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Blood Culture-Negative Endocarditis: Individualized Diagnosis, Management
CONTENTS
N OV E M B E R / D E C E M B E R 2 0 2 2
4 Hip pain in a young child
8 Strong family history of heart disease
25 Rash may be signal of systemic disease
35 Suicide: Are You Liable?
FEATURES
8 Arrhythmogenic Right Ventricular Cardiomyopathy: a Case of Mistaken Identity
Clinicians should have a high index of suspicion for ARVC in patients with unexplained sudden cardiac arrest, syncope, or arrhythmia and a strong family history of similar events.
15 Blood Culture-Negative Endocarditis: Individualized
Diagnosis, Management
Primary care providers are on the frontline in the prompt identification of potential blood culture-negative endocarditis cases.
30 Breast Cancer Update: a Diagnosis That Extends
Beyond the Patient
A case in which genetic testing for breast cancer may have affected the outcome in a 35-year-old woman.
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4 Web Roundup
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25 Dermatologic Look-Alikes
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35 Legal Advisor
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Violaceous Rash
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Hip Pain and Limp in Young Child
A 5-year-old boy presents with right hip pain and a limp. The patient’s mother con rms that the child has not had any recent viral infection, fever, chills, or sweats. The child is acting ne other than the limp and occasional complaints of hip pain. On physical examination, the patient has a mild decrease in hip abduction and internal rotation on the right side compared with the left side.
WHAT IS THE BEST TREATMENT OPTION? • Activity modi cation based on symptoms • Physical therapy for hip strengthening • Hip abduction bracing • Femoral varus osteotomy
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Clinicians should consider ARVC in patients with unexplained sudden cardiac arrest, syncope, or arrhythmia and family history of similar events.
An estimated 20% of sudden cardiac deaths in younger patients are caused by ARVC.
A68-year-old White woman is brought to the emergency department by ambulance after experiencing chest pain, palpitations, and shortness of breath for 1 hour prior to arrival. Vital signs recorded by emergency medical technicians on arrival at the patient’s home show a blood pressure of 200/100 mm Hg, pulse of 110 beats per minute, and oxygen saturation of 94% on room air. The patient has a single-lead electrocardiography recording from her smartwatch showing premature ventricular contractions (PVCs) occurring at a rate of 6 per minute (Figure, page 10).
Electrocardiography in the emergency department shows no evidence of acute coronary syndrome. Cardiac enzymes are negative. The patient has never used tobacco products and has wellcontrolled hypertension and hyperlipidemia. However, the patient reports a strong family history of sudden cardiac arrest and syncope with cardiac arrhythmias from arrhythmogenic right ventricular cardiomyopathy (ARVC). These family members all had a mutation in the desmosomal protein (DSP) gene that controls the interlinking of cardiac cells.
The patient previously tested negative for this gene mutation. Four out of 10 of her first- and second-degree relatives with the DSP gene mutation have been diagnosed with ARVC and have had implantable cardiac defibrillators (ICD) placed. The patient is admitted to the cardiac unit for further evaluation. Computed tomography angiography
Continues on page 10
reveals abnormal wall movement in the left ventricle. Cardiac catheterization is performed the following day and shows a 50% blockage in the left anterior descending artery that does not require stenting. The hospital course is uneventful and the patient is discharged 1 day later with instructions to follow up with her cardiologist. The patient later sought a second opinion at the ARVD/C Program at Johns Hopkins University.
Discussion
Arrhythmogenic right ventricular cardiomyopathy is an underdiagnosed cause of sudden cardiac arrest, especially in young, athletic adults; although people of all ages may be affected. An estimated one-fifth of cases of sudden cardiac death in people younger than 35 years of age are attributed to ARVC.1 The condition involves progressive remodeling of cardiac muscle with fat and fibrosis and affects primarily the right ventricle, although the left ventricle can also be affected, especially in those with the DSP gene mutation.2
Symptoms of Arrhythmogenic Right Ventricular Cardiomyopathy
Sudden cardiac death is often the first symptom of ARVC. However, many people with ARVC have subtle signs and symptoms of cardiac arrhythmias that go unreported and unrecognized until a syncopal event or sudden cardiac death occurs. Palpitations and severe tachycardia may occur with or without preceding exertion. Lightheadedness and dizziness often precede the syncopal event. Episodic anginal chest pain that resolves spontaneously may occur in the weeks and months prior to the sudden cardiac arrest. If untreated, ARVC may progress to heart failure and death.1
Family History
The index patient (proband) in this family was a 45-year-old first cousin once removed who experienced sudden cardiac arrest at her home after a vigorous exercise session. She was resuscitated after she collapsed in her front yard. The diagnosis of ARVC was delayed for over a year until her child’s pediatrician suggested genetic testing. Two family members (first cousin and aunt of the proband) subsequently experienced sudden cardiac arrests. The proband’s mother (the patient’s first cousin) experienced a severe cardiac arrhythmia during hospitalization for an unrelated illness prior to the proband’s cardiac event and had an ICD placed. Other family members who tested positive for the same DSP gene mutation included 2 of the proband’s 3 children as well as the proband’s brother and 1 of his 2 children. The proband’s 29-year-old first cousin once removed (the case patient’s great niece) was diagnosed with ARVC after a syncopal event of unknown etiology with elevated cardiac enzymes that was initially diagnosed as myocarditis. Genetic testing of this relative revealed the DSP mutation. Other family members declined testing.
