Prompt diagnosis and therapy are keys to reducing mortality Extrapulmonary tuberculosis, part 5: Pericardial involvement key words: Tuberculosis, Pericarditis, Pericardial effusion

Tuberculosis that involves the pericardium is considered one of the more severe extrapulmonary manifestations of the disease. In the August 2005 issue of The Journal of Respiratory Diseases, we reviewed less severe extrapulmonary manifestations of tuberculosis (pleural and lymph node disease). Other, more severe forms of extrapulmonary involvement were reviewed in the September, November, and December 2005 issues. In this article, we focus on the presentation, diagnosis, and treatment of tuberculous pericarditis. We will also briefly review the epidemiology of this disease.

EPIDEMIOLOGY

The pericardium is more commonly affected by tuberculosis than is the cardiovascular system. In countries in which the prevalence of tuberculosis is high, it is an important cause of pericardial disease. In the United States, pericardial tuberculosis is more prevalent in the black population than in the white population.¹ It is also common in patients with diabetes, chronic renal failure, and HIV/AIDS--as are other forms of tuberculosis.^1,2 Most patients are between 20 and 50 years of age on initial presentation.

Typically, pericardial involvement is secondary to tuberculosis elsewhere in the body. Between 1% and 8% of patients with pulmonary tuberculosis have pericardial disease as well.^3,4 However, tuberculous pericarditis can be the sole manifestation of tuberculosis. This possibly reflects direct seeding from infected mediastinal nodes, which are not detected on routine chest radiographs. In fact, the lymphatic drainage of the pericardium spares the hilar lymph nodes, which are relatively easily detected on chest radiographs.

The causative pathogen in tuberculous pericarditis is usually Mycobacterium tuberculosis. Atypical mycobacteria are uncommon in patients without HIV infection.¹

PATHOPHYSIOLOGY

There are 4 stages of tuberculous pericardial involvement: dry, effusive, absorptive, and constrictive.⁵ These stages may occur sequentially, but more frequently there is some overlap. In addition, in long-standing cases, inflammation and fibrosis may eventually affect the myocardium, resulting in myocardial atrophy.^6,7

The earliest stage of tuberculous pericarditis appears to be a primary hypersensitivity response to tuberculoprotein(s). In the effusive stage, the amount of pericardial fluid may vary from 10 mL to 3 L. Pyopericardium, or gross pus in the pericardium, has also been described. Constrictive pericarditis results from the formation of epithelioid granuloma with Langhans-type giant cells--with or without caseation necrosis and later fibrosis.

CLINICAL PRESENTATION

The clinical features of tuberculous pericarditis are variable and depend on the duration of the disease. Tuberculous involvement of the pericardium may be acute or chronic. Only 20% of patients with tuberculous pericarditis have an acute presentation, although acute disease is more common in countries in which the prevalence of tuberculosis is high.

Acute involvement usually manifests as pericarditis. The patient presents with severe retrosternal pain and, occasionally, left-sided precordial pain that radiates to the back. The pain is accentuated by deep breathing, coughing, change in posture, and swallowing. Classically, the pain is relieved by leaning forward in sitting position and is aggravated by lying supine. The pain is associated with fever.

On auscultation, there is a pericardial rub, which is characteristically described as a high-pitched superficial scratching or grating sound best elicited when firm pressure is applied on the diaphragm in the left side precordial region during expiration.

More often, patients present with some form of chronic pericarditis, such as chronic pericardial effusion, cardiac tamponade, chronic constrictive pericarditis, or effusive-constrictive pericarditis. Usually, chronic pericarditis represents the typical progression of the disease, which eventually occurs in most patients when diagnosis and treatment are delayed. However, some patients with pericardial tuberculosis present initially with sequelae of chronic constrictive pericarditis without having gone through an initial stage of pericardial effusion.

In chronic tuberculous pericarditis, constitutional symptoms typically seen on presentation include fever, anorexia, malaise, weight loss, and nonspecific chest pain. Dry cough with dyspnea may also be present. On examination, there may be a pericardial rub and ankle edema. The chest radiograph may show cardiomegaly.

Effusive disease

Patients with pericardial effusion often present initially with cardiac tamponade. However, the pathophysiological manifestation of effusive disease depends on the rate of fluid accumulation. Small amounts of pericardial fluid that accumulate rapidly may result in cardiac tamponade, while large effusions that accumulate over weeks may exist without tamponade.

Constrictive disease

Patients who have chronic constrictive pericarditis present with features of systemic as well as pulmonary venous congestion; they frequently have exertional dyspnea, orthopnea, ankle edema, and ascites. Important clinical signs of constrictive disease evident on examination include a prominent y descent in jugular venous pressure (JVP) and a Kussmaul sign (with an increase in JVP on inspiration). Approximately one third of patients have pulsus paradoxus. Importantly, there is no cardiomegaly.

