This woman presented with several months of constitutional and respiratory symptomatology, but recently an acute exacerbation of her respiratory symptoms and pleuritic chest pain had forced her to visit the ER. These complaints primarily indicate a pulmonary and/or pericardial involvement. The clinical hallmarks of pericarditis are pleuritic chest pain and a fricition rub, and both were present in this patient. Pericarditis (PC) refers to the inflammation of the pericardium, which covers the heart surface and the proximal part of the great vessels. The pericardium is a 1.0 mm thick membrane of dense collagen lined by a single layer of mesothelial cells. It consists of two layers, the inner or visceral continues with the outer myocardial tissue, and the outer or parietal attaches to the sternum, diaphragm and adventitia of great vessels. Between these two layers there is a virtual space that normally contains about 15 to 50 mL of fluid (filtered plasma), which serves as a lubricant to the heart surfaces. Normally, the pericardial tissue is thin and semitransparent, but with inflammation it reacts by exuding fibrin, fluid, polymorphonuclear leukocytes and/or mononuclear cells. Acute pericarditis may resolve without sequelae. However, if there is proliferation of fibrous tissue, neovascularization and scarring, the end result will be a loss of elasticity (compliance), restriction of heart filling and constrictive pericarditis. The pleuritic pain is classically described as a retrosternal sharp, stabbing, knife-like quality pain, which worsens with inspiration, lying down and swallowing, and improves sitting up and leaning forward. The reasons for the exacerbation and ease of the pain have to do with the position of the heart relative to the rest of the mediastinal structures, which impact on how the pericardium is pulled and stretched, or relaxed. The radiation of the pain relates to the visceral reflections of the pericardium, and is mostly to the shoulder and neck (trapezius muscle). The pain is common in acute infectious pericarditis, whereas insidious accumulation of fluid in the pericardial sac (usually due to non-infectious etiologies) may go unnoticed. The ability of the pericardium to accommodate fluid subacutely or chronically depends on the ratio between production, reabsorption and pericardial distensibility properties. The latter, are a function of the pericardial connective tissue components, which allow for progressive remodeling. With slow accumulation of fluid, or progressive cardiac hypertrophy, the volume of the pericardial sac increases by slippage of the collagen fibers in the parietal layer. With extreme increases of volume, disruption of the collagen fibers can occur. If the increase in pericardial fluid develops too rapidly for the stiff pericardium to respond, tamponade may ensue (see below).
The other critical finding on physical examination was the presence of a friction rub. This variably coarse, scratchy, velcro-like sound, is best heard over the left sternal border, and when the patient is not breathing. It has three components: the atrial systole, the ventricular systole and the rapid ventricular filling. The ventricular systolic component is the loudest and most commonly appreciated. The sound is made when the two roughened and inflamed pericardial layers slide against each other during the cardiac cycle. A disappearing pericardial rub initially heard in a patient who continues to deteriorate clinically, is reason for concern. It implies that the pericardial fluid is increasing and the layers are not in contact at all. The continued accumulation of fluid in the pericardial sac results in interference with heart chamber filling, which leads to increased intracardiac pressures, decreased venous return and eventually a decrease in stroke volume and cardiac output (if untreated, these will eventually lead to death). All these pathophysiological events translate in to the classic Beck's triad of hypotension, jugular venous distension, and low intensity or muffled heart sounds, characteristic of cardiac tamponade. Normally, during inspiration, there is a decrease in intrathoracic pressure, which increases venous return. When the heart pressures are higher, the pulmonary venous blood is prevented from easily entering the left atrium. This causes a decrease in arterial pulse pressure and pulsus paradoxus becomes evident. The latter, is a decrease in systolic blood pressure by more than 10 mm Hg (rarely > 15) during inspiration, because of the decreased venous return. The progressive restriction of ventricular filling triggers a series of compensatory mechanisms similar to those observed in congestive heart failure (CHF). These include an increase in the heart rate, since the stroke volume becomes fixed (there is tachycardia with an abbreviated filling period); peripheral vasoconstriction; and the secretion of humoral or hormonal and renal factors (due to restriction of atrial distensibility there is no significant secretion of the atrial natriuretic factor). In our patient this was evident in the signs and symptoms resembling CHF (e.g. progressive dyspnea, hypoxemia, weakness, passive liver congestion).
