Lyme disease: A case report of a 17-year old male with fatal Lyme carditis E. Yoon, E. Vail, G. Kleinman, P.A. Lento, S. Li, G. Wang, R. Limberger, J.T. Fallon PII: DOI: Reference:
S1054-8807(15)00025-3 doi: 10.1016/j.carpath.2015.03.003 CVP 6835
To appear in:
Cardiovascular Pathology
Received date: Revised date: Accepted date:
8 February 2015 15 March 2015 16 March 2015
Please cite this article as: Yoon E, Vail E, Kleinman G, Lento PA, Li S, Wang G, Limberger R, Fallon JT, Lyme disease: A case report of a 17-year old male with fatal Lyme carditis, Cardiovascular Pathology (2015), doi: 10.1016/j.carpath.2015.03.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Lyme disease: A case report of a 17-year old male with fatal Lyme carditis.
Department of Pathology and 3Microbiology, Westchester Medical Center and New York
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1
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E Yoon1, E Vail1, G Kleinman1, PA Lento1, S Li2, G Wang3, R Limberger4 and JT. Fallon1
Medical College, Valhalla, NY, USA Department of Pediatrics, New York Medical College, Maria Fareri Children’s Hospital,
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2
Wadsworth Center, New York State Department of Health, Albany, NY, USA
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4
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Valhalla, NY, USA
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No funding was necessary and used for this manuscript.
ACCEPTED MANUSCRIPT Abstract: Lyme disease is a systemic infection commonly found in the northeastern, mid-Atlantic
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and north-central regions of the United States. Of the many systemic manifestations of Lyme disease, cardiac involvement is uncommon and rarely causes mortality. We describe a case of a
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17-year-old adolescent who died unexpectedly after a 2-week viral-like syndrome. Postmortem examination was remarkable for diffuse pancarditis characterized by extensive infiltrates of
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lymphocytes and focal interstitial fibrosis. In the cardiac tissue, Borrelia burgdorferi was
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identified via special stains, immunohistochemistry and PCR. The findings support Borrelia burgdorferi as the causative agent for his fulminant carditis and that the patient suffered fatal
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Lyme carditis. Usually, Lyme carditis is associated with conduction disturbances and is a treatable condition. Nevertheless, few cases of mortality have been reported in the literature.
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Here, we report a rare example of fatal Lyme carditis in an unsuspected patient.
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Keywords: carditis; Lyme carditis; Borrelia burgdorferi; ventricular tachycardia; pediatric; arrhythmia; myocarditis; heart block; spirochetes; Lyme disease
ACCEPTED MANUSCRIPT Introduction: Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. It is
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the most common vector-borne illness in the United States with disease prevalence highest in the northeastern, mid-Atlantic and north-central states1, 2. Early Lyme disease is typically
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characterized by a skin rash (erythema chronicum migrans), fever, fatigue, arthralgias and myalgias3. If untreated, the infection can disseminate and can cause various manifestations
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depending on the potential sites of secondary involvement, including the nervous, cardiovascular
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and musculoskeletal systems4. Of these, Lyme carditis is a relatively rare sequel and occurs in only 4%-10% of untreated patients5. Most commonly, adult patients with cardiac involvement
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present with a variable degree of self-limited atrioventricular conduction disturbance 5-7. Lyme carditis in children is even less common, but can also present with a spectrum of clinical
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derangements ranging from asymptomatic first-degree heart block to fulminant myocarditis6.
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Nevertheless, Lyme carditis is a self-limited condition and full recovery is typically expected with timely supportive care and antibiotic therapy6. In the literature, few cases of fatal Lyme
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carditis have been reported in adults8-9. In this paper, we report a case of fatal Lyme carditis in a previously healthy 17-year old male.
Case Report: In the summer, a 17-year old previously healthy male was suffering from a 2 - week history of a viral syndrome manifested by sore throat, cough and occasional fever. The patient initially visited his pediatrician for nonspecific symptoms of upper respiratory tract infection, fever, malaise, and body aches. At that time of the visit, rapid group A streptococcus test, throat
ACCEPTED MANUSCRIPT cultures and serology tests for Lyme disease and anaplasmosis were all negative. A couple of days later, the patient developed diarrhea and light-headedness and was reported to have
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photophobia by his parents. However, a few days after his visits, he was found lying
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unresponsive on his lawn. He was resuscitated at the scene by EMS and immediately transported to a regional hospital for further work up and treatment. At the hospital, he was noted to have
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ventricular tachycardia (120 bpm), mild hypotension (104/46 mmHg) and fever (101.4 F). The
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patient also had rapid, shallow, grunting-like respiration with foamy secretions in his mouth and
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dilated but reactive pupils. His mental status and overall clinical condition deteriorated rapidly.
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Initial lab values included a leukocytosis (20.2 x 103/ µL), hyperglycemia (157 mg/dL), elevated creatinine (1.7 mg/dL) and abnormal liver enzymes (AST=71 IU/L; AST=115 IU/L).
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Troponin and other cardiac enzymes were not elevated. Urinalysis was remarkable for hematuria
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(2+) and proteinuria (3+). A urine toxicology screen was negative. No additional postmortem
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toxicology studies were performed. A lumbar puncture revealed clear cerebrospinal (CSF) fluid with an elevated number of leukocytes (153 cells/µL, predominantly mononuclear leukocytes) and red blood cells (14 cells/µL). Chest x-ray revealed an enlarged heart but head CT showed no abnormalities. EKG revealed unusual P axis, nonspecific ST abnormality and prolonged PR interval (0.24 seconds).
The patient was transported to our tertiary medical center; en route, he developed ventricular tachycardia that required electrical cardioversion. On arrival, he was on mechanical ventilation, unresponsive (Glasgow Coma Score of 3 out of 15) and had intermittently palpable
ACCEPTED MANUSCRIPT pulses. Attempts made to stabilize his rhythm were unsuccessful. Despite significant resuscitative efforts, he rapidly progressed from ventricular fibrillation to pulseless electrical
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activity and finally to asystole.
