British Cardiovascular Society



First Reported Case of Giant Cell Myocarditis and Acute Lyme Disease Infection: A Potential Link or Unfortunate Coincidence?

Dr. Alexander Carpenter*, Dr. Peter Scott and Dr. Sern Lim

*Corresponding author, Severn Deanery

Case

A 40 year old lady presented with a 10 day history of breathlessness, palpitations and chest tightness. The palpitations were short-lived, regular and rapid, and associated with pre-syncope. She visited her local general physician who organised some routine blood tests and a Chest X-ray which revealed cardiomegaly, bilateral opacification and bilateral pleural effusions consistent with congestive heart failure. Based on these results, the physician advised hospital admission.

On initial examination, her blood pressure was 100/70 and her Jugular Venous Pressure (JVP) was elevated to her earlobe. She had reduced air entry and crepitations auscultated at both lung bases. An electrocardiogram (ECG) revealed markedly low amplitude QRS complex with an incomplete right bundle branch block morphology. Serum blood analysis revealed normal routine blood tests including inflammatory markers. High Sensitivity Troponin T was elevated at 2788mmol/L. She was transferred to the Coronary Care Unit at our hospital.

She had a significant occupational exposure to wildlife, including recent travel to Eastern Europe to study bats several months prior to admission. She was a non-smoker with minimal alcohol intake and no significant past medical history of note.

A Computed Tomography Pulmonary Angiogram (CTPA) was organised which confirmed cardiomegaly and bilateral large pleural effusions, with a suggestion of bilateral basal ground-glass changes. Urgent transthoracic echocardiography revealed a non-dilated left ventricle with severe systolic impairment, mild-moderate functional mitral regurgitation and a small pericardial effusion. (Fig C)

Interestingly Lyme disease acute serological markers returned as IgG positive, indicating acute infection. Other autoimmune and serological markers of cardiomyopathy were negative.

Aggressive intravenous diuresis was commenced with an initial clinical improvement. Urgent cardiac magnetic resonance imaging (MRI) was requested and the case with discussed with the local transplant centre who accepted for transfer and assessment. Despite aggressive diuresis, over the next 3 days she continued to increase in weight with a persistently low blood pressure. There was worsening derangement of renal and hepatic function. She was commenced on intravenous dobutamine and noradrenaline and transferred emergently to the transplant centre.

Shortly after arrival she suffered a ventricular tachycardia (VT) cardiac arrest, though was successfully resuscitated. Cardiac biopsy and right heart catheter study were performed, the latter confirming elevated filling pressures and a reduced cardiac output of 2.2 L/min (Table 1). The biopsy results demonstrated large areas of patchy but diffuse myocyte loss / necrosis associated with a marked inflammatory infiltrate including lymphocytes and quite prominent eosinophils. Numerous multinucleate giant cells were seen, which appeared to be of myogenic origin. There was no iron, amyloid or established fibrosis. These histological features were felt to be consistent with a diagnosis of Giant Cell Myocarditis (GCM).

The patient was reviewed by the surgical team with a view to possible mechanical support as a bridge to transplant. Immunosuppressive therapy was initiated with a combination of ciclosporin, azathioprine and prednisolone. Unfortunately, she experienced a further VT arrest later that evening, for which resuscitation was unsuccessful.

|Right atrium |A: 24mmHg, V: 23mmHg |

|Right ventricle |37/4mmHg, EDP 13mmHg |

|Pulmonary artery |30/22mmHg, mean 26mmHg |

|Pulmonary capillary wedge |A: 23mmHg, V: 25mmHg, mean 22mmHg |

|Cardiac output (thermodilution) |2.2 L/min |

Table 1: Right heart catheter study values (EDP; end diastolic pressure)

Discussion

GCM is an uncommon but aggressive inflammatory cardiomyopathy. It is rapidly progressive and often fatal. Indeed, all cases prior to 1987 were identified only during post-mortem examination. It has been variously referred to as Idiopathic Giant Cell Myocarditis, Fiedler’s Myocarditis, Pernicious Myocarditis, Granulomatous Myocarditis and Acute Idiopathic Interstitial Myocarditis. The incidence is estimated to be as high as 5% of patients diagnosed with idiopathic, interstitial or viral myocarditis. The mean age of onset is 42.6 +/- 12 years with no gender predominance and average chronology approximately one month from onset to hospital presentation(1).

