Pediatric Fungal Endocarditis


Background

Fungal endocarditis (FE) is a rare infection in pediatrics. Its incidence is increasing because more neonates are in intensive care units (ICUs), are undergoing cardiac surgical procedures, and are receiving hyperalimentation (CHA).

Fungal endocarditis rarely affects native valves. Rather, it occurs most frequently in neonates as part of a disseminated fungal infection,in patients following cardiac surgery, and in those who develop an intracardiac thrombus or valvular injury due to the presence of a central venous catheter (CVC).

Fungal endocarditis is often difficult to diagnose because the presentation may be nonspecific, and the disease typically occurs in otherwise critically ill patients with confusing clinical pictures. [1]

Pathophysiology

In pediatrics, one fourth of fungal endocarditis cases have systemic candidal infection with cardiac involvement. These usually occur as a right-sided intracardiac thrombus at the site of valvular injury due to the presence of a central venous catheter (CVC).

Fungal endocarditis may complicate intracardiac surgery as well as complicate intrathoracic or systemic fungal infection in those at highest risk.

Epidemiology

Frequency

International

Fungi cause 0-12% (average 1.1%) of infectious endocarditis cases in children worldwide. Thus, the incidence rate is approximately 1.5-4 cases per 10 million children. Most published series are from the United States and other developed countries. Two thirds of fungal endocarditis is candidal. Among those in the neonatal intensive care unit (NICU), 1% develop disseminated candidal infection. Despite recent rises in frequency, this remains a rare infection, with reported cases numbering less than a few hundred in patients of any age.

Data are too limited to document the incidence of fungal endocarditis in the developing world. As many risk factors for the disease are associated with advanced medical care, a direct relationship between the availability of these technologies and the frequency of this infection is likely present.

Mortality/Morbidity

Prognosis is improving because of advances in intensive and operative care, but the survival rate remains less than 25%.

The mortality rate remains 75-90% because of the difficulty in making the diagnosis, lack of effective antifungal antibiotics, need for surgical intervention in most cases, presence of underlying or predisposing conditions, and frequent comorbid conditions in these typically critically ill neonates and children.

Complications

The most common complications in survivors are associated with embolic phenomena, postoperative issues, and underlying or predisposing conditions.

Race

No racial predisposition is present.

Sex

A slight male predominance is observed.

Age

Increasingly, the age distribution of cases is bimodal. The number of cases reported is rising in neonates and, gradually with age, in adults in their second decade of life.

CLINICAL PRESENTATION


History

Patients with fungal endocarditis (FE) may have a history of cardiac surgery complicated by symptoms of infection, such as fever, deteriorating cardiac status, embolic phenomena, and dehiscence.

a history of intrathoracic or systemic fungal infection with spread to the heart is rare.

Physical

On rare occasions, fungal endocarditis presents as typical bacterial endocarditis, with fever, weight loss, splenomegaly, splinter hemorrhages, Roth spots (pale retinal lesions with surrounding hemorrhage), Osler nodes (painful nodular lesions on the finger and/or toe pads), petechiae, Janeway lesions (painless hemorrhagic plaques on the palms and/or soles), arthritis, and a new or changing heart murmur.

Often, an indwelling central venous catheter (CVC) is present. The use of CVC for central hyperalimentation (CHA) is an additional risk factor.

Occasionally, positive blood culture results or positive culture results of other tissues and fluids (despite negative blood culture results) are the only evidence.

Cardiac involvement, without other symptoms or signs of infection, may be the only clinically apparent feature.

An inflow obstruction (superior vena cava syndrome with cough, hoarseness, dysphagia, and/or a full sensation in the ears) due to an infected thrombus may be the sole manifestation of disease.

In neonates, symptoms are often nonspecific and include apnea and bradycardia, hypothermia, poor perfusion, feeding intolerance, increased ventilatory support, and evidence of septic emboli. Rarely, a new or changing heart murmur is present.

