Although chest pain is a common chief complaint among pediatric patients, cardiac pathology historically has accounted for a small percentage of cases. However, the emergence of COVID-19 and particularly its potential for leading to multisystem inflammatory syndrome has changed the threshold for the evaluation of cardiac etiologies of chest pain. This evaluation often includes measurement of the serum cardiac troponin I level. We present a case of a 16-year-old male athlete who presented to an outside emergency department with chest pain and was found to have elevated serum troponin I levels. Despite sports restriction, his troponin level remained elevated for months in the absence of other clinical findings and he was subsequently referred to our outpatient pediatric cardiology clinic. Further laboratory evaluation revealed that, in addition to troponin I, the assay measured an immune complex of uncertain significance formed by anti-troponin I antibodies bound to troponin I, known as macrotroponin. Delayed clearance of this complex from the bloodstream can result in overestimation of troponin I levels that can affect clinical management and create anxiety for our patients and their families. Macrotroponin complex deserves increased recognition among the research and clinical communities, especially in the pediatric realm.
Chest pain is a common symptom among pediatric patients who present to outpatient clinics and emergency departments. Cardiac etiologies account for only approximately 1% of cases.1,2 Chest pain in the pediatric population is most often ascribed to musculoskeletal, respiratory, or idiopathic etiologies.2
Although most cases of pediatric chest pain are benign, clinicians often feel compelled to exclude other, more malignant, etiologies. Providers frequently adopt algorithms that balance the need to exclude serious pathology with the desire to undertake cost-effective testing. These workups typically include a thorough patient history and physical examination and often an electrocardiogram (ECG). More extensive testing may then include an echocardiogram or other advanced imaging.1,3
Cardiac troponin I or T (cTnI or cTnT) levels, a mainstay of adult evaluation of chest pain, may be ordered in pediatrics, especially in the emergency department setting. Troponin is a complex of 3 subunits: troponin C, I, and T. Troponin I is the regulatory subunit, which plays a crucial role in muscle contraction.4 Cardiac isoforms of troponin can be used to assess the risk of acute cardiac injury. This risk assessment is performed by assays created by different manufacturers. The assays function through a combination of capture and detection antibodies that attach to specific epitopes of the troponin molecule to measure serum levels. The composition of these antibodies varies between manufacturers and the assay formulation.5,6 In our laboratory, cTnI is detected using the Abbott Architect High Sensitivity assay.
Although the likelihood of acute coronary syndromes in the pediatric population is low, measurement of serum troponin levels is still an important ancillary tool to use as an indicator for other cardiac etiologies of chest pain.7,8 This evaluation has been especially relevant in the current era of COVID-19, in which patients may present later with cardiac involvement as part of multisystem inflammatory syndrome in children.
We present the case of a previously healthy 16-year-old athlete found to have elevated serum troponin I levels after an initial episode of chest pain. Despite sports restriction, elevated troponin I levels persisted in the absence of other clinical findings.
A previously healthy 16-year-old boy was referred to our institution’s outpatient clinic for evaluation of persistently elevated troponin I levels associated with a prior episode of chest pain that had resolved. The patient is a competitive tennis player with pertinent family history of sudden cardiac death of his maternal grandfather in his 40s. The patient was playing tennis, when he began to experience sharp, midsternal chest pain with radiation to the left side of his neck. The pain continued with rest and was accompanied by shortness of breath. He was evaluated at an outside emergency department in a primarily adult center, where physical examination and ECG (Fig 1) were unremarkable. Laboratory work revealed cTnI 4 times the upper limit of normal (ULN) (VITROS 5600). He was subsequently admitted for serial monitoring of troponin and observation. Echocardiogram and computed tomography of the heart and coronary arteries showed no abnormalities. The patient’s symptoms resolved, troponin levels decreased, and he was discharged from the hospital with instructions to follow-up. Notably, the day after discharge, he experienced symptoms consistent with a viral upper respiratory infection.
In follow-up with his local cardiologist, the patient’s cTnI levels remained elevated during sports restriction and peaked at 60 times the ULN (ARCHITECT STAT Assay). Creatinine kinase levels were within reference range. Follow-up echocardiograms showed normal ventricular function. Additionally, a cardiac magnetic resonance imaging scan, obtained 26 days after the episode of chest pain, was normal.
He was eventually referred to our institution for further workup. A cardiac stress test was negative for significant ST segment changes, and pre- and posttest troponin levels were stable. There was no evidence of inflammation based on erythrocyte sedimentation rate and C-reactive protein levels. Rheumatologic laboratories and eye examination for uveitis were normal. The patient denied further symptoms, though his troponin ranged from 2 to 3 times ULN in our follow-up. At 3 months, based on joint decision making with family, he was cleared for slow introduction of activity with 30-day ambulatory cardiac telemetry and monitoring. He remained asymptomatic with resumption of activity. However, his troponin levels rose modestly compared with his postpresentation nadir when tested at various regional laboratories (Fig 2). The initial troponin leak was likely secondary to myocarditis given the presence of upper respiratory symptoms temporally related to onset of chest pain. With extensive reassuring workup and lack of symptoms during the recovery period, the sustained elevation of troponin was believed to be noncardiac in origin.