Features typically include rapidly progressive left-sided or biventricular heart failure –which is the presenting feature in ~75%(2) – and often complicated by conduction abnormalities and ventricular tachycardia, seen in approximately 15% and 29% of cases respectively(1), often with limited response to conventional heart failure medical therapy. Some modern case series report atrioventricular block as the presenting feature as commonly as heart failure(3). Definitive diagnosis requires left or right ventricular Endo-Myocardial Biopsy (EMB) which has a class 1 indication in fulminant myocarditis(4) and a reported sensitivity of 80-85% in the diagnosis of GCM(5). This increases significantly with repeat biopsies, particularly if guided by evidence of areas of active inflammation or infiltration on imaging such as MRI or Positron Emission Tomography (PET)(3). This typically shows multinucleated giant cells, lymphocytes, diffuse or multifocal inflammatory infiltrate and eosinophilia, with a variable degree of fibrosis(2,6).

Historically there has been debate as to whether GCM and Cardiac Sarcoidosis (CS) represented a single disease entity, owing to high levels of giant cells present in both. However there have subsequently been distinctions observed both pathologically and clinically, with GCM demonstrating increased myocyte necrosis and carrying a substantially worse prognosis(1). The prognosis of GCM is poor, with rates of death or cardiac transplantation reaching 70% within 1 year and almost 90% overall(2), with little evidence of recovery of left ventricular function(7).

Cardiac Magnetic Resonance (CMR) imaging provides robust differentiation of CS (8,9) but so far there are only sporadic case reports describing CMR investigation of GCM (10–12), showing heterogeneous areas of sub-endocardial and mid-wall fibrosis demonstrated on late gadolinium enhancement imaging, all eventually diagnosed via EMB. At present, however, there are no established reliable markers for the diagnosis of GCM by CMR, and EMB remains the gold standard. CMR is helpful, however, in excluding other causes for fulminant heart failure.

EMB can be continued as a surveillance measure. Treatment has traditionally revolved around the use of immunosuppressive therapy including cyclosporine(23,24), pulsed and long-term steroids with transplant-free survival reported as low as 10% at five years(1). There are reports of successful outcomes following use of contemporary immunosuppressive agents including azathioprine(3), mycophenalate mofetil , Rabbit Anti-Thymocyte Globulin (ATG) and tacrolimus as well as biological agents such as muromonab(23). With these novel immunosuppressive combination therapies, transplant-free survival has been reported at approximately 75% at one year(3,23). Due to the sudden-onset, rapidly progressive nature of the disease with an often fatal outcome, aggressive immunosuppression and early transplantation is advocated.

There is an established link with systemic autoimmune disease and in particular myasthenia gravis(13) and inflammatory bowel disease(14,15). Furthermore, there are suggestions of associations with thymoma(16), drug hypersensitivity(17), measles myocarditis(18) and even syphilis(19). The exact aetiological mechanism, however, remains unknown.

Although no previous link with Lyme Disease and GCM has been documented to date, Lyme Disease has been linked with Giant Cell Arteritis (GCA) in case reports(20) and indeed a ‘Lyme carditis’ with features mimicking those of GCM(21). Lyme carditis has long been described as a cardiac manifestation of systemic Lyme disease, with prominence of conduction defects and more rarely, heart failure. Diagnosis is made by serological testing, but myocardial biopsy shows extensive lymphocytic infiltration and necrosis with variable fibrosis. Occasionally, spirochetes can be directly visualised or Borrelia Burgdorferi detected by Polymerase Chain Reaction (PCR) of affected tissues(22). Although there is currently no established link between GCM and Lyme Disease, the similarity in clinical presentation and pathological findings begs the question as to whether they could represent states on a spectrum of disease, with GCM as manifestation of those most severe forms and Lyme disease as one possible cause.

Conclusion

Giant Cell Myocarditis is an aggressive and rapidly progressive cardiomyopathy which often presents with early heart failure and/or conduction deficits. In the absence of rapid and aggressive management including immunosuppression and transplant, the prognosis is poor. Endomyocardial biopsy should not be delayed as it may provide a definite diagnosis. Though known to be associated with several systemic illnesses, similar histological appearance and the association in this case raises the possibility of a link between giant cell myocarditis and Lyme disease, which warrants further investigation.

References:

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