The Constricted Heart: A 31-Year-Old Man with a Case of Constrictive Tuberculous Pericarditis

Introduction

Constrictive pericarditis is a rare cause of diastolic heart failure with an incidence of less than 0.1% per year [1,2]. It occurs due to chronic inflammation of the pericardium secondary to various etiologies [1]. Clinical presentation ranges from an asymptomatic state, with incidental findings on cardiac imaging, to end-stage heart failure [2]. Chronic inflammation and the resultant fibrotic process cause adherence of the parietal and visceral pericardial layers, which makes them rigid and obliterates the pericardial space [1]. The initial presentation of constrictive pericarditis is often chronic in nature and associated with symptoms of congestion, such as weight gain and peripheral edema, and decreased perfusion indicated by dyspnea, particularly on exertion, and worsening fatigue [3]. Examination findings include jugular venous distension, and, in some cases, pulsus paradoxus, a phenomenon in which there is a greater than a 10-mmHg drop in systolic blood pressure during the inspiration phase of the respiratory cycle [3].

In a study of 67 patients with tuberculous constrictive pericarditis, pulsus paradoxus was found in 48% of patients [4]. Patients can also have volume overload signs on examination, such as ascites and lower-extremity edema [3]. Outside the United States and globally, tuberculosis is the most common cause of constrictive pericarditis [3,5]. Within the United States, idiopathic and post-viral etiologies are more common and make up 40% to 60% of cases [3]. Other causes include post-pericardiectomy syndromes, post-cardiac surgery complications, and post-mediastinal radiation sequelae [3]. Constrictive pericarditis can also present as a cardiac manifestation of connective tissue disorders and autoimmune conditions [3].

Tuberculosis (TB) diagnostic tests have varied detection rates, and acid-fast bacilli (AFB) presence in pericardial fluid or case-ating granulomas on pericardial biopsy is the most sensitive way to diagnose TB-induced pericardial disease [6]. AFB sputum samples are often negative, without pulmonary involvement [7,8]. TB pericardial disease can range from exudative pericardial fluid accumulation, resulting in tamponade-like physiology, to constrictive fibrotic pericardial scarring [6,9]. Diagnostic markers, such as adenosine deaminase and interferon-gamma, in pleural and pericardial fluid support a diagnosis of TB mediastinal disease [4].

Current guidelines for the diagnosis of TB are based on suspicion for latent infection, versus pulmonary or extra-pulmonary TB disease, and have differing strengths of recommendation and quality of evidence [10]. When testing for latent TB in individuals with increased risk factors (immigration from a high burden country, high risk congregate setting, recent exposure to an active case), interferon-γ release assay testing is preferred, especially when the individual is greater than 5 years old, with low or intermediate disease progression risk, and with suspicion justifying latent TB infection testing [10]. When testing for active TB disease, AFB smear microscopy is strongly recommended in patients with suspicion for pulmonary TB [10]. Per the guidelines, it is important to note that false-negative AFB results are not sufficient to rule out disease, and testing of 3 sputum specimens is recommended to improve sensitivity of the AFB testing, given common variation in sputum sample quality [10]. While sputum induction is recommended as the initial sampling method for pulmonary TB testing, flexible bronchoscopy with sampling in patients with poor sputum expectoration or negative AFB is recommended [10]. Guidelines also support measuring adenosine deaminase level testing, and AFB smear microscopy of bodily specimens collected in patients with suspected pulmonary or extrapulmonary TB [10]. Regarding extrapulmonary TB, nucleic acid amplification testing and histological examination are recommended to be performed on specimens collected from suspected extrapulmonary TB sites [10].

In constrictive pericarditis, hemodynamic measurements on heart catheterization has served as a criterion standard but is invasive [11]. Transthoracic echocardiogram with Doppler is recommended for diagnostic testing by professional cardiology organizations, such as the American College of Cardiology and European Society of Cardiology [3]. Key findings consistent with a diagnosis of constrictive pericarditis include increased pericardial thickness, inferior vena cava dilation without collapse on inspiration, and exaggerated septal bounce [3]. On Doppler imaging, hemodynamic changes include abnormalities during early diastolic filling of the ventricles and increased flow velocities in diastolic filling through the tricuspid valve during inspiration [3]. Definite management for constrictive pericarditis is pericardiectomy, with a broad range of mortality and success rates based on risk factors, disease advancement, and the presence of myocardial involvement [3]. In addition, symptomatic management with diuretics can be used to reduce congestion and/or as palliation for non-surgical candidates [3].

