Fever and Chest Pain - Cardiac Etiologies
The complaint of fever and chest pain warrants a thorough consideration of cardiac causes. Symptoms such as dyspnea on exertion, orthopnea, and palpitations should be actively identified. Knowledge of a recent viral illness, surgical procedure or intravenous drug use may be helpful in identifying an inciting event. Likewise, risk factors such as a prosthetic valve or previous episodes of endocarditis should be identified. The physical examination may yield a wealth of clues such as a new heart murmur, pericardial rub, petechiae, splenomegaly or peripheral stigmata of embolic disease (e.g. Janeway lesions, Osler nodes, splinter hemorrhages). Electrocardiography should be obtained on all patients with chest pain, regardless of the presence or absence of fever, and may show evidence of myocardial involvement. While most laboratory studies are nonspecific, cardiac biomarkers may reveal active, ongoing myocardial injury. Blood cultures are indispensable to the isolation of causative microorganisms. Echocardiography may be an important diagnostic tool for guiding treatment and the potential need for surgical intervention. Fever and chest pain may occasionally present together in the patient with acute coronary syndrome or aortic dissection. While this would be unusual, the astute physician should always consider these catastrophic cardiac diseases in any patient who presents with chest pain. However, the bulk of the evaluation should focus on the three classic cardiovascular causes of fever and chest pain: pericarditis, myocarditis and infective endocarditis (see Table 2).
Table 2: Cardiac Etiologies of Chest Pain and Fever
Risk factors Presentation Management Pericarditis Idiopathic
Sharp, retrosternal pain
Pericardial friction rub
Signs of tamponade
± Cardiac biomarkers
ECG: diffuse ST elevations
Variable, Asymptomatic à Chest pain à Failure
± S3 or S4
+ Cardiac biomarkers if acute ECG: ± ST-T changes
Diuretics, ACE-inhibitors, Beta-blockers
± inotropes, assist device or heart transplant
Intravenous drug use
ECG: ± conduction abnormalities
Acute inflammation of the pericardium is known as pericarditis and accounts for approximately 5% of all causes of chest pain presenting to the ED. Acute pericarditis may be complicated by the development of a pericardial effusion that, if significant enough to compress the cardiac chambers, may produce cardiac tamponade. More than 80% of cases of acute pericarditis are idiopathic or presumably viral in origin. Among many others, commonly implicated viruses have included the enteroviruses (Coxsackie A & B), adenovirus, Epstein Barr virus (EBV), cytomegalovirus (CMV), and parvovirus B19. Given the self-limited nature of most cases of acute pericarditis, a definitive etiology is often not pursued. Less common infectious causes of acute pericarditis may include bacterial, tuberculosis and fungal infection. These are more likely to be seen in the immunocompromised patient. Autoimmune diseases such as SLE and rheumatoid arthritis represent some of the most common noninfectious causes of pericarditis. Uremia, trauma and cardiac surgery are other well-known noninfectious causes. While primary tumors of the pericardium are rare, metastatic breast and lung cancer as well as lymphoma may spread to the pericardium, producing large and often hemorrhagic effusions. Pericarditis may occur within days after an acute transmural myocardial infarction as a result of contact with inflamed and healing myocardium. It may also occur weeks to months later as an autoimmune-mediated response known as Dressler’s syndrome.
Acute pericarditis classically presents with sharp, retrosternal chest pain that is sudden in onset. It typically worsens with deep inspiration, with coughing, or when the patient is supine. It may be improved with sitting upright and leaning forward. The pain may radiate to one or both trapezius ridges, as both phrenic nerves traverse the anterior pericardium to innervate these muscle groups. Pain may also be referred to the neck, shoulders, or arms, making it difficult to differentiate from the pain of pulmonary embolism and myocardial ischemia or infarction. Patients frequently present with fever, malaise and myalgias in association with their chest pain, reminiscent of a viral prodrome, though the former may be absent in the elderly. A pericardial friction rub is highly specific for pericarditis and can be heard at one time or another in as many as 85% of cases of acute pericarditis. It is described as a high-pitched raspy sound best auscultated at the left sternal border with the patient leaning forward on end expiration.
A pericardial friction rub may be heard throughout the respiratory cycle and persists even when the patient is asked to hold their breath, distinguishing it from a pleural rub. The commonly held belief that a pericardial rub results from the chafing of the two inflamed pericardial layers against one another is likely inaccurate, as a rub may be heard even in the presence of a large effusion separating the layers. Tachycardia, hypotension, jugular venous distension and pulsus paradoxus (a decrease in systolic blood pressure of more than 10 mmHg with inspiration) are suggestive of cardiac tamponade. While low-grade fevers are common, a temperature above 38º C is concerning for purulent bacterial pericarditis.
