Screening sarcoidosis patients for cardiac sarcoidosis: What the data really show
2019; Elsevier BV; Volume: 154; Linguagem: Inglês
10.1016/j.rmed.2019.05.007
ISSN1532-3064
Autores Tópico(s)Occupational exposure and asthma
ResumoCardiac sarcoidosis is a major cause of death in sarcoidosis patients. In most series, cardiac sarcoidosis is second only to pulmonary sarcoidosis in causes of death related to sarcoidosis [[1]Huang C.T. Heurich A.E. Sutton A.L. Lyons H.A. Mortality in sarcoidosis. A changing pattern of the causes of death.Eur. J. Respir. Dis. 1981; 62: 231-238PubMed Google Scholar], although cardiac sarcoidosis has been found to be the leading cause of death in some reports [[2]Hu X. Carmona E.M. Yi E.S. Pellikka P.A. Ryu J. Causes of death in patients with chronic sarcoidosis.Sarcoidosis Vasc. Diffuse Lung Dis. 2016; 33: 275-280PubMed Google Scholar,[3]Perry A. Vuitch F. Causes of death in patients with sarcoidosis. A morphologic study of 38 autopsies with clinicopathologic correlations.Arch. Pathol. Lab Med. 1995; 119: 167-172PubMed Google Scholar]. More importantly, the deaths from cardiac sarcoidosis may occur suddenly and early after diagnosis, relating to the development of a small focus of granulomatous inflammation in a strategically vulnerable portion of the cardiac conduction system. In fact, a large proportion of deaths from cardiac sarcoidosis may be sudden in patients in whom a diagnosis of cardiac sarcoidosis or even sarcoidosis was undetected pre-mortem [[4]Tavora F. Cresswell N. Li L. Ripple M. Solomon C. Burke A. Comparison of necropsy findings in patients with sarcoidosis dying suddenly from cardiac sarcoidosis versus dying suddenly from other causes.Am. J. Cardiol. 2009; 104: 571-577Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar]. This last observation is not surprising given that autopsy series of sarcoidosis patients have detected up to five times the frequency of cardiac sarcoidosis that was clinically detected while they were alive [[5]Silverman K.J. Hutchins G.M. Bulkley B.H. Cardiac sarcoid: a clinicopathological study of 84 unselected patients with systemic sarcoidosis.Circulation. 1978; 58: 1204-1211Crossref PubMed Scopus (764) Google Scholar]. The potential for an early and rapid fatal outcome from cardiac sarcoidosis is in contradistinction to deaths from pulmonary sarcoidosis that usually are a result of sarcoidosis-induced pulmonary fibrosis [[6]Judson M.A. Strategies for identifying pulmonary sarcoidosis patients at risk for severe or chronic disease.Expert Rev. Respir. Med. 2017; 11: 111-118Crossref PubMed Scopus (23) Google Scholar] that takes a long time to develop such that these deaths typically occur 5–25 years after diagnosis [[1]Huang C.T. Heurich A.E. Sutton A.L. Lyons H.A. Mortality in sarcoidosis. A changing pattern of the causes of death.Eur. J. Respir. Dis. 1981; 62: 231-238PubMed Google Scholar]. Because of the potential for an early and unexpected death from cardiac sarcoidosis, it is imperative that every sarcoidosis patient be screened for cardiac involvement. Despite the importance of screening for cardiac sarcoidosis, an exact screening algorithm has not yet been validated. Various groups and societies have made specific and sometimes conflicting recommendations [7Hamzeh N.Y. Wamboldt F.S. Weinberger H.D. Management of cardiac sarcoidosis in the United States: a Delphi study.Chest. 2012; 141: 154-162Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 8Birnie D.H. Sauer W.H. Bogun F. et al.HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.Heart Rhythm : Off. J. Heart Rhythm Soc. 2014; 11: 1305-1324Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar, 9Hunninghake G.W. Costabel U. Ando M. et al.ATS/ERS/WASOG statement on sarcoidosis. American thoracic society/European respiratory society/world association of sarcoidosis and other granulomatous disorders.Sarcoidosis Vasc. Diffuse Lung Dis. 1999; 16: 149-173PubMed Google Scholar]; furthermore, the data to support these recommendations are lacking. The 2 major objectives of a good screening test are: a) detection of disease at an asymptomatic stage when treatment can be more effective than after the patient develops signs and symptoms, and b) identification of risk factors for developing the disease such that the disease can be prevented or attenuated by modifying these risk factors [[10]Herman C. What makes a screening exam "good"?.The virtual mentor : VM. 2006; 8: 34-37Crossref PubMed Scopus (52) Google Scholar]. To fulfill these objectives, a screening test and the disease it screens for must meet the following criteria: a) be capable of detecting a high proportion of disease in its preclinical state (high sensitivity); b) safe to administer; c) of reasonable cost; d) lead to demonstrated improved health outcomes; and e) must be widely available as must the interventions that follow a positive result [[11]Affairs AMACoS. Commercialized Medical Screening (Report A-03). 