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Autopsy was performed on the same day of his death at the treating hospital. Postmortem
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examination revealed cardiomegaly (570g) with biventricular hypertrophy (left ventricle = 2 cm, right ventricle = 1.5 cm). The pericardial sac contained 25 mL of clear yellow fluid and the
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epicardial surface of both ventricles was remarkable for areas of patchy, white discoloration. The major histopathology finding was that of a diffuse lymphocytic pancarditis (Figure 1 A, B, C).
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Microscopic examination of the grossly noted white areas on the epicardial surface of the heart was remarkable for focal myocardial interstitial fibrosis. A Warthin-Starry stain revealed
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frequent presence of spirochetes in the ventricular myocardium (Figure 1 D). Neuropathological
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examination confirmed a clinical suspicion of lymphocytic meningoencephalitis and radiculitis;
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however, no viral cytopathic changes or perivascular inflammatory infiltrates were identified by a neuropathologist. Additional autopsy findings included hepatomegaly (2000 g) with congestion and chronic active hepatitis, chronic thyroiditis, acute bronchopneumonia, pulmonary edema (2220 g, combined weight) and skeletal myopathy with segmental fiber necrosis. The cause of death was determined to be secondary to myocarditis caused by spirochetal infection, with an associated systemic inflammatory process involving the lungs, meninges, spinal nerve roots, liver, thyroid and skeletal muscle.
ACCEPTED MANUSCRIPT Additional laboratory tests were performed at the Wadsworth Center, New York State Department of Health (Albany, New York) to identify possible etiologic infectious pathogens.
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Enzyme-linked immunosorbent assay (ELISA) was positive for Lyme borreliosis (B.
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burgdorferi). This was subsequently confirmed by IgM Western blot testing (Table 1). Additional testing of CSF, serum, as well as fresh and preserved tissues for both common and
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rare viral and bacterial pathogens determined that B. burgdorferi was present in fresh liver and
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myocardial tissue but not in the spleen, kidney, lung, brain or CSF (Table 1). The presence of B. burgdorferi in myocardium, lung and brain tissues was also subsequently confirmed by the
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Centers for Disease Control (CDC) by immunohistochemistry staining and PCR on (Table 2). This array of molecular and biologic tests supported our suspicion of early disseminated
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infection of B. burgdorferi with the subsequent unfortunate consequence of fatal Lyme carditis.
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Discussion:
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Lyme disease is the most common tick-borne infectious disease in North America and in countries with temperate climates in Eurasia10. The CDC reports that the incidence of Lyme disease increased 101% between 1992 to 200611. Approximately 30,000 cases of Lyme disease were reported in the United States in 20138, 12. Classically, the clinical manifestations of Lyme disease are divided into three stages: early localized, early disseminated and late infection13. The early localized infection of Lyme disease occurs 7-10 days after a tick bite and most typical presentation is non-specific influenza-like symptoms13, 14. Characteristic skin rash and erythema migrans are present in up to 80% of the patients during the early localized stage13, 15. In the early disseminated infection, which occurs weeks to months later, patients can have secondary skin
ACCEPTED MANUSCRIPT lesions, lymphadenopathy, migratory joint and muscle pain, and meningitis associated with cranial nerve involvement and Lyme carditis1, 6, 13, 14, 16. During the early disseminated infection,
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fatalities from Lyme disease are uncommon but rare cases have been reported9. In the late
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infection of Lyme disease, patients persistently have episodes of arthritis which can severely damage the large joints. Diagnosis is usually based on the recognition of the characteristic
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clinical presentation and antibody response to B. burgdorferi by enzyme-linked immunosorbent
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assay (ELISA) and Western blotting11. However, tests for antibodies should not be used for screening persons with only nonspecific symptoms because positive predictive values in these
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patients is poor and false negative results remain high, occurring in as many as 50% of cases17.
Lyme carditis is potentially lethal if not treated promptly. Lyme carditis is reported to
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occur as early as 4 days and as late as 7 months (median 21 days) after the initial infection4, 14. In
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the United States, Lyme carditis occurs in up to 10% of infected adult patients and in up to 16% of infected pediatric patients 6, 11, 16. Interestingly, Lyme carditis is reported to occur three times
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more frequently in males than in females 16, 18. 94% of patients with Lyme carditis presented with non-specific flu-like symptoms (fever, malaise, headache, arthralgia and/or myalgias), making Lyme carditis difficult and unexpected diagnosis6.
Lyme carditis can either cause a self-limited conduction derangement of varying degrees of atrioventricular block (AVB) or, less commonly, more severe non-specific cardiac arrhythmias 6, 11, 14, 16
. One study showed that out of 105 patients with Lyme carditis, 49% of patients had
third degree of AVB, 16% had second-degree and 12% had first degree AVB 18. Another study,
ACCEPTED MANUSCRIPT which looked at 207 cases of early disseminated Lyme disease in pediatric patients, found 33 (15.9%) had carditis and 14 out of 33 patients (42%) had advanced heart block including nine
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patients with complete heart block and four patients with severely depressed systolic ventricular
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function6. Ultimately, few of the patients required mechanical ventilation, temporary pacing or extracorporeal membrane oxygenation6. Although, Lyme carditis predominantly presents with
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various degree of heart block, patients can, rarely, present with severe and potentially fatal
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ventricular and supraventricular tachycardias alone19, 20, 21. The patient in this case report also
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presented with unremitting ventricular tachycardia.
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It is noted that the conduction disturbances associated with Lyme carditis are not static and can rapidly fluctuate and progress from first degree to third degree AVB within minutes
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causing alternating tachycardias and bradycardias6, 11, 14, 19, 22. Few authors have hypothesized
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that the fluctuating degree of AVB may be secondary to coinciding pericarditis6, 14. Therefore, it
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is important to recognize various cardiac manifestations of Lyme carditis and if these patients become hemodynamically unstable and present with severe heart block, more invasive interventions are required in addition to antibiotic therapy11. Despite the possibility of severe heart block or cardiogenic shock, Lyme carditis is usually a transient illness with excellent prognosis and, with appropriate therapy, should be associated with full recovery within 1-6 weeks6, 8.
