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CASE REPORT Fever and Peripheral Emboli in an Immunocompetent Host: A Case of Aspergillus Endocarditis Derek Yung 1, Sadiya Kukaswadia 1, Asma Ali 1, Shariq Haider 2 and Omid Salehian 3 1 Department of Medicine. 2Division of Infectious Diseases. 3Division of Cardiology, McMaster University, Hamilton, Ontario, Canada. Abstract: Despite diagnostic and therapeutic advances in medical, surgical, and critical care, the mortality rate for Aspergillus endocarditis remains dismal (approaching 100%). We report a case of a 49 year old immunocompetent woman with recent aortic valve prosthesis who presents with fever, chills, sweats, left facial droop, left arm weakness, petechial rash and cyanotic toes. Initial trans-esophageal echo was normal but a repeat study revealed a 9 × 5 mm vegetation abutting the aortic prosthesis. Microbiological correlation could not be documented despite the presence of persistent fever through serial blood cultures, and the diagnosis of Aspergillus fumigatus endocarditis was ultimately made on embolectomy specimen when she developed an ischemic right leg. Aggressive medical treatment was initiated with intravenous voraconazole, liposomal amphotericin-B and heparin. The timing of surgical intervention was contemplated, but was precluded by multiple comorbidities. She succumbed to her illness after developing cerebral herniation following intraparenchymal hemorrhage. The effectiveness of combined medical intervention and surgical valve replacement for Aspergillus endocarditis is therefore contingent on high diagnostic suspicion and early echocardiographic detection in a high risk individual with features of culture-negative endocarditis. Introduction Aspergillus is a common ubiquitous mold and the broad spectrum of invasive disease attributed to these fungi has traditionally been observed in the immunosuppressed population. Endocarditis is a rare and serious disease manifestation of Aspergillus infection and the combination of poor recognition and lack of effective therapies has led to dismal prognosis. In the immunocompetent host, factors that have been implicated include prolonged broad-spectrum antibiotic use, indwelling central venous catheters, intravenous drug use, and previous valvular disease or surgery. The latter has become more relevant with increasing use of intracardiac devices and prostheses and may account for at least 50% of documented Aspergillus endocarditis cases. A case of endocarditis secondary to Aspergillus fumigatus post cardiac valve replacement surgery is described, and challenging issues pertaining to diagnosis and management will be discussed. Case Presentation A 49-year-old immunocompetent woman was admitted to hospital with a two day history of progressive fever, chills, sweats, left facial droop, left arm weakness, petechial rash and cyanotic toes. Two months prior, she had a redo aortic valve replacement with a #23 Cardbomedic™ mechanical aortic valve for progressive stenosis of previous mechanical prosthesis which was implanted for rheumatic stenosis. She had a history of rheumatic fever as a child, requiring aortic and mitral mechanical valve replacements at age 18 and 39 respectively. Other medical history was significant for hypertension, hyperlipidemia, atrial fibrillation requiring atrioventricular nodal ablation and pacemaker implantation in 1999, remote left arm deep venous thrombosis (DVT) and breast cancer in remission treated successfully with surgery and radiation therapy. Her medications included aspirin, warfarin, and ramipril. There was no history of prolonged antibiotic or intravenous drug use. On initial examination she was febrile at 102 oF with otherwise stable vital signs and normal level of consciousness. Neurologically a left facial droop with forehead sparing was present. Auscultation revealed crisp and normal metallic opening and closure clicks of the aortic prosthesis, and a previously Correspondence: Omid Salehian, McMaster University Medical Centre, 1200 Main Street West, Room 3U8, Hamilton, ON, L8N 3Z5, Canada. Tel: (905)521-2100; Ext: 73822; Fax: (905)521-5053; Email: [email protected] Copyright in this article, its metadata, and any supplementary data is held by its author or authors. It is published under the Creative Commons Attribution By licence. For further information go to: http://creativecommons.org/licenses/by/3.0/. Clinical Medicine: Cardiology 2008:2 229–234 229 Yung et al documented grade 2/6 murmur was heard at the left sternal border. No extra heart sounds were audible and no signs of heart failure were present. Inspection of the extremities revealed a petechial rash over the medial aspect of the left thigh, and purplish cyanotic discoloration of the left big toe and right fifth toe. No other embolic or immunologic phenomena of endocarditis were detected. Initial blood work was unremarkable with a hemoglobin of 11.7 g/dL, platelet count of 400,000 /uL, white blood cell count of 8,500/uL, and normal renal function, liver enzymes and cardiac markers. Immunologic work up including a screening panel for vasculitic and connective tissue processes (ie. endonuclear antibodies and antineutrophil cytoplasmic antibodies) was negative and immunocompetency was verified through normal CD 4 and CD 8 counts. The international normalized ratio (4.8), erythrocyte sedimentation