Pediatrics

Endocarditis

OVERVIEW: What every practitioner needs to know

Are you sure your patient has Endocarditis? What are the typical findings for this disease?

For the purpose of this chapter we are considering endocarditis to be infective endocarditis (IE), principally bacterial, unless specified to be due to another cause. It may be difficult to distinguish acute versus subacute endocarditis. An illness with a fairly sudden onset, high fever, and a septic-like presentation is presumed to be acute endocarditis, while an illness with continuous malaise that may wax and wane for weeks or months is considered to be subacute endocarditis.

Subacute endocarditis can be evaluated methodically and treatment can be delayed while awaiting results of laboratory and imaging tests, while acute endocarditis usually needs to be treated expeditiously. Classic signs of endocarditis such as splinter hemorrhages, Osler nodes, Roth spots, and Janeway lesions are usually associated with subacute endocarditis.

Osler nodes are the result of immune phenomena, presumably circulating antigen-antibody complexes that activate complement. Other lesions are usually caused by fragments of infected valves causing microabscesses in terminal vessels. Large valve fragments may cause blockage of larger vessels.

The most common symptoms of endocarditis are fever, malaise, and weight loss. Heart failure, myalgia/arthralgia, chest pain, and focal neurologic symptoms may also be evident at presentation.

Signs on physical examination most often include fever, splenomegaly, petechiae, and embolic phenomena. A new or changed cardiac murmur, clubbing, splinter hemorrhages, Osler nodes, Roth spots, and Janeway lesions may be present.

Laboratory findings:

The most common laboratory findings include positive blood cultures (usually the majority of cultures drawn are positive), elevated erythrocyte sedimentation rate, elevated C-reactive protein, anemia, and positive rheumatoid factor (may be present in chronic or subacute endocarditis).

What other disease/condition shares some of these symptoms?

Conditions that can mimic endocarditis include the following:

Bacterial sepsis due to streptococci, staphylococci, meningococci, pneumococci

Acute rheumatic fever

Kawasaki Disease

Lyme disease

Infective intravascular (endothelial) foci such as mycotic aneurysms, or thrombophlebitis

Collagen-vascular disorders such as rheumatoid arthritis, antiphospholipid syndrome, and lupus

Macrophage activation syndrome

What caused this disease to develop at this time?

Risks for development of infective endocarditis:

In the past, rheumatic heart disease was the major underlying condition predisposing to infective endocarditis. However, rheumatic heart disease has virtually disappeared in children in Western countries, although it may still be important in poorer or developing countries.

Congenital heart disease: conditions with regurgitant jets are most commonly risks for infective endocarditis. Early surgical correction in infancy reduces the risk.

Prosthetic valves and conduits, especially in the first 6 months after insertion.

Indwelling intravascular catheters ending in the great vessels or the heart.

High grade bacteremia-producing procedures, such as dental manipulation (especially manipulation of the gingival margin), and urological procedures when the urine is infected, and contaminated intravenous solutions. These risks are especially dangerous in children with underlying cardiac malformations.

In adults, calcific atherosclerotic heart disease, previous infective endocarditis, and illegal injection drug use are important risks that are rarely causes of endocarditis in children.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Blood cultures should be performed immediately in suspected IE. In subacute IE, analysis of 3-5 sets (aerobic and anaerobic) over 24 hours is recommended. These should be separate venipunctures. In acute IE it may be necessary to take as few as 3 sets over 30-60 minutes before starting empiric antibiotic treatment. If cultures are negative after 7 days and IE is still suspected, repeat the cultures and consider using special media such as fungal cultures and media supplemented with vitamin B6 (for Abiotrophia). Cultures should be held up to 3 weeks if there is a concern about culture-negative endocarditis.

If children with underlying risk factors for IE are to be treated with antibiotics for a febrile illness, never take only one blood culture because it may be impossible to sort out the meaning of a possible contaminant. Always take >1 blood culture.

