Endocarditis is the inflammation of the endocardium, the innermost lining of the heart. Endocarditis may be due to infective or non-infective etiologies. Fungal endocarditis is an infrequent but debilitating condition with a poor prognosis. The disease can present as native valve endocarditis, prosthetic valve endocarditis, inflammation of the endocardial surface, and cardiac device-related infective endocarditis. Diagnosing fungal endocarditis is challenging; therefore, a high index of suspicion is required to arrive at a diagnosis.
Candida spp., in particular, C. albicans are the most common causative organisms of fungal endocarditis. Non-albicans species associated with fungal endocarditis include C. parapsilosis, C. tropicalis, and C. glabrata. Aspergillus sp. including, A. flavus, A. fumigatus, and A. niger are also common organisms causing fungal endocarditis. Aspergillus species are found to be more prevalent in prosthetic valves endocarditis. Other organisms associated with fungal endocarditis are Histoplasma species, Cryptococcus neoformans, Trichophyton species, Microsporum species, Fusarium species, Paecilomyces species, and Pseudallescheria boydii. Similar organisms are associated with fungal endocarditis in children. Candida infection rates decrease and Aspergillus infection rates increase with older age in children through the age of 19.
Fungal endocarditis rarely occurs in healthy individuals and is associated with immunocompromised states, intravenous drug use, prolonged antibiotic use, and long-term parenteral nutrition use. Individuals with prosthetic heart valves or with a history of reconstructive cardiac surgery also have a higher risk of fungal endocarditis. Native valve fungal endocarditis can occur in organ transplants recipients who are on immunosuppressive agents, patients with myelodysplastic syndrome, and patients on long-term glucocorticoids and cytotoxic drugs.
Candida species are commensal organisms in the gastrointestinal tract, lower genital tract and oral cavity. They are of less medical importance in an immunocompetent individual due to their inherent low virulence. The risk of candidiasis increases dramatically if the host of immunocompromised due to various reasons.
Aspergillus spp. are a ubiquitous organism in the environment. Renovation of old buildings, including hospitals and contaminated air conditioning systems, may be the source of infection as the airborne transmission is common for Aspergillus spp. Extension from pre-existing intra-thoracic foci, venous access devices, or contamination of prosthetic valves is less common.
Source of fibrin/platelet bed, infection risk, impaired host defense mechanisms, and fungal adherence/virulence factors are necessary elements leading to fungal endocarditis.. The first step in the pathophysiology of the fungal endocarditis is the inoculation and colonization of the bloodstream by the yeast or molds. The next step is associated with the conversion of blastospores into a filamentous form also known as phenotypic switching, which allows for adherence to the endocardium and invasion. Different factors such as cell surface proteins in the fungal wall, the int1p protein in Candida species, and leucocyte-induced adhesion molecule allow for adherence to the heart valves. Fungal adhesion is followed by proliferation and tissue destruction.
At initial presentation, it is very difficult to differentiate fungal endocarditis from bacterial endocarditis. Fungal endocarditis usually presents as sub-acute endocarditis. The most common presentation in all patients with fungal endocarditis is fever, which is usually prolonged (more than 2 weeks) and is often associated with chills, sweating, and fatigue. A new murmur, previously unrecognized murmur, or change in the quality of previously recognized murmur is another common finding in patients with suspected fungal endocarditis. Other clinical signs of fungal endocarditis include peripheral embolization in the extremities, brain, lung, kidneys, and gastrointestinal tract. Septic pulmonary embolism usually presents with fever, dyspnea, pleuritic chest pain, cough, and hemoptysis. Embolism to the gastrointestinal tract may present as an acute abdomen secondary to acute mesenteric ischemia. With valvular destruction, a patient with fungal endocarditis may present with heart failure. The patient can also present with clinical signs ranging from weight loss, clubbing, petechial rash, splenomegaly, hypotension, septic shock, and death. It is rare to see peripheral findings unique to particular fungal infections, such as cutaneous macro-nodules (in candidiasis).
Since morbidity and mortality associated with fungal endocarditis is high, early diagnosis is needed for appropriate antimicrobial therapy and consideration for surgery. The diagnosis of fungal endocarditis is difficult due to the poor yield from blood cultures which are positive in less than 50% of the time.. Laboratory techniques such as lysis centrifugation can improve the yield from blood cultures. The blood culture yield of yeast is better than mold.