Other non-specific cardiac complications of Lyme include pericarditis, endocarditis, myocarditis, pericardial effusion, myocardial infarction, coronary artery aneurysm, QT- interval
ACCEPTED MANUSCRIPT prolongation, dilated cardiomyopathy, degenerative cardiac valvular disease and congestive heart failure 6, 11, 19, 14, 16, 23, 24, 25. These are uncommon but have been reported either as isolated events
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or in combinations. Diffuse myocardial involvement may lead to subsequent cardiomegaly, left
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ventricular dysfunction and clinical congestive heart failure as seen in 10-15% of patients with
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Lyme carditis18, 26.
Lyme borreliosis-associated cardiac tissue injury is complex process. It involves both
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direct myocardial invasions by B. burgdorferi evidenced by presence of spirochetes and immunologic and autoimmunologic processes of the host leading to an exaggerated
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inflammatory response, seen by extensive transmural inflammatory infiltrates comprise of predominantly B lymphocytes and plasma cells which leads to myocyte damage and necrosis 6, 9, . As Lyme disease is an evolving process, Lyme carditis can resemble various cardiac
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14, 18, 27, 28, 29
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conditions, depending on the stage of cardiac involvement9, 30. Even in the literature, a spectrum of variable pathologic cardiac manifestations has been reported: Marcus et al31 found pancarditis
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with diffuse lymphoplasmacytic infiltrates in a 66-year old male; Cary et al30 described pericarditis, focal myocarditis and prominent endocardial fibrosis in a 31-year old male; and Tavora et al9 described pancarditis with infiltrates of lymphocytes, macrophages and plasma cells with scattered eosinophils in a 37-year old male. There is no consensus in diagnostic histologic criteria to this date. Typically, during the early stage of the disease, the presence of perivasculitis, prominent eosinophils and an absence of fibrosis may mimic hypersensitivity carditis9. However, in the later ‘resolving’ stage, there are prominent areas of fibrosis and less inflammation can be observed30. Therefore if suspicious, special stains, such as Warthin-Starry
ACCEPTED MANUSCRIPT or Steiner stains, can reveal rare spirochete organisms, consistent with Borrelia sp. between
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myocytes and will support the diagnosis of Lyme carditis during active inflammation6.
While our patient showed extensive pancarditis with infiltrates of lymphocytes and
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multiple foci of interstitial fibrosis, this appears, to our knowledge, to be the first case of fatal
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Lyme carditis in an adolescent patient with a superimposed systemic inflammatory process involving multiple organs. In conclusion, diffuse lymphocytic pancarditis and interstitial fibrosis
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identified at autopsy may suggest a diagnosis of undetected Lyme carditis. Laboratory testing such as immunohistochemistry, PCR or ELISA for B. burgdorferi can be useful in identification
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of the underlying causative agent.
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Acknowledgments
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The authors gratefully acknowledge the assistance of Drs. S Wong, K St. George, K Musser, S Zaki, and R Rockwell, P Kurpiel, C Hertzog, L Squires, K Reiber and A Rotans for laboratory testing and investigation of this case.
ACCEPTED MANUSCRIPT References: [1]
Rosenfeld M, Beckerman B, Ward M, Sama A. Lyme carditis: Complete AV dissociation
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with episodic asystole presenting as syncope in the emergency department. J Emerg Med. 1999;17:661-4.
Centers for Disease Control and Prevention. CDC Surveillance for Lyme disease-United States, 1992-2006. MMWR 2008;57:1-9.
Kugeler K, Griffith, K, Mead PS. A review of death certificates listing Lyme disease as a
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[3]
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[2]
[4]
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cause of death in the United States. Clin Infect Dis. 2011;52:364-47. Steere AC, Coburn C, Glickstein L. The emergence of Lyme disease. J Clin Invest.
[5]
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2004;113:1093-101.
Robinson T, Herman L, Birrer R, Wallis K. Lyme Carditis: A rare presentation in an
Costello J, Alexander M, Greco K, et al. Lyme carditis in Children: Presentation,
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[6]
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unexpected setting. Am J Emerg Med. 1998;16:265-9.
predictive factors and clinical course. Pediatrics. 2009;123:835-41. Karmacharya P, Aryal M. Heart stopping tick. World J Cardiol. 2013;5:148-50.
[8]
Centers for Disease Control and Prevention. Three sudden cardiac deaths associated with
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[7]
Lyme carditis-United States, November 2013-July 2013. MMWR 2013;62:993-6. [9]
Tavora F, Burke A, Ling L, Franks TJ, Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction. Cardiovasc Pathol 2008;17:103-7.
[10] Stanek G, Wormser G, Gray J, Strle F. Lyme borreliosis. The Lancet 2012;379:461-70. [11] Steere AC. Lyme disease. N Engl J Med. 2001;345(2):115-25 [12] Reported cases of Lyme disease by state or locality, 2004-2013. ([cited 2014, Aug 27]. Available from: http://www.cdc.gov/lyme/stats/chartstables/reportedcases_statelocality.html
ACCEPTED MANUSCRIPT [13] Depietropaolo D, Powers J, Gill J. Diagnosis of Lyme disease. Am Fam Physician 2005;72(2):297-304.
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[14] Fish AE, Pride YB, Pinto DS. Lyme carditis. Infect Dis Clin N Am 2008;22:275-88.