Her clinical history had two epidemiologic facts that were extremely important to the overall approach to her illness. First, her immune competence was in question because of the significant risk factors of past intravenous drug use, her spouse being HIV-infected, and the presence of oral thrush. Thus, the index of suspicion for HIV-infection was extremely high as her HIV status was unknown. Secondly, her daughter, who was HIV-infected, had been diagnosed with pulmonary tuberculosis (TB) that did not require hospitalization, and was convalescing in the patient's house. All these elements make our patient a special host, not only because of her possible increased exposure to TB, but also due to a probable dysfunctional immune system which would render her abnormally susceptible to TB (HIV-infection increases both primary TB infection and reactivation). In addition to HIV altering the natural history and epidemiology of TB, there appears to be an equally important influence of TB on the course of HIV-infection. TB can cause CD4 lymphopenia, which reverses after treatment; and TB-related immune activation may increase HIV replication as well. Even more startling is the observation that TB may accelerate the course of HIV disease. Patients dually infected with HIV and TB have worse outcomes (development of opportunistic infections and death) than their counterparts without TB. From a global perspective, TB may be one of the most common HIV-related opportunistic infections.
The cause of death in this patient was a combination of disseminated tuberculous infection, predominantly in the heart (pericardium) and lungs, with a likely underlying acquired immunodeficiency. The pericardial findings demonstrated acute severe fibrino-purulent pericarditis, with adhesions and thickening of the pericardium. The hallmark of her immunodeficiency was the almost complete absence of granuloma formation. This observation suggests that the normal initial mechanisms to contain mycobacterial infection were not in place, and were probably due to cellular immune defects coupled with a lack of immune activation which coordinates the cellular and tissue interaction. The TB pericarditis is rare but a serious complication of tuberculosis. It can lead, in about 30-50% of the cases, to constricitive pericarditis (even if treated), with a particularly higher prevalence in immunosuppressed individuals (especially those with HIV infection). Mycobacterium tuberculosis (MTB) reaches the pericardium via lymphatic or contiguous spread from a lung or a lymph node (peritracheal, peribronchial or mediastinal) focus; or hematogenously from a distant site. Initial stage involves fibrin deposition and multiple granulomas formation with abundant viable MTB. This is followed by a slow accumulation of a serous or sero-sanguineous pericardial effusion, usually without symptoms. Once the effusion is absorbed, further granuloma formation occurs and the pericardium thickens with dense fibrous tissue and collagen deposits. The final stage occurs when the pericardial space is obliterated by dense adhesions, the parietal pericardium thickens and most granulomas are replaced by fibrous tissue and calcification. All these changes result in a markedly constructive pericardium, where small increments of fluid will produce significant increases in intracardiac pressures, leading to decreased cardiac output. Other causes of pericarditis that must be included in the differential diagnosis are the idiopathic and viral (usually benign, self-limited), purulent pericarditis (fatal if untreated), and the non-infectious group which includes collagen-vascular disease, drugs, post-trauma, malignancies, and uremia.
The laboratory and other diagnostic tests for pericarditis may be nonspecific and may reflect the nature of the underlying disease. In general, there may be mild CK-MB elevation (our patient had a modest CK and transaminase increase), which suggests subepicardial myocarditis (contiguous spread). In this case the local invasion to a third of the myocardial thickness reflects the total inability to contain and control the TB infection. Again this is a manifestation of her severely compromised cellular immune response. In addition, abnormal liver function tests may indicate chronic congestion, as seen in cases of CHF. Although, there usually are no systolic abnormalities (except with coexistent myocardial lesions), the constricition of the pericardium resembles the clinical features of CHF (there is diminished functional heart volume, with decreased stroke volume and low cardiac output). The chest x ray may be normal, since only pericardial volumes of above 200-250 mL may present as cardiomegaly. Therefore, a normal cardiac silhouette on CXR does not exclude acute or small pericardial effusions. Although the pericardium does not produce electrical activity, the ECG is abnormal in about 90% of the cases of pericarditis, probably reflecting subepicardial inflammation. The usual changes involve diffuse ST elevation, and after recovery, T wave abnormalities may persist. In addition, the typical low voltage complexes result from the damping of electrical activity due to the pericardial effusion. The echocardiogram may be the most important test to perform in someone suspected of having a pericardial effusion. It not only can accurately detect small volumes, but it can also estimate the pericardial thickness and overall cardiac function. Furthermore, it may even be used to do an ultrasound guided pericardiocentesis both for therapeutic and diagnostic (fluid examination) purposes.
The autopsy findings in this woman were specific for the significant disseminated TB infection, and evident cardiovascular failure. By the time of her presentation, both the TB and her immunodeficiency were at such an advanced stage, that it would have been extremely difficult to reverse the effects of any of them. Her death, under these circumstances was unavoidable.
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