1. Tick-borne Diseases and Cardiomyopathy
Presentation of 3 Cases with Discussion
Kenneth B. Liegner, M.D.
ILADS Conference
Newton, MA
October 28, 2007

2. Background
Substantial literature exists for carditis from Lyme disease including cardiomyopathy.
Fatal case of pancarditis with Lyme and babesiosis co-infection reported by Marcus et. al
Bartonellae, rickettsiae, piroplasms and mycoplasms also have been reported to cause carditis
Besides Babesia microti, WA-1, and MO-1 a wide range of piroplasms/theileri exist in wildlife and ticks in nature.
Test methods to detect the full diversity of piroplasms found within ticks are not clinically available.
The extent of human disease caused by diverse piroplasms almost certainly remains incompletely defined at present.

3. Case 1 Slide 1 First seen by me, 7/05.
58 y.o. Maine Army National Guard, previously healthy.
8/01 On training maneuvers in coastal New Brunswick, Canada, camping in field with high grasses X 2 ½ weeks. Deer in vicinity. Tents had no “floor” canvas.
Noted circular bruise-like area left shin, orange to grapefruit-sized – no known history of trauma, no known tick attachments while on maneuvers.
6+ weeks later, flu-like symptoms, back pain, chills, night sweats, joint pain, limping, numbness in legs; later fatigue, cognitive problems, decreased stamina & endurance.

4. Case 1 Slide 2
Summer ’02 – Felt unwell. EKG: Complete heart block – pacemaker placed.
Lyme suspected but tests negative.
Dyspnea developed with impairment on PFTs
Coronary angiography: virtually normal coronary arteries & normal EF. No CHF.
Chest CT prominent mediastinal LN; sarcoid considered; Para-tracheal & cervical LN Bx: non-necrotizing granulomas ? Consistent with sarcoid but not felt definitely diagnostic.
A physician felt Lyme plausible (30 kDa band on Lyme Western blot) – tetracycline applied 2/04-7/04 with benefit; Biaxin & Plaquenil 7/04-6/05 – heart block did not resolve and patient remained pacemaker dependent. Para-tracheal and mediastinal lymphadenopathy improved following antibiotic treatment. PFTs improved with ABx.
4/05 Ventricular tachycardia on EPS – Pacemaker removed and Defibrillator/Pacemaker inserted.
Despite maximum doses of Sotalol, recurrent VT with repeated automatic defibrillator discharges.

5. Case 1 Slide 3 7/05 minocycline begun.
VT episodes appeared to have subsided and VT was not inducible with defibrillator testing/programming 2 weeks after minocycline begun.
Initial labs obtained at my evaluation 7/05: ESR 45 mm/hr IgG Lambda on Immunofixation Coxsackie B1-B6 negative Lyme Western blots: Stony Brook: ELISA (-); IgM 41 (30) IgG 30 MDL: IgM 41 IgG no bands IgeneX: IgM ,30,34,45, IgG

6. Case 1 Slide 4 (Initial labs & diagnostics, continued)
Bm IgG IFA 1:20 Igenex; Quest Bm FISH Neg.
Brain SPECT: severe global cortical hypo-pefusion with heterogeneity; white matter involvement noted.
Angiotensin converting enzyme 141 (ULN 67).
Thick & thin Giemsa smears for babesia/piroplasms negative.

7. Case 1 Slide 5 Subsequent Testing
5/06 Stony Brook ELISA Neg WB IgM (72) IgG (29,93)
5/06 IgeneX IgM ,39 IgG ,39
5/06 IgeneX Bm IFA +1:20, Bm FISH neg.
8/06 Stony Brook ELISA Neg WB: IgM 41 IgG 41,93
8/06 IgeneX: IgM +41, IgG ,39
8/06 Bm Quest & IgeneX neg

8. Case 1 Slide 6 Treatment Interventions and Outcome
Minocycline 7/05-present
Plaquenil added 1/06-5/06 (arguably therapeutic both for Lyme and Sarcoid)
Prednisone by pulmonologist for possibility of sarcoid late Winter/early Spring ‘06-
4/06 Repeat echocardiogram: decreased EF to 30-35% with moderately severe global hypo-kinesis – worsening occurred after Prednisone added. LVEF had never been impaired until prednisone utilized.
Discussion held with patient by his pulmonologist regarding consideration of cardiac transplantation as a possibly necessary contingency.
Empiric addition of malarone for possibility of babesiosis/piroplasmosis 5/06-11/06.
8/06 Repeat Echo 60%.
Repeat Echo 11/06 still 60%
One episode of VT 1/07 felt related to hypokalemia.
Patient has strong sense that mino & malarone was responsible for dramatic turn-around in status and feels that Prednisone did not improve his condition (and resulted in impaired LVEF).
Complication of anti-microbial Rx: grey-blue skin pigmentation lower extremities secondary to minocycline.
CHB never reversed despite antimicrobial Tx; unusual for Lyme disease alone.
Global status substantially recovered and satisfactory quality of life.

