12th March 2024

Cardiac Involvement in Infectious Disease

Infective Endocarditis

Background

Infective endocarditis (IE) defines an infection involving the innermost lining of the heart- the endocardium. It includes infections affecting the cardiac valves, the chordae tendineae and the mural endocardium. The incidence of IE is rising and is estimated at 3-10 cases per 100,000 per year. Despite recent advancements relating to diagnosis and management of IE, prognosis remains poor, with an inpatient mortality of approximately 22%. Risk factors for IE include the following:

• Previous history of IE
• Presence of prosthetic heart valves
• Specific types of congenital heart disease
• Presence of cardiac devices or intravascular catheters
• History of intravenous drug use

Frequent aetiological agents involved in IE are listed below:

• Streptococci viridans
• Staphylococcus aureus
• Enterococci 
• Coagulase-negative staphylococci
• Brucella species
• Coxiella burnetii
• Culture-negative Haemophilus species, Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens and Kingella species (HACEK group of organisms)

Clinical manifestations

The majority of patients will present with nonspecific symptoms, including fever, rigors, lethargy and weight loss. Other signs associated with IE include:

• A new or changing murmur: this can be found in up to 85% of patients
• Splinter haemorrhages: septic emboli from the heart valve become lodged in small capillaries and are visible beneath the nail bed
• Roth’s spots: pale lesions on the retina surrounded by a rim of haemorrhage usually diagnosed by fundoscopy. 
• Acute renal failure: occurs in up to 30% of patients and is an independent risk factor for inpatient mortality.
• Janeway lesions: non-tender haemorrhagic macules present over the soles and palms caused by septic microemboli.
• Osler’s nodes: tender nodules found on the tips of fingers and toes due to a local immunological response caused by immune complex deposition within the skin. 
• Embolic sequelae: due to the migration of septic thrombi from the heart. In left-sided IE, the brain and spleen are the most common site of embolism, whereas right-sided IE can lead to pulmonary emboli. Ischemic strokes are a common complication of cerebral emboli. 

Diagnosis

Blood tests may show raised inflammatory markers (CRP and ESR) with leukocytosis. While these tests are not specific for IE, they can reflect the severity of IE-induced sepsis. Blood cultures are essential for identifying the organisms involved, and three sets of blood cultures from different venipuncture sites should be taken before initiating empirical antibiotic therapy. 

Transthoracic echocardiography (TTE) can look for evidence of IE in the form of valvular vegetations, abscess formation or prosthetic valve dehiscence. Due to the high virulence associated with Staphylococcus aureus, positive blood cultures with this organism is an indication for performing a TTE to exclude IE.

Where TTE is negative or inconclusive, but the suspicion for IE remains high, transoesophageal echocardiography  (TOE) offers superior views and is advised. The latter is also recommended in suspected cases of IE in patients with prosthetic valves. 

Other imaging for diagnosis of cardiac involvement includes 18F-FDG PET/CT and Cardiac CT.

Modified Duke’s Criteria

The modified Duke’s criteria uses echocardiographic findings, blood culture results and clinical signs to risk stratify the likelihood of IE. For diagnosis of IE, the following must be fulfilled:

• 2 major criteria OR
• 1 major and 3 minor criteria OR
• 5 minor criteria

Major criteria: Microbiological:

• Growth of typical IE organisms from two separate blood cultures (Streptococcus viridans, Strep. gallolyticus (formerly S . bovis), Staphylococcus aureus, HACEK group, Community-acquired enterococci
• Microorganisms typical for IE from persistently positive blood cultures (two positive blood cultures drawn 12h apart or all three or majority of four positive blood cultures with first and last samples drawn more than 1 hour apart)
• Single blood culture or serology positive for Coxiella burnetii

Major criteria: Imaging:

• TTE/TOE showing vegetations/abscess/pseudoaneurysm/intracardiac fistula/valve perforation/new dehiscence of prosthetic valve/
• 18F-FDG PET/CT showing abnormal activity around prosthetic valve implantation site (if valve was implanted more than three months ago)
• Paravalvular lesions on Cardiac CT 

Minor criteria:

• Risk factors for IE (IVDU, structural cardiac pathology)
• Fever 
• Immunological phenomena (Osler’s nodes, Roth’s spots, Glomerulonephritis)
• Vascular phenomena
• Positive blood cultures failing to meet major criteria.

