Dyspnoea in a patient with biopsy-proven pulmonary sarcoidosis: the challenges in diagnosing cardiac sarcoidosis

Abstract

A man in his 60s with biopsy-proven pulmonary sarcoidosis, not on treatment, presented with 6 weeks of dyspnea to the emergency department. ECG showed first-degree atrioventricular block and CT thorax demonstrated progressive pulmonary sarcoidosis with new multifocal consolidation. Antibiotics were initiated.

A brain natriuretic peptide was elevated at 2024 ng/L and echocardiogram showed global left ventricular systolic dysfunction. Coronary angiogram revealed normal coronary arteries, and cardiac positron emission tomography and MRI demonstrated patterns compatible with cardiac sarcoidosis. The patient significantly improved with diuresis; he was started on prednisone, methotrexate and standard heart failure therapies.

We outline the difficulties of attributing cardiac causes of dyspnoea in a patient with known pulmonary sarcoidosis given the rarity of cardiac involvement. We review proposed diagnostic criteria for cardiac sarcoidosis using enhanced imaging techniques without requiring invasive myocardial biopsy. This case discussion also highlights nuances in managing cardiac sarcoidosis based on the best available evidence and expert consensus.

Background

Sarcoidosis is a rare condition characterised by an amplified immune response to unknown antigens, leading to the formation of granulomas in various organs.¹ It occurs in 4.7 to 64 in 100 000 and is most prevalent among northern European and African-American populations.¹ Although sarcoidosis was recognised over 120 years ago, it remains a difficult to diagnose on initial presentation as the cause is not entirely known and manifestations multifaceted.¹

Sarcoidosis most commonly presents with respiratory symptoms and chest imaging showing bilateral hilar lymphadenopathy with or without diffuse micronodular pulmonary infiltration.¹ Thirty to 50% of patients develop extrapulmonary manifestations usually ophthalmologic or cutaneous¹; cardiac involvement is rare and challenging to diagnose.²

Cardiac sarcoidosis is a serious condition with a 5-year survival of 60% to 75%.³ Its presentation can range from silent myocardial granulomas to arrhythmias, ventricular failure or sudden cardiac death.³ It usually occurs in the context of established disease in another organ but less commonly presents de novo as ‘clinically isolated cardiac sarcoid’.⁴

We report a case of a man with known pulmonary sarcoidosis who presented with dyspnoea, ultimately diagnosed as cardiac sarcoidosis. This report aims to review important modalities of investigation when cardiac sarcoidosis is suspected. High-quality evidence for management principles is lacking; however, we summarise accepted treatments based on recently published international consensus statements.

Case presentation

A man in his 60s with biopsy-proven pulmonary sarcoidosis presented to hospital with exertional dyspnoea. Dyslipidaemia and hypertension were his cardiac risk factors. His medical history included chronic kidney disease secondary to renal sarcoidosis, osteoporosis and gout. His medications were ramipril, amlodipine, rosuvastatin, allopurinol, risedronate and budesonide inhaler.

He endorsed a 6-week history of worsening dyspnoea with accompanying upper respiratory tract symptoms, chills, night sweats and myalgias for 2 weeks. His exercise tolerance was limited. He denied symptoms of angina, syncope or significant oedema. His heart rate was 90 bpm, blood pressure 109/74 mm Hg, temperature 36.6°C, and respiratory rate of 20 bpm with oxygen saturation of 88% on ambient air. This improved to 94% on 2 L of supplemental oxygen. Examination was notable for bilateral crackles on chest auscultation, trace pedal oedema and a jugular venous pressure at one centimetre above the sternal angle.

Investigations

Initial investigations showed a normal complete blood count, stable creatinine and hypercalcaemia (table 1). A high-sensitivity troponin was elevated at 400 ng/L, with a peak of 550 ng/L on day 1 of admission. ECG demonstrated first-degree atrioventricular (AV) block with a PR interval of 256 ms (time between atrial and ventricular depolarization) and T wave inversions in V3–V6. CT thorax demonstrated increased interstitial markings and bronchial wall thickening predominantly in the lower lobes reported as progressive pulmonary sarcoidosis. New multifocal consolidation seen in the right lower lobe and lingula suggested superimposed bacterial pneumonia, and intravenous ceftriaxone was initiated.

Table 1.