9. Case 1 Slide 7 Considerations & Discussion
Did this patient have Lyme disease?
Did this patient have babesiosis/piroplasmosis???
Did he have sarcoidoisis?
Did he have two or three of these conditions?
Did Lyme disease trigger sarcoid or a sarcoid-like illness?
Did he require anti-borrelial and anti-piroplasm/anti-babesia treatment???
Did he require Prednisone application?
Was combined Prednisone and anti-microbial therapy necessary and beneficial in his case?
Would he have recovered without some or all of the applied treatments?

10. Case 2 Slide 1
(First seen 12/05) 54 y.o. WM; extensive epidemiologic risk for tick exposures in MA, Pacific NW, Virginia, Minnesota, Maine. At least 12 known tick attachments; no known EM rashes.
11/03 CHF develops. Non-smoker. Previously physically fit and active. Normal coronary arteries on angiography, but dilated cardimyopathy. Developed syncope secondary to VT which was recurrent which co-incided with onset of CHF. Pacer/defibrillator placed. Recurrent bouts of paroxysmal AF as well which have triggered defibrillator.
Medical/cardiologic treatment: Coreg (carvedilol), aldactone, Diovan(valsartan), digoxin, Coumadin, furosemide prn.
Sarcoid r/o’d. + history of Ehler-Danlos syndrome
7/05 a prior physician found suspicious bands on Lyme WB and + anti-bodies against WA-l babesiosis; Rx by prior physician included Ketek, Doryx, Omnicef, Flagyl. On Ketek and Mepron developed AF and was cardioverted.
10/05 increasing dyspnea and decreasing exercise tolerance. Fevers and night sweats. Igenex Lyme WB 6 bands
IV Rocephin X 28 days Nov/Dec 2005 with some benefit. Increased exercise tolerance.

11. Case 2 Slide 2
11/03 EF when CHF first diagnosed: 20%; LV ED diameter 7.3 cm.
2/06 EF following antibiotic and anti-babesia Rx increased to 35% & LV ED diameter 6.3 cm (decreased by 13.6 %) global hypokinesis; LV moderately dilated; RV mildly dilated & decreased systolic function

12. Case 2 Slide 3 Pertinent labs/diagnostics
11/03 Coxsackie AB B1-B6 neg
10/05 IgeneX Lyme WB: IgG IgM ++31 IND 23
10/05 Quest WA-1 1:128 (NL< 1:64); Bm IFA negative
7/05 MDL Lyme WB IgG 31 Lyme C6 Neg Lyme ELISA neg
7/05 Stony Brook ELISA neg WB IgG 30 kDa
8/05 Bartonella henselae IFA neg
Heavy metals neg
12/05: IgM 308 (ULN 271)
12/05 Stony Brook: ELISA neg WB IgG 30 kDa
12/05 MDL: Mycoplasma fermentans PCR 24,900 copies /ml
Sonoma Co.DOH WA-1 IFA 1:640

13. Case 2 Slide 4 Treatment and Course
12/05 after sequeing off 28 days course of IV CFTRX, oral minocycline begun. Malarone added after one month for combined Rx vs. Lyme and WA-l babesiosis.
Remained on mino & malarone 12/05 at least through 10/06 when patient was “lost to follow-up”.
Progressively improving sense of well-being and exercise capacity. Dysrhythmias become a “non-issue” since 10/05. Atrial-ventricular dys-synchrony resolves. Patient avers addition of Malarone conferred most dramatic symptomatic improvement; sweats resolved with Malarone. Able to walk 4 4 MPH and play basketball X 40 minutes, able to bike 10 miles.
Repeat Mycoplasma fermentans MDL negative.
Last labs 9/06: Quest WA-l 1:256 (NL < 1:64)
Quest Bm IFA Neg
Stony Brook Lyme ELISA neg WB:IgM neg IgG 30,41 (34)
MDL Lyme WB IgG 31, 41 IgM No bands
IgeneX: IgM 23,31,39,41
IgG Positive , 34, 39
(negative by CDC criteria)