In general, it is not recommended that blood cultures be taken through an indwelling intravascular catheter due to the high rate of contamination possible with this approach. If a catheter-associated infection is suspected, simultaneous peripheral and central quantitative or semi-quantitative cultures may be useful. If a catheter is considered to be the possible source of bacteremia, it should be removed and the distal end cultured by the semi-quantitative roll-plate technique to determine whether there is contamination from a catheter as the source of bacteremia.

CBC with manual differential. Increased white blood cell count with left shift is common in IE, as is anemia.

Standard chemistries including electrolytes, liver and renal function tests help determine the extent of systemic perturbation.

C-reactive protein and erythrocyte sedimentation rate (CRP and ESR), which are usually elevated in infective endocarditis.

Immunologic and rheumatologic tests including rheumatoid factor, cryoglobulins (elevated in IE), complement (CH50, C3, C4), which may be depressed in IE. These and other tests for inflammation may serve as baseline values when assessing response to treatment.

If cultures are sterile and IE is still suspected, consider serologic tests for Coxiella burnetii, Legionella species, Brucella, Chlamydia, and Bartonella. If a valve is surgically removed, the clinician can diagnose infection due to these organisms by in situ hybridization. Immunofluorescence and polymerase chain reaction for fastidious microorganisms in blood samples may also be helpful.

Would imaging studies be helpful? If so, which ones?

  • Standard chest radiographs, frontal and lateral should be performed. Cardiomegaly may be seen in heart failure. In right-sided endocarditis, septic pulmonary emboli may be evident.

  • Echocardiography is the best way to visualize lesions of valvular and non-valvular endocarditis. Initially, transthoracic echocardiography (TTE) may be sufficient, especially in small children with thin abdominal walls. If TTE does not reveal a lesion or the results are not clear-cut, transesophageal echocardiography (TEE) may be employed, which may allow better visualization. TTE in children appears to be more sensitive than TTE in adults. Color Doppler echocardiography also increases the sensitivity of echocardiography. TEE may be the procedure of choice in suspected prosthetic valve endocarditis or when there is a need for imaging of perivalvular lesions.

  • If there is suspicion of endovascular lesions outside of the heart, or of emboli in the extremities, ultrasound or arteriography may be indicated.

  • If there are any neurologic signs or symptoms, cranial magnetic resonance imaging (MRI) with MR arteriography is indicated. If there are gastroenterological signs or symptoms, perform abdominal ultrasound looking for liver, spleen, kidney or perirenal abscesses.

Confirming the diagnosis

Figure 1 provides the algorithm from the American Heart Association, which is the approach to the use of echocardiography for individuals suspected of having infective endocarditis. The algorithm is for both adults and children, but it is less likely that TEE would be required in a small child as TTE more frequently provides an optimal image.

Figure 1.

An approach to the diagnostic use of echocardiography (echo). *High-risk echocardiographic features include large and/or mobile vegetations, valvular insufficiency, suggestion of perivalvular extension, or secondary ventricular dysfunction (see text). For example, a patient with fever and a previously known heart murmur and no other stigmata of IE. High initial patient risks include prosthetic heart valves, many congenital heart diseases, previous endocarditis, new murmur, heart failure, or other stigmata of endocarditis. Rx indicates antibiotic treatment for endocarditis. From Baddour LM. Wilson WR. Bayer AS. Fowler VG Jr. Bolger AF. Levison ME. Ferrieri P. Gerber MA. Tani LY. Gewitz MH. Tong DC. Steckelberg JM. Baltimore RS. Shulman ST. Burns JC. Falace DA. Newburger JW. Pallasch TJ. Takahashi M. Taubert KA. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease. Council on Cardiovascular Disease in the Young. Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia. American Heart Association. Infectious Diseases Society of America.Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation 2005;111:e394-434. Used by permission.

