A Previously Healthy Teenager with Anasarca

PRESENTATION

A 16-year-old boy with no chronic medical problems presents with several weeks of progressive lower extremity edema, facial swelling, and dyspnea on exertion, accompanied by several daily episodes of loose, nonbloody stools. There is no history of fever, upper respiratory tract symptoms, abdominal pain or nausea, joint pain, eye pain or blurry vision, rashes, or ulcers. He does have a history of facial acne for which he had previously taken isotretinoin. There has been no recent travel. On physical examination, vital signs are normal. He appears tired but in no acute distress. There is decreased aeration at both lung bases, no audible murmurs or gallops, a distended and nontender abdomen, and marked lower extremity and periorbital edema.

Laboratory studies show a mildly elevated creatinine level of 1.0 mg/dL (88 μmol/L), a low albumin level of 1.8 g/dL (18 g/L), and normal liver enzyme levels. Stool testing for α₁-antitrypsin is elevated 20-fold. His electrolyte levels, urinalysis findings, coagulation markers, and inflammatory markers are normal. His chest radiograph shows a small right pleural effusion and no cardiomegaly. Based on his symptoms, presence of anasarca, and hypoalbuminemia with an elevated fecal α₁-antitrypsin level, he is admitted to an outside institution for further evaluation with a working diagnosis of protein-losing enteropathy (PLE). An echocardiogram demonstrates normal intracardiac anatomy and systolic function. His electrocardiogram shows sinus rhythm with diffuse low voltages and flat Twaves (Fig 1A). In the setting of stool protein loss, a more extensive gastroenterologic evaluation is undertaken, which is normal. He is started empirically on prednisone therapy and a low-fat diet but requires standing infusions of 25% albumin and furosemide for management of third-spacing with fluid overload. Despite these interventions, his ascites worsens and he develops respiratory distress. Due to clinical worsening, he is transferred to our institution for specialized evaluation.

Figure 1.

Cardiac testing showing abnormal lymphatic drainage and septal motion. A. Patient’s electrocardiogram demonstrating normal sinus rhythm, flattened T waves, and diffuse low-voltage QRS complexes. B and C. Magnetic resonance lymphangiography after contrast injection into the liver lymphatic bed showing abnormal connections to the duodenum (arrows) with near-complete duodenal opacification by contrast (star) (B) and after contrast injection into the inguinal lymph node revealing a slightly dilated and tortuous thoracic duct (arrows), collection of tortuous vessels in the left supraclavicular region (star), but no evidence of contrast leak into the chest or peritoneum (C). D and E. Representative echocardiographic images from the patient in apical four-chamber two-dimensional view showing normal chamber size, preserved biventricular systolic function, and prominent septal bounce (seen in supplementary video) (D) and in parasternal long-axis two-dimensional view in early diastole with notable echobright pericardium (arrows) (E).

DISCUSSION

Lymphatic Evaluation

PLE refers to the rapid loss of serum proteins into the intestinal lumen, and the etiology can be divided into acquired and congenital causes. Acquired PLE is caused by either increased gut permeability due to an inflammatory process in the intestinal epithelium (eg, inflammatory bowel, autoimmune disease, or infection) or abnormal flow of lymph directed into the duodenum from an anatomical problem or lymphatic obstruction (eg, Fontan circulation or right-sided heart failure). Congenital lymphatic abnormalities can be seen in conditions such as neurofibromatosis, Noonan syndrome, and Turner syndrome.

During the past decade, we have developed a programmatic approach at our institution to patients with lymphatic disorders. (1)(2) We perform specialized magnetic resonance imaging (MRI) of the lymphatic system by injecting gadolinium contrast into various lymphatic compartments. (3) This patient had findings pathognomonic for PLE; with contrast injection into the liver lymphatic system, abnormal lymphatic networks are seen around the bowel (Fig 1B, arrows) with contrast leak into the bowel (Fig 1B, star). However, this patient had additional findings not generally seen in patients with isolated PLE. Approximately 1.5 L of lymphatic fluid was drained from the pleural space, indicating that the lymphatic abnormalities were not confined only to the abdomen. The MRI further showed that the thoracic duct was patent but slightly dilated and tortuous (Fig 1C, arrows), with a cluster of dilated lymphatic vessels in the left supraclavicular region (Fig 1C, star).

This finding is usually seen only in patients who have thoracic duct outlet obstruction or elevated central venous pressures because the thoracic duct drains directly into the central venous system at the level of the innominate vein. Cardiac catheterization showed strikingly elevated filling pressures, including a right atrial mean pressure of 14 mm Hg (normal, 3–5 mm Hg), right ventricular end-diastolic pressure of 20 mm Hg (normal, 3–7 mm Hg), and left ventricular end-diastolic pressure of 24 mm Hg (normal, 6–9 mm Hg). These elevated filling pressures are indicative of diastolic dysfunction and are transmitted to the innominate vein and thoracic duct, explaining the dilated lymphatic channels.

