Native valve Aspergillus fumigatus endocarditis in a patient with autoimmune hepatitis on low dose systemic corticosteroids: A case report

Abstract

Aspergillus infectious endocarditis (IE) is a rare cause of culture-negative endocarditis. The main risk factors are severe immunosuppression and prosthetic heart valve. We describe a case of Aspergillus fumigatus IE on a native mitral valve in a patient with autoimmune hepatitis in remission while on low dose corticosteroids. The case is unique due to the patients’ low initial risk for invasive fungal disease, its clinical presentation and successful management with emergency surgery and antifungal therapy. After literature review we have not found a similar case report. The patient presented with right-sided eyesight deterioration due to endophthalmitis. Vitrectomy was performed and Aspergillus fumigatus grew on culture. IE on a native mitral valve was confirmed with echocardiography. The patient developed signs of acute heart failure soon after hospital admission and was diagnosed with several septic emboli (kidney, spleen, thumb, right common femoral artery). He was initially treated with surgical valve replacement, dual antifungal therapy with liposomal amphotericin B (LAmB) and voriconazole and vitrectomy, including intravitreal amphotericin B application. Long-term triazole therapy was not possible due to hepatotoxicity. The patient was maintained on intermittent LAmB for 12 months and is without signs of recurrence ten months after therapy was discontinued. Aspergillus can cause invasive infection in patients with autoimmune hepatitis on low dose corticosteroids. Early diagnosis followed by emergency surgical valve replacement and systemic antifungal therapy can improve prognosis. Additional studies are needed to evaluate alternative methods and duration of antimicrobial therapy following Aspergillus IE.

Highlights

• •Aspergillus fumigatus infectious endocarditis is rare.
• •Emergency surgical valve replacement with systemic antifungal therapy is crucial.
• •Intermittent liposomal amphotericin B can prevent Aspergillus endocardtis reccurence.

Introduction

Fungal IE is rare and usually occurs in severely immunocompromised hosts, especially those with prosthetic heart valves. Aspergillus species, most commonly A. fumigatus, cause approximately 20–30% of fungal IE, which accounts for approximately 5% of all IE [1], [2]. In addition to prosthetic heart valve, the most common risk factors are hematologic malignancy, corticosteroid or cytotoxic therapy, prolonged antibiotic exposure, bone marrow or solid organ transplant [1], [2].

Mortality is high (50–96%) due to the underlying condition, delayed diagnosis, rapid progression of infection and high risk of embolization due to large vegetations [3], [4]. Most guidelines recommend early valve replacement in combination with antimicrobial therapy [3], [4]. Voriconazole is the treatment of choice and some authors recommend combination therapy with LAmB or an echinocandin. Long-term or even life-long suppressive therapy is recommended due to high risk of recurrence [3], [4]. Poor survival rates limit the data and recommendations on optimal medical therapy.

We present a case of successful treatment of Aspergillus fumigatus IE on a native valve in a patient with autoimmune hepatitis on low dose corticosteroids.

Case presentation

A 47-year-old male presented to the Department of Ophthalmology with acute right-side eyesight deterioration. One day before admission he experienced red spots, followed by the appearance of a foggy curtain on the right eye. His eyesight worsened rapidly on the day of admission. He had a history of autoimmune hepatitis with subacute hepatic failure four months prior, that had been well controlled by systemic methylprednisolone (64 mg initially, decreased to 8 mg maintenance dose. He developed steroid induced diabetes, that was treated with insulin. He denied drug use. He had no previous eye surgery or vision problems. He lived with his family, had a pet hamster and was recently cleaning mold from home walls.

On initial examination, the patient was vitally stable, with a fever of 38.2 °C, visual acuity in the right eye was decreased to counting fingers. Fundoscopy revealed hyperemia of the optic nerve disc, extensive white premacular infiltration with poor view of the macula, peripheral intraretinal bleeding, Roth spots, and thickened white exudates in the peripheral vitreous. Initial blood tests showed elevated white blood cells (14.4 ×10⁹/L; normal range: 4.0 – 10.0 ×10⁹/L), decreased platelet count (131 ×10⁹/L; normal range: 140 – 340 ×10⁹/L) and normal hemoglobin level. Serum creatinine was normal. Liver function tests were elevated (alanine aminotransferase (ALT) 1.13 μcat/L (normal range: <0.70 μcat/L), aspartate aminotransferase (AST) 0.9 μcat/L (normal range: <0.60 μcat/L), alkaline phosphatase 3.36 μcat/L (normal range: 0.5–1.5 μcat/L), gamma glutamyl-transferase 12.68 μcat/L (normal range <0.62 μcat/L)). C-reactive protein (CRP) (42 mg/L; normal levels: <8 mg/L), sedimentation rate (SR) (57 mm/h, normal levels: <15 mm/h) and lactic acid dehydrogenase (LDH) (12.38 μcat/L, normal range: 2.33–4.83 μcat/L) were elevated, while procalcitonin was normal. Serum galactomannan antigen and beta-D-glucan assays were elevated, 2.7 ELISA index (>0.5 is positive) and > 523 pg/ml (>80.0 pg/ml is positive), respectively. Serologies for toxoplasmosis and Lyme disease were negative. Vitrectomy with aqueous and vitreous fluid sampling was performed on the same day with signs of extensive pre-macular infiltration (suggesting fungal etiology), intraretinal hemorrhage and a severely damaged macula. Vancomycin and ceftazidime were applied into vitreous fluid and systemic intravenous antibiotics (moxifloxacin and flucloxacillin) were initiated. Due to suspicion of fungal etiology intravenous fluconazole was prescribed on day 2. A. fumigatus grew on culture from four vitreous fluid samples, blood cultures were negative.

