Tuberculous Pericarditis: A Review

Introduction

Tuberculosis (TB) is the commonest cause of pericardial disease in the regions where TB is endemic, and is associated with high mortality and long term disability even with antituberculosis treatment (ATT) [1, 2, 3, 4, 5, 6]. A definite diagnosis requires demonstration of tubercle bacilli in the pericardial fluid or on the histopathological section of the pericardium [6]. However, in conditions where a definitive diagnosis is difficult to make, radio-imaging or evidence of tuberculosis in any other organ establishes the diagnosis [6]. To illustrate, we describe a patient who presented with prolonged fever and was subsequently diagnosed as pericardial TB. He was successfully treated with ATT and adjuvant steroid therapy.

An illustrative case

A 29-year-old male presented with history of fever for one month. Fever was low grade, maximum documented up to 102°F, associated with evening rise of temperature, chills, night sweats and involuntary weight loss. On admission, patient was hemodynamically stable. Cardiac auscultation found muffed heart sounds. Other systemic examination was normal. Laboratory investigation showed the peripheral leukocyte count 5.1x109/l and the erythrocyte sedimentation rate of 54 mm per hour. A chest radiograph revealed slightly enlarged cardiac silhouette and blunting of bilateral costo-phrenic angles. A 2D echocardiography showed moderate pericardial effusion. Subsequently, a contrast enhanced computed tomography of chest revealed pericardium wall enhancement with pericardial effusion and bilateral pleural effusion (Figure 1). Pleural fluid examination showed an exudative effusion with elevated adenosine deaminase (ADA) (52 U/L; reference <40), and no malignant cells. An HIV serology was negative. Urine analysis did not show any proteinuria. Ultrasound imaging of the abdomen was normal.

With a presumptive diagnosis of pericardial TB, patient was started on four drugs ATT along with prednisolone. At one month follow up, patient was asymptomatic and a repeat 2D echocardiography showed significant resolution of the pleuro-pericardial effusion.

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Epidemiology

TB pericarditis is caused by Mycobacterium tuberculosis and is found in 1-2% of the cases of pulmonary tuberculosis [7]. Sub-Saharan Africa and the part of Asia carry largest number of TB pericarditis patients. In these endemic regions, TB is responsible for majority of clinically significant pericardial effusion (50- 70% in non-HIV infected cases and 90% in HIV-infected cases) [8, 9]. In Africa, the disease has a high association with HIV; whereas in Asia, it is usually seen in non-HIV, immunocompetent cases. In Europe and North America, TB pericarditis is rare and is usually considered as a disease of immigrant population from TB endemic areas [2, 10, 11].

It can occur at any age, and males are affected more common than females [1]. Case fatality rates are 3 times higher in HIV infected cases than in non-HIV cases [4].

Pathogenesis

Pericardial involvement results due either to direct extension from adjacent mediastinal lymph nodes or to hematogenous spread. TB pericarditis has 4 pathologic stages [5]:

a) Fibrinous exudation with polymorphonuclear leukocytosis, relatively abundant tubercle bacilli, and early granuloma formation with loose organization of macrophages and T cells; b) Serosanguinous effusion with a predominantly lymphocytic exudate; c) Absorptive stage - effusion absorption with organization of granulomatous caseation and pericardial thickening caused by fibrin, collagenosis, and ultimately, fibrosis; and d) Constrictive scarring - fibrosis or fibrocalcification of the visceral and parietal pericardium is causing diastolic filling defect and constrictive pericarditis.

HIV positive patients with low CD4 counts usually have less granulomatous inflammation, significant pericardial effusion and lower incidence of constrictive scarring stage as compared to non-HIV patients [12].

Clinical Features

Pericardial TB usually occurs in three major forms [1, 5]

Diagnosis

The diagnosis of pericardial TB is not always straight forward; and mainly depends on echocardiography, chest imaging (usually CT or MRI), pericardial fluid analysis and evidence of TB elsewhere in the body. An electrocardiogram (ECG) and a chest radiograph are abnormal in almost all cases of TB pericardial effusion. ECG usually shows nonspecific ST segment and T wave abnormalities. The PR segment deviation and the ST segment elevation characteristic of acute pericarditis is uncommon [15, 16]. Low voltage QRS complexes suggest a large pericardial effusion. Electrical alternans, a pathognomonic for cardiac tamponade, occurs very rarely.

On chest radiograph, pericardial effusion appears as an enlarged and rounded cardiac silhouette, and may produce a characteristic “money bag” or “water bottle” appearance of the heart. Echocardiography is the first line investigation for all suspected cases of pericardial disease [6]. A significant amount of pericardial effusion with fibrinous material of “porridge like” appearance suggests exudative effusion, but is not specific for TB [6].

