A 72-year-old man arrived at the emergency department with progressive exertional dyspnea, orthopnea, and paroxysmal dyspnea crisis, which lasted for 2 weeks.
History of the present illness
One month before admission, the patient was studied by a general practitioner as a result of a 15-kg weight loss during the previous 3 months, as well as hyporexia and asthenia. He reported occasional fever, mainly in the evenings. For this reason, tumor markers and abdominal echography were performed, without pathologic findings, and a gastroesophageal endoscopy only manifested a hiatal hernia.
In addition, he experienced slow but progressive worsening of his New York Heart Association functional class during the last 2 months. He had required an emergency department admission with congestive heart failure. A bilateral pleural effusion was documented, and he was admitted under treatment with diuretics and angiotensin-converting enzyme inhibitors.
His medical history included hyperuricemia with occasional gout attacks, benign prostatic hyperplasia, and typhoid fever in his childhood. Any cardiac disease was not previously known, but he had been told about a cardiac murmur several years before. In 2010, he was admitted to the hospital for acute prostatitis, and a severe mitral regurgitation was diagnosed with normal ventricular function. He did not require any procedures due to its asymptomatic course, but was required to be followed at an outpatient clinic.
Social and family history
The patient had worked as taxi driver until his retirement. He stopped smoking 30 years prior, and he had a 14 pack-year history of smoking, without a history of alcohol or drug abuse. Any family disease was not known at that time.
Medications on admission
The patient was treated with colchicine for gout, tamsulosin for benign prostatic hyperplasia, and enalapril and furosemide since his last hospital admission.
On physical examination, he had a fever (38°C), normal and symmetric blood pressure, periorbicular xanthelasmas, and a systolic murmur mostly on the heart apex, with crackles in both lower lung fields. His vital signs were stable. Signs of right-sided heart failure were not observed. Peripheral pulses were present and symmetric.
Laboratory and radiologic evaluations
His white blood cell count was 17,000 (mostly neutrophils), his hemoglobin level was 11 gm/dl, and his inflammation markers were clearly elevated (erythrocyte sedimentation rate of 57 mm/hour and C-reactive protein level of 5 mg/dl).
The first thoracic radiographic examination showed minimal bilateral pleural thickening and signs of left-sided heart failure. A new echocardiogram was performed, confirming severe mitral regurgitation due to posterior veil prolapse and string breaking, with preserved systolic function. A transesophageal echocardiogram showed no evidence of valve vegetation. Blood cultures and serologies for Bartonella species, Coxiella burnetii, Brucella species, Legionella species, and Treponema pallidum were obtained, and all were negative.
A thoracoabdominal computed tomography (CT) scan was performed, highlighting circumferential thickening of the aorta from the right brachiocephalic trunk output to the iliac arteries, in addition to pleural thickening, centrilobular and paraseptal emphysema, and septal thickening associated with patchy ground-glass opacities mainly in both lung apices. Perirenal fat infiltration was observed.
Temporal artery echography was performed, with no pathologic findings. Further evaluation with aortic and cardiac magnetic resonance imaging (MRI) evidenced diffuse pericardial thickening surrounded by epicardial fat infiltration, and confirmed the circumferential aorta and bilateral pleural thickening (Figure 1).
On positron emission tomography (PET), high metabolism in the tissue surrounding the thoracic and abdominal aorta, iliac arteries, and abdominal branches was demonstrated, as well as hypermetabolism of both pleurae mainly on the paravertebral side and weak uptake in the perirenal fat (Figure 2). Despite the absence of bone pain, bone gammagraphy showed abnormal increased labeling of the metaphyseal ends of the long bones, such as the distal femora, proximal tibia, and to a lesser extent, in the proximal humera. In addition, the patient reported a history of several months of sexual dysfunction, finding a hypogonadotropic hypogonadism pattern in the hormonal analysis. Subsequently, we found infiltration of the retroorbital fat in the cerebral MRI, without pituitary involvement.
A 72-year-old man with a history of asymptomatic severe mitral regurgitation was admitted with weight loss and hyporexia and with occasional fever and heart failure secondary to the worsening of mitral valve disease. The most relevant findings in the first approach studies were the thickening and hypermetabolism of the periaortic tissue and pleura.