rate (67 mm/h, normal ⬍30 mm/h), and CRP (33.5 mg/L, normal ⬍3 mg/L) were elevated. Multiple blood cultures were negative. Computed tomography (CT) of the head showed (Fig. 1) two localized areas of acute infarction in the right insular cortex and right frontal lobe, the latter with a focal region of intraparenchymal hemorrhage. This clinical presentation was highly suspicious of peripheral embolic phenomena to the brain. However, initial trans-esophageal echocardiography did not reveal a cardiac source of embolization. Without a clear diagnosis no specific therapy was initiated. The presence of mechanical valvular prosthesis in the setting of intracranial hemorrhage required judicious anticoagulation with intravenous heparin, and discontinuation of aspirin and warfarin therapy. The intermittent fevers continued in the presence of new onset photosensitivitiy and Figure 1. Brain computed tomography (without contrast) showing the right frontal lobe infarct (arrow). 230 Clinical Medicine: Cardiology 2008:2 Fever and peripheral emboli in an immunocompetent host bilateral conjunctival injection, stable neurologic symptoms, and negative serial blood cultures. One week after admission, acute pulseless right leg ischemia ensued necessitating urgent embolectomy. The embolectomy specimen ultimately grew Aspergillus fumigatus, and repeat transesophageal echocardiogram (next day) revealed a 9 × 5 mm vegetation abutting the posterior aspect of the bileaflet aortic prosthesis associated with increased valve gradients (Fig. 2). Aggressive medical treatment was initiated with intravenous voraconazole 330 mg twice a day, and intravenous liposomal amphotericin-B 400 mg daily. The timing of surgical intervention was contemplated, but was precluded by multiple comorbidities mainly the intracranial emboli associated with generalized seizures, and the risk of intracranial hemorrhage with full anticoagulation required for the bypass run. The patient had also developed Escherichia coli urinary tract infection, and Figure 2. A) Transesophageal echocardiogram view in midesophageal window showing a short-axis view of the aortic mechanical prosthesis. There is a mobile echodensity (arrow) seen in the posterior aspect of the prosthesis. B) Long-axis view of the aortic mechanical prosthesis showing the same echodensity (arrow). Clinical Medicine: Cardiology 2008:2 231 Yung et al unremitting right-sided flank pain. Radiological correlation via repeat CT scans documented a large left parietal brain infarct (Fig. 3), and embolic phenomena to the right kidney and spleen. Given the brain CT findings and the patient’s clinical condition intravenous heparin was discontinued and anticoagulation was reversed using vitamin K and fresh frozen plasma. Intravenous phenytoin was initiated for the seizures and the patient was intubated in order to implement hyperventilation to treat the increased intracranial pressure. Her level of consciousness continued to deteriorate and ultimately she succumbed to her illness after developing cerebral herniation. Autopsy results confirmed multifocal microencephalitic microabscesses in the brain consistent with aspergillus meningitis and aspergillomas. Discussion Fungal endocarditis accounts for roughly 1.3%–6% of all cases of endocaridits[1, 2], and complicates approximately 0.1% of all valve prostheses[2, 3]. Aspergillus endocarditis is second only to Candida as a cause of fungal endocarditis and accounts for approximately one in every four cases of fungal endocarditis. Although numerous Aspergillus species have been historically isolated, Aspergillus fumigatus accounts for the vast majority (60%–90%) of cases reported followed by Aspergillus terreus (5%–20%)[2]. Men are affected more commonly than women[4], at a mean age of 40[2]. As depicted by our patient, one of the greatest challenges and predictors of survival is early recognition. An approach to recognition and management of Aspergillus endocarditis is shown in Table 1. The clinical presentation of Aspergillus endocarditis tends to be non-specific and limited to fever, a new or dynamic heart murmur and major peripheral emboli[1, 2, 4, 5]. The latter is the initial presenting feature in 69%–83% of case, resulting in neurologic impairment in up to 30% of cases[6]. Less common presentations include congestive heart failure or sepsis. The prolonged mean time to diagnosis is estimated at 41 days from symptom onset[1]. With the advent Figure 3. Brain computed tomography (with contrast) showing effacement of all cisterns and There is a new extensive infarct in the territory of the left middle cerebral artery involving frontal parietal occipital and posterior temporal areas. 232 Clinical Medicine: Cardiology 2008:2 Fever and peripheral emboli in an immunocompetent host Table 1. Approach to patient with possible Aspergillus endocarditis. 