Processing of blood cultures can be tedious and time-consuming. Quicker non-culture tests have been developed for the diagnosis of fungemia. Mannan antigen is a cell wall constituent of Candida spp. For candidemia, mannan antigen and antibody have a sensitivity and specificity of 83% and 86% respectively. Another cell wall polysaccharide of a fungal wall, 1,3 b-D-glucan, has a sensitivity and specificity of 69.9% and 87.1% respectively. Similarly, detection of galactomannan along with 1,3 b-D-glucan can help to diagnose fungal endocarditis caused by Aspergillus species.
The histopathological examination is prudent in culture-negative cases and often helps to determine the diagnosis from the examination of the explanted valve, peripheral emboli, or systemic ulcers.. The molecular methods, such as polymerase chain reaction (PCR) to detect fungal nuclear material like DNA in blood or in explanted valves, can expedite the diagnosis.
Echocardiography is an important tool in diagnostic evaluation. Characteristically, the lesions are large, left-sided (bilateral lesions are common in immunocompromised patients), and occasionally non-valvular. Echocardiography can also detect abscesses of the valve ring. Trans-esophageal echocardiography is more sensitive and specific for the diagnosis of endocarditis than transthoracic echocardiography.
A multi-disciplinary approach is required for the management of fungal endocarditis. Early valve replacement surgery of the infected valve (natural or prosthetic) should be recommended (class I indication) in almost all patient with fungal endocarditis, and a long course of anti-fungal medication should be initiated.
The initial anti-fungal treatment for Candida spp. endocarditis should be lipid formulation of amphotericin B with or without flucytosine or a high-dose echinocandin (caspofungin or micafungin or anidulafungin). Once the patient has stabilized and follow up blood cultures are negative, step-down therapy with oral fluconazole (if susceptible) is recommended. If candida isolate is not susceptible to fluconazole, oral voriconazole or posaconazole can be considered.
Infected pacemakers and cardiac defibrillators should be removed, and anti-fungal therapy should be initiated. For ventricular assist devices that cannot be removed, the anti-fungal regimen should be started, and chronic suppressive therapy with fluconazole (if susceptible) should be continued as long as the device is in place.
The endocarditis caused by Histoplasma capsulatum is managed with the lipid formulation of amphotericin B followed by oral itraconazole for at least 12 months. For Aspergillus endocarditis, voriconazole is used for both induction and long-term suppression.
Fungal endocarditis is a serious infection with an extremely high morbidity and mortality. These patients are best managed by a multidisciplinary team that consists of a cardiologist, infectious disease specialist, intensivist, cardiac surgeon and an internist. More important these patients are ideally managed by an ICU nurse. The key to lowering the mortality is early detection and treatment. Any patient who fails to respond to antifungal agents should be referred to a cardiac surgeon. Some of these patients may require radical debridement and or valve replacement. However, even with surgical treatment, survival rates are low. Patients who are immunocompromised tend to have the worst outcomes. In most case reports, recurrence is common and the risk of embolization has been high.
