Case Presentation
This is the case of a 44-year-old woman who initially presented in August 2020 for evaluation of worsening dyspnea and bilateral lower extremity swelling for two weeks. She also complained of unintentional weight loss of about 7.3 kilograms (16 pounds) in the preceding three months. The patient reported a remote history of intravenous opioid abuse; she quit seven years before and was enrolled in a methadone program for recovery. She also had a long-standing history of asthma and chronic Hepatitis C infection with unsuccessful treatment twenty years ago due to medication intolerance. At the time of her presentation, her vitals were significant for tachycardia of 113 beats per mins and a low-grade fever of 99.7F. Her physical examination revealed a distended abdomen, marked splenomegaly, and bilateral lower extremity pitting edema. Heart and lung sounds were normal, with normal jugular venous pressure, no pericardial friction rub, and no stigmata of endocarditis. Her laboratory reports revealed pancytopenia, elevated transaminase levels, elevated creatinine suggestive of acute kidney injury, and a deranged coagulation profile. The Hepatitis C antibody tested was positive, however, the Hepatitis C quantitative polymerase chain reaction for ribonucleic acid was negative. Human Immunodeficiency Virus (HIV) testing and other serologies were negative.
Ultrasound Duplex doppler of the lower extremities bilaterally were negative for deep vein thromboses. Computed tomography (CT) of the abdomen and pelvis and CT angiogram with pulmonary embolism protocol on her presentation ruled out pulmonary embolism and were significant for two small nodules on the liver (likely hemangiomas), severe splenomegaly with several non-specific splenic nodules and mild dilatation of the biliary tree. She was admitted for further evaluation and management. During the initial days of her admission, blood cultures taken on her presentation were found to be positive for Candida parapsilosis,and she was started on liposomal Amphotericin B and fluconazole (seeTable 2 for sensitivity results of the organism). A 2-D transthoracic echo revealed a large vegetation on the left aortic cusp protruding into the left ventricular outflow tract. A transesophageal echocardiogram (TEE) confirmed it to be an 11 x 4 mm soft tissue mobile mass on the ventricular surface of the left coronary cusp of the aortic valve (Figure 1) . She remained persistently pancytopenic during her admission, and a bone marrow biopsy done for further evaluation revealed a monocellular bone marrow with trilineage hematopoiesis and megakaryocytic atypia.
Her cultures remained positive for C. parapsilosis for four weeks despite maximal therapy with different antifungals, limited by her underlying liver disease (Child-Pugh class B), including caspofungin and micafungin. A repeat TEE showed an increase in the size of vegetation to 11 x 16 mm. Due to the absence of concrete clinical trial data, it was difficult to frame a definitive therapeutic strategy, especially the need for valvular surgery. Based on the recommendations of published observational studies, she ultimately had an aortic valve replacement with a number 23 bovine Edwards aortic valve studies after clearing her fungemia. Cultures of the valve taken during the procedure were positive for Candida parapsilosis . Her post-operative stay was complicated by recurrent atrial flutter with a 4:1 atrioventricular block, which was adequately ablated, and she was subsequently started on anticoagulation. She received six weeks of antifungal therapy post-procedure with intravenous micafungin, after which her blood cultures remained negative for fungal growth. She was eventually discharged home on oral fluconazole for three to six months with outpatient follow-up. However, she was non-compliant with therapy and non-compliant with follow-up.
In November 2022, she returned to the emergency department with a three-day history of sudden onset, constant, severe left upper quadrant pain associated with multiple episodes of non-bilious, non-bloody emesis. She denied fever, chills, diarrhea, constipation, hematemesis, hematochezia, bloating, or abdominal distension. She also reported poor oral intake and a decreased appetite. Vitals included a blood pressure of 138/91 mmHg, a pulse rate of 88 beats per minute, a respiratory rate of 18 per minute, a temperature of 97.8 F, and oxygen saturation of 97% at room air. Her physical exam was significant for left upper quadrant tenderness without clinical features of localized or generalized peritonitis. Other aspects of the physical exam were within normal limits. Her initial laboratory investigations were significant for mild normocytic anemia, leucopenia, elevated aspartate and alanine aminotransferases, and alkaline phosphatase (Table 1 ).
