The Heart of the Matter: Secondary Hypogammaglobulinemia and Constrictive Pericarditis

Abstract

Constrictive pericarditis is the final common result of a number of processes that affect the pericardium. Establishing the diagnosis and determining the underlying etiology of constrictive pericarditis are often a diagnostic rendezvous. Here, we describe a patient that presented to the general practitioner with edema, ascites and weight gain and was found to have constrictive pericarditis secondary to an inflammatory myofibroblastic tumor of the mediastinum. Interestingly, she had a relative lack of cardiorespiratory complaints and aside from the edema and mildly elevated jugular venous pressure, she had an unremarkable cardiac and pulmonary exam. During the diagnostic evaluation for constrictive pericarditis, she was found to have hypogammaglobulinemia and profound lymphocytopenia. A stool alpha-1-antitrypsin level was sent and was elevated, which confirmed the diagnosis of protein-losing enteropathy, a rare but important complication of constrictive pericarditis. This case highlights important diagnostic considerations and management of these complications for the general practitioner.

Table of Contents Summary:

We review a case of protein-losing enteropathy and secondary hypogammaglobulinemia in a patient that developed constrictive pericarditis secondary to an inflammatory myofibroblastic tumor.

Case Presentation

A 14-year-old previously healthy girl presented with a 3-week history of progressive lower extremity edema, abdominal distension, and weight gain. She denied shortness of breath, chest pain or orthopnea and did not have rashes or fevers. She endorsed mild dyspnea on exertion with running or climbing two flights of stairs. She was evaluated by her primary care physician and laboratory evaluation was notable for hypoalbuminemia (albumin 2.7, reference 3.7-5.6g/dL), elevated aspartate aminotransferase (AST 58, reference 10-40U/L), and normal urinalysis. An abdominal ultrasound demonstrated an inhomogeneous liver, small bilateral pleural effusions, and ascites. She was admitted to the hospital for further evaluation. Physical exam revealed a normal pulmonary evaluation, but her cardiac exam was notable for jugular venous distention (10cm), positive Kussmaul sign, 2+ pitting edema extending to the knees, and a liver edge palpable 3cm below the costal margin. Chest radiographs demonstrated a large soft tissue density along the left mediastinum causing a mass effect on the trachea and left main bronchus (Figure 1A). Further evaluation with a chest/abdomen/pelvis computed tomography (CT) demonstrated constrictive pericarditis, congestive hepatopathy, moderate pleural effusions with ascites, and mediastinal and hilar lymphadenopathy (Figure 1B). There were no splenic, liver, or pulmonary lesions. The echocardiogram revealed dilated atria with dilated hepatic veins and inferior vena cava, which failed to compress during inspiration concerning for elevated right-sided pressure, a finding that can be seen in restrictive cardiomyopathy and constrictive pericarditis (Figure 2). There was dyskinetic interventricular septal motion with abnormal tissue doppler indices supporting diastolic dysfunction with preserved systolic function. Exaggerated septal shifting with respiration, a pathognomonic finding for constrictive pericarditis, was also observed (Figure 2). To better differentiate between constrictive pericarditis and restrictive cardiomyopathy, the patient was referred for cardiac catheterization which revealed elevated but equal end diastolic pressures, with RVEDP=LVEDP=20mmHg (normally 3-8mmHg with RVEDP<LVEDP) and ventricular interdependence, which confirmed the diagnosis of constrictive pericarditis. Cardiac MRI reinforced the findings seen on CT scan, echocardiogram, and cardiac catheterization, demonstrating pericardial thickening and enhancement, dilated IVC and findings consistent with ventricular interdependence.

Figure 1.

A) Chest x-ray at presentation demonstrating soft tissue density (blue arrow), and mass effect causing deviation of the trachea (red arrowhead) and left main bronchus (red arrow). B) Chest CT scan obtained upon admission showing pericardial thickening (red arrow) and area concerning for necrotic mediastinal lymphadenopathy (blue arrow). C) Intra-operative photographs demonstrating two cystic structures (blue arrows).

Figure 2.

Echocardiogram demonstrating biatrial enlargement (left panel) and exaggerated septal shifting with respiration (middle and right panels).

Other labs obtained included a normal uric acid, ceruloplasmin, lipase, erythrocyte sedimentation rate, c-reactive protein, and a negative antinuclear antibody and smooth muscle antibody. She had a normal white blood cell count but low absolute lymphocyte count of 800/cumm, and hemogloblin of 15.8 g/dl. Her infectious testing was negative including: HIV, Bartonella serology, Blastomyces serology, CMV serology, Hepatitis A/B/C testing, toxoplasma serology, histoplasma urine antigen and serology, T-spot, and EBV IgG+/ IgM equivocal. She underwent biopsy via video-assisted thoracoscopic surgery and chest tube placement due to persistent pleural effusion. Intra-operatively, the mediastinal masses appeared as two cystic structures and clear gelatinous fluid was noted (Figure 1C).