14. Case 3 Slide 1
49 y.o. WM, resident of a southwestern U.S. state. Previously healthy, physically active, hiker, camper, runner in mountainous and wooded regions of the West and the Pacific Northwest. One probable engorged tick attachment 1984 without obvious illness. No history of ECM.
12/04 “heart irregularity” noted on insurance physical; advised to follow-up with personal physician but did not do so. Retrospective review showed AF.
Spring ’06 noted “heart flutter” while back-packing. Cardiologist found atrial fibrillation and echo with markedly reduced 25% (NL 55%) with dilated LV. Coumadin started.
Fall ’06 cardiac cath: normal coronary arteries. LV enlarged; EF 20%.
Coxsackie viral titers NEG. Echoviral titers NEG. EBV IgG AB+; CMV AB +; RMSF AB NEG; PCRS Bb, Bh, NEG;
11/06 Lyme MDL: IgG 39,41 (faint 28, 60) IgM faint 41.
11/06 Lyme Stony Brook: IgM 41 (18,62) IgG (37)
11/06 Lyme Igenex: IgM ++41 IgG faint 23,31,39
11/06 WA-l AB NEG; Bm FISH NEG
11/06 AB and PCR’s NEG Bh; AB HME/HGE NEG.

15. CASE 3 Slide 2 1/07 Lyme ELISA Stony Brook POSITIVE
Stony Brook WB: IgM 41 (18,64)
IgG (37)
1/07 MDL: IgG 39,41 and faint ,28,30, IgM
faint 41
1/07 IgeneX: IgM
IND 34,39
IgG
IND 39
ANA + 1:80 homogeneous
ACE NORMAL
C3/C4 & C1Q IMMUNE COMPLEXES NORMAL
HANTAVIRUS AB NEG
1/07 Bm IFA’s, FISH, IgeneX NEG

16. CASE 3 Slide 3
Despite severely compromised cardiac function patient has minimal symptoms and does not endorse shortness of breath on exertion.
Does not endorse multi-system symptoms as often seen in Lyme disease; has only some mild arthralgia in knees, mild cervicalgia, myalgia, occasional tinnitus, questionable paresthesias.

17. CASE 3 Slide 4
1/07 Cardioverted into NSR but reverted to AF within one week
Minocycline 200 mg/day begun 12/06
Malarone added 2/07 for strictly empiric therapy to cover possible piroplasm co-infection
Repeat echo 5/07 after 6 months minocycline combined for the final 3 months with malarone: No improvement in 20 %. AF continued.
Minocycline and malarone discontinued 6/07.
Patient decides to pursue evaluation for possible trial of Valganciclovir with Dr. Stanford U. Medical Center in view of strongly elevated IgG antibody titers to CMV, EBV, and HHV6.
Meanwhile, repeat Echocardiogram 2months after discontinuing mino/malarone shows improvement in EF to 30-35% (prior to any use of valganciclovir); Not clear but it is possible anti-microbial treatment might have been responsible for improvement.
Intent for patient to undergo either pharmacologic attempts to restore sinus rhythm or catheter ablation of pulmonary vein region of left atrium.

18. SUMMARY
Carditis including cardiomyopathy can be caused by tick-borne infections.
Patients with cardiomyopathy deserve thorough evaluation for exposure to tick-borne diseases as possible treatable/reversible etiologies. Other causes for cardiomyopathy must be systematically assessed as well.
Close collaboration/cooperation with a cardiolgist is mandatory.
If there is clinical and/or laboratory evidence of one tick-borne infection consider the possibility that other tick-borne co-infections might be operative; it may be prudent to cover the most likely “bases” empirically in dealing with this potentially life-threatening illness, given the insensitivity of current test methods and the fact that borreliae, rickettsiae/ehrlichiae, piroplasms, bartonellae species, and mycoplasms all can cause carditis.
Minocycline combined with malarone would seem a rational and economical regimen that would cover most of the tick-transmissible bacterial/parasitic infections in patients who are felt to have evidence of tick-borne etiology for their carditis. Other regimens may be also be acceptable. Systematic comparison of optimal regimens have not been undertaken due to the relative rarity of cardiomyopathy as a complication of tick-borne illness.

19. SUMMARY (cont’d)
General physicians, cardiologists and other health care professionals need to be educated to consider tick-borne illness as one possible etiology of cardiomyopathy.
Antimicrobial treatment can sometimes reverse the myocardial dysfunction and abolish life-threatening dysrhythmias and congestive cardiomyopathy and can avert catastrophic outcomes. Early recognition and appropriate treatment, as in other manifestations of Lyme disease, seem most likely to result in optimal outcomes; late diagnosis can result in irreversible cardiac injury and death. Late application of treatment might result less responsiveness due to scarring of myocardium and/or conduction system.
One might want to be circumspect about the use of azalides in patients with carditis/cardiomyopathy because these agents can sometimes prolong the QT interval and may be pro-arrhythmic in that setting.