On day 3, transthoracic and transesophageal echocardiography showed three (up to 2 cm) large vegetations on the posterior mitral valve leaflet with moderate mitral regurgitation and valve destruction (Fig. 1, Fig. 2). The same day, the patient was transferred to the Department of Infectious Diseases for treatment of a newly diagnosed mitral valve IE. On admission, the patient was stable, his blood pressure 110/78 mmHg, heart rate 96 bpm, body temperature 36.9 °C, oxygen saturation 97%. His right eye was red and the eyelids swollen, his vision improved to 3 m. A loud systolic heart murmur was present over the entire precordium, but heard best over the apex. A tender nodule was present on the left thumb, suggesting Osler’s node (Fig. 3). No other septic emboli were seen. Chest, abdominal and head computed tomography (CT) were performed. Chest CT showed a 3 × 2 cm large consolidation with cavitation in the left upper pulmonary lobe and small nodular ground-glass consolidations bilaterally. Septic emboli were found in his right kidney and spleen. Head CT did not show any central nervous system complications. Fluconazole was switched to intravenous LAmB (5 mg/kg/day) and intravenous voriconazole (6 mg/kg twice daily for two doses, followed by 4 mg/kg twice daily). Amphotericin B was also applied into vitreous fluid. Systemic antibiotics were stopped. Methylprednisolone was switched to budesonide on the advice of the patients’ gastroenterologist to decrease immunosuppression.

Fig. 1.

Tridimensional reconstruction of mitral valve vegetation as seen with transesophageal echocardiography.

Fig. 2.

Mitral valve vegetation as seen with transesophageal echocardiography.

Fig. 3.

Oslers’ node.

On day 4, the patients’ clinical condition worsened. He was dyspneic, required 2 L/min of supplemental oxygen and was tachycardic up to 110 bpm. The patient had a sudden onset of severe pain in the right leg, which was pale and pulseless distally from knee joint, suggesting possible arterial embolus. The patient was sent for emergency mitral valve replacement and common femoral artery embolectomy after CT angiography confirmed common femoral artery embolus causing acute limb ischemia. Intraoperative mitral valve tissue histology revealed invasion by branching fungal hyphae on Grocott methenamine silver (GMS) stain. Post-operative recovery was complicated by Dressler syndrome and required pericardiocentesis (culture and Aspergillus multiplex PCR from pericardial fluid were negative). His cardiac function improved after surgery and initiation of heart failure therapy, with follow-up echocardiography showing no residual signs of IE. His eyesight improved, but was still foggy. Follow-up Aspergillus galactomannan assays were negative. He was treated with the combination of parental LAmB and voriconazole for four weeks, followed by peroral voriconazole monotherapy for one week, which was switched to LAmB due to hepatopathy (γ-GT 63.8 µcat/L; normal <0.92; alkaline phosphatase 13.3 µcat/L; normal <1.92; AST 2.1 µcat/L; normal below 0.58; ALT 3.9 µcat/L; normal below 0.77). Drug induced liver injury (DILI) due to voriconazole was assumed despite frequent therapeutic drug monitoring (TDM) and optimal voriconazole serum levels. Liver biopsy showed hepatic regeneration after recent hepatitis, thereby excluding reactivation of autoimmune hepatitis. On LAmB hepatic enzymes decreased, however, his kidney function worsened (eGFR 45). After 2 weeks, upon patients’ request and good clinical condition, he was discharged on peroral triazole therapy. He was treated with voriconazole (300 mg twice daily) for one week, followed by isavuconazole for 2 weeks, with increase in cholestatic enzymes in both cases. He was switched to intermittent LAmB 3,4 mg/kg once weekly as maintenance therapy for a total of 12 months.