2005http://www.ama-assn.org/ama/pub/category/13628.htmlGoogle Scholar]. The sensitivity of a screening test should be prioritized at the expense of specificity when the disease is serious and curable in its preclinical phase. However, high specificity of a screening test may be desired over sensitivity when the costs or risks of further testing are significant. In the case of screening for cardiac sarcoidosis, sensitivity seems to be stressed over specificity, as diagnostic algorithms have stressed the need for confirmatory diagnostic testing despite positive results on tests that are deemed highly specific [[8]Birnie D.H. Sauer W.H. Bogun F. et al.HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.Heart Rhythm : Off. J. Heart Rhythm Soc. 2014; 11: 1305-1324Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar,[12]Kim J.S. Judson M.A. Donnino R. et al.Cardiac sarcoidosis.Am. Heart J. 2009; 157: 9-21Crossref PubMed Scopus (271) Google Scholar,[13]Hamzeh N. Steckman D.A. Sauer W.H. Judson M.A. Pathophysiology and clinical management of cardiac sarcoidosis.Nat. Rev. Cardiol. 2015; 12: 278-288Crossref PubMed Scopus (67) Google Scholar]. The data concerning the approach to screening for cardiac sarcoidosis are relatively meager and somewhat conflicting. The major screening tests for cardiac sarcoidosis that have been examined include eliciting symptoms of cardiac sarcoidosis, electrocardiogram, transthoracic echocardiogram, and 24-h Holter monitoring. In two studies that analyzed these screening tests (Fig. 1) [[14]Mehta D. Lubitz S.A. Frankel Z. et al.Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing.Chest. 2008; 133: 1426-1435Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar,[15]Kouranos V. Tzelepis G.E. Rapti A. et al.Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis.JACC Cardiovasc. Imag. 2017; 10: 1437-1447Crossref PubMed Scopus (113) Google Scholar], each test individually had a mean sensitivity of less than 65%, rendering them all as poor screening tests when used in isolation. Eliciting symptoms of cardiac sarcoidosis had the highest sensitivity for these four screening tests. In terms of their specificity, one study found them all to have a mean specificity of greater than 95% [[14]Mehta D. Lubitz S.A. Frankel Z. et al.Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing.Chest. 2008; 133: 1426-1435Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar], whereas another found that only the specificity of echocardiography reached that level [[15]Kouranos V. Tzelepis G.E. Rapti A. et al.Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis.JACC Cardiovasc. Imag. 2017; 10: 1437-1447Crossref PubMed Scopus (113) Google Scholar]. One study found that a combination of all four of these tests raised the sensitivity for the diagnosis of cardiac sarcoidosis to 100% [[14]Mehta D. Lubitz S.A. Frankel Z. et al.Cardiac involvement in patients with sarcoidosis: diagnostic and prognostic value of outpatient testing.Chest. 2008; 133: 1426-1435Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar], whereas another found that combining any three of the tests raised the mean sensitivity from 72 to 84% [[15]Kouranos V. Tzelepis G.E. Rapti A. et al.Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis.JACC Cardiovasc. Imag. 2017; 10: 1437-1447Crossref PubMed Scopus (113) Google Scholar]. The value of adding echocardiography to the combination of eliciting cardiac symptoms and electrocardiography for cardiac sarcoidosis screening has been a controversial issue [[7]Hamzeh N.Y. Wamboldt F.S. Weinberger H.D. Management of cardiac sarcoidosis in the United States: a Delphi study.Chest. 2012; 141: 154-162Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar,[8]Birnie D.H. Sauer W.H. Bogun F. et al.HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis.Heart Rhythm : Off. J. Heart Rhythm Soc. 2014; 11: 1305-1324Abstract Full Text Full Text PDF PubMed Scopus (777) Google Scholar]. In the one report, the addition of echocardiography to the combination of eliciting cardiac symptoms and electrocardiography minimally raised the sensitivity from a mean of 69% to 73% (Fig. 1, Kouranos) [[15]Kouranos V. Tzelepis G.E. Rapti A. et al.Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis.JACC Cardiovasc. Imag. 2017; 10: 1437-1447Crossref PubMed Scopus (113) Google Scholar]. The extremely high specificity of echocardiography suggests that this test still has a role in that a positive test coupled with an additional positive test may exceed the diagnostic threshold for cardiac sarcoidosis [[15]Kouranos V. Tzelepis G.E. Rapti A. et al.Complementary role of CMR to conventional screening in the diagnosis and prognosis of cardiac sarcoidosis.JACC Cardiovasc. Imag. 2017; 10: 1437-1447Crossref PubMed Scopus (113) Google Scholar]. However, the low sensitivity of echocardiography for the diagnosis of sarcoidosis suggests that its role is limited in identifying additional cases beyond what can be detected by eliciting cardiac symptoms or other forms of testing. Because of its high sensitivity and specificity, some have considered using a “diagnostic test” such as cardiac nuclear magnetic resonance imaging (CMR) as part of the screening algorithm [[16]Hena K.M. Yip J. Jaber N. et al.Clinical course of sarcoidosis in world trade center-exposed firefighters.Chest. 