Biochemical profile of patient at initial presentation

Laboratory measurement (units)	Reference range	Patient
Haemoglobin, g/L	140–180	133
White cell count, x109/L	4.0–11.0	6.7
Neutrophil count, x109/L	2.0–7.5	5.0
Lymphocyte count, x109/L	1.5–4.0	0.9
Platelet count, x109/L	150–400	224
Sodium, mmol/L	135–145	137
Potassium, mmol/L	3.2–5.0	4.3
Chloride, mmol/L	100–110	107
Bicarbonate, mmol/L	23–29	23
Creatinine, µmol/L	64–110	181 (baseline 160)
Calcium, mmol/L	2.20–2.62	2.86
Albumin, g/L	38–50	39
High sensitivity troponin, ng/L	<= 26	400 (peak 550)

On day 2 of admission, he developed signs of volume overload with worsening oedema and raised jugular venous pressure. A brain natriuretic peptide (BNP) was elevated at 2024 ng/L (acute heart failure unlikely if ≤100 ng/L at any age). His dyspnoea improved significantly with intravenous furosemide. The initial ECG changes and development of heart failure prompted further investigations for cardiac causes of dyspnoea.

An echocardiogram on day 2 showed global left ventricular (LV) systolic dysfunction with an ejection fraction of 35%, severe mitral regurgitation and a trace pericardial effusion (no previous comparisons available). Myocardial perfusion imaging on day 3 demonstrated multiple fixed patchy defects in the left anterior descending and right coronary artery territories. He underwent a coronary angiogram on day 6 showing normal coronary arteries and mild pulmonary hypertension. Cardiac positron emission tomography (PET) scan on day 6 demonstrated multiple patchy areas of significant fluorodeoxyglucose (FDG) uptake and cardiac MRI on day 13 showed severe diffuse late gadolinium enhancement involving approximately 50% of the total LV mass; patterns consistent with cardiac sarcoidosis.

Differential diagnosis

Initially his symptoms were attributed to progressive pulmonary sarcoidosis and superimposed pneumonia. The cardiology service attributed the troponin rise and ECG changes to demand ischaemia secondary to pulmonary infection, rather than acute coronary syndrome. A cardiac cause of dyspnoea was suspected when he did not improve with intravenous antibiotics and subsequently developed signs of volume overload. Cardiac diagnostics including BNP and echocardiography confirmed the suspicion of heart failure with reduced ejection fraction. The global LV dysfunction and lack of wall motion abnormalities on echocardiogram, and fixed patchy defects on myocardial perfusion imaging, are atypical for ischaemic cardiomyopathy and favoured an alternative diagnosis. However, his cardiac risk factors necessitated an angiogram to definitively rule out coronary disease. His pre-existing history of biopsy-proven pulmonary sarcoidosis raised suspicion for cardiac involvement. Further investigations with cardiac PET and cardiac MRI demonstrated features consistent with cardiac sarcoidosis.

Treatment

Given a high index of suspicion for cardiac sarcoidosis, prednisone 30 mg was initiated empirically after FDG-PET scan was completed, but before results were available, as per expert consensus.⁵ On day 12, methotrexate was added as combination therapy is favoured over prednisone alone when LV dysfunction and/or ventricular arrhythmias are present.⁶ Septra was also started for Pneumocystic jiroveci pneumonia (PJP) prophylaxis.

His symptoms dramatically improved with prednisone and methotrexate treatment. He continued on oral furosemide and ramipril. Spironolactone and metoprolol were added for concurrent heart failure management. A repeat CT chest on day 13 showed significant improvements in bilateral reticular markings, bronchial wall thickenings and consolidation (figure 1). In hindsight, the initial radiographic changes likely represented heart failure rather than worsening pulmonary sarcoidosis in discussion with radiology. Continuous telemetry monitoring captured multiple episodes of non-sustained ventricular tachyarrhythmias (NSVTs). An automatic implantable cardioverter defibrillator (ICD) was inserted for primary prevention.

Figure 1.

Comparative CT thorax on admission vs day 13. First row demonstrates axial images of bilateral upper lung lobes comparing initial CT scan (left) with subsequent CT scan after diuresis and immunosuppression (right). Second row depicts axial images of bilateral lower lung lobes comparing initial CT scan (left) with subsequent CT scan after diuresis and immunosuppression (right). Both images on the right demonstrate marked improvement in bilateral reticular markings, bronchial wall thickening and consolidation.

