Inflammatory cardiomyopathy of possibly overlapping aetiology: a case posing treatment dilemma and potential association.

We report on a 52-year-old Brazilian immigrant woman with past histories of chronic kidney disease and uveitis, presenting with symptomatic atrioventricular block. Her country of origin being endemic for Trypanosoma cruzi infection, we suspected Chagas disease as the aetiology, diagnosis of which was confirmed by serological tests. Further systemic workup identified an emerging nodular lesion in the lung, which turned out to be a sarcoid epithelioid granuloma on biopsy. Involvement of the kidneys and eyes was suggestive of systemic extension of the lung sarcoidosis. Although imaging modalities did not detect inflammatory foci in the myocardium, the rare coexistence of histologically proven sarcoidosis raised the intriguing concept of cardiac manifestation having arisen from two possibly overlapping aetiologies: Chagas disease and cardiac sarcoidosis. The case highlights a treatment dilemma increasingly likely to be encountered in this globalized world, and also raises the potential, but intriguing, association of these two diseases.

Introduction

Pathological features of myocardial cell infiltration, as well as their common arrhythmic manifestations, are the hallmarks of inflammatory cardiomyopathies. The ‘infection‐provoked inflammation’, including that caused by Trypanosoma cruzi ( ) parasites in Chagas disease, and the ‘sterile autoinflammation’ seen in cardiac sarcoidosis, are two distinct forms of inflammation leading to a shared arrhythmic condition of the heart. , Accordingly, the treatment approach towards a common cardiac manifestation can vary from targeting the causal pathogen to regulating the autoreacting immune cells. Here, we report on a Brazilian immigrant presenting with symptomatic atrioventricular (AV) block accompanying a Chagas disease diagnosis, who concomitantly developed a lung sarcoidotic granuloma with possible systemic extension. This rare coexistence not only points to a treatment dilemma, anticipated to be increasingly encountered in this globalized world of exploding immigration, but also raises an intriguing association.

Case report

A 52‐year‐old Brazilian woman was referred to our cardiology department for assessment of her syncopal episodes. Her first syncope had occurred 2 years earlier, and ever since, she complained of occasional lightheadedness. She lacked any sensation of palpitations, and had not experienced any symptoms or limitations during ordinary activities (New York Heart Association functional Class I). Baseline 12‐lead electrocardiogram (ECG) showed normal QRS amplitudes and ST‐T morphology, and was only remarkable for left anterior hemiblock (Figure ). X‐ray showed no signs of cardiomegaly or pulmonary congestion. Laboratory examination showed mild elevation in her plasma brain natriuretic peptide level (64.2 pg/dL; reference range <18.4 pg/dL), and a moderately elevated serum creatinine of 1.55 mg/dL, corresponding to an estimated glomerular filtration rate of 28.6 mL/min/1.73 m2. Myocardial defects, such as ventricular wall thinning and aneurysms, were absent, and wall motion appeared normal on echocardiographic examination. Telemetry ECG documented no evidence of ventricular tachyarrhythmias but instead revealed a prolonged period of intermittent AV block with 2:1 conduction which, after extensive evaluation, carried the highest probability of being the cause of her symptoms (Fig. ).

Figure 1

Clinical findings and the results of Trypanosoma cruzi serological testing. (A) The baseline electrocardiogram was remarkable only for left anterior hemiblock. (B) The telemetry electrocardiogram revealed advanced 2:1 atrioventricular block with a ventricular response rate of 33 beats per minute. (C) A lateral flow immunoassay (Trypanosoma Detect Rapid Test; InBios, Seattle, USA) detected a positive band (arrowhead). (D) In the enzyme‐linked immunosorbent assay ( IgG CELISA II; CELLABS, Sydney, Australia), absorbance at 450 nm was measured. Each row indicates negative control (NC), positive control (PC) and the patient's sample, all measured in duplicates. Samples suggested a positive result.

Given that the patient originated from Brazil, a country endemic for infection, and had harboured a positive family history, Chagas cardiomyopathy was sought for as the aetiology. The patient's serum was tested on multiple serological testing platforms to detect anti‐trypanosomal antibodies. The ARCHITECT Chagas assay (Abbott, Chicago, USA) screened ‘positive’ with an enhanced 9.54 signal‐to‐cutoff index (≥1 signal‐to‐cutoff index, as threshold for a positive result). Her positive serology was confirmed by two additional immunoassay platforms, namely the Trypanosoma Detect Rapid Test (InBios, Seattle, USA) and the IgG CELISA II assay (CELLABS, Sydney, Australia) (Figure ). While neither the haemoculture nor the genomic amplification by polymerase chain reaction detected persistent parasitemia, the results from serological testing confirmed that she had been chronically infected with , meeting the WHO diagnostic criteria for chronic Chagas disease. Her current state, characterized by arrhythmic presentation preceding structural or functional myocardial defects, was suggestive of early stage B1 cardiomyopathy. With a disorder of AV conduction being her sole ECG abnormality, she ranked in the lowest risk category (Rassi score of 0) indicative of 10% 10 year mortality rate.