Radio-imaging (CT or MRI) may enable diagnosis at an early stage by showing the nature and amount of effusion, the pericardial thickening (>3 mm) and other findings suggestive of TB [2, 17]. Accompanying active pulmonary parenchymal lesions occur in almost one third cases. The pleural effusion is seen in almost half of the cases [7, 10, 18]. The characteristic mediastinal or tracheobronchial lymphadenopathy i.e. >10 mm size, central necrosis, conglomerated, sparing of hilar lymph nodes favors the diagnosis of TB. Therefore, microscopy and culture of the sputum or the broncho-alveolar lavage fluid, pleural fluid analysis, trans-bronchial needle aspiration from mediastinal nodes may be very helpful in establishing the diagnosis.

A diagnostic pericardiocentesis under echocardiographic guidance is recommended, whenever possible. In 80% cases, tuberculous pericardial effusion is hemorrhagic. The effusion is typically a protein rich exudate with predominance of lymphocytes or monocytes and a raised ADA level [6, 11]. Pericardial ADA cutoff reference range of 30-60 IU/L has almost 90% sensitivity and 70% specificity [8, 9]. Pericardial lysozyme and interferon-γ levels have also shown diagnostic utility, however data are limited and are not widespread available due to technical problems [9, 19].

Demonstration of tubercle bacilli in the pericardial fluid by direct smear microscopy, culture or polymerase chain reaction (PCR) establishes a definite diagnosis. Microscopy with Ziehl-Neelson staining has a very low diagnostic yield. Culture of pericardial fluid using Lowenstein-Jensen or double strength Kirchner medium grows Mycobacterium tuberculosis in up to two third of cases; however results may not be available for weeks, which limits the clinical utility. Quantitative PCR testing for nucleic acids of M. tuberculosis (Xpert MTB/RIF) in pericardial fluid has lower sensitivity than culture; but can detect pericardial TB in less than 2 hours and simultaneously detects a gene responsible for resistance to rifampicin, rpoB [6, 11].

Diagnostic pericardial biopsy is rarely done for diagnosis of pericardial TB in endemic regions and is not required before starting empirical treatment. In non endemic areas, pericardial biopsy must be considered before considering empirical ATT. Presence of granulomatous inflammation with or without caseous necrosis or acid fast bacilli on histopathology confirms the diagnosis in up to two third of cases; But, it needs expertization in the procedure and in advanced cases, may show only fibrosis. Tuberculin skin test (Mantoux) is not helpful in the diagnosis of pericardial TB in adults [6].

For endemic areas, when pericardiocentesis or pericardial biopsy is not possible, the European Society of Cardiology 2015 guidelines proposed a diagnostic score of >6 to make the presumptive diagnosis of pericardial TB, based on the following criteria: fever (1), night sweats (1), weight loss (2), globulin level >40 g/L (3), and peripheral leukocyte count <10x109/L(3) [6]. In this condition, ATT should be started immediately [6].

Treatment

Treatment regimen of ATT for pericardial TB is generally the same as that for pulmonary TB (for both HIV infected and non-HIV cases). Initially, an intensive phase consisting of four drugs, isoniazid (5 mg/kg/day), rifampin (10 mg/kg/day), pyrazinamide (15-30 mg/kg/day), and ethambutol (15-25 mg/kg/day) is given for 2 months and is followed by a continuation phase of isoniazid and rifampin (same dosing) for 4 months [6].

Adjunctive corticosteroid therapy has long been used to decrease the pericardial inflammation which results in effusion and constriction. However, the benefit of steroid treatment in terms of mortality and constrictive pericarditis is controversial. In a study from South Africa, 143 patients with TB pericarditis and constrictive physiology were randomized to receive placebo or prednisolone for first 11 weeks of ATT [21]. Rapid clinical recovery and reduced requirement for pericardiectomy were noted in adjuvant steroid group. However, a recent large randomized trial (the IMPI study) involving 1400 patients showed that adjunctive prednisolone did not improve the combined all cause death outcomes and was associated with increased incidence of HIV associated malignancies [22]. But, the incidences of constrictive pericarditis and hospitalization were both significantly decreased. Of the patients enrolled in this trial, more than 70% of the enrollees lack a microbiological diagnosis, and two thirds were HIV infected and most of them were not on antiretroviral treatment. A supplemental analysis including HIV-negative patients showed a small mortality benefit.

In conclusion, adjunctive corticosteroids may be used in patients with tuberculous pericarditis without HIV infection. In HIV-infected patients, it should not be routinely administered [6]. The suggested regimen is prednisolone 60 mg daily for 4 weeks, followed by 30 mg daily for 4 weeks, 15 mg daily for 2 weeks, and 5 mg daily for 1 week [21].

Pericardiectomy is required in the setting of persistent constrictive pericarditis despite 1-2 months of ATT.

Chronic constrictive pericarditis requires extended pericardiectomy [6].

Conclusion

Pericardial TB is the commonest cause of significant pericardial effusion, cardiac tamponade, effusive- constrictive pericarditis, and CCP in sub-Saharan Africa and parts of Asia, and carries high mortality and morbidity. In these TB endemic areas, a definite diagnosis of TB pericarditis may not be established in most cases. ATT with or without adjuvant steroid therapy should be started promptly. Prolonged fever with pericardial effusion and thickened pericardium in a patient from TB endemic area is TB pericarditis until proven otherwise.