hemorrhage from a ruptured mycotic aneurysm (Patient 7). The second died from cardiac tamponade secondary to a suture line tear involving a prosthetic Dacron aortic graft placed four weeks earlier during aneurysmectomy. No evidence of infection could be found at the graft suture lines at autopsy, although vegetations were demonstrated on the prosthetic aortic valve ring. Therefore, endocarditis could not be implicated as the cause of death. Exclusive aortic valve disease was demonstrated pathologically in three patients: one with a prosthetic aortic valve (Patient 4) and two without known preexisting heart disease (Patients 3 and 7). A fourth patient (Patient 5) with congenital heart disease (ventricular septal defect and aortic insufficiency) had clinically unchanged findings on cardiac examination during the endocarditis episode, and aortic valve involvement could not be definitively established. A fifth patient had clinical evidence of pre-existing mitral valve disease (Patient 6). In the nonantibiotic-treated patients, pathologic evaluation at autopsy demonstrated new mitral valve disease in a patient with pre-existing aortic valve disease (Patient 1). A second patient (Patient 2) displayed “mitral and aortic valvulitis” [3] with vegetations present only on a stenosed mitral valve. Of the three survivors (Patients 3, 5, and 6), follow-up information is available on two. Both Patients 3 and 5 were described as doing well at nine and 12 months’ follow-up, respectively.

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COMMENTS In our patient, the identity of the pathogen as N. subflava was clearly established, having been isolated independently by separate microbiology laboratories and identified in accordance with current nomenclature [ 11. On the basis of criteria proposed by Von Reyn et al [ 151, our patient would be assigned a label of “probable” in view of the presence of a new regurgitant murmur, vascular phenomena, and persistently positive blood culture results. However, with the additional echocardiographic findings, it is virtually certain that our patient had endocarditis involving primarily the mitral valve with a subacute presentation. Aside from intravenous drug use, cirrhosis may have been contributory to the pathogenesis of infection in our patient by such a nonvirulent organism. In several autopsy reports and retrospective reviews [ 16-191, an association has been noted between cirrhosis and endocarditis. Furthermore, an increased incidence of bacteremia, often without a clearly identifiable source, has been found in cirrhotic patients and has been associated with a less favorable prognosis [ 19-221. These findings may reflect underlying immune dysfunction [23-261. Of concern in our patient was the persistent fever. The majority of antibiotic-treated patients in our review had defervescence or improvement within 48 hours of therapy initiation. In one patient (Patient 7) protracted fever was associated with embolic complications. The precise explanation of prolonged fever in our patient remains unclear. The organism was sensitive to the antibiotics administered, and adequate serum bactericidal levels were documented. Although hectic fever patterns have been associated with myocardial abscesses [27], new electrocardiographic conduction abnormalities and echocardiographic findings for myocardial abscess were not present in our patient. In patients with active endocarditis, such electrocardiographic findings as new-onset atrioventricular and interventricular conduction disturbances are highly specific but not very sensitive for the detection of aortic ring abscess [ 17,28,29]. Similarly, echocardiography is also relatively insensitive for myocardial abscess detection [30]. Other clinical features of myocardial abscess including predominant aortic valve endocarditis with insufficiency and pericarditis were not present in our patient [29]. Furthermore, several noninvasive studies failed to demonstrate evidence of hepatic abscess, gallbladder empyema, and osteomyelitis. There was concern that possible infection of the mesocaval prosthetic graft was the source of continued fever, but the patient did well without graft replacement. Despite the demonstration of echo densities on the mitral and aortic valves, significant cardiac complications failed to develop in our patient. The absence of

NEISSERIA SUBFLAVA ENDOCARDITIS-POLLACK ET AL

cardiac complications was also a feature of three of the five antibiotic-treated patients previously described. In contrast to our patient, acute aortic insufficiency developed on a previously normal aortic valve in Patients 3 and 7. The finding of exclusive left-sided cardiac valvular disease in our patient is consistent with the general pattern of valve involvement in the other reported cases of N. subflava endocarditis. None of the previously reported cases, however, involved patients who were intravenous drug abusers. The particular valve affected in drug addicts varies in different series, with some noting primarily aortic or mitral valve involvement [31,32], and others describing predominant tricuspid valve endocarditis occurring singly or associated with multiple valve infection [33,34]. Autopsy studies in opiate addicts and others dying from endocarditis suggest that valve infection can occur on anatomically normal valves in many instances [35]. The relative ability to affect normal valves may be a function of the organism’s virulence. Other factors implicated include bacterial adherence properties, titer of agglutinating antibodies, and size of bacterial inoculum [36]. If relatively nonvirulent pathogens are involved, underlying cardiac disease and precipitating events and factors predisposing to bacteremia are often regarded as necessary prerequisities and were identified in the majority of cases of N. subflava endocarditis. Noncardiac complications of endocarditis were identified in three of the five antibiotic-treated patients among the cases reviewed, but could not be conclusively established in our patient. The initial hematuria and pyuria reflected a coincident urinary tract infection in view of culture evidence implicating a different pathogen from that found in blood cultures. Lumbar puncture to assess for neurologic complications was refused by the patient. The initial liver function abnormalities most likely reflected underlying hepatobiliary tract disease, as opposed to an embolic complication of endocarditis. The favorable outcome in our patient is consistent with other cases of N. subflava endocarditis treated with antibiotics. Only one endocarditis-related death was reported among the patients receiving antibiotics (Pa-

tient 7). The outcome contrasts with studies suggesting that vegetations detected by echocardiography identify a subset of patients with a poorer prognosis manifested by an increased incidence of embolic episodes, congestive heart failure, need for valve replacement, and death [37-441. There was concern regarding the embolic potential of our patient’s large, pedunculated, mobile mitral valve echo density (vegetation) as well as the possible development of significant mitral valve dysfunction, which would necessitate surgical intervention. However, a major embolic event or hemodynamic deterioration did not occur. Several investigators [41,43] have suggested that vegetation size and structure do not correlate with the tendency to embolize. On the other hand, Sheikh et al 1451, analyzing serial M-mode echocardiograms of active bacterial endocarditis limited to the mitral valve, found that larger vegetations are more likely to embolize. It has also been suggested that no characteristic alteration in vegetation size during treatment and convalescence, as estimated by serial echocardiography, predicts the efficacy of medical therapy [4 1,431. However, Stafford et al [46] found that in antibiotic-treated patients, vegetations tend to become smaller and more echo-reflective with healing. Moreover, the disappearance of valvular vegetations during convalescence has been described [43,45]. Thus, the echocardiographic disappearance of our patient’s large mitral vegetation without a clinical event compatible with embolization and the stable appearance over time of the aortic echo density are not necessarily unusual. In conclusion, the first case of N. subflava endocarditis in an intravenous drug user is detailed and contrasted with seven previously reported cases of N. subflava endocarditis identified in the world literature. Although definitive conclusions with statistical significance are difficult to achieve in view of the limited case numbers, the majority of cases reviewed featured: (1) clear predisposing heart disease, (2) precipitating events or factors predisposing to bacteremia, (3) leftsided heart valve predilection, (4) recognizable noncardiac complications, and (5) favorable outcome with medical therapy. In antibiotic-treated patients, cardiac complications occurred only in those with active aortic endocarditis on a previously normal valve.

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