Electrocardiography is often diagnostic for acute pericarditis. While the pericardium itself is electrically inert, epicardial inflammation from an overlying pericarditis progresses through four classic stages. Stage 1 is marked by diffuse, upward concave ST-segment elevations with reciprocal ST-segment depressions in aVR and V1. PR-segment depression may be seen in most leads with the exception of aVR and V1. These changes are seen within the first hours of initial symptoms and may last up to two weeks before returning to baseline, defined as stage 2. As inflammation and injury progresses into the second and third weeks, stage 3 is characterized by diffuse T-wave inversions. Stage 4 marks the resolution of these T-wave inversions, though some may persist indefinitely. While these four stages are seen less frequently now as a result of early therapy, the presence of diffuse ST-segment elevations seen in stage 1 still remains a cardinal marker of acute pericarditis. Low voltage QRS complexes may hint at the presence of a pericardial effusion.
EKG demonstrating typical changes of pericarditis. Stage 1 is marked by diffuse, upward concave ST-segment elevations with reciprocal ST-segment depressions in aVR and V1.
Laboratory evaluation in the patient with acute pericarditis may reveal an elevated white blood cell count, erythrocyte sedimentation rate and serum C-reactive protein. Renal function should be assessed to exclude uremia as an etiology. In selected cases, tuberculin skin testing, antinuclear antibody and rheumatoid factor may aid diagnosis. Serum biomarkers such as creatine kinase (CK-MB) and serum cardiac troponin I (cTnI) may be elevated in at least a third of the cases of acute pericarditis and likely reflect superficial myocardial inflammation and injury. Significant serum cTnI elevations are only seen in the presence of ST-segment elevation on ECG in pericarditis. Unlike in acute coronary syndrome, elevated serum cTnI is not associated with a poorer prognosis in acute pericarditis. However, persistent serum cTnI elevation for more than two weeks may be suggestive of myocarditis, which does carry a poorer prognosis.
Echocardiography is both appropriate for and frequently obtained in the context of acute pericarditis to evaluate for the presence of a pericardial effusion . While the discovery of an effusion may help solidify a diagnosis of pericarditis, the absence of one cannot rule it out. In most instances, routine pericardiocentesis has been demonstrated to have very low diagnostic yield. A pericardial effusion with evidence of tamponade however is a clear indication to proceed to pericardiocentesis or surgical drainage. Likewise, an effusion suspected to be secondary to purulent, tuberculosis or neoplastic pericarditis warrants sampling of the pericardial fluid to obtain a definitive diagnosis through bacterial culture, fluid cytology and, if indicated, polymerase chain reaction (PCR) for tubercle bacilli. In cases of ineffective pericardiocentesis, tamponade recurs, or the course of pericarditis is prolonged, pericardial biopsy may be considered.
24 year old with ESRD and shortness of breath. Evaluation revealed a massive pericardial effusion requiring surgical drainage.
Most cases of acute idiopathic or viral pericarditis respond well to supportive care and symptom relief with non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethacin and ibuprophen. Aspirin is preferred in patients with recent myocardial infarction or coronary artery disease, while indomethacin should be avoided because of its adverse impact on coronary blood flow. Colchicine has recently been shown to be a safe and effective adjunct to conventional NSAID therapy in controlling pain and decreasing the risk of recurrent pericarditis. Systemic steroids should be reserved for recurrent pericarditis unresponsive to NSAIDs and colchicine or cases of acute pericarditis linked to an underlying autoimmune or connective tissue disease. Use of steroids in acute pericarditis has been associated with increased likelihood of recurrence.
Myocarditis can be either an acute or chronic inflammatory process of the myocardium, triggering focal myocyte necrosis and fibrotic deposition. It is a commonly recognized cause of sudden unexplained cardiac death in young adults. Depending on the degree of injury, myocarditis may be complicated by dilated cardiomyopathy and left ventricular dysfunction. In the United States, viral infections remain the most frequently identified cause of acute myocarditis. As in pericarditis, enteroviruses (Coxsackie B), adenovirus, EBV, CMV and parvovirus B19 in addition to other viruses including influenza A, herpes simplex virus 1 (HSV-1), human herpesvirus 6 (HHV-6) and the human immunodeficiency virus (HIV) have been implicated in this disease process. Bacterial and fungal infections make up a small minority of the remaining infectious causes. Worldwide, protozoal infection with Trypanosoma cruzi, better known as Chagas’ disease, remains a predominant cause of acute myocarditis and dilated cardiomyopathy. Noninfectious causes include toxins such as anthracyclines (doxorubicin) and cocaine as well as hypersensitivity reactions to tricyclic antidepressants, antibiotics (penicillins, sulfonamides) and antipsychotics (clozapine). Sarcoidosis, scleroderma and SLE have also been implicated. Recently, an association has been drawn between smallpox vaccination and increased incidence of myocarditis in military personnel after widespread inoculations.