Several case reports have detailed the pathophysiology and presentation of constrictive pericarditis of tuberculous etiology, which lends to the knowledge base of the multisystemic manifestations of TB and differences in presentations based on risk factors and comorbidities [12–15]. In this case report, we describe a 31-year-old man with pertinent risk factors, new onset cardiac symptoms, constitutional symptoms with positive multi-modal cardiac imaging findings, and infectious diagnostic testing leading to a diagnosis of tuberculous constrictive pericarditis.

Case Report

A 31-year-old man presented to his primary care physician for routine immigration screening. Focused pulmonary examination was remarkable for crackles and rhonchi, and there was evidence of cardiomegaly and focal consolidation on chest X-ray. Azithromycin was started due to concern for an atypical pneumonia, but his symptoms did not improve, and subsequent computed tomography (CT) of the chest revealed moderatesized bilateral pleural effusions and a moderate-to-large pericardial effusion. He subsequently presented to the Emergency Department on the recommendation of his primary care physician for further workup. He reported a 2-week history of fever, chills, fatigue, chest tightness, dyspnea, and orthopnea. On evaluation, he was afebrile, normotensive, and tachycardic, with a heart rate of 110 beats per min, and had an oxygen saturation of 95% on room air. Pertinent examination findings included jugular venous distension, decreased basilar breath sounds bilaterally, muffled heart sounds, a pericardial friction rub, and bilateral lower extremity edema. He had no significant past medical, surgical, or family history of cardiac disease, malignancy, or autoimmune disease. Of note, he emigrated from Rwanda 2 years prior. There was no history of alcohol, tobacco, or drug use.

Laboratory investigations were notable for elevated brain natriuretic peptide (603 pg/mL), C-reactive protein (6.98 mg/dL), and D-dimer (13 000 ng/mL), and a low white blood cell count of 3.6 K/uL. High-sensitivity troponin levels were normal. Electrocardiogram demonstrated sinus tachycardia, with a rate of 111 beats per min and an “S1Q3T3” pattern (Figure 1). Infectious workup included a negative HIV antigen-antibody screen and negative blood and urine cultures. The AFB stain was negative on 3 separate sputum samples, and bronchoscopy with bronchoalveolar lavage specimen was also negative for AFB, leading to low suspicion for pulmonary tuberculosis. CT of the abdomen and pelvis was negative for an intraabdominal pathology, and no lymphadenopathy was noted. Further neurology workup was deferred, as he had no focal neurological deficits, and his symptoms were primarily cardiac in nature. A QuantiFERON-TB Gold assay was positive.

Transthoracic echocardiogram showed a mildly reduced left ventricular (LV) ejection fraction of 45%, a mildly dilated right ventricle with mildly decreased function, pericardial thickening, moderate pleural effusions, and findings concerning for constrictive physiology, with exaggerated septal respiratory bounce and fixed lateral wall of the left ventricle (Figure 2A–2F, Video 1). On transthoracic echocardiogram Doppler, the inferior vena cava and hepatic veins were dilated, with diastolic flow reversal in the hepatic vein (Figure 3B, 3C). Variations in mitral inflow velocities were also noted in the inspiratory and expiratory phases of the respiratory cycle (Figure 3A, 3D). Repeat chest CT revealed a large circumferential pericardial effusion, with diffuse pericardial thickening, right ventricular (RV) dilation, interventricular septal flattening, contrast reflux into the inferior vena cava, large bilateral pleural effusions, and an acute left lower lobe segmental pulmonary embolism with infarction. He underwent diagnostic and therapeutic thoracocentesis, which was exudative by Light’s criteria with a serum lactate dehydrogenase level of 207 U/L, serum protein level of 5.9 g/dL, pleural fluid lactate dehydrogenase level of 107 U/L, and pleural fluid protein level of 3.3 g/dL.

Subsequent right heart catheterization (Table 1) showed elevated right-sided pressures and evidence of concordance and discordance on simultaneous LV-RV tracings (Figure 4). He had angiographically normal coronary arteries, with an elevated LV end diastolic pressure of 18 mmHg. Cardiac magnetic resonance imaging demonstrated circumferential pericardial thickening (up to 5 mm) and bilateral pleural effusions (Figure 5A–5C). There was no myocardial involvement, and he did not have any evidence of myocarditis. Findings on cardiac magnetic resonance imaging and right heart catheterization in the context of a positive TB QuantiFERON Gold assay led to the presumptive diagnosis of tuberculous pericarditis, without pulmonary involvement.