20. SUMMARY (cont’d) FOOD FOR THOUGHT:
How many cases of “idiopathic” cardiomyopathy might result from occult TBDs?????
What is the excess cost to society for congestive cardiomyopathies and refractory life-threatening dysrhythmias (e.g. Atrial fib, ventricular tachycardias and ventricular fibrillation) requiring pacemakers, implanted automatic defibrillators, hospitalizations and expensive drug therapies and/or cardiac transplantation due to missed diagnoses of tick-borne carditis??? What is the extent of avoidable personal suffering for patients and their families consequent to failure to diagnose and treat carditis/cardiomyopathy due to TBDs???

21. PERTINENT REFERENCES BORRELIAE
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 Sep;103(3):374-6.
PMID: [PubMed - indexed for MEDLINE]
Vlay SC, Dervan JP, Elias J, Kane PP, Dattwyler R.
Ventricular tachycardia associated with Lyme carditis.
Am Heart J May;121(5): No abstract available.
PMID: [PubMed - indexed for MEDLINE]
Stanek G, Klein J, Bittner R, Glogar D.
Borrelia burgdorferi as an etiologic agent in chronic heart failure?
Scand J Infect Dis Suppl. 1991;77:85-7.
PMID: [PubMed - indexed for MEDLINE]
Isolation of Borrelia burgdorferi from the myocardium of a patient with
longstanding cardiomyopathy.N Engl J Med Jan 25;322(4): No abstract available.
PMID: [PubMed - indexed for MEDLINE]
Gasser R, Lercher P, Klein W. Lyme Carditis and Borrelia-Associated Dilated Cardiomyopathy. Heart Failure Reviews 1999, 3:

22. PERTINENT REFERENCES (continued)
BABESIOSIS/PIROPLASMS
Armstrong PM, Katavolos P, Caporale DA, Smith RP, Spielman A, Telford SR
3rd. Diversity of Babesia infecting deer ticks (Ixodes dammini).
Am J Trop Med Hyg Jun;58(6):
PMID: [PubMed - indexed for MEDLINE]
Persing DH, Conrad PA.
Babesiosis: new insights from phylogenetic analysis.
Infect Agents Dis Dec;4(4): Review.
PMID: [PubMed - indexed for MEDLINE]
Persing DH, Herwaldt BL, Glaser C, Lane RS, Thomford JW, Mathiesen D,
Krause PJ, Phillip DF, Conrad PA.
Infection with a babesia-like organism in northern California.
N Engl J Med Feb 2;332(5):
PMID: [PubMed - indexed for MEDLINE]
Herwaldt B, Persing DH, Precigout EA, Goff WL, Mathiesen DA, Taylor PW,
Eberhard ML, Gorenflot AF.
A fatal case of babesiosis in Missouri: identification of another piroplasm
that infects humans.
Ann Intern Med Apr 1;124(7):

23. PERTINENT REFERENCES (cont’d)
BARTONELLA, EHRLICHEA, RICKETTSIAE, MYCOPLASMA
Shah SS, McGowan JP. Rickettsial, ehrlichial and Bartonella infections of the myocardium and pericardium. Front Biosci Jan 1;8:e Review. PMID: [PubMed - indexed for MEDLINE]
Paz A, Potasman I Mycoplasma-associated carditis. Case reports and review. Cardiology. 2002;97(2):83-8. Review. PMID: [PubMed - indexed for MEDLINE]
Jahangir A, Kolbert C, Edwards W, Mitchell P, Dumler JS, Persing DH.
Fatal pancarditis associated with human granulocytic Ehrlichiosis in a
44-year-old man. Clin Infect Dis Dec;27(6):
PMID: [PubMed - indexed for MEDLINE]
Meininger GR, Nadasdy T, Hruban RH, Bollinger RC, Baughman KL, Hare JM.
Chronic active myocarditis following acute Bartonella henselae infection (cat
scratch disease). Am J Surg Pathol Sep;25(9):
PMID: [PubMed - indexed for MEDLINE]
Walker DH, Paletta CE, Cain BG Pathogenesis of myocarditis in Rocky Mountain spotted fever. Arch Pathol Lab Med Apr;104(4):171-4.PMID: [PubMed - indexed for MEDLINE]