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• W2296832009 abstract "Fatal Lyme carditis caused by the spirochete Borrelia burgdorferi rarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology. Interstitial lymphocytic pancarditis in a relatively characteristic road map distribution was present in all cases. Cardiomyocyte necrosis was minimal, T cells outnumbered B cells, plasma cells were prominent, and mild fibrosis was present. Spirochetes in the cardiac interstitium associated with collagen fibers and co-localized with decorin. Rare spirochetes were seen in the leptomeninges of two cases by immunohistochemistry. Spirochetes were not seen in other organs examined, and joint tissue was not available for evaluation. Although rare, sudden cardiac death caused by Lyme disease might be an under-recognized entity and is characterized by pancarditis and marked tropism of spirochetes for cardiac tissues. Fatal Lyme carditis caused by the spirochete Borrelia burgdorferi rarely is identified. Here, we describe the pathologic, immunohistochemical, and molecular findings of five case patients. These sudden cardiac deaths associated with Lyme carditis occurred from late summer to fall, ages ranged from young adult to late 40s, and four patients were men. Autopsy tissue samples were evaluated by light microscopy, Warthin-Starry stain, immunohistochemistry, and PCR for B. burgdorferi, and immunohistochemistry for complement components C4d and C9, CD3, CD79a, and decorin. Post-mortem blood was tested by serology. Interstitial lymphocytic pancarditis in a relatively characteristic road map distribution was present in all cases. Cardiomyocyte necrosis was minimal, T cells outnumbered B cells, plasma cells were prominent, and mild fibrosis was present. Spirochetes in the cardiac interstitium associated with collagen fibers and co-localized with decorin. Rare spirochetes were seen in the leptomeninges of two cases by immunohistochemistry. Spirochetes were not seen in other organs examined, and joint tissue was not available for evaluation. Although rare, sudden cardiac death caused by Lyme disease might be an under-recognized entity and is characterized by pancarditis and marked tropism of spirochetes for cardiac tissues. Lyme disease is caused by the spirochete Borrelia burgdorferi in North America and transmitted by certain species of Ixodes ticks. Approximately 30,000 cases are reported annually in the United States, but the actual number may be 10-fold higher.1Hinckley A.F. Connally N.P. Meek J.I. Johnson B.J. Kemperman M.M. Feldman K.A. White J.L. Mead P.S. Lyme disease testing by large commercial laboratories in the United States.Clin Infect Dis. 2014; 59: 676-681Crossref PubMed Scopus (287) Google Scholar Other Borrelia species in the B. burgdorferi sensu lato complex, including Borrelia afzelii and Borrelia garinii, cause Lyme disease in Europe. Clinical symptoms are largely dermatologic, neurologic, and musculoskeletal. In the United States, cardiovascular symptoms occur in approximately 1.1% of reported cases,2Forrester J.D. Meiman J. Mullins J. Nelson R. Ertel S.H. Cartter M. et al.Centers for Disease Control and PreventionNotes from the field: update on Lyme carditis, groups at high risk, and frequency of associated sudden cardiac death–United States.MMWR Morb Mortal Wkly Rep. 2014; 63: 982-983PubMed Google Scholar can manifest as conduction block,3Forrester J.D. Mead P. Third-degree heart block associated with lyme carditis: review of published cases.Clin Infect Dis. 2014; 59: 996-1000Crossref PubMed Scopus (70) Google Scholar, 4Fish A.E. Pride Y.B. Pinto D.S. Lyme carditis.Infect Dis Clin North Am. 2008; 22 (vi): 275-288Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar and, when recognized, usually resolve with appropriate antibiotics.5Wormser G.P. Dattwyler R.J. Shapiro E.D. Halperin J.J. Steere A.C. Klempner M.S. Krause P.J. Bakken J.S. Strle F. Stanek G. Bockenstedt L. Fish D. Dumler J.S. Nadelman R.B. The clinical assessment, treatment, and prevention of lyme disease, human granulocytic anaplasmosis, and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America.Clin Infect Dis. 2006; 43: 1089-1134Crossref PubMed Scopus (1563) Google Scholar Fatal myocarditis is rare, with only four cases reported before 2013 in the United States6Cary N.R. Fox B. Wright D.J. Cutler S.J. Shapiro L.M. Grace A.A. Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node.Postgrad Med J. 1990; 66: 134-136Crossref PubMed Scopus (47) Google Scholar, 7Marcus L.C. Steere A.C. Duray P.H. Anderson A.E. Mahoney E.B. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium.Ann Intern Med. 1985; 103: 374-376Crossref PubMed Scopus (171) Google Scholar, 8Tavora F. Burke A. Li L. Franks T.J. Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction.Cardiovasc Pathol. 2008; 17: 103-107Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and Europe,9Reimers C.D. de Koning J. Neubert U. Preac-Mursic V. Koster J.G. Muller-Felber W. Pongratz D.E. Duray P.H. Borrelia burgdorferi myositis: report of eight patients.J Neurol. 1993; 240: 278-283Crossref PubMed Scopus (75) Google Scholar including three cases with detailed pathology findings.6Cary N.R. Fox B. Wright D.J. Cutler S.J. Shapiro L.M. Grace A.A. Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node.Postgrad Med J. 1990; 66: 134-136Crossref PubMed Scopus (47) Google Scholar, 7Marcus L.C. Steere A.C. Duray P.H. Anderson A.E. Mahoney E.B. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium.Ann Intern Med. 1985; 103: 374-376Crossref PubMed Scopus (171) Google Scholar, 8Tavora F. Burke A. Li L. Franks T.J. Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction.Cardiovasc Pathol. 2008; 17: 103-107Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In 2013, the CDC reported three additional cases of fatal carditis associated with Lyme disease.10Centers for Disease Control and PreventionThree sudden cardiac deaths associated with Lyme carditis - United States, November 2012-July 2013.MMWR Morb Mortal Wkly Rep. 2013; 62: 993-996PubMed Google Scholar The most frequently described pathologic findings in Lyme disease correlate with the clinical stages of disease.11Duray P.H. The surgical pathology of human Lyme disease. An enlarging picture.Am J Surg Pathol. 1987; 11 Suppl 1: 47-60Crossref PubMed Scopus (61) Google Scholar, 12Duray P.H. Steere A.C. Clinical pathologic correlations of Lyme disease by stage.Ann N Y Acad Sci. 1988; 539: 65-79Crossref PubMed Scopus (141) Google Scholar In early localized disease (3 to 30 days after tick bite), skin biopsy specimens of erythema migrans show lymphohistiocytic perivascular dermatitis, whereas in late-stage disease (months to years after tick bite), synovial biopsy specimens for arthritis classically show synovium with villous proliferation, lymphoplasmacytic infiltrates, and microangiopathic change.13Johnston Y.E. Duray P.H. Steere A.C. Kashgarian M. Buza J. Malawista S.E. Askenase P.W. Lyme arthritis. Spirochetes found in synovial microangiopathic lesions.Am J Pathol. 1985; 118: 26-34PubMed Google Scholar Lyme carditis occurs most frequently during early disseminated Lyme disease, generally days to weeks after tick bite. Endomyocardial biopsy specimens and autopsy findings show edema, subendocardial infiltrates (on biopsy specimen), pancarditis (on autopsy) with perivascular interstitial infiltrates, increased collagen deposition, and limited cardiomyocyte necrosis.7Marcus L.C. Steere A.C. Duray P.H. Anderson A.E. Mahoney E.B. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium.Ann Intern Med. 1985; 103: 374-376Crossref PubMed Scopus (171) Google Scholar, 8Tavora F. Burke A. Li L. Franks T.J. Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction.Cardiovasc Pathol. 2008; 17: 103-107Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 14Duray P.H. Clinical pathologic correlations of Lyme disease.Rev Infect Dis. 1989; 11: S1487-S1493Crossref PubMed Scopus (64) Google Scholar, 15de Koning J. Hoogkamp-Korstanje J.A. van der Linde M.R. Crijns H.J. Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease.J Infect Dis. 1989; 160: 150-153Crossref PubMed Scopus (81) Google Scholar Largely European studies of central nervous system pathology during early disseminated to late-stage disease have described brain and spinal cord meningeal and perivascular infiltrates, gliosis, microglial activation and glial nodules,16Bertrand E. Szpak G.M. Pilkowska E. Habib N. Lipczynska-Lojkowska W. Rudnicka A. Tylewska-Wierzbanowska S. Kulczycki J. Central nervous system infection caused by Borrelia burgdorferi. Clinico-pathological correlation of three post-mortem cases.Folia Neuropathol. 1999; 37: 43-51PubMed Google Scholar involvement of cranial nerves17Miklossy J. Kuntzer T. Bogousslavsky J. Regli F. Janzer R.C. Meningovascular form of neuroborreliosis: similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis.Acta Neuropathol. 1990; 80: 568-572Crossref PubMed Scopus (47) Google Scholar in addition to peripheral nerve infiltrates, and axonal degeneration.18Meurers B. Kohlhepp W. Gold R. Rohrbach E. Mertens H.G. Histopathological findings in the central and peripheral nervous systems in neuroborreliosis. A report of three cases.J Neurol. 1990; 237: 113-116Crossref PubMed Scopus (48) Google Scholar Other fatal complications reported include a case of acute respiratory distress syndrome,19Kirsch M. Ruben F.L. Steere A.C. Duray P.H. Norden C.W. Winkelstein A. Fatal adult respiratory distress syndrome in a patient with Lyme disease.JAMA. 1988; 259: 2737-2739Crossref PubMed Scopus (32) Google Scholar and neonatal death after transplacental transmission.20Schlesinger P.A. Duray P.H. Burke B.A. Steere A.C. Stillman M.T. Maternal-fetal transmission of the Lyme disease spirochete, Borrelia burgdorferi.Ann Intern Med. 1985; 103: 67-68Crossref PubMed Scopus (171) Google Scholar, 21MacDonald A.B. Gestational Lyme borreliosis. Implications for the fetus.Rheum Dis Clin North Am. 1989; 15: 657-677PubMed Google Scholar By histopathology, spirochetes have been reported in skin,22Berger B.W. Erythema chronicum migrans of Lyme disease.Arch Dermatol. 1984; 120: 1017-1021Crossref PubMed Scopus (92) Google Scholar, 23Berger B.W. Kaplan M.H. Rothenberg I.R. Barbour A.G. Isolation and characterization of the Lyme disease spirochete from the skin of patients with erythema chronicum migrans.J Am Acad Dermatol. 1985; 13: 444-449Abstract Full Text PDF PubMed Scopus (94) Google Scholar, 24Van Mierlo P. Jacob W. Dockx P. Erythema chronicum migrans: an electron-microscopic study.Dermatology. 1993; 186: 306-310Crossref PubMed Scopus (15) Google Scholar synovium,13Johnston Y.E. Duray P.H. Steere A.C. Kashgarian M. Buza J. Malawista S.E. Askenase P.W. Lyme arthritis. Spirochetes found in synovial microangiopathic lesions.Am J Pathol. 1985; 118: 26-34PubMed Google Scholar ligament,25Haupl T. Hahn G. Rittig M. Krause A. Schoerner C. Schonherr U. Kalden J.R. Burmester G.R. Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis.Arthritis Rheum. 1993; 36: 1621-1626Crossref PubMed Scopus (110) Google Scholar spleen,26Cimmino M.A. Azzolini A. Tobia F. Pesce C.M. Spirochetes in the spleen of a patient with chronic Lyme disease.Am J Clin Pathol. 1989; 91: 95-97Crossref PubMed Scopus (18) Google Scholar, 27Rank E.L. Dias S.M. Hasson J. Duray P.H. Johnson R.C. Magnarelli L.A. Fister R.D. Human necrotizing splenitis caused by Borrelia burgdorferi.Am J Clin Pathol. 1989; 91: 493-498Crossref PubMed Scopus (6) Google Scholar leptomeninges,17Miklossy J. Kuntzer T. Bogousslavsky J. Regli F. Janzer R.C. Meningovascular form of neuroborreliosis: similarities between neuropathological findings in a case of Lyme disease and those occurring in tertiary neurosyphilis.Acta Neuropathol. 1990; 80: 568-572Crossref PubMed Scopus (47) Google Scholar and heart7Marcus L.C. Steere A.C. Duray P.H. Anderson A.E. Mahoney E.B. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium.Ann Intern Med. 1985; 103: 374-376Crossref PubMed Scopus (171) Google Scholar, 15de Koning J. Hoogkamp-Korstanje J.A. van der Linde M.R. Crijns H.J. Demonstration of spirochetes in cardiac biopsies of patients with Lyme disease.J Infect Dis. 1989; 160: 150-153Crossref PubMed Scopus (81) Google Scholar, 28Hajjar R.J. Kradin R.L. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 17-2002. A 55-year-old man with second-degree atrioventricular block and chest pain.N Engl J Med. 2002; 346: 1732-1738Crossref PubMed Scopus (21) Google Scholar using silver stains. However, spirochetes often are not visualized, as documented in confirmed cases of neuroborreliosis,16Bertrand E. Szpak G.M. Pilkowska E. Habib N. Lipczynska-Lojkowska W. Rudnicka A. Tylewska-Wierzbanowska S. Kulczycki J. Central nervous system infection caused by Borrelia burgdorferi. Clinico-pathological correlation of three post-mortem cases.Folia Neuropathol. 1999; 37: 43-51PubMed Google Scholar fatal myocarditis,6Cary N.R. Fox B. Wright D.J. Cutler S.J. Shapiro L.M. Grace A.A. Fatal Lyme carditis and endodermal heterotopia of the atrioventricular node.Postgrad Med J. 1990; 66: 134-136Crossref PubMed Scopus (47) Google Scholar, 8Tavora F. Burke A. Li L. Franks T.J. Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction.Cardiovasc Pathol. 2008; 17: 103-107Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar and lymphocytoma cutis,29Colli C. Leinweber B. Mullegger R. Chott A. Kerl H. Cerroni L. Borrelia burgdorferi-associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases.J Cutan Pathol. 2004; 31: 232-240Crossref PubMed Scopus (149) Google Scholar likely because of low numbers of spirochetes and high background seen in conventional silver stains. PCR can identify (or detect) B. burgdorferi DNA in tissue,8Tavora F. Burke A. Li L. Franks T.J. Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction.Cardiovasc Pathol. 2008; 17: 103-107Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 29Colli C. Leinweber B. Mullegger R. Chott A. Kerl H. Cerroni L. Borrelia burgdorferi-associated lymphocytoma cutis: clinicopathologic, immunophenotypic, and molecular study of 106 cases.J Cutan Pathol. 2004; 31: 232-240Crossref PubMed Scopus (149) Google Scholar and, more recently, immunohistochemistry (IHC) has been used to show borrelial antigens in clinical specimens30Eisendle K. Grabner T. Zelger B. Focus floating microscopy: “gold standard” for cutaneous borreliosis?.Am J Clin Pathol. 2007; 127: 213-222Crossref PubMed Scopus (60) Google Scholar and in experimental models.31Imai D.M. Feng S. Hodzic E. Barthold S.W. Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection.Lab Invest. 2013; 93: 900-910Crossref PubMed Scopus (23) Google Scholar B. burgdorferi possesses numerous adhesins that bind host extracellular matrix molecules, including glycosaminoglycans, fibronectin, collagen, and the small proteoglycan decorin,32Brissette C.A. Gaultney R.A. That's my story, and I'm sticking to it–an update on B. burgdorferi adhesins.Front Cell Infect Microbiol. 2014; 4: 41Crossref PubMed Scopus (42) Google Scholar which mediate tissue tropism, pathogenicity, and immune invasion. In experimentally infected mice, B. burgdorferi binding to decorin has been implicated in spirochete cardiac tissue tropism.31Imai D.M. Feng S. Hodzic E. Barthold S.W. Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection.Lab Invest. 2013; 93: 900-910Crossref PubMed Scopus (23) Google Scholar, 33Lin Y.P. Benoit V. Yang X. Martinez-Herranz R. Pal U. Leong J.M. Strain-specific variation of the decorin-binding adhesin DbpA influences the tissue tropism of the lyme disease spirochete.PLoS Pathog. 