The differential diagnosis included infectious, neoplastic, and systemic diseases with clinical features compatible with those presented in our patient.
Regarding the findings of weight loss, fever, and worsening of previous mitral regurgitation, the diagnosis of infective endocarditis was considered. Several blood cultures were negative, as well as serologic tests for blood culture–negative endocarditis, such as Bartonella species, Coxiella burnetii, Brucella species, and Legionella species. Furthermore, there was not any evidence of vegetation on transesophageal echocardiography or clinical signs of endocarditis at the physical examination.
Given the presence of this thickened aorta, a differential diagnosis of the causes of aortitis has to be made. Infectious aortitis is not very common, but we first intended to exclude it, considering the severity of its clinical course. Mycotic aneurisms represent 2.6% of all aortic aneurisms, and the thoracic aorta is the most frequent site of occurrence. They are usually associated with infectious endocarditis (). Infectious aortitis can be produced by several bacteria, with Staphylococcus, Streptococcus pneumoniae, Enterococcus, and Salmonella species being the most prevalent ([1, 2]). Salmonella infection usually affects the endothelium, also causing mycotic aneurysm, the most common endovascular manifestation. Aortic infections by unusual bacteria such as Listeria monocytogenes, Bacteroides fragilis, and Campylobacter fetus have also been described (). Another rare cause of aortitis is Clostridium septicum infection, showing a high association with occult colonic malignancy (). Due to the negative result of the blood cultures without antibiotic treatment, the diagnosis of endocarditis seemed unlikely. Even more, the image of the circumferential thickened aorta shown by CT was not suggestive of a mycotic aneurism.
Another possible etiology is syphilitic aortitis, which is a common manifestation of late syphilis, typically affecting the ascending thoracic aorta. Serologic tests for syphilis were negative in this case. Tuberculosis is another rare cause of aortitis, which is associated with a mycotic aortic aneurysm usually involving the descending aorta, frequently as a result of a contiguous infective focus extension to the aortic wall. In our patient, there were no other typical findings on the CT scan, and a tuberculin skin test was also negative.
Fungal aortitis is extremely rare, and is caused by Aspergillus species and Candida albicans ([5, 6]). Aspergillus aortitis is frequently related to cardiac surgery and normally leads to fatal multiple organ dissemination ([5, 7]). In this patient, there was no previous cardiac surgery and the blood cultures were all negative.
Systemic inflammatory diseases
The most frequent cause of aortitis is large vessel vasculitis, i.e., giant cell arteritis and Takayasu arteritis (). Thoracic aneurysm occurs in as many as 11% of patients with giant cell arteritis, and it is usually a late manifestation that can appear in asymptomatic patients (). There is a higher risk of aortic dissection in these patients. It is suggested that patients undergo aorta imaging studies when extracranial vascular involvement is found. In the presence of aortitis in a patient age 72 years with a high erythrocyte sedimentation rate, the most likely diagnosis would be giant cell arteritis. Although these facts do not completely exclude the diagnosis, the absence of headache, visual disturbances, jaw claudication, or symptoms of polymyalgia rheumatica, together with the normal exploration and echography of the temporal arteries, made this diagnosis very unlikely.
In Takayasu arteritis, aortic involvement is very common and occurs mostly in the abdominal aorta, detecting stenotic lesions as well as aortic aneurysm in the aortography (). It typically affects young women and causes a decrease in arterial pulse palpation, provoking a significant difference in systolic blood pressure between the arms, findings that were not found in this case.
Sarcoidosis is a systemic inflammatory disease that can affect virtually any organ system. The lungs, musculoskeletal system, heart, and cutaneous and central nervous systems are the organs typically involved. Large vessel disease is not usually related to this clinical entity. Nevertheless, some published cases in the literature have described an association between Takayasu arteritis and sarcoidosis, suggesting that the vasculitis that affected the aorta would even be a rare complication of sarcoidosis (). Our patient showed pulmonary interstitial and musculoskeletal involvement, with absence of the typical features such as uveitis and erythema nodosum.
Aortitis also would be associated with other systemic inflammatory disorders, such as ankylosing spondylitis, rheumatoid arthritis, polyarteritis nodosa, systemic lupus erythematosus, Cogan's syndrome, and Behçet's disease, causing most typically aortic aneurysm. Neither signs nor symptoms of these diseases were found in our patient.