The proband later had a heart transplant after she experienced rapid disease progression with severe heart failure. No
FIGURE. Smartwatch single-lead electrocardiography recording demonstrates premature ventricular contractions.
deaths occurred in the case patient’s generation and subsequent generations, but the high incidence of past sudden premature deaths suggested that ARVC was present in the family for several generations. The case patient’s parents were second cousins and the incidents of sudden premature cardiac death occurred in both the paternal and maternal lines, including the patient’s father who died of a sudden cardiac arrest at the age of 56 years.
Arrhythmogenic Right Ventricular Cardiomyopathy Diagnosis
A comprehensive workup for ARVC includes an exercise stress test, echocardiography, and 30-day trial with a Holter monitor. The definitive study for diagnosis of ARVC is cardiac magnetic resonance imaging, but such studies require interpretation by a radiologist with extensive experience with ARVC. Further testing may include an electrophysiology study and cardiac CT angiography. Genetic testing is important for diagnosing the disease, but not all gene mutations that cause ARVC have been identified. Currently, mutations in the following genes have been implicated in ARVC: plakophilin-2 (PKP2), desmoglein-2 (DSG2), desmocollin-2 (DSC2), desmoplakin (DSP), and plakoglobin (JUP).1 All mutations are dominant. The condition has incomplete penetrance as some people with a gene mutation do not show any signs or symptoms of the disorder. Negative genetic testing may not necessarily rule out the diagnosis as ARVC can occur in the absence of identifiable genetic mutations and, thus, may be a gene-elusive disease.3
Treatment
Arrhythmias can be controlled with appropriate medications, including β-blockers and antiarrhythmic agents. Many patients will require ICD. Cardiac catheter ablation may be necessary to eliminate irritable foci. Lifestyle changes are essential; patients who continue vigorous exercise or endurance sports participation will likely experience a rapid progression of the disease and increase their risk for sudden cardiac arrest. Arrhythmogenic right ventricular cardiomyopathy is progressive and incurable. Heart failure is common and must be treated aggressively to slow progression. When the heart becomes weakened and medical therapy is no longer effective in preventing heart failure, heart transplantation is an option for suitable candidates. Many patients are diagnosed in the second to fourth decades of life and may experience severe distress and disability.4 Family members should undergo genetic testing.5
Case Resolution
The patient in this case underwent a thorough workup at a local cardiac specialty center and the results were reviewed by the ARVD/C center at Johns Hopkins University. She did not have any of the pathologic changes that characterize ARVC, such as scarring of the ventricles. She was eventually diagnosed with a hiatal hernia that, once appropriately treated, resolved the episodic chest pain that she continued to experience after the initial hospitalization. The patient continued to do well with only minor episodes of palpitations, arrhythmias, and chest pain during the 18 months following hospitalization.
Conclusion
Arrhythmogenic right ventricular cardiomyopathy is an underdiagnosed genetic cardiomyopathy that causes significant disability and raises the risk for sudden cardiac death in those affected. Clinicians encountering unexplained sudden cardiac arrest, syncope, or arrhythmia in a patient with a strong family history of similar events or who carries the genetic mutation should suspect ARVC. The condition is treatable and, although progressive, patients can live a normal lifespan with frequent monitoring, medical management, and ICD placement. Heart transplantation may be required to extend life for appropriate candidates. Because of lack of provider education about ARVC and related cardiomyopathies, evaluation of patients at a specialized ARVC center is recommended.6 ■
Kathy Holmes Dexter, MLS, MHA, MPA, PA-C, CAQ-Psych, is an associate professor and assistant dean for Clinical Practice at Augusta University College of Allied Health Sciences in Augusta, Georgia.