In neonates, Janeway lesions, petechiae, splinter hemorrhages, and evidence of multiple septic emboli have been reported, although Osler nodes and Roth spots have not been reported.

In the postoperative period, patients may have symptoms such as fever, cardiac decompensation, a new or changing heart murmur, evidence of embolic phenomena, and dehiscence.

Superior vena cava syndrome may manifest as hoarseness, swelling of the face, wheezing or stridor, and/or venous engorgement.

Causes

No particular inheritance patterns are associated with fungal endocarditis.

Causal organisms include the following:

  • Candida species (two thirds of all reported cases) [2]

  • Aspergillus species (particularly in postoperative patients, with spread from systemic and pulmonary infections, and in immunocompromised hosts) [34]

  • Histoplasma capsulatum (causes pericarditis more frequently)

  • Blastomyces dermatitidis, Cryptococcus neoformans, [5Coccidioides immitis (mostly pericarditis; rarely endocarditis)

  • Mucor species, Torulopsis glabrata, Trichosporon beigelii, Fusarium species (rare)

  • Pseudallescheria boydii (prosthetic valve endocarditis)

  • Scedosporium species [6]

Risk factors include the following:

  • Neonatal period

  • History of cardiac surgery (eg,palliative shunt procedures, complex intracardiac repairs, vascular patches, vascular grafts, prosthetic valves) [7]

  • CVC in place

  • CHA

  • Broad-spectrum antibacterial therapy

  • Intravenous drug use

  • Preexisting valvular lesion or injury, such as congenital heart disease (eg, ventricular septal defect, atrial septal defect, patent ductus arteriosus, tetralogy of Fallot), [7bacterial endocarditis, rheumatic heart disease

  • Transient fungemia after bowel surgery

  • Any condition associated with immune compromise (eg, transplantation, leukemia)

Fungal endocarditis rarely affects native valves.

Fungal endocarditis may spread from intrathoracic (particularly pleural-based) infections.

DDx


Diagnostic Considerations

Important considerations

Clinicians should consider fungal endocarditis or make the diagnosis in the appropriate context.

Avoid failure to diagnose fungal endocarditis because of negative blood cultures.

Other problems to consider

Other conditions to consider in patients with suspected fungal endocarditis include the following

  • Intracardiac thrombus

  • Postoperative cardiac infection

  • Postoperative wound infection

  • Pulmonary hypertension

  • Congenital heart disease

Differential Diagnoses

Workup

Laboratory Studies

In fungal endocarditis (FE), blood cultures may be persistently positive despite therapy, especially with Candida infection. However, culture is often negative; less than one half of candidal endocarditis cases yield positive blood cultures, and other causative organisms are even less frequently identified in blood.

Culture of urine, sputum, cerebrospinal fluid, synovial fluid, lymph node, and/or bone marrow may offer the only evidence of systemic fungal infection.

The CBC count may reveal leukocytosis with or without a left shift. Thrombocytopenia may be seen with fungal infections in general in the neonate.

Erythrocyte sedimentation rates and/or C-reactive protein levels may be elevated, although this is unusual in neonates.

Urinalysis may demonstrate hematuria, proteinuria, and/or casts.

Urine for Histoplasma antigen may be positive.

Polymerase chain reaction (PCR) on blood and/or valve tissue has been described. [8]

Imaging Studies

Chest radiography

Chest radiography may reveal cardiomegaly.

Chest radiography may indicate embolic pulmonary infiltrates or pleural effusions.

Echocardiography

Transthoracic echocardiography is less sensitive than transesophageal echocardiography but is also less invasive.

Vegetations and intracardiac thrombi are the most common types but are still rare.

Echocardiography may demonstrate pericardial effusion.

Normal valves are rarely involved.

Echocardiography may suggest myocardial abscesses.

Echocardiography may demonstrate associated myocarditis or pericarditis.

Magnetic resonance imaging

Magnetic resonance imaging is particularly useful in identifying ring abscesses.

Other Tests

Fungal smears and cultures of operative specimens

Electrocardiography is usually nonspecific, although it may demonstrate supraventricular arrhythmias, QRS changes, and/or marked T-wave changes, particularly with myocarditis.