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[15] Biesiada G, Czepiel J, Lesniak MR, Garlicki A, Mach T. Lyme disease: review. Arch Med Sci. 2012;8:978-82
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[16] Lelovas P, Dontas I, Bassiakou E, Xanthos T. Cardiac implications of Lyme disease,
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diagnosis and therapeutic approach. Int J Cardiol 2008;129:15-21. [17] Shapiro E. Lyme Disease. N Engl J Med 2014;370:1724-31
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[18] van der Linde MR. Lyme carditis: clinical characteristics of 105 cases. Scand J Infect Dis Suppl 1991;77:81-4
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[19] Jenson TB, Dalsgaard D, Johansen JB. Cardiac arrest due to torsades de pointes
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ventricular tachycardia in a patient with Lyme Carditis. Ugeskr Laeger. 2014;176:35 [20] Greenberg YJ, Brennan JJ, Rosenfeld LE. Lyme myocarditis presenting as fascicular
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8:323-4
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tachycardia with underlying complete heart block. J cardiovasc Electrophysiol. 1997;
[21] Midttun M, Videbaek J. Serious arrhythmias in Borrelia infections. Ugeskr Laeger. 1993; 155:2147-50
[22] Allal J, Coisne D, Thomas P, et al. Manifestation cardiaques de la maladie de Lyme. [Cardiac manifestations of Lyme disease]. Ann Med Interne 1986;137:372–4 [23] Lorcerie B, Boutron MC, Portier H, Beuriat P, Ravvisy J, Martin F. Manifestations pericardiques de la maladie de Lyme. [Pericardial manifestations of Lyme disease]. Ann Med Interne 1987;138:601–3.
ACCEPTED MANUSCRIPT [24] Stanek G, Klein J, Bittner R, Glogar D. Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy. N Engl J Med
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1990;322:249–52.
A three year follow-up. Kardiol Pol 2013; 71:283-5
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[25] Konopka M, Kuch M, Braksator W et al. Unclassified cardiomyopathy or Lyme carditis?
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[26] Saba S, VanderBrink BA, Perides G, et al. Cardiac conduction abnormalities in a mouse
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model of Lyme borreliosis. J Interv Card Electrophysiol 2001;5:137–43. [27] Rostoff P, Gajos G, Konduracka E, Gackowski A, Nessler J, Piwowarska W. Lyme
Cardiol. 2010 Oct 8;144:328-33
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carditis: epidemiology, pathophysiology, and clinical features in endemic areas. Int J
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[28] Schnarr S, Franz JK, Krause A, Zeidler H. Infection and musculoskeletal conditions:
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Lyme borreliosis. Best Pract Res Clin Rheumatol 2006;20:1099–118. [29] Cadavid D, Bai Y, Hodzic E, et al. Cardiac involvement in non-human primates infected
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with the Lyme disease spirochete Borrelia burgdorferi. Lab Invest 2004;84:1439–50.
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[30] Cary NR, Fox B, Wright DJ, et al. Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node. Postgrad Med J 1990;66:134–6. [31] Marcus LC, Steere AC, Duray PH, Anderson AE, Mahoney EB. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium. Ann Intern Med 1985;103:374-6
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ACCEPTED MANUSCRIPT
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Figure 1. Diffusely infiltrated with lymphocytes and plasma cells between individual myocytes: (A) epicardial surface, (B) myocardium, (C) endocardium (H&E, 200x). (D) Spirochete within myocardium, Warthin-Starry Stain (1000x)
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ACCEPTED MANUSCRIPT
Figure 2. Diffusely infiltrated with lymphocytes highlighted by CD20, CD4 and CD8 and macrophages
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highlighted by CD 163 (200x)
ACCEPTED MANUSCRIPT
Wadsworth Laboratory NYS DOH Test results Real-time PCR Real-time RT- PCR ELISA PRNT Real-time PCR Real-time PCR Real-time PCR Real-time PCR Real-time PCR Real-time PCR Real-time RT- PCR IFA titer Real time RT- PCR IFA titer PRNT Real time RT- PCR Real time RT-PCR Real-time RT-PCR IFA titer PRNT IFA titer
Not detected Not detected Non-reactive Negative Not detected Not detected Not detected Not detected Not detected Not detected Not detected < 16, normal Not detected < 16, normal Negative Not detected Not detected Not detected < 16, normal Negative < 16, normal
RNA
Real-time RT-PCR
Not detected
Antibodies DNA DNA
CSF, Serum Serum CSF CSF
Negative Negative Negative
DNA
CSF
DNA DNA IgG, IgM IgG, IgM IgG, IgM DNA C6 IgG IgM
CSF Serum Serum Serum CSF Serum Serum Serum
PRNT Real-time PCR Multiplex real-time PCR Multiplex real-time PCR PCR Real-time PCR IFA titer IFA titer IFA titer Real-time PCR ELISA Western IgG Blot Western IgM blot
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Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae
Streptococcus Group B Mycoplasma pneumoniae Rickettsia spp. Spotted fever group Typhus fever group Borrelia burgdorferi
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Serum CSF CSF CSF CSF CSF CSF, serum CSF Serum CSF Serum Serum CSF CSF CSF Serum Serum Serum
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CSF CSF, serum
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Arbovirus Western equine encephalitis virus Powassan virus
DNA RNA IgM Antibodies DNA DNA DNA DNA DNA DNA RNA IgG RNA IgG Antibodies RNA RNA RNA IgG Antibodies IgG
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Enterovirus RNA Cache Valley virus California serogroup virus
Result
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Herpes Simplex virus 1 Herpes Simplex virus 2 Cytomegalovirus Varicella-zoster virus Epstein-Barr virus Human herpes virus 6 Eastern equine encephalitis virus Saint Louis encephalitis virus
Method
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Adenovirus West Nile virus
Specimen
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Test
Negative Negative Negative Non-reactive < 64, normal < 64, normal Negative Positive Equivocal Reactive
Table 1. Wadsworth NYS DOH report. IFA, Immunofluorescent assay; ELISA, Enzyme-linked immnosorbent assay; RT-PCR, reverse transcriptase polymerase chain reaction; PRNT, Plaque Reduction Neutralization Test.
ACCEPTED MANUSCRIPT Centers for Disease Control (CDC) Pathology report Test
Result
Heart
WS for spirochetes
Positive
IHC for Treponema spp
Positive
WS for spirochetes IHC for Treponema spp
PCR for Borrelia burgdorferi
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Table 2. CDC Pathology Report.