Management

Native valve endocarditis is typically treated with antibiotic duration of 2-6 weeks. Prosthetic valve endocarditis requires treatment for longer than 6 weeks (see Table 1).

Table 1: Treatment and duration of antibiotics in IE. Adapted from 2015 ESC Guidelines for the management of infective endocarditis

Approximately half of patients with IE will eventually require surgery as a result of complications. Indications for cardiac surgery include:

• Heart Failure: aortic/mitral valve IE resulting in severe regurgitation with subsequent cardiogenic shock or pulmonary congestion. 
• Perivalvular extension: this can lead to formation of abscesses resulting in atrio-ventricular blocks and acute coronary syndromes.
• Resistant infection: fever and blood cultures remaining positive 7-10 days after antibiotic initiation
• Fungal aetiology: IE caused by these organisms have a low chance of being successfully treated with antibiotics alone
• Prevention of septic emboli: size of vegetations are associated with an increased risk of embolisation to the brain and lungs. Aortic or mitral vegetations >10mm on echocardiography are an indication for surgical escalation. 

As per the ESC 2018 update, antibiotic prophylaxis is currently recommended only for those patients with the highest risk of IE undergoing invasive dental operations. Those deemed to be at highest risk of I.E include one of three groups:

• Patients with a prosthetic valve or have had cardiac valve repair with prosthetic material
• Patients with previous IE
• Patients with untreated cyanotic heart disease

Antibiotics currently licensed for prophylaxis include either Amoxicillin or Ampicillin. Clindamycin can be used in cases of Penicillin allergy.

References

• 2015 ESC Guidelines for the Management of Infective Endocarditis. Available at https://academic.oup.com/eurheartj/article/36/44/3075/2293384 
• BMJ Best Practice Infective Endocarditis. Available at https://bestpractice.bmj.com/topics/en-gb/3000215
• Khan et al 2016. International Guideline Changes and the Incidence of Infective Endocarditis: a Systematic Review. Available at https://pubmed.ncbi.nlm.nih.gov/27621836/
• How to achieve IE prophylaxis 2018. Available at: https://www.escardio.org/Journals/E-Journal-of-Cardiology-Practice/Volume-16/vol16no33

Myocarditis

Background 

Myocarditis is defined as evidence of inflammation within the myocardium that is not of ischaemic origin. As a result of the clinical manifestations of myocarditis being so variable, the true incidence is impossible to determine. However, studies have reported that myocarditis is present in up to 9% of routine postmortem examinations. Prognosis is variable and dependent on the underlying cause of myocarditis. The majority of patients with viral myocarditis are asymptomatic and improve spontaneously, whilst other patients may present in acute decompensated cardiac failure requiring intensive care support. 

Aetiology 

Causes of myocarditis include:

• Viral: coxsackie A/B most common, adenovirus, influenza, EBV, SARS-CoV-2, polio virus, CMV, HHV-6, 
• Infections: bacterial (Brucella, Mycoplasma, Haemophilus influenzae, Mycobacteria) and fungal (Aspergillus, Candida)
• Protozoan: Trypanosoma cruzi (causing Chagas disease), Toxoplasmosis 
• Drugs:/Toxins: cyclophosphamide, anthracyclines, ethanol, cocaine
• Autoimmune conditions: inflammatory bowel disease, connective tissue diseases, sarcoidosis
• Vaccinations: smallpox vaccine, SARS-COV-2 vaccine

Pathology

Viruses induce myocardial damage in a variety of ways. Enteroviral replication causes cytopathic damage, triggering both cellular and humoral immune responses. The resultant myocardial necrosis releases self-antigens, which are detected by the immune system. These self-antigens have the capability to induce auto-immune reactions within the myocardial tissue, which further exacerbates myocarditis.