2018; 153: 114-123Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,[17]Prezant D.J. Dhala A. Goldstein A. et al.The incidence, prevalence, and severity of sarcoidosis in New York City firefighters.Chest. 1999; 116: 1183-1193Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. Although CMR may not be an attractive screening test by virtue of its exorbitant cost, it has been found to be useful to incorporate this test into screening algorithms on the basis of clinical data [[16]Hena K.M. Yip J. Jaber N. et al.Clinical course of sarcoidosis in world trade center-exposed firefighters.Chest. 2018; 153: 114-123Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar,[17]Prezant D.J. Dhala A. Goldstein A. et al.The incidence, prevalence, and severity of sarcoidosis in New York City firefighters.Chest. 1999; 116: 1183-1193Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar]. Diagnostic tests such as CMR and possibly cardiac positron emission tomography (PET) may have additional benefits in that they may not only be useful to diagnose cardiac sarcoidosis but also to provide prognostic information concerning the likelihood of future adverse events [[18]Blankstein R. Osborne M. Naya M. et al.Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis.J. Am. Coll. Cardiol. 2014; 63: 329-336Crossref PubMed Scopus (439) Google Scholar,[19]Coleman G.C. Shaw P.W. Balfour Jr., P.C. et al.Prognostic value of myocardial scarring on CMR in patients with cardiac sarcoidosis.JACC Cardiovasc. Imag. 2017; 10: 411-420Crossref PubMed Scopus (133) Google Scholar]. Another approach to screening for cardiac sarcoidosis involves identifying specific risk factors for cardiac sarcoidosis through a statistical analysis of sarcoidosis cohorts. This approach was undertaken by a Polish group that developed a point system involving an abnormal electrocardiogram (1 point), cardiac-related symptoms (1 point), extra-thoracic sarcoidosis (1 point), progressive disease on chest radiograph (1 point), elevated serum level of N-terminal of the prohormone brain natriuretic peptide (2 points), and male sex (2 points) where 5–6 points had an likelihood ratio of 6.7 (95% confidence interval 3–14) of the patient having cardiac sarcoidosis and 7–8 points had a likelihood ratio of infinity (95% confidence ratio 1.2 to infinity). This analysis would need to be validated in other cohorts. Potential additional screening tests include global longitudinal strain detected by echocardiography [[20]Felekos I. Aggeli C. Gialafos E. et al.Global longitudinal strain and long-term outcomes in asymptomatic extracardiac sarcoid patients with no apparent cardiovascular disease.Echocardiography (Mount Kisco, N.Y.). 2018; 35: 804-808Crossref PubMed Scopus (14) Google Scholar], serum biomarkers of cardiac injury [[21]Date T. Shinozaki T. Yamakawa M. et al.Elevated plasma brain natriuretic peptide level in cardiac sarcoidosis patients with preserved ejection fraction.Cardiology. 2007; 107: 277-280Crossref PubMed Scopus (24) Google Scholar,[22]Kandolin R. Lehtonen J. Airaksinen J. et al.Usefulness of cardiac troponins as markers of early treatment response in cardiac sarcoidosis.Am. J. Cardiol. 2015; 116: 960-964Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar], and signal average electrocardiography that in one sarcoidosis cohort had a specificity of 100% in the subgroup with an unfiltered QRS duration of <100 ms [[23]Schuller J.L. Lowery C.M. Zipse M. et al.Diagnostic utility of signal-averaged electrocardiography for detection of cardiac sarcoidosis.Ann. Noninvasive Electrocardiol. 2011; 16: 70-76Crossref PubMed Scopus (40) Google Scholar]. In summary, the approach to screening sarcoidosis patients for cardiac sarcoidosis is not standardized as there are inadequate data to make specific reliable recommendations. However, the following statements are valid.•Eliciting cardiac symptoms has a higher sensitivity as an individual screening maneuver than electrocardiography, echocardiography, and Holter monitoring.•The addition of either electrocardiography, echocardiography, or Holter monitoring to eliciting cardiac symptoms minimally raises the sensitivity for detecting cardiac sarcoidosis.•Among electrocardiography, echocardiography, and Holter monitoring, Holter monitoring raises the sensitivity for detecting cardiac sarcoidosis to the greatest degree, albeit not beyond a diagnostic threshold.•Echocardiography is highly specific for the diagnosis of cardiac sarcoidosis; and although a positive echocardiogram coupled with other positive findings may exceed the diagnostic threshold for cardiac sarcoidosis, usually clinicians require a diagnostic test (CMR or cardiac PET scan) for confirmation because of the potential consequences of device placement and potentially toxic therapy.•There is evidence that diagnostic tests such as CMR and cardiac PET scanning may have a role in the screening algorithm, although the high cost of these tests make them unattractive. It is hoped that accumulating data will rapidly get to the heart of this issue. MAJ is a consultant for Biogen.
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