While the diagnosis of IE may be obvious in some cases, if the diagnosis is not definite (or when doing prospective or retrospective clinical research relating to IE), one of the methods used for diagnosis of IE is the so-called Duke Criteria. A number of studies, mostly in adults, have demonstrated excellent specificity and sensitivity. Table Irepresents the strength of the diagnosis, and Table II gives definitions of the criteria (taken from the original paper from the Duke Medical Center by Durack et al.)

Table I.

Duke clinical criteria for diagnosis of infective endocarditis

Table II.

Definitions of terms used in the Duke Criteria for the diagnosis of infective endocarditis

Organisms causing infective endocarditis in infants and children

Bacteria

*-Viridans streptococcus is most common, but is an especially important cause of subacute endocarditis

-Enterococcus

*-Staphylococcus aureus

-Coagulase-negative staphylococci

*-Hemolytic streptococci, Groups A, B (in neonates and elderly), C, G, D

-Streptococcus pneumoniae

-Gram-negative rod species including Pseudomonas aeruginosa (uncommon in pediatrics except catheter-associated endocarditis)

-HACEK organisms. Include Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae,

Fungi

-Candida albicans

-Non albicans Candida species

-Aspergillus species

-Cryptococcus neoformans

-Many others responsible for rare cases

Others

-Coxiella burnetii (rickettsial cause of Q fever)

-Chlamydiae

Culture-negative endocarditis (probably less than 5% of cases of infective endocarditis using contemporary methods of organism identification)

If you are able to confirm that the patient has Endocarditis, what treatment should be initiated?

While the mainstay of treatment is appropriate antibiotics, when acute IE presents with cardiac failure or a septic-like picture, aggressive institution of fluid resuscitation and pharmacologic cardiac support are the first steps in treatment. Such patients should be treated in intensive care units, if available.

Empiric or presumptive antibiotic therapy (Table III) for infective endocarditis in children, begun before isolation of the causative agent, is based on the common causative microorganisms. Each of the antibiotics recommended is bactericidal; bacteriostatic agents are considered to be less effective than bactericidal drugs in the treatment of IE. The following tables represent empiric antibiotic treatment prior to identification of the infecting organism and definitive treatment (Table IV and Table V) for the most common causes of infective endocarditis.

Table III.

Antibiotic treatment of the most common bacterial causes of infective endocarditis in children and oung adults

Table IV.

Length of treatment of infective endocarditis

Table V.

Recommended doses of antibiotics to treat common causes of infective endocarditis

What are the adverse effects associated with each treatment option?

The adverse effects of antibiotic treatment of IE are the same as with antibiotic treatment of other conditions: allergic manifestations, drug fever, specific effect of each agent on the gastrointestinal tract, kidneys, liver, bone marrow, etc. Because treatment of IE is prolonged, assessment for side effects of antibiotics is important, as is determination of drug levels for aminoglycosides, vancomycin and any other antibiotics with unpredictable blood levels. Prolonged antibiotic treatment can result in suppression of normal flora and colonization with exogenous microorganisms including antibiotic-resistant species and fungi. Therefore secondary infections manifest by urinary tract infections, catheter-associated infections and nosocomial pneumonia may all be related to prolonged antibiotic therapy.

What are the possible outcomes of Endocarditis?

Most children with the most common cause of IE (Viridans streptococci) do well and have complete resolution . Some children may require cardiac valve surgery, either because of failure of antibiotic treatment or damage to a heart valve causing heart failure. While decisions regarding surgical intervention must be individualized, below are recommendations for when cardiac surgery should be strongly considered. (adapted from Fowler VG, et al. Endocarditis and Intravascular Infections. In Mandel GL, et al., eds. Principles and Practice of Infectious Diseases, 7th ed. Philadelphia: Churchill Livingstone Elsevier; 2010: pp 1067-1112)

1. Uncontrolled congestive heart failure

2. More than one serious systemic embolic episode.

3. Uncontrolled infection

4. Physiologically significant valve dysfunction.

5. Ineffective antimicrobial therapy (e.g., in fungal IE)

6. Resection of mycotic aneurysms

7. Most cases of prosthetic valve IE caused by more antibiotic-resistant pathogens (e.g., staphylococci, enteric Gram-negative bacilli)

8. Local suppurative complications including perivalvular or myocardial abscesses.

Echocardiographic demonstration of vegetations >10 mm, as well as increase in the size of vegetations, are predictors of a complicated course. However, there is controversy whether this represents an indication for surgery.