Clinical manifestations

The presentation of myocarditis can vary, ranging from asymptomatic to signs and symptoms of heart failure. Signs and symptoms include:

• Chest pain, which is often sharp in nature
• Shortness of breath
• Palpitations secondary to electrical disturbance causing arrhythmias 
• Fever
• Heart failure: peripheral oedema, orthopnoea, PND 

Given myocarditis is often due to a viral illness, patients may report a preceding viral or respiratory illness and present with viral complaints, including rash, joint pains, anorexia, vomiting and diarrhoea. 

Diagnosis

Blood tests typically show raised inflammatory markers (ESR and CRP). Cardiac enzymes troponin and CK-MB are also raised, reflecting myocardial injury. Of note, normal troponin values do not exclude myocarditis. 

Common ECG findings in myocarditis include ST segment elevation and T wave inversion. Conduction abnormalities such as AV blocks will be evident on the ECG. Prolongation of the QRS is an independent risk factor for mortality. 

Where myocarditis is suspected, patients should have an echocardiogram with subsequent serial echocardiograms as follow-up. Typical findings include regional wall motion abnormalities, depressed right or left ventricular ejection fraction, pericardial effusion or global ventricular dysfunction. 

Coronary angiogram is recommended in all patients to exclude coronary artery disease as a cause of the clinical picture. Cardiovascular magnetic resonance (CMR) imaging is useful in providing a non-invasive study which can aid in the diagnosis of myocarditis. Typical features diagnostic of myocarditis include increased oedema and late gadolinium enhancement.  

The gold standard for definitive diagnosis of myocarditis is endomyocardial biopsy (EMB). This has the added value that it can help identify the aetiology of myocarditis. Samples from EMB are analysed by RT-PCR amplification of the viral genomes and immunohistochemistry. 

Management 

Treatment is symptomatic with hemodynamically stable patients with myocarditis-induced heart failure managed with beta-blockers, angiotensin- converting enzyme inhibitors and diuretics. Specific antiviral agents are available based on the EMB viral PCR results, but these should be given after seeking specialist advice from the microbiology team. 

Patients with signs of heart failure with haemodynamic instability are managed in a high-dependence critical care setting where cardiovascular support can be provided and workup initiated for potential cardiac transplantation. 

Patients should avoid excessive physical activity for six months following myocarditis. This advice is the same for athletes and non-athletes. 

Clinical outcomes in myocarditis remain highly variable. Up to half of patients with acute myocarditis show a resolution of their symptoms within the first few weeks. However, up to 25% of patients will deteriorate further and either die as a result or progress to severe dilated cardiomyopathy. 

References

• Caforio et al. 2013. Current State of Knowledge on Aetiology, Diagnosis, Management, and Therapy of Myocarditis: a Position Statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. European Heart Journal. Available at https://pubmed.ncbi.nlm.nih.gov/23824828/
• Myocarditis. BMJ Best Practice 2022. Available at https://bestpractice.bmj.com/topics/en-gb/244
• Pericarditis. BMJ Best Practice 2022. Available at https://bestpractice.bmj.com/topics/en-gb/3000214
• Manda YR, Baradhi KM. Myopericarditis. 2021 Jul 26. Available at https://pubmed.ncbi.nlm.nih.gov/30521197/

Rheumatic Fever

Pathophysiology

Rheumatic fever is a multi-systemic inflammatory reaction instigated by a preceding streptococcal group A infection which was improperly or inadequately treated. The streptococcal infection typically occurs around two to three weeks prior to this syndrome. Principal organs involved include the heart, joints and skin. 