References
1. Smoot K. ARVD/C patient resources. Johns Hopkins Heart and Vascular Institute. Accessed September 22, 2022. https://www.hopkinsmedicine.org/ heart_vascular_institute/centers_excellence/arvd/patient_resources.html 2. Corrado D, Basso C. Arrhythmogenic left ventricular cardiomyopathy. Heart. 2022;108(9):733-743. 3. Gao C, Pan J, Li J. Refractory electrical storm in a 50-year-old man. Circ Cardiovasc Imaging. 2020;13(7):e010164. 4. Peters MN, Katz MJ, Alkadri ME. Diagnosis of arrhythmogenic right ventricular cardiomyopathy. Proc (Bayl Univ Med Cent). 2012;25(4):349-353. 5. Yuan ZY, Cheng LT, Wang ZF, Wu YQ. Desmoplakin and clinical manifestations of desmoplakin cardiomyopathy. Chin Med J (Engl). 2021;134(15):1771-1779. 6. Sharma A, Assis F, James CA, et al. Misdiagnosis of ARVC leading to inappropriate ICD implant and subsequent ICD removal - lessons learned. J Cardiovasc Electrophysiol. 2019;30(10):2020-2026.
Infective endocarditis affects 15 per 100,000 people in the US.
Epidemiologic considerations for endocarditis are complex as there can be infective and noninfective causes. Once a patient is hospitalized for endocarditis, the mortality rate is estimated to be 10%.1 This underscores the importance of early recognition, workup, and treatment by the primary care provider. However, early diagnosis is complicated by the nonspecific and generalized symptoms of the disease such as fever, chills, weight loss, cough, hemoptysis, and/or malaise. The differential diagnosis for this presentation is sizable.2 In patients with clinical suspicion of endocarditis, prompt workup including 3 sets of blood cultures taken at 30-minute intervals within 48 hours is warranted.2 If the cultures have no growth after 7 days but the clinician still suspects endocarditis, then the search begins for the cause of blood culture-negative endocarditis (BCNE).3
Infective endocarditis affects 15 per 100,000 people in the United States and the number continues to rise.1,4 Blood culture-negative endocarditis represents 2% to 7% of cases of infective endocarditis.5 Patients can present with noninfective BCNE that is related to autoimmune diseases, cancer, and other comorbidities.6 In clinical practice, confirmation of the appropriate diagnosis in cases of BCNE can be quite challenging. Endocarditis, whether culture positive or negative, requires an individualized treatment plan owing to the diversity in epidemiologic causes. Timely diagnosis is critical in the optimal management of this infection.
CARDIOLOGY: ENDOCARDITIS Patient history is more important than the physical examination when assessing for blood culture-negative endocarditis.
TABLE 1. Pertinent Questions for Suspected Blood Culture-Negative Endocarditis Patients3
Have you recently taken antibiotics?
Have you been exposed to cats or homeless shelters?
Have you been exposed to sheep, cattle, or goats?
Have you had intravascular catheter/hemodialysis?
Do you have a history of immunosuppression?
Do you have a history of infective endocarditis?
Do you have a history of PE or DVT?
DVT, deep vein thrombosis; PE, pulmonary embolism
TABLE 2. European Society of Cardiology 2015 Modified Criteria for Diagnosis of Infective Endocarditis2
Major Criteria Minor Criteria
• Persistently positive blood cultures from 2 seperate culture sets • Echocardiogram: vegetation, dehiscense of prosthetic valve, abscess, valvular perforation, or aneurysm • Abnormal findings around the prosthetic valve 18F-FDG
PET/CT (if the prosthesis was implanted for >3 months) or radiolabelled leukocytes
SPECT/CT • Cardiac CT demonstrating paravalvular lesions • Predisposing cardiac condition or
IV drug use • Fever >38.0 °C • Vascular: emboli, hemorrhages,
Janeway lesions, aneurysms, • Immunlogic: glomerulonephritis,
Osler nodes, Roth spots, rheumatoid factor • Positve blood cultures not meeting major criteria
CT, computed tomography; PET, positron emission tomography; SPECT, single photon emission computerized tomography
History and Physical Examination
Evaluation of BCNE is challenging. Patient history is often more important than the physical examination when assessing for BCNE. The key questions to ask during the patient history are listed in Table 1. 3
First, it is necessary to investigate if the patient has recently taken antibiotics. Antibiotic use is the primary cause of BCNE.7 Inquiring about exposure to farm animal helps determine if serology for Brucella spp or Coxiella burnetti needs to be obtained.6 To recognize Bartonella hensalae, it is appropriate to question patients about exposure to cats, body lice, and residence in a homeless shelter.6
The Duke criteria is a popular tool to aid in diagnosis of endocarditis. The criteria incorporate aspects of patient history, physical examination, and workup. Physical examination findings that must be evaluated when applying the Duke criteria are presence/absence of Osler nodes, Janeway lesions, splinter hemorrhages, petechiae, new regurgitation murmurs, and neurologic changes.8 A new cardiac murmur is present in 85% of patients with BCNE.8 Although not all patients will present with these findings, their correlation with the disease can expedite workup and management for endocarditis.