In addition to cardiac complications, surgery may be required to drain abscesses anywhere in the body. This is especially difficult in cerebral complications. Management of cerebral abscesses and cerebral aneurysms must be made in collaboration with neurosurgeons, keeping in mind that anticoagulation carries a significant risk of cerebral hemorrhage in patients with IE.

What causes this disease and how frequent is it?

IE is a sporadic disease with no geographic predisposition and little gender or socioeconomic predisposition in children. This is in contradistinction to the situation for adults, among whom there is a male preponderance linked with such social and behavioral factors as intravenous drug abuse and atherosclerotic heart disease. IE may be a complication of a prolonged septic process in another organ. This may occur in the presence of an indwelling central venous cannula, which acts as a nidus for clot and vegetation formation in the right side of the heart. The average age of adults with infective endocarditis is rising, an increase occurring most notably among older men.

The incidence of infective endocarditis is estimated as 1.7‑4 cases per 100,000 population per year in the United States and other developed countries. The incidence in developing countries is difficult to estimate because expensive equipment is required to make the definitive diagnosis with maximum sensitivity, and survival of children with cyanotic heart lesions is probably poor. The rate of hospital admissions for infective endocarditis in adults has been falling during the antibiotic era, but the rate of endocarditis in children has been rising.

Infective endocarditis can occur at any age but is uncommon in infants. Most studies don't indicate the strength of the diagnosis so studies may include cases diagnosed clinically that are not really IE. A recent study in which cases were deemed definite or possible using the Duke criteria came from Olmstead County, Minnesota. The incidence ranged 5-7.9 cases per 100,000 person-years with a trend to an increase from 1970-2006. For each year, the rate in men was greater than that in women.

The mean age for IE has been rising in past decades, but recent studies have shown an increase in hospital-acquired IE due to the frequent use of indwelling intravascular catheters. In general, community-acquired IE organisms come from the patients' own flora, while healthcare-associated IE can either be from the patients' own flora or caused by exogenous organisms. It has long been believed that dental manipulation is a frequent cause of the bacteremia that precedes IE, but data do not support this belief.

How do these pathogens/genes/exposures cause the disease?

The pathogenesis of most pediatric IE cases relates to turbulent blood flow or the effect of a foreign body in contact with the endocardium. Turbulent blood flow is usually related to congenital heart disease when there is a jet of flow from high to low pressure. The jet may be across an atrial or ventricular septal defect or from regurgitation through an incompetent valve. Turbulent flow causes erosion of the endothelium and deposition of platelet‑fibrin thrombi on abnormal valvular or mural surfaces, allowing bacteria to implant on these thrombi.

The congenital cardiac lesions most frequently associated with infective endocarditis in children include tetralogy of Fallot, ventricular septal defects, aortic stenosis, aortic regurgitation, patent ductus arteriosus, and transposition of the great vessels. Infective endocarditis associated with mitral valve prolapse is rare in children. In rheumatic, atheromatous, or calcific heart disease, organisms may become trapped in diseased valves or mural plaques during episodes of bacteremia or fungemia.

Other clinical manifestations that might help with diagnosis and management.

Less usual manifestations of IE include:

Cerebral complications presenting as stroke, cerebellar signs, changing level of consciousness

Gastrointestinal manifestations such as vomiting, nausea, splenic tenderness, splenic enlargement or splenic rupture.