Positive
Negative
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Lung
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PCR for Borrelia burgdorferi
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Specimen
Negative Negative
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WS, Warthin-Starry stain; IHC, Immunohistochemical staining; PCR, polymerase chain reaction
S1054-8807(15)00025-3 doi: 10.1016/j.carpath.2015.03.003 CVP 6835
To appear in:
Cardiovascular Pathology
Received date: Revised date: Accepted date:
8 February 2015 15 March 2015 16 March 2015
Please cite this article as: Yoon E, Vail E, Kleinman G, Lento PA, Li S, Wang G, Limberger R, Fallon JT, Lyme disease: A case report of a 17-year old male with fatal Lyme carditis, Cardiovascular Pathology (2015), doi: 10.1016/j.carpath.2015.03.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Lyme disease: A case report of a 17-year old male with fatal Lyme carditis.
Department of Pathology and 3Microbiology, Westchester Medical Center and New York
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1
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E Yoon1, E Vail1, G Kleinman1, PA Lento1, S Li2, G Wang3, R Limberger4 and JT. Fallon1
Medical College, Valhalla, NY, USA Department of Pediatrics, New York Medical College, Maria Fareri Children’s Hospital,
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2
Wadsworth Center, New York State Department of Health, Albany, NY, USA
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4
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Valhalla, NY, USA
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No funding was necessary and used for this manuscript.
ACCEPTED MANUSCRIPT Abstract: Lyme disease is a systemic infection commonly found in the northeastern, mid-Atlantic
RI P
T
and north-central regions of the United States. Of the many systemic manifestations of Lyme disease, cardiac involvement is uncommon and rarely causes mortality. We describe a case of a
SC
17-year-old adolescent who died unexpectedly after a 2-week viral-like syndrome. Postmortem examination was remarkable for diffuse pancarditis characterized by extensive infiltrates of
NU
lymphocytes and focal interstitial fibrosis. In the cardiac tissue, Borrelia burgdorferi was
MA
identified via special stains, immunohistochemistry and PCR. The findings support Borrelia burgdorferi as the causative agent for his fulminant carditis and that the patient suffered fatal
ED
Lyme carditis. Usually, Lyme carditis is associated with conduction disturbances and is a treatable condition. Nevertheless, few cases of mortality have been reported in the literature.
PT
Here, we report a rare example of fatal Lyme carditis in an unsuspected patient.
AC
CE
Keywords: carditis; Lyme carditis; Borrelia burgdorferi; ventricular tachycardia; pediatric; arrhythmia; myocarditis; heart block; spirochetes; Lyme disease
ACCEPTED MANUSCRIPT Introduction: Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi. It is
RI P
T
the most common vector-borne illness in the United States with disease prevalence highest in the northeastern, mid-Atlantic and north-central states1, 2. Early Lyme disease is typically
SC
characterized by a skin rash (erythema chronicum migrans), fever, fatigue, arthralgias and myalgias3. If untreated, the infection can disseminate and can cause various manifestations
NU
depending on the potential sites of secondary involvement, including the nervous, cardiovascular
MA
and musculoskeletal systems4. Of these, Lyme carditis is a relatively rare sequel and occurs in only 4%-10% of untreated patients5. Most commonly, adult patients with cardiac involvement
ED
present with a variable degree of self-limited atrioventricular conduction disturbance 5-7. Lyme carditis in children is even less common, but can also present with a spectrum of clinical
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derangements ranging from asymptomatic first-degree heart block to fulminant myocarditis6.
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Nevertheless, Lyme carditis is a self-limited condition and full recovery is typically expected with timely supportive care and antibiotic therapy6. In the literature, few cases of fatal Lyme
AC
carditis have been reported in adults8-9. In this paper, we report a case of fatal Lyme carditis in a previously healthy 17-year old male.
Case Report: In the summer, a 17-year old previously healthy male was suffering from a 2 - week history of a viral syndrome manifested by sore throat, cough and occasional fever. The patient initially visited his pediatrician for nonspecific symptoms of upper respiratory tract infection, fever, malaise, and body aches. At that time of the visit, rapid group A streptococcus test, throat
ACCEPTED MANUSCRIPT cultures and serology tests for Lyme disease and anaplasmosis were all negative. A couple of days later, the patient developed diarrhea and light-headedness and was reported to have
T
photophobia by his parents. However, a few days after his visits, he was found lying
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unresponsive on his lawn. He was resuscitated at the scene by EMS and immediately transported to a regional hospital for further work up and treatment. At the hospital, he was noted to have
SC
ventricular tachycardia (120 bpm), mild hypotension (104/46 mmHg) and fever (101.4 F). The
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patient also had rapid, shallow, grunting-like respiration with foamy secretions in his mouth and
MA
dilated but reactive pupils. His mental status and overall clinical condition deteriorated rapidly.
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Initial lab values included a leukocytosis (20.2 x 103/ µL), hyperglycemia (157 mg/dL), elevated creatinine (1.7 mg/dL) and abnormal liver enzymes (AST=71 IU/L; AST=115 IU/L).
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Troponin and other cardiac enzymes were not elevated. Urinalysis was remarkable for hematuria
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(2+) and proteinuria (3+). A urine toxicology screen was negative. No additional postmortem
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toxicology studies were performed. A lumbar puncture revealed clear cerebrospinal (CSF) fluid with an elevated number of leukocytes (153 cells/µL, predominantly mononuclear leukocytes) and red blood cells (14 cells/µL). Chest x-ray revealed an enlarged heart but head CT showed no abnormalities. EKG revealed unusual P axis, nonspecific ST abnormality and prolonged PR interval (0.24 seconds).
The patient was transported to our tertiary medical center; en route, he developed ventricular tachycardia that required electrical cardioversion. On arrival, he was on mechanical ventilation, unresponsive (Glasgow Coma Score of 3 out of 15) and had intermittently palpable
ACCEPTED MANUSCRIPT pulses. Attempts made to stabilize his rhythm were unsuccessful. Despite significant resuscitative efforts, he rapidly progressed from ventricular fibrillation to pulseless electrical
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activity and finally to asystole.