2014; 10: e1004238Crossref PubMed Scopus (59) Google Scholar Here, we report the pathologic, immunohistochemical, molecular, and serologic findings of five cases of sudden cardiac death associated with Lyme disease and show marked tropism of spirochetes for heart tissue, providing insight into the pathogenesis of Lyme myocarditis. Partial data on three of the five patients have been published previously10Centers for Disease Control and PreventionThree sudden cardiac deaths associated with Lyme carditis - United States, November 2012-July 2013.MMWR Morb Mortal Wkly Rep. 2013; 62: 993-996PubMed Google Scholar; together, these and additional data are reported here and provide a broader description of a rare disease. Autopsy specimens were submitted to the CDC Infectious Diseases Pathology Branch and Bacterial Diseases Branch Laboratories in 2013 to 2014 by medical examiners and state public health laboratories. All cases with laboratory evidence of B. burgdorferi infection were included. A median of 3 (range, 1 to 5) cardiac specimens were submitted per case. Other tissues were evaluated as available and are described later. Autopsy tissues from patients were submitted to the CDC as part of a public health investigation, and did not require review by an institutional review board. In an effort to maintain family confidentiality, data are presented in summary form and specific ages are not provided. Hematoxylin and eosin, Warthin-Starry (WS), and trichrome stains were performed according to standard protocols using Leica ST5020 multistainer (Leica, Buffalo Grove, IL), Dako Artisan Link autostainers (Dako, Carpinteria, CA), and manual methods, respectively. Slides for the WS stain were cut at 5-μm thickness to maximize detection of spirochetes. IHC was performed using a polymer-based indirect immunoalkaline phosphatase detection system with a fast red chromogen for the colorimetric detection of an antibody/polymer complex (Biocare Medical, Concord, CA). B. burgdorferi IHC was performed using rabbit polyclonal antibody (immunized against a whole-cell preparation) (ab34970; Abcam, Cambridge, MA), used at a 1:1000 dilution with proteinase K pretreatment.31Imai D.M. Feng S. Hodzic E. Barthold S.W. Dynamics of connective-tissue localization during chronic Borrelia burgdorferi infection.Lab Invest. 2013; 93: 900-910Crossref PubMed Scopus (23) Google Scholar Internal validation data showed that this assay cross-reacts with Borrelia hermsii and Treponema pallidum, but does not detect Leptospira species (data not shown). A mouse monoclonal antibody against B. burgdorferi flagellin (clone H9724), used at a 1:2000 dilution (gift from Barbara Johnson, Division of Vector Borne Diseases, CDC) was used for confirmation (data not shown). To evaluate for cardiomyocyte injury, IHC for complement components C4d and C9 was performed as previously described.34Jenkins C.P. Cardona D.M. Bowers J.N. Oliai B.R. Allan R.W. Normann S.J. The utility of C4d, C9, and troponin T immunohistochemistry in acute myocardial infarction.Arch Pathol Lab Med. 2010; 134: 256-263PubMed Google Scholar, 35Paddock C.D. Liu L. Denison A.M. Bartlett J.H. Holman R.C. Deleon-Carnes M. Emery S.L. Drew C.P. Shieh W.J. Uyeki T.M. Zaki S.R. Myocardial injury and bacterial pneumonia contribute to the pathogenesis of fatal influenza B virus infection.J Infect Dis. 2012; 205: 895-905Crossref PubMed Scopus (128) Google Scholar Mouse monoclonal antibodies against CD3 (M7254; Dako) and CD79a (sc20064; Santa Cruz Biotechnology, Dallas, TX) were used at 1:100 and 1:500 dilutions, respectively. Rabbit polyclonal antidecorin (immunized against a recombinant protein epitope tag) (HPA003315; Sigma Aldrich, St. Louis, MO) was used at a 1:100 dilution.36Henke A. Grace O.C. Ashley G.R. Stewart G.D. Riddick A.C. Yeun H. O'Donnell M. Anderson R.A. Thomson A.A. Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer.PLoS One. 2012; 7: e42516Crossref PubMed Scopus (36) Google Scholar To evaluate for co-infections, IHC for Heartland virus was performed as previously described.37Muehlenbachs A. Fata C.R. Lambert A.J. Paddock C.D. Velez J.O. Blau D.M. Staples J.E. Karlekar M.B. Bhatnagar J. Nasci R.S. Zaki S.R. Heartland virus-associated death in tennessee.Clin Infect Dis. 2014; 59: 845-850Crossref PubMed Scopus (60) Google Scholar IHC for Powassan virus used hyperimmune mouse ascitic fluid (courtesy of Pierre Rollin, CDC), which is known to detect Powassan virus antigens in formalin-fixed, paraffin-embedded (FFPE) human tissues at a 1:1000 dilution. IHC for Anaplasma phagocytophilum used horse polyclonal antibody (gift from Richard E. Cortsvet, Louisiana State University), which is known to detect A. phagocytophilum in FFPE human tissues at a 1:1000 dilution. DNA were extracted from FFPE tissues as previously described using the QIAamp DNA Mini Kit (Qiagen, Valencia, CA).38Guarner J. Bhatnagar J. Shieh W.J. Nolte K.B. Klein D. Gookin M.S. Penaranda S. Oberste M.S. Jones T. Smith C. Pallansch M.A. Zaki S.R. Histopathologic, immunohistochemical, and polymerase chain reaction assays in the study of cases with fatal sporadic myocarditis.Hum Pathol. 