Pulmonary manifestations such as dyspnea, chest pain, clubbing, pneumonia (common with right-sided IE)

Peripheral embolic lesions manifested as an acute pulseless limb, conjunctival petechiae, and renal abscess or infarction.

What complications might you expect from the disease or treatment of the disease?

IE can be related to disease in any organ because septic emboli can be transmitted through the arterial circulation throughout the body. Right-sided endocarditis can be related to septic emboli going to the lungs. Careful physical examination, diagnostic imaging and complete laboratory evaluation are required in order to avoid missing any complications.

In addition, allergic and toxic side effects of prolonged antibiotic treatment are common. Since antibiotics are generally delivered through the intravenous route, complications of prolonged intravascular cannulae, including bacteremia, phlebitis, and unexplained fever, may complicate the course of IE treatment.

Are additional laboratory studies available; even some that are not widely available?

One of the difficult problems in the diagnosis of IE is so-called culture-negative IE. The incidence of culture-negative IE has been decreasing as better microbiologic tests have become available, so some organisms formerly difficult to detect are now being detected. Unfortunately, these tests are not universally available. Such tests include continuous monitoring blood culture systems (e.g., BACTEC), enriched media to detect nutritionally fastidious microorganisms and slow-growing organisms, serologic studies for rickettsioses such as Q fever, Chlamydiae, Bartonella, direct immunofluoresence of heart valve tissue for Chlamydiae, Coxiella burnetii, Legionella, and PCR tests for these and other unculturable microorganisms.

How can Endocarditis be prevented?

In 2007 new guidelines regarding antibiotic prophylaxis for the prevention of infective endocarditis were published by the American Heart Association in Circulation (Wilson W, et al. Prevention of infective endocarditis: guidelines from the American Heart Association. Circulation 2007;116:1736-1754). At that time there were significant changes from the previous guideline published in 1997. Previously, the American Heart Association guidelines recommended antimicrobial prophylaxis to prevent infective endocarditis in patients with underlying cardiac conditions who underwent bacteremia-producing procedures. These included dental procedures, but also procedures involving the respiratory, gastrointestinal and genitourinary tracts, if the procedures included incision across mucosal surfaces contaminated with microorganisms.

Recent reanalysis of the pathogenesis of infective endocarditis has created some doubt as to whether prophylaxis aimed at treating these episodes of bacteremia would really prevent a significant number of cases of infective endocarditis, and whether it would justify all of the costs and risks associated with antibiotic use in these situations. The new guidelines were simpler and more restrictive.

These guidelines were endorsed by the American Academy of Pediatrics. Recommendations for prophylaxis were limited to those undergoing dental procedures considered to be high-risk. Thus, the emphasis in the new document shifted away from a focus on dental procedures and antibiotic prophylaxis toward a greater emphasis on improved access to dental care and oral health. Instead of a focus on procedures that are most likely to cause bacteremia, the emphasis is placed on patients with underlying cardiac conditions associated with the highest risk of adverse outcome from IE (Table VI and Table VII). The procedures for which endocarditis prophylaxis is recommended are limited only to dental procedures in which there is invasion or manipulation of the gingival margin, which is richest in the organisms that are implicated in infective endocarditis.

Table VI.

Cardiac conditions associated with the highest risk of adverse outcome from endocarditis for which prophylaxis with dental procedures is recommended

Table VII.

Recommendations for antibiotics for a dental procedure when the above conditions exist

What is the evidence?

Evidence level. The American Heart Association statement included evidence levels. The information regarding use of transesophageal echocardiography is Class 1, evidence level A (evidence from multiple randomized clinical trials). Most first-choice antibiotic treatment regimens in this chapter are also Class 1, evidence level A. For many of the alternative antibiotic treatment recommendations, the level of evidence is IB (evidence from a single randomized or nonrandomized trial). Regarding treatment recommendations for prosthetic-valve endocarditis, HACEK organisms, resistant organisms, and culture-negative endocarditis, the level is lower such as Class IIa and evidence level C (weight of evidence in favor, consensus opinion of experts) or lower. Recommendations for surgical consideration are IB, but the level of evidence for surgery based upon echocardiographic findings is lower.