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Autopsy was performed on the same day of his death at the treating hospital. Postmortem
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examination revealed cardiomegaly (570g) with biventricular hypertrophy (left ventricle = 2 cm, right ventricle = 1.5 cm). The pericardial sac contained 25 mL of clear yellow fluid and the
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epicardial surface of both ventricles was remarkable for areas of patchy, white discoloration. The major histopathology finding was that of a diffuse lymphocytic pancarditis (Figure 1 A, B, C).
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Microscopic examination of the grossly noted white areas on the epicardial surface of the heart was remarkable for focal myocardial interstitial fibrosis. A Warthin-Starry stain revealed
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frequent presence of spirochetes in the ventricular myocardium (Figure 1 D). Neuropathological
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examination confirmed a clinical suspicion of lymphocytic meningoencephalitis and radiculitis;
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however, no viral cytopathic changes or perivascular inflammatory infiltrates were identified by a neuropathologist. Additional autopsy findings included hepatomegaly (2000 g) with congestion and chronic active hepatitis, chronic thyroiditis, acute bronchopneumonia, pulmonary edema (2220 g, combined weight) and skeletal myopathy with segmental fiber necrosis. The cause of death was determined to be secondary to myocarditis caused by spirochetal infection, with an associated systemic inflammatory process involving the lungs, meninges, spinal nerve roots, liver, thyroid and skeletal muscle.
ACCEPTED MANUSCRIPT Additional laboratory tests were performed at the Wadsworth Center, New York State Department of Health (Albany, New York) to identify possible etiologic infectious pathogens.
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Enzyme-linked immunosorbent assay (ELISA) was positive for Lyme borreliosis (B.
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burgdorferi). This was subsequently confirmed by IgM Western blot testing (Table 1). Additional testing of CSF, serum, as well as fresh and preserved tissues for both common and
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rare viral and bacterial pathogens determined that B. burgdorferi was present in fresh liver and
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myocardial tissue but not in the spleen, kidney, lung, brain or CSF (Table 1). The presence of B. burgdorferi in myocardium, lung and brain tissues was also subsequently confirmed by the
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Centers for Disease Control (CDC) by immunohistochemistry staining and PCR on (Table 2). This array of molecular and biologic tests supported our suspicion of early disseminated
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infection of B. burgdorferi with the subsequent unfortunate consequence of fatal Lyme carditis.
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Discussion:
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Lyme disease is the most common tick-borne infectious disease in North America and in countries with temperate climates in Eurasia10. The CDC reports that the incidence of Lyme disease increased 101% between 1992 to 200611. Approximately 30,000 cases of Lyme disease were reported in the United States in 20138, 12. Classically, the clinical manifestations of Lyme disease are divided into three stages: early localized, early disseminated and late infection13. The early localized infection of Lyme disease occurs 7-10 days after a tick bite and most typical presentation is non-specific influenza-like symptoms13, 14. Characteristic skin rash and erythema migrans are present in up to 80% of the patients during the early localized stage13, 15. In the early disseminated infection, which occurs weeks to months later, patients can have secondary skin
ACCEPTED MANUSCRIPT lesions, lymphadenopathy, migratory joint and muscle pain, and meningitis associated with cranial nerve involvement and Lyme carditis1, 6, 13, 14, 16. During the early disseminated infection,
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fatalities from Lyme disease are uncommon but rare cases have been reported9. In the late
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infection of Lyme disease, patients persistently have episodes of arthritis which can severely damage the large joints. Diagnosis is usually based on the recognition of the characteristic
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clinical presentation and antibody response to B. burgdorferi by enzyme-linked immunosorbent
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assay (ELISA) and Western blotting11. However, tests for antibodies should not be used for screening persons with only nonspecific symptoms because positive predictive values in these
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patients is poor and false negative results remain high, occurring in as many as 50% of cases17.
Lyme carditis is potentially lethal if not treated promptly. Lyme carditis is reported to
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occur as early as 4 days and as late as 7 months (median 21 days) after the initial infection4, 14. In
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the United States, Lyme carditis occurs in up to 10% of infected adult patients and in up to 16% of infected pediatric patients 6, 11, 16. Interestingly, Lyme carditis is reported to occur three times
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more frequently in males than in females 16, 18. 94% of patients with Lyme carditis presented with non-specific flu-like symptoms (fever, malaise, headache, arthralgia and/or myalgias), making Lyme carditis difficult and unexpected diagnosis6.
Lyme carditis can either cause a self-limited conduction derangement of varying degrees of atrioventricular block (AVB) or, less commonly, more severe non-specific cardiac arrhythmias 6, 11, 14, 16
. One study showed that out of 105 patients with Lyme carditis, 49% of patients had
third degree of AVB, 16% had second-degree and 12% had first degree AVB 18. Another study,
ACCEPTED MANUSCRIPT which looked at 207 cases of early disseminated Lyme disease in pediatric patients, found 33 (15.9%) had carditis and 14 out of 33 patients (42%) had advanced heart block including nine
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patients with complete heart block and four patients with severely depressed systolic ventricular
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function6. Ultimately, few of the patients required mechanical ventilation, temporary pacing or extracorporeal membrane oxygenation6. Although, Lyme carditis predominantly presents with
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various degree of heart block, patients can, rarely, present with severe and potentially fatal
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ventricular and supraventricular tachycardias alone19, 20, 21. The patient in this case report also
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presented with unremitting ventricular tachycardia.
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It is noted that the conduction disturbances associated with Lyme carditis are not static and can rapidly fluctuate and progress from first degree to third degree AVB within minutes
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causing alternating tachycardias and bradycardias6, 11, 14, 19, 22. Few authors have hypothesized
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that the fluctuating degree of AVB may be secondary to coinciding pericarditis6, 14. Therefore, it
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is important to recognize various cardiac manifestations of Lyme carditis and if these patients become hemodynamically unstable and present with severe heart block, more invasive interventions are required in addition to antibiotic therapy11. Despite the possibility of severe heart block or cardiogenic shock, Lyme carditis is usually a transient illness with excellent prognosis and, with appropriate therapy, should be associated with full recovery within 1-6 weeks6, 8.