A chest radiograph cleared the chest for any significant infiltrates. A right upper quadrant ultrasound scan was significant for a benign, small liver hemangioma with no evidence of gallstones and a normal common bile duct. A computed tomography (CT) of the abdomen and pelvis was significant for splenomegaly with a large splenic infarct, a dilated splenic vein, two small hemangiomas within the liver, and a right ovarian cyst (Figure 2 ). Given her prior history of endocarditis with aortic valvular repair and a new finding of splenic infarction, there was a high clinical suspicion of endocarditis, and blood cultures were sent on admission, and an echocardiogram was ordered. A 2-D transthoracic echocardiogram showed no valvular vegetation, no regional wall motion abnormalities, and a normal left ventricular ejection fraction of 60–65%. Blood cultures taken on admission were negative for two days. The patient had resolution of her left lower quadrant pain and vomiting, remained afebrile with a normal white cell count, and was discharged to follow-up outpatient with cardiology for a transesophageal echocardiogram in the next three days, follow-up with hematology for hypercoagulable workup, and follow-up with infectious diseases. One day after discharge, blood culture resulted positive for the growth Candida species at three days. The patient was called and readmitted to the hospital, where she was started on antifungal therapy with caspofungin. Beta-D glucan was noted to be more than 500 pg/nl. The Candida species was later identified again asCandida parapsilosis . Transesophageal echocardiography demonstrated a bioprosthetic aortic valve with normal movement and a 5mm x 5mm nodular thickening of the right coronary cusp with no definitive endocarditis. Again, blood cultures remained positive for a prolonged period, and a long QT interval required the addition of a different, newer antifungal agent, isavuconazole. Isavuconazole commenced because it can shorten the QT-interval, unlike the older azole antifungals. A repeat transthoracic echocardiogram was done, which showed a bioprosthetic aortic valve with normal valvular motion, mild periventricular thickening (likely postoperative changes), and a 5 x 8mm non-mobile echogenic density attached to the right coronary cusp, likely a calcification versus a healed vegetation. A repeated CT of the chest, abdomen, and pelvis showed no pulmonary findings and similar abdominal findings of splenomegaly and splenic infarct as the initial CT on admission. A CT of the face showed no significant facial soft tissue swelling or abscess—mild paranasal sinus mucosal disease involving the maxillary sinuses and extensive dental disease. A gallium scan showed marked splenomegaly, and activity was identified in the region of the lower extremities, suggestive of marrow expansion, unchanged from previous imaging. Blood cultures were repeated every forty-eight hours, and with three consecutive negative blood cultures, she was discharged in December 2022 to complete six weeks of therapy with isavuconazole and to follow up with Cardiology and Infectious Diseases outpatient.
One month later, in January 2023, the patient followed up with her primary care physician for complaints of dizziness, persistent nausea, and vomiting. She had
repeated blood cultures that were positive for Candida parapsilosis . Isavuconazole was discontinued because of patient-reported side effects (persistent dizziness), and she was again started on intravenous micafungin. A repeat transesophageal echocardiography illustrated two 6mm mobile slender echocardiographic densities attached to the ventricular surface of the aortic bioprosthetic valve leaflets suggestive of endocarditis (Figure 3 ). Cardiothoracic surgery was consulted, and she had a redo aortic valve replacement with a number 21 bovine Edwards bioprosthetic aortic valve. Cultures of the aortic valve done at the operation were again positive for Candida parapsilosis . Post-procedure, she received six weeks of IV micafungin; her blood cultures remained negative for fungal growth. Following completion of IV micafungin she was transitioned to oral fluconazole 400 mg daily. She followed up with infectious diseases in February and March 2023, where she remained asymptomatic and clinically stable.