Heterophile antibody interference was suspected as a possible etiology. Measurements of patient cTnT, an alternate biomarker for cardiac injury not available in our institution’s laboratory, was obtained to compare with cTnI levels. cTnT returned within normal limits (Roche Cobas), 4.5 months after the initial episode of chest pain, which confirmed suspicion for false persistent elevation of cTnI. Subsequently, plasma was incubated in heterophile-blocking tubes (Scantibodies Laboratory Inc, Santee, CA) before troponin analysis. This procedure resulted in no change in measured troponin level, ruling out heterophile interference. Further testing was performed by treatment of plasma with polyethylene glycol, according to the protocol described by Lam et al, to remove high-molecular-weight proteins.9 In the absence of heterophile antibodies, significantly reduced troponin recovery (<34.6%) following the polyethylene glycol treatment is consistent with the presence of macrotroponin complex. This procedure resulted in a reduction of troponin immunoreactivity to 3% of the original value in our patient. The persistent elevation of cTnI after initial myocardial insult resulted from delayed clearance of macrotroponin complex from his bloodstream. The patient has continued to do well and is participating in competitive tennis.
Measurement of serum troponin levels is an important diagnostic tool within the workup of chest pain when there is clinical concern for cardiac etiology. In the pediatric population, elevated troponin is most often secondary to myocarditis.7,8,10 With the emergence of COVID-19, there has been increased diligence to the evaluation for myocarditis because it is frequently a feature of multisystem inflammatory syndrome in children.11 Additionally, there has been recent concern about rare cases of myocarditis associated with certain COVID-19 vaccinations.12 In our patient’s case, the initial rise of cTnI levels was likely the result of myocardial injury from viral myocarditis. However, his troponin levels did not normalize as expected. Levels tend to normalize after a week but in some cases a return to baseline after myocarditis can take up to 3 weeks after symptom resolution.10 As described, a cause of this persistent positive test could be due to macrotroponin.
Macrotroponin complex is a large molecule formed by circulating immunoglobulins that bind to troponin. These large complexes exhibit delayed serum clearance compared with standard troponin molecules. The macrotroponin complex could produce erroneous results on troponin assays because of the inability of the assay to distinguish between these 2 molecules.9 Clinical studies on macrotroponin complex are limited in the pediatric population to 2 published case reports13,14 and inclusion of this age group in cohorts of adult-focused studies.15 Community prevalence of autoantibodies against cTnI in healthy blood donors was measured in 1 study to be 12.7%.16 Another study found that 55% of adult samples with elevated cTnI have evidence for some degree of macrotroponin interference.17
Different troponin assays have varying sensitivities to detect macotroponin.17 Currently, the cause for these differing sensitivities is believed to be multifactorial with possibilities including specific formulations of each assay and potential steric hindrance caused by the complex interfering with each assay.15,17 Recent literature has mainly demonstrated false elevations because of macrotroponin to be an issue with high-sensitivity assays; however, there is also some indication that this issue confounds some contemporary assays.15 Our data further corroborate this potential.
Even with evolving literature concerning macrotroponin complex, its clinical significance is unclear.9 Little is known about the etiology of macrotroponin or its half-life. However, literature has demonstrated that the presence of this complex does not exclude concurrent cardiac pathologies.18 Our patient’s original workup was performed using a VITROS 5600 assay, which has previously been shown to be less affected by interference from macrotroponin.15 This demonstrates the high likelihood that our patient sustained an acute myocardial injury. Additionally, troponin levels in our patient exhibited a clear peak before decreasing. This rise and fall of troponin are most likely secondary to a mild case of viral myocarditis. Interestingly, patients with concomitant cardiac disease and macrotroponin complex may exhibit a delayed peak of troponin values and a subsequent prolonged decline to lower, albeit above reference range, values.19 This would explain our patient’s asymptomatic peak in troponin after his viral symptoms subsided.
Our case demonstrates the utility in using cTnT as another important clinical tool. Although there are cases of macrotroponin complex involving cTnT,20 this phenomenon appears to be less prevalent and there is no definitive evidence for risk of concurrent macro-cTnT in patients with macro-cTnI. As applied to our patient, the cTnT assay lacked sensitivity to detect macrotroponin complex. This assay could therefore be used to elucidate his clinical course and, in the future, could be used to evaluate for potential cardiac injury.
In patients who exhibit persistent elevation in troponin after symptom resolution, consideration should be made regarding analytical interference from macrotroponin complex. Timing of ordering testing to confirm the presence of macrotroponin complex would depend on the clinical presentation of the patient and clinical suspicion with subsequent follow-up.
This case highlights a little-known cause for persistently elevated cTnI in pediatric patients. Clinicians faced with a similar patient should consider the possibility of macrotroponin interference. Cases such as ours can create significant anxiety for young patients and their families. Through more awareness and recognition of macrotroponin as an entity, these worries around uncertainty could be more swiftly dispelled.
Mr Harberg performed chart review and literature review, drafted the initial manuscript, and reviewed and revised the manuscript. Drs Al-Mousily and Jackson performed direct patient care and literature review and reviewed and revised the manuscript. Drs Akter and Babic performed laboratory analysis and literature review and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no potential conflicts of interest to disclose.