Other non-specific cardiac complications of Lyme include pericarditis, endocarditis, myocarditis, pericardial effusion, myocardial infarction, coronary artery aneurysm, QT- interval
ACCEPTED MANUSCRIPT prolongation, dilated cardiomyopathy, degenerative cardiac valvular disease and congestive heart failure 6, 11, 19, 14, 16, 23, 24, 25. These are uncommon but have been reported either as isolated events
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or in combinations. Diffuse myocardial involvement may lead to subsequent cardiomegaly, left
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ventricular dysfunction and clinical congestive heart failure as seen in 10-15% of patients with
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Lyme carditis18, 26.
Lyme borreliosis-associated cardiac tissue injury is complex process. It involves both
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direct myocardial invasions by B. burgdorferi evidenced by presence of spirochetes and immunologic and autoimmunologic processes of the host leading to an exaggerated
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inflammatory response, seen by extensive transmural inflammatory infiltrates comprise of predominantly B lymphocytes and plasma cells which leads to myocyte damage and necrosis 6, 9, . As Lyme disease is an evolving process, Lyme carditis can resemble various cardiac
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14, 18, 27, 28, 29
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conditions, depending on the stage of cardiac involvement9, 30. Even in the literature, a spectrum of variable pathologic cardiac manifestations has been reported: Marcus et al31 found pancarditis
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with diffuse lymphoplasmacytic infiltrates in a 66-year old male; Cary et al30 described pericarditis, focal myocarditis and prominent endocardial fibrosis in a 31-year old male; and Tavora et al9 described pancarditis with infiltrates of lymphocytes, macrophages and plasma cells with scattered eosinophils in a 37-year old male. There is no consensus in diagnostic histologic criteria to this date. Typically, during the early stage of the disease, the presence of perivasculitis, prominent eosinophils and an absence of fibrosis may mimic hypersensitivity carditis9. However, in the later ‘resolving’ stage, there are prominent areas of fibrosis and less inflammation can be observed30. Therefore if suspicious, special stains, such as Warthin-Starry
ACCEPTED MANUSCRIPT or Steiner stains, can reveal rare spirochete organisms, consistent with Borrelia sp. between
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myocytes and will support the diagnosis of Lyme carditis during active inflammation6.
While our patient showed extensive pancarditis with infiltrates of lymphocytes and
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multiple foci of interstitial fibrosis, this appears, to our knowledge, to be the first case of fatal
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Lyme carditis in an adolescent patient with a superimposed systemic inflammatory process involving multiple organs. In conclusion, diffuse lymphocytic pancarditis and interstitial fibrosis
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identified at autopsy may suggest a diagnosis of undetected Lyme carditis. Laboratory testing such as immunohistochemistry, PCR or ELISA for B. burgdorferi can be useful in identification
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of the underlying causative agent.
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Acknowledgments
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The authors gratefully acknowledge the assistance of Drs. S Wong, K St. George, K Musser, S Zaki, and R Rockwell, P Kurpiel, C Hertzog, L Squires, K Reiber and A Rotans for laboratory testing and investigation of this case.
ACCEPTED MANUSCRIPT References: [1]
Rosenfeld M, Beckerman B, Ward M, Sama A. Lyme carditis: Complete AV dissociation
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with episodic asystole presenting as syncope in the emergency department. J Emerg Med. 1999;17:661-4.
Centers for Disease Control and Prevention. CDC Surveillance for Lyme disease-United States, 1992-2006. MMWR 2008;57:1-9.
Kugeler K, Griffith, K, Mead PS. A review of death certificates listing Lyme disease as a
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cause of death in the United States. Clin Infect Dis. 2011;52:364-47. Steere AC, Coburn C, Glickstein L. The emergence of Lyme disease. J Clin Invest.
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2004;113:1093-101.
Robinson T, Herman L, Birrer R, Wallis K. Lyme Carditis: A rare presentation in an
Costello J, Alexander M, Greco K, et al. Lyme carditis in Children: Presentation,
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[6]
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unexpected setting. Am J Emerg Med. 1998;16:265-9.
predictive factors and clinical course. Pediatrics. 2009;123:835-41. Karmacharya P, Aryal M. Heart stopping tick. World J Cardiol. 2013;5:148-50.
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Centers for Disease Control and Prevention. Three sudden cardiac deaths associated with
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Lyme carditis-United States, November 2013-July 2013. MMWR 2013;62:993-6. [9]
Tavora F, Burke A, Ling L, Franks TJ, Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction. Cardiovasc Pathol 2008;17:103-7.
[10] Stanek G, Wormser G, Gray J, Strle F. Lyme borreliosis. The Lancet 2012;379:461-70. [11] Steere AC. Lyme disease. N Engl J Med. 2001;345(2):115-25 [12] Reported cases of Lyme disease by state or locality, 2004-2013. ([cited 2014, Aug 27]. Available from: http://www.cdc.gov/lyme/stats/chartstables/reportedcases_statelocality.html
ACCEPTED MANUSCRIPT [13] Depietropaolo D, Powers J, Gill J. Diagnosis of Lyme disease. Am Fam Physician 2005;72(2):297-304.
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[14] Fish AE, Pride YB, Pinto DS. Lyme carditis. Infect Dis Clin N Am 2008;22:275-88.
