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CASE REPORT
Year : 2022 | Volume
: 32
| Issue : 4 | Page : 225-228
Nonbacterial thrombotic endocarditis with atypical presentation as overt congestive heart failure
Davide Restelli, Olimpia Trio, Cristina Poleggi, Maurizio Cusmà Piccione, Roberta Manganaro, Giuseppe Certo, Concetta Zito, Giuseppe Andò
Department of Clinical and Experimental Medicine, Section of Cardiology, University of Messina, Azienda Ospedaliera Universitaria Policlinico “Gaetano Martino,” Messina, Italy
Correspondence Address:
Giuseppe Certo
Department of Clinical and Experimental Medicine, Section of Cardiology, Via Consolare Valeria, University of Messina, 98124 Messina
Italy
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jcecho.jcecho_42_22
Nonbacterial thrombotic endocarditis (NBTE) is a form of endocarditis associated with malignancy or autoimmune disorders. Diagnosis remains a challenge as patients are often asymptomatic up to embolic events or rarely, valve dysfunction. We report a case of NBTE with uncommon clinical presentation and identified with multimodal echocardiography. An 82-year-old man presented to our outpatient clinic reporting dyspnea. Past medical history included hypertension, diabetes, kidney disease, and unprovoked deep-vein thrombosis. On physical examination, he was apyretic, mildly hypotensive, and hypoxemic, had a systolic murmur and lower limbs edema. Transthoracic echocardiography revealed severe mitral regurgitation due to verrucous thickening of the free margin of both leaflets, increased pulmonary pressure, and dilated inferior vena cava. Multiple blood cultures were negative. Transesophageal echocardiography confirmed “thrombotic” thickening of mitral leaflets. Nuclear investigations were highly suggestive of multi-metastatic pulmonary cancer. We did not further proceed with the diagnostic workup and prescribed palliative care. Lesions seen on echocardiography were suggestive of NBTE: they involved both sides of mitral leaflets, close to the edges, had irregular shape and echo density, a broad base, and no independent motion. Criteria for infective endocarditis were not met and the final diagnosis was paraneoplastic NBTE due to underlying lung cancer. We remark the lack of definitive recommendations about the treatment of NBTE and the only role of anticoagulation to prevent systemic embolism. We have reported a case of NBTE presenting with atypical symptoms and likely related to the prothrombotic state induced by underlying lung cancer. Provided the unconclusive microbiological tests, multimodal imaging has played a crucial role in the final diagnosis.
Keywords: Deep-vein thrombosis, femoral condyles osteonecrosis, Libman–Sacks endocarditis, lung cancer, marantic endocarditis, mitral disease, mitral insufficiency, nonbacterial thrombotic endocarditis, transesophageal echocardiography, transthoracic echocardiography, verrucous endocarditis
Nonbacterial thrombotic endocarditis (NBTE) is a form of endocarditis caused by sterile vegetations on cardiac valves. This condition, also known as marantic or verrucous or Libman–Sacks endocarditis,[1] is often associated with malignancy, systemic lupus erythematosus (SLE), or antiphospholipid antibody syndrome, and in most cases, it involves left side valves.[1],[2],[3],[4],[5],[6] NBTE is a rare disease mostly found postmortem with a reported prevalence of about 1%–1.5% at autopsy,[6],[7] but recently reported up to 3.7%.[8]
The pathogenesis of NBTE is still unclear. The initial process appears to be a valvular endothelial injury in the setting of a systemic hypercoagulable and inflammatory state. Then, occurs deposition of platelet thrombi, immune complexes, inflammatory cells, and fibrin in the affected tissue, ultimately resulting in vegetations that may dislodge and cause systemic embolisms.[2],[3],[5],[6]
Diagnosis of NBTE remains a challenge as patients are often asymptomatic until their first embolic event or more rarely, the occurrence of significant valve dysfunction.[2],[3],[9] A high clinical suspicion is thus crucial for the diagnosis. A definitive diagnosis can be made only pathologically by autopsy or surgical specimens, as no laboratory tests can confirm NBTE. However, comprehensive laboratory examination is mandatory to rule out differential diagnoses, mainly infective endocarditis (IE). Transesophageal echocardiography (TEE) plays a central role in the diagnosis of NBTE due to its sensitivity and specificity to assess the characteristics of the valvular lesions.[4],[10],[11]
Treatment of NBTE is not well-defined and targeted guidelines are lacking.[2],[3],[4],[12] Indications for cardiac surgery (vegetation excision or valve replacement) are the same as for IE[13] and the underlining disease requires treatment as well. In the case of conservative treatment, echocardiography is an invaluable tool to monitor the progression or resolution of the disease during the follow-up.