Ten months after discontinuation of treatment the patient remained clinically stable, with no signs of IE recurrence and with improvement of liver function. In terms of immunosuppression, the decision to switch from budesonide to azathioprine was deferred for a year. His eyesight improved after surgery for right-sided cataracts but did not recover completely. His serum creatinine remains elevated, but stable, fungal markers are negative. Frequent clinical and laboratory monitoring is planned.

Discussion

We report a case of A. fumigatus IE on a native mitral valve complicated by several septic emboli (endophthalmitis, emboli to the spleen, right kidney, left thumb and right common femoral artery) in a patient on low dose corticosteroids due to autoimmune hepatitis and with steroid induced diabetes.

In our case, the patient was initially admitted due to endogenous right-sided endophthalmitis. The most common cause of hematogenous endophthalmitis is bacterial seeding following bacteremia. An echocardiogram was performed to exclude endocarditis as the source of infection. According to the modified Duke criteria, the diagnosis of endocarditis was definite, since the patient had echocardiographically confirmed mitral valve vegetations, fever, several arterial emboli and immunologic phenomena (Osler’s node, Roth spots). In addition, A. fumigatus was established as etiology on mitral valve vegetation histology and microbiology. The patient was immunocompromised and had changes suggesting fungal etiology during vitrectomy. Fortunately, intravitreal samples were sent for culture and diagnosed A. fumigatus as the causative agent, since blood cultures are often negative in fungal endocarditis.

Native valve fungal endocarditis in a patient without severe immunosuppression or previous cardiac abnormality is rare. According to two case series, one involving 53 and the other 38 cases, the most common underlying risk factors were artificial heart valve and hematologic malignancy, followed by solid organ and hematopoietic transplant, intravenous drug use and diabetes [1], [2]. Individual case reports describe Aspergillus IE in a patient after splenectomy or without any risk factors [5], [6]. In our case, the underlying risk factors were low dose corticosteroid therapy and diabetes with autoimmune hepatitis in remission. However, these factors do not imply severe immunosuppression associated with invasive aspergillosis. To our knowledge, this is the first case report of Aspergillus IE on a native mitral valve in a patient with underlying autoimmune hepatitis on low dose corticosteroid therapy.

As was the case in our patient, fungal endocarditis is usually associated with large valve vegetations and high risk of septic embolization leading to high mortality [1], [3]. Here, early diagnosis with positive vitreous fluid samples was crucial as blood cultures were negative. Fortunately, the patient did not suffer any central nervous system complications which allowed early and successful valve replacement. Based on current guidelines and a recent case series showing the benefits of dual antifungal therapy, the patient was initially treated with the combination of LAmB and voriconazole [2]. After a good initial clinical response, long-term triazole suppressive therapy was planned. However, due to triazole hepatotoxicity and the lack of evidence of successful alternative therapy, maintenance antifungal therapy was a dilemma. Based on reports of good clinical outcome with outpatient parental antifungal therapy (OPAT) with intermittent LAmB in several centers in the Netherlands and Belgium and intermittent high dose LAmB as prophylaxis to reduce the risk of invasive fungal infection in high-risk haemato-oncology patients we used a similar approach with LAmB once per week [7], [8]. However, LAmB dosage was lower as compared to other centers since we assumed the patient had low risk of recurrence (ie. no longer on immunosuppression, autoimmune hepatitis in remission). We also took into consideration his decreased kidney function. Due to triazole side effects, drug-drug interactions and the increasing voriconazole resistance in A. fumigatus isolates across Europe, additional evidence-based data is needed on the efficacy of intermittent LAmB therapy to provide alternative treatment options in patients with invasive aspergillosis [9], [10].

The case is unique because of the clinical presentation, patients’ initial low risk for invasive aspergillosis and successful management despite poor prognosis and side effects associated with first-line antifungal therapy. Aspergillus can be the cause of endogenous endophthalmitis even in patients with non-traditional risk factors for invasive fungal diseases. If fungal etiology is suspected, appropriate antimicrobial tests and echocardiography should be done early. Rapid diagnosis is associated with early treatment and improved survival. Additional research is needed on the efficacy of intermittent LAmB or new peroral antifungals for long-term antifungal therapy.

Funding sources

Not applicable.

CRediT authorship contribution statement

Kordis Manja: Conceptualization, Writing – original draft. Hafner Matjaz: Writing – review & editing. Ksela Jus: Writing – review & editing. Azman Juvan Katja: Writing – review & editing. Sulak Marko: Writing – review & editing. Logar Mateja: Writing – review & editing, Supervision.

Declaration of Interest Statement

None.