Anticoagulation with intravenous heparin for pulmonary embolism and diuresis with intravenous furosemide was initiated for volume overload symptoms. Given the presumptive diagnosis of tuberculous pericarditis and positive QuantiFERON-TB Gold assay, rifampicin, isoniazid, pyrazinamide, and ethambutol (RIPE) therapy was initiated. Given his medical stability, the initial treatment plan was medical therapy and evaluation for pericardiectomy as an outpatient. However, his clinical condition deteriorated, resulting in readmission 3 weeks later. He underwent a pericardiectomy and developed severe hypotension on anesthesia induction requiring aggressive resuscitation. Preoperative transesophageal echocardiogram demonstrated a LV ejection fraction of 60%, severely depressed RV systolic function, moderate mitral regurgitation, severe tricuspid regurgitation, and pericardial constriction. Intraoperative findings were notable for a thickened and extremely adherent pericardium (Figure 6A) and large pleural effusions. Resected pericardial tissue and exudative pleural fluid cultures were negative on AFB stain, but the pleural fluid adenosine deaminase level was elevated (21 U/L; reference <9.2 U/L). Pericardial histopathology examination revealed necrotizing caseating granulomas and Langerhans multinucleated cells in the background of lymphocytes and histiocytes, consistent with TB infection (Figure 6B–6D). Gram stain and AFB stain of the pericardial specimen was negative for any visible organisms (Figure 6E, 6F).

He remained hemodynamically unstable throughout surgery, due to severe RV dysfunction. His postoperative course was complicated by cardiogenic shock requiring vasopressors, inotropes, and an intra-aortic balloon pump. On postoperative day 2, he had a pulseless electrical activity arrest after self-extubation. Return of spontaneous circulation was achieved after 7 min of cardiopulmonary resuscitation. He underwent mediastinal hematoma evacuation and right lung decortication on postoperative day 15 for a large right mediastinal hematoma. His clinical course improved with recovery of RV systolic function, and he was discharged on postoperative day 25 on RIPE therapy, furosemide, and warfarin. He was seen in cardiothoracic surgery and cardiology clinics 2 weeks later and was doing well on a 6-month course of RIPE therapy and close monitoring by the local health department. The patient was compliant with RIPE therapy and had no reported adverse effects from his treatment. A repeat chest CT scan showed complete resolution of mediastinal hematoma and pleural effusions.

Discussion

This case report depicts the need to have a high index of suspicion for constrictive pericarditis of tuberculous etiology in patients with cardiac symptoms, risk factors, and positive diagnostic modalities. It is important to note that although the patient had 3 negative sputum cultures and a negative bronchoalveolar lavage AFB staining, he had a positive QuantiFERON-TB Gold test and necrotizing granulomas on histopathology, supporting the caveat in the recent guidelines that a negative AFB stain does not necessarily correlate with the absence of an active TB infection [10]. In addition, this diagnosis was confirmed by the presence of elevated adenosine deaminase and case-ating granulomas on histopathology, lending credence to the need to interrogate fluid and tissue specimens. In an article by Isiguzo et al, definitive criteria for the diagnosis of tuberculous pericarditis are the presence of either tubercle bacilli or caseating granuloma on histological examination of the pericardium [6], the latter of which our patient had, as depicted in the images shown.

Extensive case reports have detailed the multisystemic manifestations of TB pericarditis and different presentations in individuals with risk factors, such as the patient in this case report. John et al present a similar presentation of an otherwise healthy migrant to the United States who, in contrast to our patient, presented with cardiogenic shock with echocardiogram concerning for cardiac tamponade physiology, lending credence to the wide range of clinical presentations of tuberculous pericarditis, such as acute pericarditis, effusion-associated, constrictive, and tamponade-like physiology [12]. Likewise, depicting the devasting outcomes that can occur with late presentations of TB constrictive pericarditis, Krisnanda et al reported a case of late diffuse calcified tuberculous constrictive pericarditis [13]. This patient, in contrast to our patient, had a prior diagnosis of pulmonary TB with pericardial complications at the time that were believed to have resolved following a 12-month anti-TB treatment regimen [13]. The case study highlights the same patient 15 years later with volume overload symptoms and extensive pericardial calcification on imaging, with classic echocardiogram findings for constrictive pericarditis [13]. Not unlike our case, the operative course was complicated with hemodynamic instability; however, this patient died from multi-organ failure due to extensive mediastinal disease [13]. Our patient, although requiring an extensive postoperative course of 25 days, was otherwise healthy, without prior mediastinal TB disease, and survived with no further complications after pericardiectomy and RIPE therapy.