On day 31, he returned home on methotrexate 15 mg weekly, folic acid supplementation, prednisone 30 mg/day and Septra for PJP prophylaxis. For heart failure, he was prescribed metoprolol, ramipril, furosemide and spironolactone as well as amiodarone for NSVTs.

Outcome and follow-up

In follow-up, his methotrexate was switched to leflunomide given his renal function, and prednisone was slowly tapered. A repeat PET scan 5 months later showed decreased cardiac inflammation.

Discussion

Diagnostic considerations

Differentiating the causes of dyspnoea in patients with established pulmonary sarcoidosis can be challenging; especially since clinically apparent cardiac involvement only affects up to 5% of patients with systemic disease.³ Diagnosing cardiac sarcoid relies on histologic presence of non-caseating granulomas; however, endomyocardial biopsies are fraught with sampling error as cardiac inflammation is patchy yielding a sensitivity of 30%.^{6 7} Non-invasive myocardial imaging using FDG-PET and MRI benefit from visualising the entire myocardium to detect areas of active inflammation but lack pathognomonic findings for diagnostic confirmation.⁸ Bearing these shortcomings, diagnostic criteria for cardiac sarcoidosis have been developed.

In 2014, the first international consensus statement for diagnosing cardiac sarcoidosis was published by experts selected by the Heart Rhythm Society.⁹ The criteria allow for a diagnosis of cardiac sarcoidosis to be made by relying on histologic confirmation from non-cardiac tissue in conjunction with characteristic clinical or imaging findings of cardiac involvement.⁹ Accepted imaging modalities include FDG-PET, cardiac MRI and gallium scintigraphy. Additional criteria include the necessity to exclude other reasonable causes for symptoms.

FDG-PET uses FDG, a glucose analogue, to detect areas of active inflammation.⁸ In general, areas of active inflammation will demonstrate increased metabolism and glucose uptake with or without perfusion defects (depending on stage), while fibrous disease and scar will result in severe perfusion deficits and minimal FDG uptake.⁶ T2-weighted cardiac MRI can identify areas that are acutely inflamed, while late gadolinium enhancement suggests fibrosis and/or scar.⁷ Late gadolinium enhancement has been associated with serious outcomes including increased risk of death, halted sudden death and ventricular arrhythmias leading to ICD discharges.⁷

Our patient’s symptoms of dyspnoea with ECG changes and biopsy-proven pulmonary sarcoidosis should have raised suspicion for cardiac involvement. Clinical volume overload and global LV dysfunction on echocardiography prompted further imaging with FDG-PET, which revealed characteristic patchy uptake. Myocardial biopsy was not required for diagnostic purposes, as he had histologic confirmation of non-caseating granulomatous inflammation on previous mediastinal lymph node biopsy. Coronary angiogram was completed to rule out ischaemic cardiomyopathy given our patient’s history of hypertension and dyslipidaemia. Cardiac MRI with gadolinium enhancement was completed for prognostication. Greater than 50% of his LV mass demonstrated late gadolinium enhancement portending a poor prognosis, which clinically manifested as repeated runs of NSVT prompting ICD insertion.

Management considerations

The management of cardiac sarcoid involves a decision around immunosuppression and therapies targeted to specific clinical manifestations including cardiomyopathy, arrhythmias, heart failure and risk of sudden cardiac death.¹⁰ The most important clinical predictors of mortality are LV ejection fraction, LV end diastolic diameter and presence of sustained ventricular tachycardia (VT).⁶

There is scarce high-quality evidence for the clinical management of cardiac sarcoid complications, with studies demonstrating mixed data for the role of immunosuppression.¹¹ Despite these limitations, most expert opinions call for treatment with corticosteroids. According to Birnie et al,⁵ immunosuppression should be considered in all patients with evidence of myocardial inflammation and one of the following: Mobitz type II or third-degree heart block, frequent ventricular ectopy or NSVT, sustained ventricular arrhythmias and LV dysfunction.⁵ The recommended starting dose of prednisone is 0.5 mg/kg/day to a maximum dose of 40 mg.⁵