A pericardial knock may be heard on auscultation, but there usually are no murmurs. Detection of third and fourth heart sounds and significant mitral or tricuspid regurgitation, together with the presence of cardiomegaly and severe pulmonary hypertension, favors a diagnosis of cardiomyopathy rather than a diagnosis of chronic constrictive pericarditis.^8,9

On abdominal examination, the presence of ascites is disproportionate to the edema (ascites praecox) and congestive splenomegaly is evident. The abdominal findings in patients with constrictive pericarditis resemble those in patients with cirrhosis. However, an elevated JVP distinguishes patients in the former group from those with cirrhosis, in whom the JVP is not elevated. Patients with chronic constrictive tuberculous pericarditis also manifest signs of a protein-losing enteropathy, which results in hypoalbuminemia. Untreated chronic constrictive pericarditis can give rise to cardiac cirrhosis with associated myocardial atrophy. Patients with chronic constrictive pericarditis have a very poor prognosis after pericardiectomy.^10,11

Effusive-constrictive disease

Patients with effusive-constrictive pericarditis present with clinical features that are the result of both pericardial fluid accumulation and pericardial constriction. The features of effusion in such patients can include cardiomegaly, pedal edema, and elevated JVP with a blunt y descent. However, even after the pericardial effusion is drained, JVP typically remains elevated with a prominent y descent.

DIAGNOSIS

The differential diagnosis of pericardial disease includes a number of conditions. Among these conditions are idiopathic or viral pericarditis; infectious pericarditis; and pericarditis caused by neoplasia, collagen-vascular disorders, or uremia. In addition, pericardial disease must be distinguished from restrictive cardiomyopathy.

The differentiation of tuberculous pericarditis from idiopathic or viral pericarditis may present a diagnostic dilemma. Pericardial tuberculosis should be considered in any patient with acute pericarditis.

For patients who are HIV-positive, the development of pericardial disease may be a manifestation of either their primary HIV infection or a secondary infection with M tuberculosis, to which such patients are predisposed.

The epidemiological setting plays a very important role in raising suspicion of a tuberculous origin. However, other studies are needed to make a definitive diagnosis--or even to arrive at a working presumptive diagnosis.

Standard laboratory and imaging studies

The results of standard investigations are of some help in the diagnosis of pericardial tuberculosis. Mild anemia and an elevated erythrocyte sedimentation rate are seen in patients with tuberculous pericarditis.

An ECG may show nonspecific ST-T changes. The ECG changes found with acute pericarditis--namely, concave ST-segment elevation--are observed in fewer than 10% of cases; the 4 conventional ECG stages observed in acute viral pericarditis have not been described for tuberculosis.¹ The chest radiographic findings, however, are normal in most patients.

Results of a Mantoux test are usually positive in patients with pericardial tuberculosis.^1,7,8 A false-negative tuberculin test result may occur in patients with HIV infection or renal failure. False-positive results may occur in patients infected with nontuberculous mycobacteria and in patients who have received BCG vaccinations. It is important to appreciate that in countries in which the prevalence of tuberculosis is high, the tuberculin test results must be interpreted in the context of the clinical history and/or findings consistent with a diagnosis of tuberculosis.

Examination of pericardial fluid and tissue

The examination of pericardial fluid plays an important role in the evaluation of patients with suspected pericardial tuberculosis. On gross examination, the fluid in affected patients is straw-colored or serosanguineous; it may also be hemorrhagic. On biochemical and cytological examination, it is exudative and, during the first 2 weeks of infection, may contain polymorphonuclear leukocytes.

Later, the pericardial fluid is pre- dominantly lymphocytic with a high protein content. The fluid usually does not demonstrate M tuberculosis on a Ziehl-Neelsen-stained smear, although newer staining techniques, such as fluorochrome staining, are more sensitive for mycobacteria.¹² An elevated level of adenosine deaminase in pericardial fluid is a good marker for pericardial tuberculosis.¹³

The culture of mycobacteria in a Lowenstein-Jensen medium is a time-consuming process: it takes 6 to 8 weeks for the results to be reported, making this study of little value as far as immediate management decisions are concerned. Newer culture methods yield relatively quicker results.¹⁴

The presence of granulomas or caseation necrosis in the pericardium confirms the diagnosis of tuberculosis.¹⁵ Obtaining pericardial tissue for histological examination is difficult; recently, however, percutaneous pericardial biopsy performed with a bioptome in patients with pericardial effusion has been described.

Specialized imaging studies

Several noninvasive modalities can be very helpful in the diagnosis of tuberculous pericarditis. Echocardiography is very sensitive and specific for the diagnosis of pericardial effusion and cardiac tamponade. Echocardiographic evidence of tamponade, which shows the collapse of the right atrial or right ventricular free wall in diastole, may be obtained before the patient manifests clinical signs of tamponade.