Her past histories of chronic kidney disease and granulomatous uveitis prompted further systemic workup. Multiorgan involvement together with slight elevation in the serum lysozyme level (11.8 μg/mL; reference range 5.0–10.0 μg/mL) led to a high suspicion of systemic sarcoidosis. Lung computed tomography revealed an emerging nodular lesion in the right lower lung field, which was absent at the time she underwent a 18F‐fluorodeoxyglucose positron emission tomography (18FDG‐PET) scan 8 months earlier. On biopsy, the nodular lung lesion turned out to be an epithelioid granuloma staining positive for antigens (Figure ). The findings altogether met the criteria for lung sarcoidosis. The co‐occurrence of histologically proven, extra‐cardiac sarcoidosis brought about the intriguing concept of her cardiac manifestation having arisen from two possibly overlapping aetiologies: Chagas disease and sarcoidosis. Although the index 18FDG‐PET scan lacked signs of active cardiac inflammation, follow‐up scans are awaited, given that 10% of patients with true cardiac involvement initially return false‐negative scans. While the findings could have given crucial insight into the extent of myocardial involvement for each aetiology, assessing patterns of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging was contraindicated due to her advanced kidney disease.

Figure 2

Histopathological findings. (A) A transbronchial lung biopsy revealed noncaseating epithelioid granulomas (arrows). Scale bars represent 50 μm. (B) Immunohistochemical staining with anti‐ ( ) antibody revealed the localization of in granulomas (arrowheads). Scale bar represents 50 μm.

Since the available trypanocidal drugs lack evidence in benefiting chronic Chagas disease patients in the long term, and harbour limited safety profiles regarding their use in patients with renal impairment, their administration was suspended. The lung sarcoidosis had never been severe enough to warrant treatment, but the concomitant extrapulmonary involvement indicated the need for therapy. While harbouring the risk of parasitemia reactivation, steroid therapy was considered in order to target her evident ocular and renal sarcoidotic manifestations, as well as any potentially masked cardiac extension of the disease. Dosing and planned duration of therapy are extremely complicated decisions, especially when trypanocidal drugs are contraindicated, as in the present case, and remain yet to be agreed upon as a trade‐off between favourable response and reactivation. , Specific care has been further taken to minimize the risks of malignant arrhythmic outcome, considering the arrhythmogenic natures of the two entities. The patient is now symptom‐free after receiving a pacemaker, and any additional therapy, including an implantable cardioverter defibrillator, has been withheld on grounds that she lacks signs of life‐threatening ventricular arrhythmia.

Discussion

The patient's clinical picture of inflammatory cardiomyopathy caused by chronic infection has been complicated by the histological evidence of an extra‐cardiac sarcoidotic granuloma, which evokes the probability of its systemic extension also involving the heart. The two aetiologies may well overlap in phenotypic expression while differing in their origins of inflammation: from invasion of a parasite to sterile autoreactivity. Therefore, treatment decisions are at odds from the perspective of the interaction between exogenous factors and host immunity, and a treatment dilemma is brought about when the two diagnoses may potentially coexist. If sarcoidosis is to have any contributory role in her cardiac conduction disorder, the administration of steroids may be effective in improving the AV block and preventing future deterioration in cardiac function. In the setting of Chagas disease; however, the risk of parasitemia reactivation following steroid therapy poses a challenge in decision making. Therefore, in such a potentially overlapping presentation, it becomes essential to specify the contributory roles of each aetiology in forming the cardiac conduction abnormality.

Although not performed here due to personal contraindication issues, CMR can play an active role in this sense. CMR provides information about the spatial distribution of active inflammation and/or scarring, which aids in differentiating between the triggers of cardiac inflammation. , , The LGE pattern seen in Chagas disease resembles that of myocardial ischaemia, involving predominantly the subendocardium. This is in contrast to the typical LGEs observed in cardiac sarcoidosis following a non‐ischaemic pattern, that is the sparing of the subendocardium and the localization of enhancement in the midwall or subepicardium. , ,

Chagas disease, a neglected tropical cardiomyopathy, and cardiac sarcoidosis, a somewhat emerging diagnosis in the developed world, have previously had spatially exclusive distributions. , However, in this age of increasing globalization, where immigrants from ‐endemic regions are obtaining better access to advanced medical care, the treatment dilemma seen in the present case may be increasingly faced. Clinical stratification of conduction abnormalities following an inflammatory cardiomyopathy diagnosis thus constitutes a growing agenda.

The case also highlighted an overlooked potential association. Infectious agents, including bacteria, fungi and even viruses, and other exogenous triggers are known causes of the T lymphocyte‐mediated, autoinflammatory reaction leading to granuloma formation in sarcoidosis. While autoreactive T lymphocytes likewise play crucial roles in establishing the cardiac pathology of Chagas disease, no parasitic infection, including that of , has yet been linked to noncaseating granuloma formation or sarcoidosis onset. In fact, updates on sarcoidosis prevalence in Latin America are still lacking. , By filling in the missing epidemiological data on sarcoidosis prevalence among arrhythmic patients of Latin American background, we foresee opportunities for a loosening of the boundaries between inflammatory cardiomyopathies currently recognized as mutually exclusive entities.

Conflict of interest

None declared.

Funding

The research was supported by Science and Technology Research Partnership for Sustainable Development (SATREPS), Japan Agency for Medical Research and Development (AMED), under Grant number JP 21jm0110016.