Procedures

Cardiac catheterization

Catheterization may reveal vegetations, thrombi, or underlying cardiac abnormalities.

It should be performed with care in the context of active infection.

Postcatheterization precautions include hemorrhage, vascular disruption after balloon dilation, pain, nausea and vomiting, and arterial or venous obstruction from thrombosis or spasm.

Complications may include rupture of blood vessel, tachyarrhythmias, bradyarrhythmias, and vascular occlusion.

Contrast-enhanced central venous catheter

Contrast-enhanced central venous catheter (CVC) injection studies may reveal a catheter-associated thrombus.

Histologic Findings

Biopsy or operative specimens should be cultured and special stains should be used to reveal acute and chronic inflammation and/or fungal elements.

TREATMENT AND MANAGEMENT


Medical Care

Patients with fungal endocarditis (FE) require monitoring in an ICU setting.

Note the following:

  • In fungal endocarditis, aggressive antifungal therapy is always necessary but may not prove sufficient to completely alleviate the problem. Removal of the infected nidus is often central to management.

  • Provide inotropic support as required.

  • Remove the central venous catheter (CVC) when appropriate.

  • Decrease immune suppression as much as possible.

  • Provide supportive measures.

Consultations

Consultation with infectious diseases specialists, cardiologists, and cardiothoracic surgeons is often required.

Neonatology or critical care consultation should accompany admission to the ICU.

Transfer

Arrange for transfer if the appropriate resources are not locally available.

Diet and activity

Diet and activaty are as tolerated by the patient's condition and as needed for operative intervention.

Surgical Care

Although a small number of patients have survived with medical therapy alone, most survivors have required both medical and surgical treatment. Operative intervention is almost always required. [910Note the following:

  • Specific indications include ongoing infection (not fully responsive to medical therapy), embolic phenomena, and cardiac decompensation.

  • Delaying operation when specific indications are present is not advantageous.

  • Thrombus removal, valve replacement, and abscess resection are the most frequent procedures.

  • The occasional neonate with a line-associated candidal infection may not require operative intervention.

MEDICATION

Medication Summary

Antifungal antibiotics, frequently used in combination, are the mainstay of treatment of fungal endocarditis (FE). Fluconazole therapy has been less successful than other agents. [11In almost all reported cases of survival, surgical management was necessary to supplement antifungal medical therapy. Studies suggest that fluconazole prophylaxis may help to prevent invasive fungal infections, including endocarditis, in the newborn population. [12]

Antifungal agents

Class Summary

The mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak, alteration of RNA and DNA metabolism, or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Amphotericin B (AmBisome, Abelcet)

DOC for severe fungal infections. Fungicidal or fungistatic (depending on the organisms); best-studied drug, despite its toxicities. Although few data are available, use of one of lipid formulations (ie, lipid complex, liposome) at comparable doses is recommended.

Flucytosine (Ancobon)

Adjunct to amphotericin B that seems to have a synergistic therapeutic effect in severe fungal infections. Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against candidal and cryptococcal infections and generally used in combination with amphotericin B.

Fluconazole (Diflucan)

Although it has fewer toxicities than the preceding drugs, insufficient data and concerns about efficacy keep fluconazole a second-line drug for this infection.

Caspofungin (Cancidas)

Used to treat refractory invasive aspergillosis and poorly responsive or nonresponsive yeast infections. First of a new class of antifungal drugs (glucan-synthesis inhibitors). Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell wall.

Voriconazole (Vfend)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Posaconazole may become available as a similar, but potentially safer, alternative.

Micafungin (Mycamine)

Member of new class of antifungal agents, echinocandins, which inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells.

Indications include (1) prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and (2) treatment of esophageal candidiasis.

Anidulafungin (Eraxis)

Antifungal agent of the echinocandin class. Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls. Indicated to treat esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intraabdominal abscesses, peritonitis).

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as PO susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

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