The differential diagnosis for constrictive pericarditis was expanded to include sarcoidosis, IgG4-related disease, and malignancy. Testing of the immune system revealed an IgG level of 221 (509-1580mg/dL), with normal IgA and IgM. Additional immunology labs demonstrated low lymphocyte counts with CD3 305 (1000-2200/cumm), CD4 96 (530-1300cells/mcL), CD8 122 (330-920 cells/mcL), but normal B cell and NK cell counts. She had an adequate response to tetanus vaccine and pneumococcal titers were positive (>1.3mcg/mL) in 5 out of 12 serotypes for Prevnar 13. The next-generation sequencing of 207 genes associated with primary immunodeficiency did not reveal any underlying pathogenic variants. A stool alpha-1-anti-trypsin level was obtained and was highly elevated at 1,021mg/dL (reference <=54), which was consistent with a diagnosis of protein-losing enteropathy (PLE).

Surgical pathology returned with a diagnosis of inflammatory myofibroblastic tumor (IMT) of the mediastinum/prevascular space and tumor-specific staining for anaplastic lymphoma kinase (ALK-1) was negative. The final diagnosis was IMT leading to constrictive pericarditis and resultant protein-losing enteropathy with secondary lymphopenia and hypogammaglobulinemia. She was treated initially with prednisone and naproxen, Bactrim prophylaxis, and intravenous immunoglobulin (IVIG) before transitioning to weekly subcutaneous immunoglobulins. Eventually, she was treated with Everolimus after tumor mutational analysis revealed a phosphatase and tensin homolog (PTEN) mutation. She continued a slow steroid taper and naproxen, as well as metoprolol for pericarditis. Colchicine was added for a short time to treat the pericarditis, but was eventually discontinued due to the interaction with Everolimus. Lasix was added for recurrent edema. The mediastinal tumor decreased in size but the constrictive pericarditis remains an issue (Figure 3A–C). Due to the location and extent of the tumor she was continued on medical therapy, however she developed clinical signs of right heart failure and pericardiectomy is being reconsidered.

Figure 3.

Follow-up chest CT scan coronal (A), axial (B), and sagittal (C) views demonstrating the thickened pericardium (red arrows).

Discussion

Constrictive pericarditis can be challenging to diagnose, the presenting complaints can be vague and resemble those of restrictive cardiomyopathy, and the clinical exam is variable, especially early in the disease process. The presenting clinical manifestations in this case included minimal exertional dyspnea, weight gain, edema and expanding abdominal girth due to ascites with additional exam findings demonstrating jugular venous distension, positive Kussmaul sign, pleural effusions, and hepatomegaly. Although not documented in this case, a myriad of other symptoms may be present such as abdominal pain, nausea, chest pain, orthopnea, and exam findings such as pericardial knock, pulsus paradoxus, and pulsatile hepatomegaly. ¹ Constrictive pericarditis is characterized by a scarred, inelastic pericardium and can be the end-result of a number of pericardial disease processes. The etiology of constrictive pericarditis is variable, depends on the population being studied, and is unknown in a majority of cases. In developed countries, prior cardiac surgery or radiation therapy are major causative factors. Less common causes include connective tissue disorders, infectious/ post-infectious (such as tuberculosis) etiologies, and malignancy. ² Other rarer causes of constrictive pericarditis include Myhre syndrome, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, and IgG4-related disease. ^3–5 IgG4-related disease is an immune-mediated fibroinflammatory disorder that can involve nearly any organ and often presents with multiorgan involvement and distinct pathological features. ⁶ In this case, a diagnosis of IMT was made. These are mesenchymal neoplasms which tend to occur in the lung and abdominopelvic region, and rarely occur in the mediastinum. ^{7, 8} IMT may present in a similar manner to and must be differentiated from IgG4-related disease based on pathological features.

Children can develop PLE secondary to constrictive pericarditis, but the reports are scarce. ⁹ PLE results from a number of conditions including inflammatory diseases of the gastrointestinal tract, increased gastrointestinal permeability, and from intestinal losses of lymphatic fluid. ¹⁰ Secondary causes of PLE are commonly cardiac in origin. Examples of this include constrictive pericarditis that occurs as a result of structural heart disease, or after surgical repair of congenital heart disease, such as after the Fontan procedure. ¹¹ The mechanism of the PLE in constrictive pericarditis is likely similar to that of post-Fontan patients that develop PLE. It is hypothesized that elevated systemic venous pressures and, in particular, elevated superior caval venous pressures, lead to impaired lymphatic drainage and increased enteric lymphatic system pressures with subsequent enhanced intestinal loss of lymphatic fluid. However, additional underlying mechanisms have also been proposed. ¹¹ Regardless, in PLE, plasma proteins are lost into the gastrointestinal tract. As a result, patients develop edema, ascites, pleural effusions and hypoproteinemia. The main laboratory findings include hypoalbuminemia in the absence of proteinuria, reduced plasma concentrations of proteins including gamma globulins, and lymphopenia. Serum alpha-1-antitrypsin is a large antienzyme that is excreted into the stool largely intact; the enteric loss parallels that of albumin, the most abundant plasma protein. Increased enteric loss of serum proteins can be approximated by measuring fecal alpha-1-antitrypsin clearance, or by simply measuring a random fecal level of alpha-1-antitrypsin. ^12–15