|||Pasha AK,Lee JZ,Low SW,Desai H,Lee KS,Al Mohajer M, Fungal Endocarditis: Update on Diagnosis and Management. The American journal of medicine. 2016 Oct [PubMed PMID: 27267285]|
|||Sun XL,Zhang J,Wang GG,Zhuang XF,Yang YM,Zhu J,Tan HQ,Yu LT, Comparison of characteristics and short-term outcome from fungal infective endocarditis in prosthetic valve endocarditis versus native valve endocarditis. The American journal of cardiology. 2013 Jul 1 [PubMed PMID: 23562383]|
|||Millar BC,Jugo J,Moore JE, Fungal endocarditis in neonates and children. Pediatric cardiology. 2005 Sep-Oct [PubMed PMID: 15549616]|
|||Pasqualotto AC,Denning DW, Post-operative aspergillosis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2006 Nov [PubMed PMID: 17002605]|
|||Ellis ME,Al-Abdely H,Sandridge A,Greer W,Ventura W, Fungal endocarditis: evidence in the world literature, 1965-1995. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2001 Jan [PubMed PMID: 11118386]|
|||Pierrotti LC,Baddour LM, Fungal endocarditis, 1995-2000. Chest. 2002 Jul [PubMed PMID: 12114375]|
|||Mnge P,Okeleye BI,Vasaikar SD,Apalata T, Species distribution and antifungal susceptibility patterns of Candida isolates from a public tertiary teaching hospital in the Eastern Cape Province, South Africa. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2017 May 15 [PubMed PMID: 28513771]|
|||Ellis M, Fungal endocarditis. The Journal of infection. 1997 Sep [PubMed PMID: 9354341]|
|||Spellberg B,Edwards JE, The Pathophysiology and Treatment of Candida Sepsis. Current infectious disease reports. 2002 Oct [PubMed PMID: 12228025]|
|||Lewis RE,Lo HJ,Raad II,Kontoyiannis DP, Lack of catheter infection by the efg1/efg1 cph1/cph1 double-null mutant, a Candida albicans strain that is defective in filamentous growth. Antimicrobial agents and chemotherapy. 2002 Apr [PubMed PMID: 11897612]|
|||Varghese GM,Sobel JD, Fungal endocarditis. Current infectious disease reports. 2008 Jul [PubMed PMID: 18765100]|
|||Cook RJ,Ashton RW,Aughenbaugh GL,Ryu JH, Septic pulmonary embolism: presenting features and clinical course of 14 patients. Chest. 2005 Jul [PubMed PMID: 16002930]|
|||Mikulska M,Calandra T,Sanguinetti M,Poulain D,Viscoli C, The use of mannan antigen and anti-mannan antibodies in the diagnosis of invasive candidiasis: recommendations from the Third European Conference on Infections in Leukemia. Critical care (London, England). 2010 [PubMed PMID: 21143834]|
|||Maertens JA,Klont R,Masson C,Theunissen K,Meersseman W,Lagrou K,Heinen C,Crépin B,Van Eldere J,Tabouret M,Donnelly JP,Verweij PE, Optimization of the cutoff value for the Aspergillus double-sandwich enzyme immunoassay. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2007 May 15 [PubMed PMID: 17443470]|
|||Lefort A,Chartier L,Sendid B,Wolff M,Mainardi JL,Podglajen I,Desnos-Ollivier M,Fontanet A,Bretagne S,Lortholary O, Diagnosis, management and outcome of Candida endocarditis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2012 Apr [PubMed PMID: 22329526]|
|||Habib G,Lancellotti P,Iung B, 2015 ESC Guidelines on the management of infective endocarditis: a big step forward for an old disease. Heart (British Cardiac Society). 2016 Jul 1 [PubMed PMID: 27288022]|
|||Pappas PG,Kauffman CA,Andes DR,Clancy CJ,Marr KA,Ostrosky-Zeichner L,Reboli AC,Schuster MG,Vazquez JA,Walsh TJ,Zaoutis TE,Sobel JD, Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016 Feb 15 [PubMed PMID: 26679628]|
|||Riddell J 4th,Kauffman CA,Smith JA,Assi M,Blue S,Buitrago MI,Deresinski S,Wright PW,Drevets DA,Norris SA,Vikram HR,Carson PJ,Vergidis P,Carpenter J,Seidenfeld SM,Wheat LJ, Histoplasma capsulatum endocarditis: multicenter case series with review of current diagnostic techniques and treatment. Medicine. 2014 Jul [PubMed PMID: 25181311]|
|||Gould FK,Denning DW,Elliott TS,Foweraker J,Perry JD,Prendergast BD,Sandoe JA,Spry MJ,Watkin RW,Working Party of the British Society for Antimicrobial Chemotherapy, Guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the Working Party of the British Society for Antimicrobial Chemotherapy. The Journal of antimicrobial chemotherapy. 2012 Feb [PubMed PMID: 22086858]|
|||Siciliano RF,Gualandro DM,Sejas ONE,Ignoto BG,Caramelli B,Mansur AJ,Sampaio RO,Pierrotti LC,Barbosa G,Golebiovski W,Lamas CWC,Fortes NRQ,Fortes CQ,Tarasoutchi F,Strabelli TMV, Outcomes in patients with fungal endocarditis: a multicenter observational cohort study. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2018 Sep 21 [PubMed PMID: 30248465]|