Diagnosis of infectious endocarditis is established in patients meeting one of the following Duke criteria: • 2 major clinical criteria; or • 1 major and 3 minor clinical criteria; or • 5 minor clinical criteria
Major and minor criteria were modified by the European Society of Cardiology in 2015 (Table 2).2 A transesophageal echocardiogram is the preferred imaging modality to evaluate for valve insufficiency and/or new vegetation.9
If the Duke criteria have been met to establish a diagnosis of endocarditis but the cultures remain negative for 7 days, more extensive investigation into the pathologic cause is needed. The approach begins by obtaining serology for C burnetti, B hensalae, and Brucella spp. 10 If these pathogens are ruled out, then rheumatology and autoimmune workup is warranted to evaluate for a noninfectious cause of endocarditis.3 A study conducted in France reported that 2.5% of 759 cases of BCNE had rheumatic arthritis, Bechet disease, or Libman-Sacks endocarditis.3 The study began by using specific laboratory tests including rheumatoid factor, antinuclear antibody, and anti-DNA antibodies to assist in the diagnosis.3
Histopathology remains the gold standard for pathologic analysis but it is not often feasible. Obtaining samples for a
histologic approach is quite invasive and often will only occur if the patient has a planned cardiac surgical procedure.10 Even if tissue samples are obtained, not all tissue is viable for the pathologic stains that would be needed.
In recent years, 16S ribosomal ribonucleic acid polymerase chain reaction (16S rRNA PCR) of excised tissue has played an important role in the diagnostic approach for BCNE.11 If a patient needs surgery for valve repair or vegetation removal, excised tissue should be sent for 16S rRNA PCR. In a prospective study of 819 cases, 16S rRNA PCR identi ed 109 distinct etiologies making it the second most important diagnostic tool (behind serology) for BCNE.11 If the patient’s history includes prior antibiotic use, PCR may demonstrate the presence of staphylococci or streptococci bacteria (responsible for 45% to 60% of culture-negative endocarditis cases).3
If the workup fails to reveal the underlying pathogen or cause, serology workup on Mycoplasma pneumonia, Legionella spp, and Chlamydia spp should be obtained.10 Serology tests are last-line options because of low prevalence of Chlamydia spp. As of 2017, only approximately 15 cases attributed to Chlamydia spp and 9 cases attributed to Mycoplasma pneumonia have been reported.10 If all diagnostic testing for endocarditis has been exhausted and no pathogen or comorbidity has been identi ed as the cause of the patient’s illness, it is time to investigate other conditions in the di erential diagnosis including atrial myxoma, antiphospholipid syndrome, and acute rheumatic fever.6
Treatment
Though treatment of endocarditis is tailored to each patient depending on history, epidemiology, risk factors, and comorbidities, empirical management is warranted. The American Heart Association (AHA) recommends treating patients empirically for acute BCNE with vancomycin and cefepime.1 For patients with subacute BCNE, AHA recommends vancomycin and ampicillin/sulbactam.6 These treatments are initiated while the speci c pathogen for BCNE is being identi ed.
The HACEK group of organisms includes Haemophilus parain uenzae, Aggregatibacter spp (aphrophilus and actinomycetemcomitans), Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae. They are responsible for 1.5% to 2% of all infective endocarditis and are managed with third-generation cephalosporins such as ceftriaxone.7 The HACEK organisms are fastidious, gram-negative bacilli that require special growth medium or longer incubation times to be isolated. If patients with HACEK infective endocarditis are treated promptly, they have an 80% to 90% chance of survival.7
Tailoring treatment and patient management to the speci c organism in BCNE results in a wide array of pharmacological choices as well as duration of therapy. Treatment times range from 3 months to greater than 18 months depending on the organism identi ed. Coxiella burnetii (Q fever) and Tropheryma whipplei are treated with doxycycline and hydroxychloroquine.2 Brucella spp are best managed with doxycycline, cotrimoxazole, and rifampin.2 The preferred approach to treatment of Bartonella spp includes doxycycline and gentamicin.2 Fungal endocarditis is best treated with amphotericin B.2 Again owing to the diversity of organisms associated with BCNE, the list of treatment recommendations for this diagnosis is extensive. Providers must use current and updated resources to select optimal pharmacological agent(s) and duration of treatment.