Hypogammaglobulinemia with lymphopenia in a teenage girl raises the suspicion for primary immune deficiency, specifically, those disorders presenting with a predominant antibody deficiency such as common variable immune deficiency. However, hypogammaglobulinemia may be secondary to a number of conditions that cause either decreased production or increased loss (such as PLE), and these conditions must be excluded in order to diagnose a primary immune deficiency. ¹⁶

Not all patients with hypogammaglobulinemia secondary to PLE will require replacement immunoglobulins. Measuring antibody responses to protein and polysaccharide vaccines allows for the evaluation of T-cell-dependent and T-cell-independent vaccine responses, respectively. Protective responses to tetanus, diphtheria, and pneumococcal antibodies should be obtained and if titers are inadequate, a vaccine challenge with the 23-valent pneumococcal polysaccharide vaccine should be performed to aid in evaluation of humoral immunity. ¹⁷ If specific protective IgG antibody titers to vaccines are preserved, this suggests preserved B cell function. A careful history of infections should be taken. The lack of clinically significant infections should be noted in this case. Unfortunately, our patient was treated with long term steroids and other immunosuppressive agents, and additional functional analyses of the immune system could not be performed.

In addition to the marked hypogammaglobulinemia, studies from patients with intestinal lymphangiectasia demonstrate profound lymphocyte depletion as well as decreased delayed type hypersensitivity and impaired rejection of skin homografts. It was noted, however, that these patients are generally without serious infections. ¹⁸ More recently, immunological studies from patients that have undergone the Fontan procedure and develop PLE demonstrate marked depression in CD4⁺ T cell counts and reversed CD4:CD8 ratio, which supports prior studies that have suggested a preferential loss of the naïve CD4⁺ T cells. ^19–21 Despite these findings, infectious complications were uncommon and opportunistic infections were not observed. ²¹

Immunoglobulin replacement therapy in acquired hypogammaglobulinemia without active infection is controversial. In this case, the patient’s lymphocyte counts (particularly the CD4 T cell count) and IgG level remained low despite treatment of the IMT and the pericardial inflammation, prompting the decision to treat with subcutaneous immunoglobulins. Over 30 years ago, IVIG was used to treat children with PLE that had concomitant recurrent bacterial infections. However, the serum IgG level fell significantly one week after administration. ²² Subcutaneous administration of immunoglobulins allows for a more steady-state level of serum immunoglobulins in patients with PLE. ^{23, 24} Close monitoring of IgG trough levels and dose adjustments are crucial in patients with ongoing gastrointestinal losses. ²⁵

Patients who develop secondary PLE are treated by addressing the underlying disease process. Indeed, pericardiectomy in patients with constrictive pericarditis can lead to marked improvement in PLE, even in patients with severe hypoalbuminemia. ^26–28 The success of pericardiectomy depends on the severity of the right heart failure and the underlying cause. The risks of the surgery itself must be accounted for. ²⁹ Definitive treatment for IMT is surgical resection, but medical management is attempted in cases where surgery is not a viable option. Our patient was treated with an mTOR inhibitor (Everolimus) when mutational analysis of the IMT revealed a PTEN mutation. Interestingly, Everolimus has also been successfully used to treat primary lymphangiectasia, its effect may be related to the impact of this medication on lymphatic endothelial cell growth. ³⁰

Conclusions

In conclusion, children presenting with edema, ascites, and hypoproteinemia should be evaluated for protein-losing enteropathy, despite the lack of concurrent gastrointestinal symptoms. PLE can occur secondary to cardiac etiologies such as constrictive pericarditis, which itself can be secondary to numerous underlying conditions. Hypogammaglobulinemia is a common finding in PLE, but care should be taken to evaluate for a history of infectious complications and to evaluate for protective vaccine responses prior to committing the patient to replacement immunoglobulin therapy. The general practitioner serves a pivotal role in the rapid recognition of this condition and commencement of the initial laboratory and diagnostic imaging studies needed to facilitate the appropriate therapy.

Abbreviations:

IVIG

intravenous immunoglobulin

IMT

Inflammatory myofibroblastic tumor

PLE

protein-losing enteropathy