Likewise, the article by Lima et al presents a similar case of an immigrant with no past medical conditions living in an endemic area with cardiac symptoms, positive cardiac diagnostic testing, and histopathology positive for necrotizing granulomas [14]. Another case report by Yousif et al depicts a patient with prior TB lymphadenitis who was found to have cardiac symptoms, requiring diuretics for symptoms palliation, with right heart catheterization and echocardiogram right heart catheterization and echo consistent with constrictive pericarditis. In this case, the patient recovered after pericardiectomy [15]. It is important to note that while adenosine deaminase was elevated past the upper limit of normal, an ideal cut-off value for adenosine deaminase remains debatable, with some requiring a level ≥40 U/L for a probable tuberculous pericarditis diagnosis [16]. Despite this, the presence of granulomas in pericardial tissue, clinical and radiological evidence, predominance of lymphocytes, and positive response to anti-TB therapy are characteristic of tuberculous pericarditis [16].

With a pathophysiology lens, constrictive pericarditis occurs due to the obliteration of the pericardial space by a thickened rigid pericardium, causing a disconnect between the intrathoracic and intracardiac spaces during respiration [5,11]. A characteristic feature of constriction is the equalization of the right- and left-sided cardiac filling pressures, due to impaired accommodation of total blood volume during diastole [1,11]. The systolic function of the heart is often unimpaired, but there is global diastolic dysfunction and impaired ventricular filling. Although right-sided heart failure predominates initially, left-sided heart failure follows. Enhanced ventricular interdependence is another constrictive physiology phenomenon [17]. During inspiration, intrathoracic pressure decreases. This reduced intrathoracic pressure does not transmit to the intracardiac space but is transmitted to the pulmonary veins outside the pericardium [5]. This disconnect reduces the pressure gradient and subsequent LV filling [5]. The intraventricular septum, due to decreased LV chamber filling, favors the right heart, and shifts into the left cavity, causing exaggerated ventricular interdependence [5]. Concurrently, increased venous return during inspiration increases RV filling [5]. The RV with no space to expand due to the rigid pericardium, shifts the intraventricular septum further into the LV, impairing stroke volume and cardiac output [5]. This presents as pulsus paradoxus, which is present in almost half of the patients with constrictive pericarditis [4].

Cardiac catheterization with biventricular pressure monitoring is the best modality to make this diagnosis [17]. Other diagnostic modalities are listed below (Table 2). Initial treatment of constrictive pericarditis is focused on treating life-threatening emergencies, and the definite therapy is pericardiectomy [1]. The patient’s functional state, disease complications, and other comorbidities affect preoperative risk assessment and outcomes [5]. Since constrictive pericarditis is a progressive disease, early intervention is key in preventing progression to end-stage heart failure [1]. For TB-induced pericarditis, treatment with RIPE therapy is also imperative in case management [9]. The prognosis and long-term survival of constrictive pericarditis vary based on etiology, with post-radiation pericarditis leading to worse survival rates relative to other etiologies [5]. Tuberculous pericarditis has been stated in some studies to have a mortality rate as high as 40% because cardiac involvement is often a poor prognostic sign [4]. The advent of effective tuberculosis therapy has decreased mortality rates from 80–90% to 8–17% in HIV-negative patients, such as our patient [7]. Pericardiectomy has a perioperative mortality as high as 7%, and success is based on preoperative risk assessment, baseline comorbidity profile, and functional status [5].

Conclusions

In summary, we highlight a multidisciplinary care pathway to the prompt diagnosis and treatment of a young individual with pertinent risk factors, relevant travel history, signs, and symptoms with supporting diagnostic modalities for tuberculous constrictive pericarditis. We depict the effectiveness of RIPE therapy and pericardiectomy and its association with good outcomes with early treatment. We also highlight key physical examination findings and findings on cardiac diagnostic modalities that support diagnosis of constrictive pericarditis, alongside guidelines for tuberculosis diagnosis, especially in the diagnosis of extrapulmonary mediastinal TB.