The prognosis of NBTE is considered poor as patients may develop thromboembolic events, cognitive impairment, and often die due to the underlying disease, as NBTE is part of the clinical picture of an already fragile patient.[2],[3]
We report a case of NBTE, detected with multimodal imaging, in an old man with undiagnosed diffuse malignancy and cardiogenic symptoms.
Case ReportAn 82-year-old gentleman presented to our outpatient clinic due to the onset, about 3 weeks before, of effort and paroxysmal nocturnal dyspnea, and cough with reddish expectoration. His past medical history was notable for arterial hypertension, type 2 diabetes mellitus, Stage IIIb chronic kidney disease, and thyroidectomy. Importantly, he reported 10 kg weight loss in the past 6 months, after having been affected by proximal deep-vein thrombosis (DVT) in the lower limbs; he was still on rivaroxaban and 20 days earlier had also received the diagnosis of osteonecrosis of the right femoral condyles. He was fully vaccinated against SARS-CoV-2 and was receiving chronic treatment with levothyroxine 125 μg, perindopril 10 mg/indapamide 2.5 mg/amlodipine 10 mg, metformin 1500 mg, rivaroxaban 20 mg, furosemide 50 mg, and spironolactone 50 mg.
On physical examination, we found apyrexia, low blood pressure (105/65 mmHg) and SpO2 (88% without oxygen supplement), an apical 3/6 holosystolic murmur, reduced lung sounds consistent with pleural effusion, hepatomegaly, jugular turgor, and lower limbs edema. The electrocardiogram was showing normal sinus rhythm (90 bpm), low QRS voltages, and unremarkable ST/T changes. With transthoracic echocardiography (TTE), we observed normal biventricular function, enlargement of both atria, severe mitral regurgitation that was due to verrucous thickening of the free margin of both leaflets [Figure 1], especially the anterior one (the effective regurgitant orifice area was 67 mm2), severe tricuspid regurgitation with increased systolic pulmonary arterial pressure (80 mmHg), and dilated inferior vena cava and hepatic veins.
Figure 1: Parasternal (a) and apical (b) long axis view showing verrucous thickening of the free margin of both mitral leaflets, more evident in the anterior leaflet (arrow) than the posterior (arrowhead). Corresponding color Doppler images (c and d) show severe mitral regurgitation. LA = Left atrium, LV = Left ventricleThe patient was then admitted to our cardiology department and treated with oxygen therapy and intravenous diuretic, with rapid improvement in cardiovascular status and hemodynamics. Blood tests showed anemia (hemoglobin 9.5 g/dL) and elevated values of creatinine (2.2 mg/dL), international normalized ratio (2.6), D-dimer (>500 ng/mL), pro brain natriuretic peptide (proBNP) (~3000 pg/mL), and thyroid-stimulating hormone (10 mU/L). Blood and urine cultures for typical and atypical IE organisms resulted negative. Laboratory screening for coagulopathy and autoimmune disease was unremarkable and the chest radiogram confirmed bilateral pleural effusion.
TEE confirmed severe mitral regurgitation and severe thickening of mitral leaflets with “thrombotic” components consistent with NBTE [Videos 1-5]. According to modified Duke's criteria and the diagnostic algorithm for IE proposed by 2015 ESC guidelines,[12] we reasonably ruled out IE and thus diagnosed NBTE. In addition, considering the occurrence of NBTE in a patient with recent weight loss, unprovoked DVT, and cough with reddish expectoration, the suspicious of malignancy was reasonable.
Being unwilling to proceed with contrast-enhanced computed tomography (CT) scan due to kidney failure, the patient underwent perfusion lung scintigraphy with low-resolution CT imaging that revealed multiple perfusion defects in the right lung and solid lesions in the left lung (the main one), left adrenal gland, lymph nodes, and multiple skeletal sites.
After 1 week, the patient was discharged in an acceptable hemodynamic condition without residual signs of fluid overload. Home therapy remained unchanged. The patient underwent ambulatory total-body positron emission tomography that confirmed a diffuse disease with maximal activity in the left lung, left adrenal gland, and multiple districts of skeleton and lymph nodes [Figure 2].
Figure 2: Total-body PET–CT imaging showing diffuse disease with maximal activity in the left lung, left adrenal gland, and in multiple districts of skeleton and lymph nodes. PET–CT = Positron emission tomography–computed tomographyIn agreement with our consultant oncologists, this clinical picture was considered highly suggestive of a multi-metastatic pulmonary neoplasm of advanced grading, complicated by multiple recurrences of subclinical paraneoplastic pulmonary embolism and NBTE. Based on clinical status and prognostic expectations and to comply with the patient's expectations, we agreed with the family not to proceed with any further invasive test or chemo/radiotherapy, and palliative home care only was prescribed. After 3 months of follow-up, the patient lives at home in a precarious status to be considered an end-of-life condition.