2007; 38: 1412-1419Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar DNA was extracted from whole blood using the QIAamp DNA Mini Kit (Qiagen) following the manufacturer's instructions. Primers and probes targeting outer surface protein A,39Straubinger R.K. PCR-Based quantification of Borrelia burgdorferi organisms in canine tissues over a 500-Day postinfection period.J Clin Microbiol. 2000; 38: 2191-2199PubMed Google Scholar flagellin,40Pahl A. Kuhlbrandt U. Brune K. Rollinghoff M. Gessner A. Quantitative detection of Borrelia burgdorferi by real-time PCR.J Clin Microbiol. 1999; 37: 1958-1963PubMed Google Scholar and plasminogen binding protein41Babady N.E. Sloan L.M. Vetter E.A. Patel R. Binnicker M.J. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue.Diagn Microbiol Infect Dis. 2008; 62: 464-466Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar were modified slightly and used for real-time PCR. PCR for outer surface protein A was performed in 25-μL volumes with 5 μL DNA extract using the QuantiTect Multiplex PCR Kit (Qiagen), and run on the Mx3005P QPCR System (Agilent, Santa Clara, CA) with cycling conditions of 95°C for 15 minutes, 45 cycles of 94°C for 1 minute, and 60°C for 1 minute. Positive controls included FFPE blocks containing cell culture isolates of B. burgdorferi (courtesy of Barbara Johnson, Division of Vector Borne Diseases, CDC). Samples were considered positive when the threshold cycle value was ≤40. PCR for flagellin and plasminogen binding protein was performed in 20-μL volumes with 5 to 10 μL of DNA extract using TaqMan Fast Universal PCR Master Mix (Life Technology, Grand Island, NY) and run on the AB 7500 FAST Dx Real-Time PCR instrument (Applied Biosystems, Grand Island, NY) with cycling conditions of 95°C for 20 seconds, 45 cycles of 95°C for 3 seconds, and 60°C for 30 seconds. Samples were considered positive if their threshold cycle value was ≤40 and less than the threshold cycle value of the positive control. PCR for Babesia microti was performed as previously described42Froberg M.K. Dannen D. Bernier N. Shieh W.J. Guarner J. Zaki S. Case report: spontaneous splenic rupture during acute parasitemia of Babesia microti.Ann Clin Lab Sci. 2008; 38: 390-392PubMed Google Scholar to evaluate for co-infection.7Marcus L.C. Steere A.C. Duray P.H. Anderson A.E. Mahoney E.B. Fatal pancarditis in a patient with coexistent Lyme disease and babesiosis. Demonstration of spirochetes in the myocardium.Ann Intern Med. 1985; 103: 374-376Crossref PubMed Scopus (171) Google Scholar At the CDC, all serologic tests were performed using patient sera and following the manufacturer's instructions. Two enzyme immunoassays were used: a whole-cell sonicate enzyme immunoassay [Vitek Immunodiagnostic Assay System (VIDAS) Lyme IgM and IgG Polyvalent Assay, bioMérieux, Inc., Durham, NC] and the C6 B. burgdorferi (Lyme) enzyme immunoassay (Immunetics, Boston, MA). IgM and IgG Western Blots (WBs) (MarDx Diagnostics, Inc., Carlsbad, CA) also were run on all patient sera. The immunoblotting results were interpreted according to the guidelines proposed by the CDC,43Centers for Disease Control and PreventionRecommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease.MMWR Morb Mortal Wkly Rep. 1995; 44: 590-591PubMed Google Scholar in which 2 of the 3 bands and 5 of the 10 bands are required for positive IgM and IgG WBs, respectively. Summary data are presented in Table 1. Briefly, ages ranged from young adult to late ‘40s. Deaths occurred in states containing counties with a high or moderate incidence of Lyme disease (New