Methotrexate is often used as a second-line agent⁵; other therapies including azathioprine, leflunomide, mycophenolate mofetil and tumour necrosis factor-alpha inhibitors have also been reported to be effective in treating systemic sarcoid.^{6 7} For example, Nagai et al demonstrated stabilisation of cardiac function in sarcoidosis with combination therapy using low-dose prednisolone with weekly administration of methotrexate.¹² Based on expert consensus, initial management in those with LV dysfunction and/or ventricular arrhythmias should entail combination therapy with prednisone and methotrexate (10 to 15 mg weekly).^{13 14} Furthermore, recommendations from over 75% of experts are that in cases of cardiac sarcoid demonstrating regions of increased metabolism on FDG-PET, immunomodulatory therapy in conjunction with steroids should be initiated.¹³ The European Respiratory Journal guideline in November 2021 stated that patients on a second immunosuppressive agent (ie, a steroid-sparing agent in addition to prednisone) did not have better outcomes than those treated with prednisone alone; however, in a retrospective study, patients on prednisone and methotrexate had improved BNP values and ejection fractions at 5 years compared with those solely on prednisone.¹⁵ Clinicians can consider the use of tumour necrosis factor-alpha inhibitors for the management of refractory cases of cardiac sarcoidosis; however, the overall level of evidence for this is limited.¹⁵ Concomitant heart failure therapies should be prescribed as clinical practice guidelines would dictate.⁶

There is minimal evidence available on the optimal duration of immunosuppressive therapy, but experts agree that decisions should be guided by clinical response and repeat testing. Based on expert consensus, initial immunosuppression should be continued at starting doses for 3 months before tapering is considered.⁵ Response to treatment should be evaluated after 3 months with repeat PET scan and if inflammation has decreased, steroids can be gradually tapered to complete a total course of at least 12 months.⁵ Recommendations for timing of imaging and therapies thereafter depend on inflammation on subsequent PET scan given that decreased FDG uptake is linked with recovery in ejection fraction.^{5 16}

AV blocks are the most commonly noted arrhythmias.⁷ Pacemaker insertion is often needed for high-degree blocks even if the block temporarily abates with steroids, and assessment for secondary causes of heart block is warranted prior to pacemaker insertion.^{7 17} Ventricular fibrillation and VT are the second most common arrhythmias.⁷ Indications for ICD implantation in a patient with cardiac sarcoidosis are generally based on standard guidelines for primary and secondary prevention. Other considerations for ICD insertion include the extent of inflammation or fibrosis noted on cardiac imaging, or concurrent placement if pacemaker is indicated given the elevated risk for sudden cardiac death.⁶ Catheter ablation for VT is usually considered after ICD implantation or if antiarrhythmic therapy is unsuccessful.⁷

Our patient demonstrated echocardiographic evidence of LV dysfunction warranting combination treatment with prednisone and methotrexate as per expert recommendations; although, differing opinions exist on the additional benefit of a second immunomodulatory therapy as initial treatment. Repeated runs of NSVT, in the context of reduced ejection fraction, prompted ICD insertion as cardiac sarcoidosis can lead to ventricular arrhythmias and sudden death.

Learning points.

• Global left ventricular (LV) systolic dysfunction with multiple fixed patchy defects on perfusion imaging in a patient with sarcoidosis should raise suspicion for cardiac involvement.

• Immunosuppression should be considered in all patients with evidence of myocardial inflammation and one of the following: Mobitz type II or third-degree heart block, frequent ventricular ectopy or non-sustained ventricular tachyarrhythmias, sustained ventricular arrhythmias and LV dysfunction.

• Histologic diagnosis of extracardiac sarcoidosis and patchy uptake on cardiac PET or late gadolinium enhancement on cardiac MRI allows for a clinical diagnosis of cardiac sarcoidosis without requiring myocardial tissue diagnosis.

• Combination therapy with corticosteroids and immunomodulatory therapy (eg, methotrexate) should be considered in cases of cardiac sarcoid complicated by ventricular arrhythmias, regions of increased metabolism on fluorodeoxyglucose-positron emission tomography or LV dysfunction.

• Atrioventricular blocks are the most common arrhythmias followed by ventricular fibrillation and tachycardia. In addition to standard indications, implantable cardiac defibrillators may be inserted based on the extent of inflammation or fibrosis noted on cardiac imaging or concurrently at the time of pacemaker insertion given the increased risk for sudden cardiac death.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.