If left untreated, up to half of patients progress to chronic rheumatic heart disease, which predisposes the individual to arrhythmias, stroke and infective endocarditis. 

In developing countries, rheumatic fever continues to remain endemic and causes significant mortality and morbidity. In these nations, rheumatic heart disease is the leading cause of cardiovascular death in people aged 50 or less.  

Streptococcal pharyngitis is a relatively common infection with highest incidence between the ages of 5 to 15 years. When untreated, Group A streptococcus causes a pathological immune response. Streptococcal antibodies cross-react against myocardial tissue, synovial tissue and parts of the central nervous system. Cardiac valve involvement is caused by monoclonal antibodies initiating lymphocyte infiltration of the endothelium, further propagating the inflammatory response. 

Clinical manifestations

Signs and symptoms of rheumatic fever include: 

• Fever 
• Erythema marginatum: an annular erythema appearing as macules and papules typically on the trunk, upper arms and legs. As the lesions progress, their outer edges become raised with central clearing. 
• Arthritis: a migratory polyarthritis primarily affecting the large joints is typically seen. Arthralgia may also be present.
• Carditis can affect more than half of patients and may affect all the layers of the cardium (pancarditis) 
• Valvular regurgitation: there is typically involvement of the valvular endothelium progressing to valvular regurgitation. The mitral valve and aortic valve are most commonly affected.
• Chorea: involuntary, irregular jerking movements. Occurs due to immunological reactions affecting parts of the basal ganglia. Chorea can present up to six months after the initial streptococcal infection.
• Subcutaneous nodules: painless lumps over the extensor surfaces of wrists, elbows, knees and ankles.

Diagnosis

Diagnosis is primarily clinical, and the Jones criteria are used to facilitate diagnosis of rheumatic fever. This requires the presence of either two major criteria or one major and two minor criteria to be fulfilled in addition to evidence of a recent streptococcal group A infection. The major and minor criteria are defined below:

Major criteria

• Carditis: serial echocardiograms are required for diagnosis and further monitoring.
• Arthritis
• Chorea 
• Erythema Marginatum 
• Subcutaneous nodules  

Minor criteria

• Arthralgia: this is difficult to differentiate from arthritis and cannot be used as a criterion if arthritis is present. 
• First-degree heart block: prolonged PR interval on electrocardiogram. This cannot be used as a criterion if carditis is present.
• Fever: >39 degrees C is typically present in the first few days of illness and can be lower in subsequent weeks
• Raised acute phase reactants: ESR and CRP during the initial weeks. These are not specific for rheumatic fever. 

Recent streptococcal infection

• Evidence of recent streptococcal group A infection is provided by a positive pharyngeal culture or raised streptococcal antibody titre. Anti-streptolysin O titre (ASOT) or DNase B titre are examples of streptococcal antibodies. 

Management 

Goals of management include:

• Eradication of underlying streptococcal infection. Once a pharyngeal culture is obtained, patients are usually started on penicillin. Following an episode of rheumatic fever, antibiotic prophylaxis is recommended to prevent further episodes. 
• Suppression of the pathological immune response. NSAIDs may help relieve arthritis and arthralgia. 
• Supportive management with angiotensin-converting-enzyme inhibitors and diuretics in rheumatic fever complicated by heart failure and severe aortic regurgitation. Cardiac valve replacement or repair may also be indicated. 

References

• Webb et al. 2015. Acute Rheumatic Fever. BMJ. Available at https://pubmed.ncbi.nlm.nih.gov/26175053/
• UpToDate. Acute rheumatic fever: Clinical manifestations and diagnosis. 2017. Available at https://www.uptodate.com/contents/acute-rheumatic-fever-clinical-manifestations-and-diagnosis
• Dodu et al. ‎1989‎. Rheumatic fever and rheumatic heart disease in developing countries. Available at https://apps.who.int/iris/handle/10665/46841