It has been suggested that echocardiographic surveillance be used for patients with HIV infection because moderate or severe effusions--which can produce life-threatening tamponade--are usually clinically unsuspected in such patients.¹⁶ Occasionally, fibrinous exudates can also be indirectly identified on echocardiography, where they appear as strands. However, an echocardiogram cannot accurately show pericardial thickening in patients with constrictive pericarditis.

CT and MRI are extremely sensitive and specific for the diagnosis of chronic constrictive pericarditis and are very useful for distinguishing constrictive pericarditis from restrictive cardiomyopathy in difficult cases. A pericardial thickness of more than 3 mm on a CT scan suggests a thickened pericardium (Figure). Indirect signs of constrictive pericarditis on a CT scan include:

•An enlarged superior and inferior vena cava.

•Narrowing of the atrioventricular groove.

•Pericardial calcification.

•A tube-like configuration of the ventricles.

The presence of mediastinal lymphadenopathy with rim enhancement/central necrosis on CT or MRI may also favor a tuberculous etiology. MRI is generally superior to CT in delineating the radiological abnormalities of tuberculous pericarditis. The only exception is that pericardial calcification is better appreciated on a CT scan than on an MRI scan. In addition to the role of CT in the diagnosis of tuberculous pericarditis, the identification of focal constriction helps in surgical planning, and the assessment of myocardial atrophy has prognostic value.^17,18

Cardiac catheterization is the gold standard for confirming the diagnosis of chronic constrictive pericarditis and for differentiating it from restrictive cardiomyopathy. The right and left atrial pressures as well as the right and left ventricular end-diastolic pressures are within 5 mm in patients with cardiac tamponade associated with tuberculosis, in contrast to the large pressure difference seen in restrictive cardiomyopathy. Moreover, x descent (systolic descent) is observed on right atrial pressure tracings in cardiac tamponade. In patients with chronic constrictive pericarditis, the right atrial tracing shows a prominent y descent (diastolic descent) with a dip-plateau wave in ventricular pressure.¹⁹

When all other investigations are inconclusive for constrictive pericarditis and the clinical suspicion is high, rapid infusion of 1 L of saline in 6 minutes can reveal the catheterization abnormalities typical of chronic constrictive pericarditis.

TREATMENT

Earlier diagnosis and effective antituberculosis therapy have reduced mortality in patients with tuberculous pericarditis from 40% to less than 15%.²⁰ In addition, the pericardial effusions resolve and chronic constrictive pericarditis does not develop in nearly half of the patients who receive prompt and effective antituberculosis treatment. In patients with no other obvious cause of pericardial effusion, empirical antituberculosis therapy should be initiated, especially in areas in which the prevalence of tuberculosis is high or if the patient has emigrated from these regions.

Pharmacotherapy

The recommended pharmacological regimen for pericardial tuberculosis consists of rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambutol for the first 2 months and rifampicin and isoniazid for the subsequent 4 months. Patients who are HIV-positive and those with atypical mycobacterial infection may need therapy of longer duration.

Adjunctive corticosteroid therapy has been shown to reduce mortality and the need for repeated pericardiocentesis.^21,22 In patients with tuberculous pericardial disease, corticosteroid therapy reduces the incidence of fibrosis and consequent long-term sequelae.

Pericardiocentesis

Pericardiocentesis has diagnostic as well as therapeutic value in patients with pericardial tuberculosis. In the absence of any contraindication, the examination of fluid obtained through pericardiocentesis helps narrow down the differential diagnosis of pericardial effusions.

In patients with cardiac tamponade resulting from tuberculous pericardial effusion, pericardiocentesis can be lifesaving. When patients have rapidly refilling effusions, drainage via a pigtail catheter in situ may be helpful; however, the high protein content of the fluid often results in catheter blockage. For life-threatening tamponade that is not amenable to pericardiocentesis or that develops in patients with recurrent effusion, open surgical drainage may be required.²¹

Pericardiectomy

This procedure is indicated for all patients with constrictive pericarditis once a plane of cleavage has clearly formed, which usually occurs after 2 to 4 weeks of antituberculosis therapy. Pericardiectomy is performed through a lateral thoracotomy or median approach, with an aim of resecting as much of the pericardium as possible without cardiopulmonary bypass.

For patients with extensive calcification, cardiopulmonary bypass is required. The left side pericardium should be released first. If the right side pericardium is removed first, the lungs will "flood" and pulmonary edema is likely to develop.^8,21 Pericardiectomy is associated with a mortality rate of about 10%. In patients with long-standing symptoms and myocardial atrophy, the mortality rate is higher.

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