Although malignancy must be considered in all patients with weight loss and fever, the other clinical findings and imaging information in our case were not suggestive of neoplasm. Even though aortic neoplastic involvement is extremely rare, we should consider the lymphomas as the first diagnostic option. A few cases of non-Hodgkin's lymphoma that affected the thoracoabdominal aorta have been published recently. The characteristic features are lymph node enlargement, pulmonary masses, pleural effusion, and periaortic mass mimicking aortic aneurysm or intramural hematoma (). This patient showed aortic and periaortic involvement, but without lymphadenopathy. Tumor markers for lymphoma were also negative.
In contrast, the pleural and pericardial effusions can be present in some of the most frequent neoplasms, such as breast, pulmonary, and lymphoma, as a sign of extension. There were no other signs in our studies that suggested any of these neoplastic diseases.
IgG4-related disease is a newly recognized disorder, characterized by different tissue infiltration by IgG4-positive plasma cells, with typical histopathologic findings such as dense lymphoplasmacytic infiltrate, a storiform pattern of fibrosis, and obliterative phlebitis (). It has been associated with thoracic and abdominal periaortitis and inflammatory aneurysms in the thoracic or abdominal aorta. It can also cause lung disease, with interstitial pneumonitis, organizing pneumonia, inflammatory pseudotumor, or lymphomatoid granulomatosis (). The presence of elevated levels of serum IgG4 occurs in 60–80% of patients (), which was normal in our case. The presence of periaortitis and pulmonary interstitial involvement would be secondary to this disease, despite normal serum levels of IgG4.
Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytic disease, which affects multiple organs, with bone involvement being the most frequent. Cardiovascular and pulmonary involvement as well as periaortic fibrosis are also very common. The diagnosis of all of these clinical entities should be made by biopsy findings and excluding infections and malignancy.
In order to achieve a definitive diagnosis, and considering the difficulty of access to the other affected localizations, a CT-guided biopsy of the pleura was performed. The biopsy samples showed markedly fibrous tissue with an inflammatory lymphoplasmacytic infiltration, revealing positive immunohistochemical stains for CD45 and CD68, isolated reactivity for S100, and negativity for CD21 and CD1a.
During the hospitalization, our patient experienced an exacerbation of left-sided heart failure. He then was evaluated for surgical reparation of the mitral valve, which was performed without incident. The intraoperative biopsy samples of the sinoatrial sulcus, periaortic fibrosis, and pericardium were compatible with the histiocytic process, displaying identical immunohistochemical results (Figure 3).
ECD is a rare form of histiocytosis, characterized by the infiltration of tissues with foamy CD68+/CD1a− histiocytes. The disease was first described by Chester under the tutelage of Erdheim in 1930 (), and since then, more than 440 cases have been published in the medical literature (until December 2012) (). It is a systemic disease with a wide range of manifestations, including typical skeletal involvement with bilateral diaphyseal and metaphyseal osteosclerosis of long bones up to extraskeletal involvement, with exophthalmos, diabetes insipidus, hypogonadotropic hypogonadism, xanthelasmas, retroperitoneal pseudofibrosis, hydronephrosis, pulmonary and pleural infiltration, and central nervous system and cardiovascular manifestations. The etiology remains unknown. The global mortality is very high, and different treatments have been proven effective, such as corticosteroids, cytotoxic agents, and autologous hematopoietic stem cell transplantation. The unique treatment that has been proven to increase survival until now is interferon alfa, becoming the first-line treatment ([15, 16]).
The patient did not experience typical bone pain, even though it was present in most of the published series. In this instance, the leading manifestations, and the ones that gave evidence of the diagnosis, were pulmonary and cardiac involvement. The extraskeletal manifestations can be observed in 98% of patients, with cardiovascular (77%) and pulmonary involvement (43–55%) being the most frequent ([15, 17]).
At the beginning, the patient stood out with weight loss and fever as well as dyspnea secondary to the interstitial pulmonary disease, the pleural infiltration, and, above all, the heart failure caused by mitral regurgitation. Although the weight loss and anorexia are not typically recognized as characteristic signs of ECD, they have been described as the symptoms of presentation in some published cases ().