York; New Hampshire, with recent travel to Connecticut; Massachusetts; and Indiana). Deaths occurred in the months of July (three deaths), August (one death), and November (one death) 2012 to 2014. Three patients were otherwise healthy. Two patients had known underlying disease: one patient had a history of Wolf-Parkinson-White syndrome, and another patient had a history of diabetes mellitus, hepatitis B, and cocaine and alcohol use. One patient had given birth approximately 6 months previously. All patients were reported to engage in outdoor activities, two patients had known exposure to ticks, and one patient reported a recent bite.Table 1Demographic and Clinical DataAge range, years (median)Young adult to late 40s (28)Male sex/n4/5State (n)NY (2), MA (1), NH (1; exposure in CT), and IN (1)Month of death (n)July (4), August (1), November (1)Otherwise healthy/n3/5Known comorbiditiesWPW (1); DM, HBV, and alcohol and cocaine use (1)Tick exposure activity/n4/5Prodrome (n)<3 weeks (3), several months (1)Recent joint pain/n3/5Dermatologic lesion/n0/5; possible spider bite (1)DM, diabetes mellitus; HBV, hepatitis B virus; WPW, Wolf-Parkinson-White syndrome. Open table in a new tab DM, diabetes mellitus; HBV, hepatitis B virus; WPW, Wolf-Parkinson-White syndrome. A prodrome was reported for each of the patients that included the following: nonspecific viral-like illness, malaise, shortness of breath, and anxiety. One of these patients also had joint and muscle pain, and the other two patients had joint pain for an unknown duration. No dermatologic lesion was documented or reported for any of the patients, although one patient was evaluated in an emergency department 1 month before death for an arm lesion diagnosed as a possible spider bite from which methicillin-resistant Staphylococcus aureus was isolated in culture. One patient underwent pre-mortem serologic screening for Lyme disease and results were negative. Lyme disease was not clinically suspected in a second patient who sought care for episodic shortness of breath; the remaining two patients did not seek medical care. For two cases, Lyme disease initially was suspected by cardiac pathology at a tissue bank transplant service (no cardiac tissue was transplanted). The remaining two patients were diagnosed at the CDC through unexplained-death investigations. At autopsy, hearts generally were enlarged (Table 2), one heart was described as diffusely mottled and soft and another heart had an odd muddled coloration with epicardial petechiae, and two patients had significant atherosclerosis. The patient with the smallest heart (380 g; normal, <350 g), who was otherwise healthy, also had the smallest body mass (61 kg), with relative cardiomegaly with a cardiac mass percentage of 0.62% (normal, 0.5%44Gaitskell K. Perera R. Soilleux E.J. Derivation of new reference tables for human heart weights in light of increasing body mass index.J Clin Pathol. 2011; 64: 358-362Crossref PubMed Scopus (39) Google Scholar). The active outdoor enthusiast had a large heart (570 g), but a 125-kg body mass, for a normal cardiac mass percentage of 0.46%. The patient with a clinical history of Wolf-Parkinson-White syndrome had a 734 g heart (cardiac mass percentage, 0.74%) with 95% stenosis of the right coronary artery, 90% stenosis of the left anterior descending coronary artery, and concentric left ventricular hypertrophy. One patient had 60% stenosis of the left anterior descending coronary artery with biventricular dilation, and another patient had focal mild atherosclerosis with biventricular dilation. Mild hepatosplenomegaly was seen in all cases.Table 2Pathologic Findings and Borrelia TestingParameters assessedFindingsNormal valuesGross autopsy findings Heart weight, range (median)380–716 (650) g250–350 g Heart weight, % range (median)0.45–0.97 (0.62)0.5% Gross cardiac findingsBiventricular dilation (1)Biventricular dilation and moderate CAD (1)Concentric LVH and severe CAD (1)Biventricular hypertrophy (1)Conc" @default.
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