The clinical presentation of myocarditis is highly variable. While some patients may be completely asymptomatic, others present acutely ill with fever, chest pain, myalgias, arthralgias, exertional dypnea, palpitations and syncope. In many cases, these symptoms may be preceded by a nonspecific viral prodrome of respiratory and gastrointestinal complaints as well as fever, malaise and headache. Some may present with symptoms consistent with acutely decompensated heart failure and hemodynamic collapse, suggesting progression to cardiomyopathy. Auscultation of the chest might reveal a third or fourth heart sound, a new heart murmur, or evidence of pulmonary congestion, all suggestive of heart failure. A drug rash might point towards a hypersensitivity reaction as a possible etiology.
Electrocardiographic changes frequently seen in myocarditis are consistent with acute injury or ischemia and may in many instances be mistaken for acute myocardial infarction. ST-segment elevation and depression, T-wave inversions and pathologic Q-waves have all been seen in cases of biopsy-proven myocarditis where myocardial infarction was initially suspected and coronary angiography was subsequently normal. In many of these cases, patients were not only young but had a dearth of coronary risk factors and had yet presented with symptomatology and electrocardiographic changes concerning for myocardial ischemia or infarct. Ventricular arrhythmias and heart block may also manifest with myocarditis and cardiomyopathy.
The serum cardiac biomarker, cardiac troponin I, is reliably elevated in patients with myocarditis early on (within one month) after initial onset of symptoms and is indicative of acute myocyte necrosis. Considered superior to CK-MB, CTnI may however have returned to normal in patients presenting several months after initial myocardial injury.
Echocardiography may demonstrate either global ventricular dysfunction or regional wall motion abnormalities consistent with a nonspecific cardiomyopathy in patients with signs of heart failure. For patients without these signs, the echocardiogram may be normal. Evolving noninvasive diagnostic strategies such as antimyosin scintigraphy and gadolinium-enhanced cardiac magnetic resonance imaging are increasingly useful tools for differentiating acute myocarditis from myocardial infarction.
Definitive diagnosis of myocarditis rests with endomyocardial biopsy. Previously considered to have low sensitivity as a result of the need for multiple biopsies to obtain a diagnostic result, the yield for biopsy has significantly improved with the advent of PCR for specific viral genomes. Immunohistochemical assays for the anti-heart autoantibodies have also helped identify cases of autoimmune-mediated myocarditis.
The treatment of acute myocarditis remains supportive. Hemodynamic optimization of heart failure is paramount and should proceed with diuretics to lower ventricular filling pressures, angiotensin-converting enzyme inhibitors to reduce vascular resistance, and eventually a beta blocker. In severe cases, intravenous inotropes, implantation of a ventricular assist device or even cardiac transplantation may become necessary. The role of immunosuppressive therapy has not borne out and remains limited to myocarditis clearly attributable to systemic autoimmune disease. Antiviral agents such as interferon beta are under evaluation at this time and have shown initial promise.
In the last thirty years, the etiology of infective endocarditis has shifted with the eradication of rheumatic fever in much of the industrialized world. While valvular diseases such as mitral valve prolapse and mitral regurgitation remain key risk factors for infective endocarditis, skin flora, primarily staphylococci, now surpass oral streptococci (viridans group streptococci) as the leading cause of infective endocarditis. In particular, Staphylococcus aureus has emerged as the predominant organism responsible for most new cases of infective endocarditis worldwide, with a significant share attributable to methicillin-resistant S. aureus. Together with Enterococcus spp., staphylococci and streptococci comprise more than 80% of all causes of infective endocarditis. Intravenous drug users may also be at heightened risk for infection with Pseudomonas aeruginosa and fungi. In addition to the typical organisms, elderly persons with degenerative valvular disease may be more prone to infection with Streptococcus bovis, which has been associated with gastrointestinal malignancy. Patients with prosthetic valves may develop infective endocarditis from coagulase-negative staphylococci and gram-negative bacteria of the HACEK group. Patients with nosocomial or healthcare-related infections from invasive surgical procedures, infected hardware and long-term hemodialysis represent a growing population at risk for staphylococcal and enterococcal endocarditis as well.