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[15] Biesiada G, Czepiel J, Lesniak MR, Garlicki A, Mach T. Lyme disease: review. Arch Med Sci. 2012;8:978-82
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[16] Lelovas P, Dontas I, Bassiakou E, Xanthos T. Cardiac implications of Lyme disease,
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diagnosis and therapeutic approach. Int J Cardiol 2008;129:15-21. [17] Shapiro E. Lyme Disease. N Engl J Med 2014;370:1724-31
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[18] van der Linde MR. Lyme carditis: clinical characteristics of 105 cases. Scand J Infect Dis Suppl 1991;77:81-4
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[19] Jenson TB, Dalsgaard D, Johansen JB. Cardiac arrest due to torsades de pointes
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ventricular tachycardia in a patient with Lyme Carditis. Ugeskr Laeger. 2014;176:35 [20] Greenberg YJ, Brennan JJ, Rosenfeld LE. Lyme myocarditis presenting as fascicular
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8:323-4
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tachycardia with underlying complete heart block. J cardiovasc Electrophysiol. 1997;
[21] Midttun M, Videbaek J. Serious arrhythmias in Borrelia infections. Ugeskr Laeger. 1993; 155:2147-50
[22] Allal J, Coisne D, Thomas P, et al. Manifestation cardiaques de la maladie de Lyme. [Cardiac manifestations of Lyme disease]. Ann Med Interne 1986;137:372–4 [23] Lorcerie B, Boutron MC, Portier H, Beuriat P, Ravvisy J, Martin F. Manifestations pericardiques de la maladie de Lyme. [Pericardial manifestations of Lyme disease]. Ann Med Interne 1987;138:601–3.
ACCEPTED MANUSCRIPT [24] Stanek G, Klein J, Bittner R, Glogar D. Isolation of Borrelia burgdorferi from the myocardium of a patient with longstanding cardiomyopathy. N Engl J Med
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A three year follow-up. Kardiol Pol 2013; 71:283-5
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[25] Konopka M, Kuch M, Braksator W et al. Unclassified cardiomyopathy or Lyme carditis?
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[26] Saba S, VanderBrink BA, Perides G, et al. Cardiac conduction abnormalities in a mouse
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model of Lyme borreliosis. J Interv Card Electrophysiol 2001;5:137–43. [27] Rostoff P, Gajos G, Konduracka E, Gackowski A, Nessler J, Piwowarska W. Lyme
Cardiol. 2010 Oct 8;144:328-33
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carditis: epidemiology, pathophysiology, and clinical features in endemic areas. Int J
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[28] Schnarr S, Franz JK, Krause A, Zeidler H. Infection and musculoskeletal conditions:
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Lyme borreliosis. Best Pract Res Clin Rheumatol 2006;20:1099–118. [29] Cadavid D, Bai Y, Hodzic E, et al. Cardiac involvement in non-human primates infected
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with the Lyme disease spirochete Borrelia burgdorferi. Lab Invest 2004;84:1439–50.
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[30] Cary NR, Fox B, Wright DJ, et al. Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node. Postgrad Med J 1990;66:134–6. [31] Marcus LC, Steere AC, Duray PH, Anderson AE, Mahoney EB. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium. Ann Intern Med 1985;103:374-6
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ACCEPTED MANUSCRIPT
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Figure 1. Diffusely infiltrated with lymphocytes and plasma cells between individual myocytes: (A) epicardial surface, (B) myocardium, (C) endocardium (H&E, 200x). (D) Spirochete within myocardium, Warthin-Starry Stain (1000x)
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Figure 2. Diffusely infiltrated with lymphocytes highlighted by CD20, CD4 and CD8 and macrophages
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highlighted by CD 163 (200x)
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Wadsworth Laboratory NYS DOH Test results Real-time PCR Real-time RT- PCR ELISA PRNT Real-time PCR Real-time PCR Real-time PCR Real-time PCR Real-time PCR Real-time PCR Real-time RT- PCR IFA titer Real time RT- PCR IFA titer PRNT Real time RT- PCR Real time RT-PCR Real-time RT-PCR IFA titer PRNT IFA titer
Not detected Not detected Non-reactive Negative Not detected Not detected Not detected Not detected Not detected Not detected Not detected < 16, normal Not detected < 16, normal Negative Not detected Not detected Not detected < 16, normal Negative < 16, normal
RNA
Real-time RT-PCR
Not detected
Antibodies DNA DNA
CSF, Serum Serum CSF CSF
Negative Negative Negative
DNA
CSF
DNA DNA IgG, IgM IgG, IgM IgG, IgM DNA C6 IgG IgM
CSF Serum Serum Serum CSF Serum Serum Serum
PRNT Real-time PCR Multiplex real-time PCR Multiplex real-time PCR PCR Real-time PCR IFA titer IFA titer IFA titer Real-time PCR ELISA Western IgG Blot Western IgM blot
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Neisseria meningitidis Streptococcus pneumoniae Haemophilus influenzae
Streptococcus Group B Mycoplasma pneumoniae Rickettsia spp. Spotted fever group Typhus fever group Borrelia burgdorferi
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Serum CSF CSF CSF CSF CSF CSF, serum CSF Serum CSF Serum Serum CSF CSF CSF Serum Serum Serum
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CSF CSF, serum
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Arbovirus Western equine encephalitis virus Powassan virus
DNA RNA IgM Antibodies DNA DNA DNA DNA DNA DNA RNA IgG RNA IgG Antibodies RNA RNA RNA IgG Antibodies IgG
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Enterovirus RNA Cache Valley virus California serogroup virus
Result
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Herpes Simplex virus 1 Herpes Simplex virus 2 Cytomegalovirus Varicella-zoster virus Epstein-Barr virus Human herpes virus 6 Eastern equine encephalitis virus Saint Louis encephalitis virus
Method
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Adenovirus West Nile virus
Specimen
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Test
Negative Negative Negative Non-reactive < 64, normal < 64, normal Negative Positive Equivocal Reactive
Table 1. Wadsworth NYS DOH report. IFA, Immunofluorescent assay; ELISA, Enzyme-linked immnosorbent assay; RT-PCR, reverse transcriptase polymerase chain reaction; PRNT, Plaque Reduction Neutralization Test.
ACCEPTED MANUSCRIPT Centers for Disease Control (CDC) Pathology report Test
Result
Heart
WS for spirochetes
Positive
IHC for Treponema spp
Positive
WS for spirochetes IHC for Treponema spp
PCR for Borrelia burgdorferi
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Table 2. CDC Pathology Report.
Positive
Negative
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Lung
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PCR for Borrelia burgdorferi
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Specimen
Negative Negative
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WS, Warthin-Starry stain; IHC, Immunohistochemical staining; PCR, polymerase chain reaction