DiscussionNBTE is a rare condition that is usually diagnosticated in patients with known autoimmune disease or malignancy in whom neurological symptoms consistent with cardioembolic cerebral ischemia are observed, or eventually with systemic infarctions.[2],[5],[6] Our patient, conversely, was referred to the cardiology department without any history of cardiogenic embolism and with signs and symptoms of heart failure, which were related to severe mitral valve regurgitation. In turn, this represents the rarest clinical presentation of NBTE, as in its natural history significant valvular insufficiency develops only at a very advanced stage, when it has already caused systemic embolism.[3] It is likely that oral anticoagulation therapy, which in this case was ongoing for 6 months, may have reduced the risk of this event.
The peculiarity of our case consists of the suspicion of malignancy raised by the typical morphology of mitral valve lesions seen at echocardiography in coexistence with history of weight loss, DVT, and osteonecrosis of femoral condyles. These two latter deserve proper attention as they can be possibly considered paraneoplastic conditions. First, an unprovoked DVT had been diagnosticated in another hospital 6 months before, had been treated with direct oral anticoagulant (DOAC), and had not been further investigated. Second, osteonecrosis of femoral condyles is often an underdiagnosed condition mostly seen in women older than 60 years. Etiology is unclear and frequently labeled as idiopathic. Among the predisposing factors, SLE, obesity, traumas, steroid therapy, excessive alcohol use, kidney transplant or dialysis, neoplasms, and conditions that can cause microvascular occlusions, such as sickle cell anemia or thalassemia, have been identified.[14],[15] None of these conditions were found in our patient beyond cancer, even if we must underscore the link between SLE and NBTE. However, given the patient's history, clinical status, and prognosis, we decided not to proceed to a complete diagnostic workup for SLE or another autoimmune disease.[16] Honestly, we believed that the most plausible cause of NBTE and osteonecrosis in our patient was lung cancer, which is one of the most frequent solid neoplasms associated.[2, 3, 5, 6, 17]
According to the diagnostic algorithm for IE proposed by the European Society of Cardiology guidelines,[12] such diagnosis could not be supported by the only presence of the imaging criterion consisting in the vegetations of the mitral leaflets, provided the lack of any minor criteria. Following the recommendations for microbiological assessment, we performed several blood cultures for typical and atypical IE organisms, and all were negative. Our final echocardiographic diagnosis was therefore NBTE. Indeed, NBTE lesions of the mitral valve most commonly involve both atrial and ventricular sides close to the edge of the leaflets.[11] Typical features are irregular shape and echo density of these wart-like sessile vegetations, with a broad base and a maximum diameter that can be as large as 1 cm, and without independent motion.[2],[5],[18],[19] all these characteristics were consistent with the case we observed.
Being aware that the definitive diagnosis is histological and unwilling to proceed with any further invasive testing, we concluded that NBTE was likely related to the advanced lung neoplasm. Concerning the treatment of NBTE, we remark the limited availability of universally recognized recommendations,[2],[3],[5],[6] that mainly originate from expert opinion and small observational case series. Anticoagulation is fundamental, with heparin as the only suggested drug, regardless of whether embolic phenomena are observed or not. Insufficient data on the use of DOAC are available, and the scant literature suggests an increased risk of embolic events in patients treated with drugs other than heparin, especially in neoplastic patients.[20] Nevertheless, given the anemia, chronic kidney disease, and other comorbidities, we decided to maintain rivaroxaban 20 mg as the unique antithrombotic therapy. Although is unknown whether NBTE improves with antineoplastic therapy,[3] we sought advice for the treatment of the underlying neoplasm, and the final decision was to prescribe only palliative home care. In addition, we did not consider cardiac surgery for the high operative risk and the reduced life expectancy.
ConclusionsWe have reported a case of NBTE presenting with atypical symptoms of heart failure and related to a prothrombotic state due to underlying advanced lung cancer. Besides laboratory and cultural tests, multimodal imaging was crucial for the diagnosis. The knowledge of typical morphology of NBTE lesions led us to investigate for an occult malignancy that was the most plausible underlying clinical condition. Given the poor prognostic expectations, we decided to maintain long-term single antithrombotic therapy with DOAC and start palliative home care. After 3 months of follow-up, no relevant clinical event has been observed.
Ethical statement
The Ethics Committee of Messina waived the need of formal ethical approval since patient's informed consent was obtained to submit this case report while maintaining anonymity.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given her consent for images and other clinical information to be reported in the journal. The guardian understands that her names and initials will not be published and due efforts will be made to conceal the patient's identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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