Clinical Course

The differential diagnosis for severe diastolic dysfunction in this patient is either restrictive cardiomyopathy or constrictive pericarditis. Review of his previous echocardiogram confirmed normal chamber sizes and systolic function (Fig 1D and online video) but in addition demonstrated a pathognomonic abnormal movement of the interventricular septum called a “septal bounce.” The bounce is caused by abnormal ventricular filling. In early diastole, the right ventricle fills first, followed suddenly by the left ventricle. Due to constriction, the septum shifts or bounces toward the right ventricle. On further review of his echocardiogram, he had hepatic vein flow reversal, significant effusions, and dense pericardial thickening (Fig 1E). This confirmed the diagnosis of constrictive pericarditis, which develops when an inflammatory pericarditis causes serous effusions and fibrotic lesions leading to pericardial thickening, adhesions, and often calcifications. The immobile pericardium causes restriction of ventricular filling, leading to heart failure and fluid overload. (4)

To determine the etiology of constrictive pericarditis, the patient underwent infectious and rheumatologic testing, which were negative. The patient underwent a radical pericardiectomy for relief of the fibrotic pericardium. At the time of surgery, direct intraoperative inspection revealed a severely thickened and densely adherent pericardium, and tissue was sent for histopathologic analysis and culture. Histopathologic analysis demonstrated fibrotic thickening of the epicardium and pericardium with evidence of diffuse, chronic inflammation. The patient recovered rapidly. A few days postoperatively, the pericardial tissue culture turned positive, growing Cutibacterium (formerly Propionibacterium) acnes. The patient’s history of facial acne was of interest, but subspecialists agreed that it is difficult to know exactly how he acquired the infection.

The patient was discharged on a 6-week course of intravenous antibiotics. His lymphatic symptoms resolved by treating his heart disease. He recovered gradually with improvement of edema, resolution of effusion and pericardial inflammation on echocardiogram, and normalization of serum albumin. At 1-year follow-up, he is physically healed but undergoing therapy for the trauma from his critical illness, multiple hospitalizations, and surgery.

Diagnosis

Constrictive pericarditis is a rare diagnosis in pediatrics, and the incidence in children is not known. It can develop as a sequela to pericarditis of any cause, including viral, bacterial, rheumatologic, neoplastic, traumatic, and iatrogenic etiologies (Fig 2). Acute bacterial pericarditis is the least common cause of pericarditis in the developed world but has the highest risk of evolving into constrictive pericarditis. (4) Up to one-third of patients with bacterial pericarditis go on to develop constrictive pericarditis. (4)(5)(6)(7)(8) Accurate diagnosis of constrictive pericarditis demands a high index of suspicion because it presents with a wide variety of symptoms that may not immediately point to a cardiac disease process. In addition, the onset of symptoms is usually subacute, with an average time to diagnosis of 6 months. (9) When constrictive pericarditis develops as a sequela of bacterial pericarditis, there is usually a history of acute illness and incomplete drainage of a purulent effusion. This was not the case in our patient because the underlying organism was less virulent. There are rare reports of constrictive pericarditis in adult patients with C acnes who had similarly severe presentations without a history of acute infectious symptoms. (10) One report of infective pericarditis found evidence of C acnes in nearly 30% patients, (11) although to our knowledge this is the first pediatric case reported. C acnes is a common skin flora anaerobe and is increasingly recognized as a causative organism in hardware, joint, and CNS infections, but it is difficult to identify in routine cultures due to its slow growth and low virulence.

Figure 2.

Etiologies of constrictive pericarditis. This patient’s clinical course is highlighted in red.

The initial diagnostic evaluation for pericarditis includes laboratory data, electrocardiography, chest radiography, and echocardiography. Advanced imaging techniques such as computed tomography or cardiac MRI and cardiac catheterization can help determine or reinforce the diagnosis. Laboratory data are often nonspecific without signs of acute inflammation. Liver function test results may be abnormal, and brain natriuretic peptide is often normal, which can differentiate constrictive pericarditis from other causes of right-sided heart failure. (12) Electrocardiography may reveal low voltages or have ST-segment or T-wave changes, such as those seen in our patient. The chest radiograph usually shows a small cardiac silhouette and may show nonspecific pulmonary edema or pleural effusion. If the pericardium is calcified, this may be visible on the chest radiograph and is more specific. (13)

Echocardiography is an important diagnostic tool for constrictive pericarditis. The echocardiogram may show both systolic and diastolic failure, abnormal movement of the ventricular septum (particularly a septal bounce), pericardial thickening, and other signs of tamponade physiology. (14) Cross-sectional imaging can further demonstrate the pericardial thickening and hemodynamic abnormalities, and cardiac catheterization will quantitatively show diastolic dysfunction.

Treatment/Management

The management of constrictive pericarditis depends on the underlying etiology and disease stage. In a small subset of patients without features of chronic disease, the inflammation can be treated medically. (15) However, nearly all patients require definitive surgical management. The preferred approach is radical pericardiectomy to remove as much pericardium as possible. (16) Adult outcome data suggest that patients do better with earlier intervention. (9) If the underlying etiology of the constrictive pericarditis is unknown, as in our patient, pathology specimens can be cultured. Constrictive pericarditis due to a bacterial infection requires prolonged antibiotics. Reported outcomes after successful pericardiectomy in children are better than those in adult studies because adults often have significant medical comorbidities and are sicker at the time of operation. (17)(18)

Lessons for the Clinician

• Constrictive pericarditis is the final common pathway of a myriad of systemic inflammatory diseases and can be fatal if undiagnosed.

• The presentation is often subacute and subtle. Classic symptoms include dyspnea, edema, and possibly chest pain and palpitations. A pericardial friction rub is not typical as the pericardium is densely adherent to the myocardium. Rather, a pericardial knock, an extra heart sound in early diastole caused by rapid cessation of ventricular filling, is the classic finding on auscultation. Progression to right-sided heart failure presents with signs of fluid overload, including jugular venous distention, pleural effusions, hepatomegaly, ascites, and peripheral edema.

• The initial diagnostic evaluation includes laboratory testing, electrocardiography, chest radiography, and echocardiography. Advanced imaging techniques such as computed tomography or cardiac magnetic resonance imaging and cardiac catheterization can help determine or reinforce the diagnosis.

• Treatment is surgical—patients require radical pericardiectomy to relieve the mechanical obstruction to adequate diastolic function, as well as medical therapy for the underlying etiology.