If a patient with endocarditis is found to have a comorbidity thought to ultimately be responsible for the disease (ie, systemic lupus erythematous [SLE]), then referral to appropriate specialist is necessary.3
Prophylactic treatment may be warranted to prevent future complications that can arise from BCNE. Anticoagulation should be discussed as atrial brillation is a common complication of
POLL POSITION
The American Heart Association recommends treating patients empirically for acute BCNE with which 2 agents?
■ Ampicillin and sulbactam ■ Vancomycin and cefepime ■ Vancomycin and ampicillin ■ Empiric treatment is not recommended 8.82%
27.94%
22.06% 41.18%
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Continues on page 24
TABLE 3. Surgical Indications for Endocarditis6
Patients with valve dysfunction who develop symptoms of heart failure
Resistant fungi or organisms
Heart block, aortic abscess, and destructive penetrating lesions
Persistent infection >5-7 days postantibiotic initiation determined by fever or bacteremia
Recurrent emboli or enlarging vegetations when on organism-specific antibiotic therapy
Severe valve vegetation and mobile vegetation >10 mm
Mobile vegetation >10 mm on anterior leaflet
valvular vegetation. The AHA also recommends anticoagulation for BCNE patients with a prior history of atrial fibrillation, prosthetic valve, deep vein thrombosis, pulmonary embolism, and/or coronary artery disease.1 Surgery is indicated in a handful of circumstances as demonstrated in Table 3. 6
Conclusion
Blood culture-negative endocarditis can be a challenging diagnosis to confirm. Primary care providers are on the frontline in the prompt identification of potential BCNE cases, allowing for prioritization of workup, management, and improved patient outcomes. A thorough history and physical examination are critical in the initial evaluation of patients with suspected BCNE. Blood culture-negative endocarditis warrants a multidisciplinary approach involving the primary care provider, cardiologist, cardiothoracic surgeon, and potentially other medical specialists (as appropriate for the patient/case) to achieve the goal of prompt and successful evaluation, management, and recovery. ■
Brittany Yacavone, PA-C, is scheduled to start the Piedmont Heart Advanced APP Fellowship Training Program in Advanced Cardiology at Piedmont Hospital in Atlanta, Georgia, in fall 2023; Elizabeth Prince-Coleman, MPA, PA-C, has been a practicing PA for almost 9 years with Augusta University Health. She also serves as the program director for the Augusta University PA Program.
References
1. Wei XB, Huang JL, Liu YH, et al. Incidence, risk factors and subsequent prognostic impact of new-onset atrial fibrillation in infective endocarditis. Circ J. 2020;84(2):262-268. 2. Habib G, Lancellotti P, Antunes MJ, et al; ESC Scientific Document Group. 2015 ESC Guidelines for the management of infective endocarditis: The task force for the management of infective endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J. 2015;36(44):3075-3128. 3. Katsouli A, Massad MG. Current issues in the diagnosis and management of blood culture-negative infective and non-infective endocarditis. Ann Thorac Surg. 2013;95(4):1467-1474. 4. Jamil M, Sultan I, Gleason TG, et al. Infective endocarditis: trends, surgical outcomes, and controversies. J Thorac Dis. 2019;11(11):4875-4885. 5. Sheibani H, Salari M, Azmoodeh E, Kheirieh A, Chaghazardi S. Culturenegative endocarditis with neurologic presentations and dramatic response to heparin: a case report. BMC Infect Dis. 2020;20(1):476. 6. Baddour LM, Wilson WR, Bayer AS, et al; American Heart Association Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2015;132(15):1435-486. 7. Revest M, Egmann G, Cattoir V, Tattevin P. HACEK endocarditis: state-of-theart. Expert Rev Anti Infect Ther. 2016;14(5):523-530. 8. McDonald JR. Acute infective endocarditis. Infect Dis Clin North Am. 2009;23(3):643-664. 9. Wang A, Gaca JG, Chu VH. Management considerations in infective endocarditis: a review. JAMA. 2018;320(1):72-83. 10. Subedi S, Jennings Z, Chen SC. Laboratory approach to the diagnosis of culture-negative infective endocarditis. Heart Lung Circ. 2017;26(8):763-771. 11. Godfrey R, Curtis S, Schilling WH, James PR. Blood culture negative endocarditis in the modern era of 16S rRNA sequencing. Clin Med (Lond). 2020;20(4):412-416.
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