We highlight in our case the presence of a previous known valve disease, although it apparently worsened at the same time that the patient lost weight and experienced a fever. The cardiac valve involvement is not very common, and the valve replacement is exceptional. In a review of 53 patients, symptomatic valvulopathy was reported in 17% (). Another article in 2004 mentioned 6 cases of valvulopathy, of which 50% had mitral regurgitation and the other 50% had aortic regurgitation (). Cardiac surgery is technically challenging in these patients. In the literature, only 3 cases of valve replacement have been described to date ([19-21]), apparently without biopsy-proven report of mitral infiltration. Even more, 2 published cases with valve disease and criteria for cardiac surgery could not be performed because of pericardial and myocardial thickening ([22, 23]).
One of the most characteristic radiologic signs of ECD is the circumferential infiltration of the periaortic tissue, constituting the typical image of a “coated aorta” (). The thoracoabdominal CT scan of our patient showed this infiltration from the aortic arch to the iliac arteries, in addition to the bilateral pleural thickening, with hypermetabolism of both locations evidenced in the PET/CT scan.
As for the cardiac involvement, MRI exhibited pericardial thickening in a diffuse and irregular form, with extensive infiltration of the epicardial and pericardial fat. Pericardial involvement is the most frequent cardiac involvement in the published series, affecting 42% of patients (), followed by myocardial infiltration, described in 30% of patients (). In a systematic cardiovascular screening based on MRI and/or CT scan, 70% of the cases showed abnormal cardiovascular imaging, with the infiltration of the right-sided heart being the most frequent finding (49% of the cases) ().
The pleural damage is relatively prevalent in ECD, with documentation in 40% of patients according to the published series (). There is a significant association between the pleural and pulmonary disease, with pleural involvement being isolated in just 5% of the patients with ECD. As in this case, the large series have shown that septal thickening and patchy ground-glass opacities are present in 32% and 12% of the patients, respectively (). The bone scintigraphy evidenced the metaphisary ends of involvement of both the superior and inferior extremities, supporting the diagnosis of ECD.
The definitive diagnosis of ECD requires the finding of fibrosis and xanthogranulomatous infiltration of the tissues, and the identification of foamy histiocytes positive for CD68 and negative for CD1a, found in 80% of the cases also negative for S100 ().
The first biopsy sample, obtained from the pleura, showed this infiltration of foamy histiocytes and occasional Touton giant cells, which are pathognomonic of this process (). The immunohistochemical techniques evidenced positivity for CD45 and CD68, although they were negative for the Langerhans cell marker (CD1a) and the dendritic cell marker (CD21). They discussed Hodgkin's lymphoma (CD15 and CD30 negative) and the presence of mesothelial cells (CD31 negative), showing isolated reactivity for S100. The subsequent intraoperative biopsy samples of the interatrial sulcus, periaortic fibrosis, and pericardium confirmed such findings. To our knowledge, this is one of the few patients with histologic confirmation of ECD in pleura, pericardium, sinoatrial sulcus, and periaortic tissue.
After a surgical procedure for mitral valve repair, the patient was treated with PEGylated interferon alfa-2b at dosages of 9 million units 3 times a week, starting 1 year ago, with excellent tolerance and improvement of the hypermetabolism images at PET scan followup. Currently, he visits the outpatient clinic, showing no signs of heart failure and with improvement of the dyspnea, resting only with asthenia. Further hospital admissions have not been required.
In summary, this is a case distinguished by an atypical presentation of ECD, considering the presence of meaningful weight loss and heart failure caused by worsening of the previously asymptomatic mitral regurgitation. The facts that provided evidence for the diagnosis were the radiologic findings of aortic, pericardial, pleural, and pulmonary involvement. The biopsy sample of the pleural thickening was the way to achieve the final diagnosis. Interferon alfa is the unique proven treatment that has shown survival improvement. The clinical and radiologic evolution of our patient at followup supports these results.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Martinez-Valle had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Los Arcos-Bertiz, Santos-Ortega, Bujan-Rivas, Martinez-Valle.
Acquisition of data. Los Arcos-Bertiz, Santos-Ortega, Rodriguez Palomares, Juanos-Iborra, Tornos-Mas, Martinez-Valle.
Analysis and interpretation of data. Los Arcos-Bertiz, Santos-Ortega, Martinez-Valle.