1. High index of suspicion is necessary 2. Routine blood cultures are almost always negative 3. Transesophageal echocardiography (should be repeated if initially negative and there is a change in patient’s clinical status) 4. Neuroimaging (due to high degree of systemic embolization) 5. Initiation of aggressive antifungal regimen (Voraconazole/Amphotericine B) 6. Involvement of cardiovascular surgery early in management of patient 7. Role for other diagnostic tests (polymerase chain reaction, galactomannan antigen detection) not clear at this time of improved echocardiographic imaging, its use in the presence of clinical suspicion in a high risk individual is quintessential. Although adherence by Aspergillus to mechanical prostheses has not been objectively evaluated in experimental studies, the role of protease mediated angio-invasiveness and gliotoxin mediated protection from phagocytic activity are well accepted virulence mechanisms which probably play an important role in prosthetic valve infections[7, 8]. Aspergillus vegetations on the valves tend to be large and readily detectable by echocardiography in 81.4% of cases, and occasionally myocardial abscess is detected in 5.9% of cases[2]. However in a patient with prosthetic valve, the sensitivity decreases to 76.5% and 61.1% with transthoracic and transesophageal echocardiography respectively. This is secondary to the confounding effect of high reflectivity from mechanical valves, and difficulty differentiating from mural thrombi due to anatomical distortion[9]. A definitive confirmation of diagnosis is dependent on microscopic, histopathological and microbiological documentation. Yet unlike Candida endocarditis, blood cultures as entailed in Duke’s criteria are almost always negative (in 70%–89% of cases) and isolation in embolic material or affected tissues is almost always necessary[2, 5, 10]. In our patient, all 11 blood cultures performed were negative and isolation of Aspergillus fumigatus was identified only upon urgent embolectomy after suffering peripheral embolization, an unfortunate but common scenario. The use of novel techniques including galactomannan antigen detection (an Aspergillus cell wall constituent), polymerase chain reaction, or nucleic acid sequence amplification, has shown a lack of sensitivity and inconsistent results, has not been sufficiently validated and requires further characterization[11–13]. Once a diagnosis is made initiating key management decisions must be made in a timely fashion. Clinical Medicine: Cardiology 2008:2 Confronting the challenge of implementing effective medical therapy has been an ongoing struggle. The mainstay of medical therapy for Aspergillus endocarditis has been intravenous Amphotericin B since its introduction in the 1955, yet the key therapeutic questions of optimal dosage, duration of therapy and rates of infusion remain controversial[14]. Nephrotoxicity is the most common concern associated with this therapy, although the intercalation of the drug into liposomes has decreased its renal toxicity[15]. Despite its fungicidal properties, the disappointing results historically observed in practice have been partly attributed to poor penetration of fibrin clots and vegetations, and titration to higher dosages (up to 5 mg/kg for liposomal Amphotericin B) is generally recommended in patients with relatively preserved renal function[16]. Itraconazole an alternative to Amphotericin B, has been inundated with problems including multiple drug interactions and variable bioavailability. In recent years, the use of Voriconazole has shown promise with a mortality benefit (hazard ratio 0.59, 0.40 to 0.88 95% CI) at 12 weeks compared to Amphotericin B therapy shown in a randomized control trial by Herbrecht and colleagues[17]. In our patient, both drugs were employed given the refractory state of her illness. The use of rifampin as a potentiating agent for Amphotericin B has not been substantiated by clinical data and independently has no activity against Aspergilli[18]. Medical therapy however is almost never sufficient. Surgery is almost empirically used as an adjunct to medical therapy, and some may argue that Aspergillus endocarditis is a standalone indication for valve replacement. The typical surgical protocol includes debridement of infected tissue, and reconstruction with biologic tissue when possible[3]. The additional magnitude of short and long term survival benefit from surgery has been long debated, and the timing of such a major operation 233 Yung et al is often precluded in these critically ill patients. The post-operative recurrence rate of Aspergillus endocarditis may approach 40%[19], and combination (medical and surgical) therapy may not necessarily improve prognosis with mortality rates exceeding 80%[1, 2]. It is therefore critical to recognize the narrow window of opportunity for surgical intervention and to proceed promptly. The American College of Cardiology and American Heart Association 2005 recommendations discuss a well accepted two phase therapy consisting of an induction phase comprised of a combination of surgical valve replacement and parenteral antifungal therapy for 6 weeks, followed by a second phase of lifelong suppressive therapy with an oral azole agent given high relapse rates[2, 10, 20, 21]. However, the effectiveness of this approach for Aspergillus endocarditis is contingent on maintaining high diagnostic suspicion and early echocardiographic detection in a high risk individual with features of culture-negative endocarditis. Aspergillus endocarditis after prosthetic valve surgery is associated with an ominous prognosis, and our inability to improve the current dismal mortality rates has been attributed to a poor implementation of effective medical and surgical interventions early before the viscous cycle of complications ensues. 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