Selected annotated references

Baddour, LM, Wilson, WR, Bayer, AS. "Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America". Circulation. vol. 111. 2005. pp. e394-e434.

This is a comprehensive review of infective endocarditis and includes many tables relating to treatment of specific organisms and situations. This review is notable in that it contains an evidence-based scoring system. Because it was published in 2005, it is due for an update.

Fowler, VG, Scheld, WM, Bayer, AS, Mandel, GL, Bennett, JE, Dolin, R. "Endocarditis and Intravascular Infections". Principles and practice of infectious diseases. Churchill Livingstone Elsevier. 2010. pp. 1067-1112.

This is an excellent up-to-date review chapter on infective endocarditis, with 864 references. The emphasis is more on adult than pediatric endocarditis.

Durack, DT, Lukes, AS, Bright, DK. "New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Duke Endocarditis Service". Am J Med. vol. 96. 1994. pp. 200-9.

Li, JS, Sexton, DJ, Mick, N. "Proposed modifications to the Duke criteria for the diagnosis of infective endocarditis". Clin Infect Dis. vol. 30. 2000. pp. 633-8.

The Durack, et al. and Li, et al. articles define the Duke Criteria and the modified Duke Criteria for diagnosis of infective endocarditis. These are most useful for cases in which the diagnosis is unclear and for standardization of diagnosis in clinical research.

Ferrieri, P, Gewitz, MH, Gerber, MA. "Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the American Heart Association Council on Cardiovascular Disease in the Young. Unique features of infective endocarditis in childhood". Circulation.. vol. 105. 2002. pp. 2115-26.

Now somewhat out-of-date and due to be revised, this is still a useful review of the particular aspects of infective endocarditis that apply to children, especially clinical findings. The antibiotic dosage table is adjusted for pediatric patients.

Wilson, W, Taubert, KA, Gewitz, M. "Prevention of infective endocarditis. Recommendations by the American Heart Association. A guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group". Circulation. vol. 116. 2007. pp. 1736-54.

This guideline was controversial when it was first published in that it considerably narrowed the patient population for whom antibiotic prophylaxis for endocarditis is recommended. The text includes the rationale for limiting antibiotic prophylaxis and also reviews the history of antibiotic prophylaxis for infective endocarditis beginning in the 1950s.

Correa de Sa, DD, Tleyjeh, IM, Anavekar, NSNS. "Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota". Mayo Clin Proc. vol. 85. 2010. pp. 422-6.

Ongoing controversies regarding etiology, diagnosis, treatment

For diagnosis of endocarditis, the Duke criteria have been recognized as affording the most sensitive and specific algorithm for diagnosis and are applied in cases where the diagnosis is not obvious and for endocarditis research.

The antibiotic choices, doses and durations of therapy suggested in this chapter conform to the recommendations of the American Heart Association and the American Academy of Pediatrics. Because of the lethality of of infective endocarditis, there is a lack of head-to-head comparison of different antibiotics and different dosages. Failure of treatment of enterococcal endocarditis using single beta-lactam antibiotic treatment demonstrated the necessity of using bactericidal antibiotics or antibiotic combinations. The recommendations for treating endocarditis in the patients with prosthetic valves or patches is less well established since surgical adjunctive treatment is such an important component of management.

The recommendations for prophylaxis which are in accord with a statement from the American Heart Association are still controversial. The 2007 statement represented a major change from previous recommendations and eliminated virtually all prophylaxis except for dental infections involving manipulation of the gums and eliminated any prophylaxis for all individuals except for those having the worst prognosis for outcome of IE. While some critics believed we would see an increase in IE following these recommendations, this has not happened.

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