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Influenza is a cause of significant morbidity and mortality worldwide, with 3 to 5 million cases reported annually.1 The 2017–2018 season has been especially devastating, with >195 000 people infected in the United States at the time of this writing and mortality above epidemic thresholds. Specifically, there have been 128 pediatric deaths, a higher total than that in recent years.2
Influenza myocarditis is a rare complication of the influenza virus, seen in ∼10% of patients.1 Cardiac manifestations can vary from mild changes on electrocardiogram (ECG) to profound hemodynamic compromise. Symptoms, such as chest pain, dyspnea, or palpitations, typically begin 4 to 7 days after viral symptoms.1 There have been few reported cases of influenza B myocarditis in children. Although skewed by publication bias, the majority of reported cases required inotropic support, and approximately half of patients did not survive.3
Given the lack of definitive data, there is no agreed on standard treatment of myocarditis. Controlled studies in the management of myocarditis in children are limited by the rarity of cases and difficulty in establishing a definitive diagnosis. Immunomodulatory therapies, such as steroids and intravenous immunoglobulin (IVIg), have become widely used for the treatment of viral myocarditis in children, and immunosuppressive medications (such as cyclosporine), which are less widely used, have been examined in few studies.4 There have been few large studies in which the efficacy of these medications are examined, but results are mixed, and there is no consensus on their appropriate use.5
Given the role played by T cells in viral myocarditis, there is a rational basis for the use of antithymocyte globulin (ATG). However, there have been no published cases of ATG treatment in children with viral myocarditis. Few case reports have revealed ATG
Influenza Myocarditis Treated With Antithymocyte GlobulinJenna A. Piccininni, MD, Marc E. Richmond, MD, Eva W. Cheung, MD, Teresa M. Lee, MD, Sabrina P. Law, MD, Linda J. Addonizio, MD, Warren A. Zuckerman, MD
Influenza is a cause of significant morbidity and mortality worldwide. Myocarditis is a rare complication of the virus and can vary widely in severity. The published cases of influenza B myocarditis in children tend to be severe with a high mortality rate. Current standard treatment of viral myocarditis is supportive care, although immunomodulatory therapies, such as steroids and intravenous immunoglobulin, are often used. T cells have been implicated in causing significant myocyte damage in myocarditis by leading to the downstream production of antibodies against viral and myocyte antigens; this has created a theoretical basis for the use of antithymocyte globulin to target T cells in these patients. We present a case of acute fulminant influenza B myocarditis in a pediatric patient that required mechanical circulatory support and improved only after treatment with antithymocyte globulin.
abstract
To cite: Piccininni JA, Richmond ME, Cheung EW, et al. Influenza Myocarditis Treated With Antithymocyte Globulin. Pediatrics. 2018;142(5): e20180884
Division of Pediatric Cardiology, Morgan Stanley Children’s Hospital of New York-Presbyterian, Columbia University Medical Center, New York, New York
Dr Piccininni performed the chart review and literature search and drafted the initial manuscript; Drs Richmond, Cheung, Lee, Law, Addonizio, and Zuckerman reviewed and revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
DOI: https:// doi. org/ 10. 1542/ peds. 2018- 0884
Accepted for publication Jul 11, 2018
Address correspondence to Jenna A. Piccininni, MD, Division of Pediatric Cardiology, Morgan Stanley Children’s Hospital of New York-Presbyterian, Columbia University Medical Center, 3959 Broadway, New York, NY 10032. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2018 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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to be beneficial in adult patients with giant-cell myocarditis, and researchers of a case series of 5 adults reported the successful use of ATG in acute fulminant lymphocytic myocarditis.6, 7 We present a case of acute fulminant influenza B myocarditis in a pediatric patient that required mechanical circulatory support and significantly improved after treatment with ATG.
CASE
We report on a 13-year-old female patient with no previous medical history who presented to a local emergency department with 2 to 3 days of upper respiratory symptoms and chest pain. Her workup was positive for influenza B by respiratory polymerase chain reaction testing and was concerning for ST segment changes on ECG and troponin elevation (peak troponin T level of 9 ng/mL). Of note, she had not been vaccinated against influenza this season. She was transferred to a tertiary center PICU where an echocardiogram revealed severely decreased biventricular function and significant pericardial effusion requiring drainage. During pericardiocentesis, she suffered cardiopulmonary arrest and was cannulated onto peripheral venoarterial extracorporeal membrane oxygenation (ECMO). She was treated with oseltamivir, intravenous methylprednisolone (6 doses of 500 mg twice daily followed by a taper initiated at 1.5 mg/kg per day in divided doses twice daily), and IVIg (1 dose of 2 g/kg on ECMO day 2). Cardiac function remained severely depressed, and she was transferred to our institution on ECMO day 4 for further management and a potential heart transplant evaluation.