Fever remains the most common clinical presentation of infective endocarditis. While the fever may be remitting in nature, it may exceed 40º C in cases of acute infective endocarditis and can be accompanied by chills and rigor. It may also be absent in the elderly and in patients with congestive heart failure, chronic renal failure, liver disease or infective endocarditis caused by less virulent organisms. Systemic symptoms such as myalgias, fatigue, malaise, night sweats, anorexia, nausea and vomiting may be seen and often predominate in subacute presentations. Up to 10% of patients with infective endocarditis may report chest pain. Heart murmurs may be heard in as much as 85% of patients. In many instances, these murmurs are preexisting. However, a new, altered or changing murmur has a strong predictive value for infective endocarditis when taken in context with established bacteremia. Peripheral embolic manifestations can be nonspecific for infective endocarditis and are increasingly infrequent due to earlier diagnosis and treatment. Classic Janeway lesions are nontender, erythematous vesicles or pustules seen on the palms and soles while Osler’s nodes are painful, subcutaneous nodules found on the pulp of the digits. Splinter hemorrhages may be seen in the nail beds of the fingers and toes. Petechiae may be seen in the conjuctiva and buccal mucosa. Pale, oval lesions surrounded by hemorrhage, known as Roth’s spots, may be noted on examination of the retina. Splenomegaly may be evident in delayed presentation or late diagnosis of endocarditis.
Blood cultures remain the cornerstone of diagnosis for infective endocarditis. Three or more sets of blood cultures should be drawn at least one hour apart (fresh stick each time preferable) prior to initiation of antibiotics. Cultures may be drawn regardless of whether the patient is febrile. Blood cultures may be negative in about 15% of cases of infective endocarditis. While this may related to prior administration of antibiotics, fastidious organisms such as Coxiella burnetti (Q fever), HACEK organisms, and fungi may require additional serologic or molecular techniques to identify. Laboratory evaluation is otherwise nonspecific. Inflammatory markers such as the erythrocyte sedimentation rate and C-reactive protein may be elevated. Leukocytosis and a normocytic anemia may or may not be present, depending on the severity of the presentation. Urinalysis may reveal proteinuria, hematuria or casts suggestive of an immune complex glomerulonephritis that may be seen with infective endocarditis.
All patients with suspected infected endocarditis should have an electrocardiogram performed. New atrio-ventricular, fascicular or bundle-branch block may signify perivalvular invasion and potential abscess formation. Aortic valve involvement is most common. Echocardiography should be employed to evaluate for intracardiac masses or vegetations , valve competence and myocardial abscess. It is reasonable to perform a transthoracic echocardiogram (TTE) first if the patient is clinically stable or if there is low clinical suspicion for infective endocarditis. Transesophageal echocardiography (TEE) should be considered if the patient is a difficult imaging candidate for TTE or there is moderate to high clinic suspicion for infective endocarditis. A negative TTE in the setting of deteriorating clinical course should prompt TEE in light of its higher sensitivity for identifying vegetations and abscesses. False-negative results in both TTE and TEE may occur if vegetations are small or have embolized. Large, mobile vegetations (> 10 mm), particularly on the anterior mitral leaflet, have the greatest potential to embolize and have been linked with increased mortality.
Arrow demonstrating vegetation on the heart valve diagnostic of endocarditis.
Remarkably, the four elements characterizing infective endocarditis first described by Sir William Osler in 1885 remain relatively unchanged: persistent bacteremia with an appropriate infectious microorganism, predisposing factors, active endomyocardial involvement and vascular phenomena. Given the protean nature of its presentation, multiple criteria have evolved throughout the years to aid with accurate diagnosis. The widely accepted Duke criteria provide a framework for diagnosis of infective endocarditis that has a sensitivity of roughly 80% (see Table 3).
In 2005, the American Heart Association published its most recent guidelines regarding antibiotic therapy for infective endocarditis, which has since been endorsed by the Infectious Disease Society of America (IDSA). Therapeutic recommendations are available in the endocarditis chapter of Empiric.
Table 3: Modified Duke Criteria for the Diagnosis of Infective Endocarditis
Blood culture positive for IE
Typical microorganisms for IE isolated from 2 separate blood cultures (Staphylococcus aureus, Viridans streptococci, Streptococcus bovis, HACEK group, or community-acquired enterococci without a primary focus)
Micoorganisms consistent with IE from persistently positive blood cultures
Single positive blood culture for Coxiella burnetti or phase I IgG antibody titer >1:800
Evidence of endocardial involvement
Echocardiogram positive for IE (oscillating intracardiac mass on a valve or supporting structures, paravalvular abscess or new dehiscence of a prosthetic valve)
New valvular regurgitation (worsening or change in pre-existing murmur is not sufficient)
Predisposing factors for IE (e.g. valvular disease, injection drug use) Fever > 38º C
Vascular phenomena (major arterial emboli, septic pulmonary emboli, mycotic aneurysm,
intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions)
Immunologic phenomena (glomerulonephritis, Osler’s nodes, Roth’s spots and rheumatoid factor)
Microbiological evidence (positive blood culture not meeting major criteria or serologic
evidence of active infection with an organism consistent with IE)
Definite infective endocarditis
2 major criteria
1 major criteria and 3 minor criteria
5 minor criteria
Possible infective endocarditis
1 major criteria and 1 minor criteria
3 minor criteria