On arrival, her ECG revealed extremely low-voltage QRS complexes with diffuse ST segment elevation (Fig 1), an echocardiogram
revealed an akinetic, nondilated heart (Fig 2 A and B), and an examination was significant for absent heart tones and pulses, with no pulse pressure on the arterial line. The steroid taper was continued, but because of the lack of clinical improvement, treatment was initiated with ATG (rabbit) on ECMO day 5. The initial plan was to administer 5 consecutive daily doses of ATG at 1.5 mg/kg per dose, which is our institutional protocol for induction therapy after a heart transplant. After the first dose, ATG was held for 2 days because of lymphopenia (white blood cell count of 12 900 with 1% lymphocytes [normal: 18.2%–49.8%]). Before starting ATG, she had thrombocytopenia (platelet count of 61 000), which remained low during treatment. She required multiple transfusions to maintain her platelet count at >80 000 as per our institutional ECMO protocol. ATG was then continued on ECMO day 8 once her lymphopenia improved. In total, she received 5 doses over 7 days with a cumulative dose of 6 mg/kg. A second 2 g/kg dose of IVIg was given while ATG was held.
Echocardiograms were performed daily on ECMO, and cardiac motion was first noted on ECMO day 8 (3 days after the first ATG dose). The following day, the aortic valve began opening, generating a pulse pressure and faint peripheral pulses. Over the span of 1 week, milrinone was added, and cardiac function continued to improve. A T-cell panel on the first day of ventricular function improvement revealed 129 CD3+ T cells per μL (normal: 1000–2200 cells per μL), with CD4+ and CD8+ cells both significantly below the normal ranges. The T-cell count, which decreased throughout the ATG course, reached a minimum of 9 T cells per μL after the fourth ATG dose. She underwent a successful ECMO decannulation on ECMO day 14 while on milrinone and epinephrine. After decannulation, she was transitioned
to oral anticongestive therapies. A brain MRI was performed before discharge for prognostication after her cardiac arrest, which revealed a subacute right basal ganglia ischemic stroke and a right frontal subdural hematoma. Clinically, her neurologic examination was significant only for slightly decreased left-sided muscle strength (4+ to 5).
She was discharged on hospital day 32 on lisinopril, digoxin, and carvedilol with follow-up by the cardiology and neurology departments. The echocardiogram at discharge revealed moderately diminished left ventricular function (left ventricular ejection fraction of 39% [normal: >55%]) and mildly diminished right ventricular function without ventricular dilation. Since discharge, her oral anticongestives have been optimized, her T-cell count has seen an uptrend to 837 cells per μL, and she continues to improve clinically. One week after discharge, an echocardiogram revealed a left ventricular ejection fraction of 42% (Fig 2C).
DISCUSSION
This is the first case in which the use of ATG in a pediatric patient with acute fulminant viral myocarditis is reported. After receiving high-dose steroids, IVIg, and mechanical circulatory support (allowing for myocardial rest), the heart continued to be akinetic. Therefore, while pursuing a transplant workup, a course of ATG was initiated, after which cardiac function began to gradually improve. The choice to use ATG was based on the fulminant nature of the case, the lack of any cardiac improvement after initial immunomodulatory therapies, and the role played by T cells in myocyte injury in myocarditis. Our institution has similarly used ATG in a previous refractory myocarditis case with similar success.
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Research suggests that the mechanism of cardiac injury in viral myocarditis occurs in 3 distinct phases. The virus enters myocytes and activates the innate immune
response. It then replicates, leading to myocyte necrosis and the exposure of intracellular antigens, which causes the initiation of an inflammatory cascade. In phase 2
(occurring from day 7 to day 28 of infection), T cells play a major role in myocyte injury via the downstream creation of antibodies against viral and cardiac antigens and the production of cytokines. Phase 3 is either the recovery phase (during which the inflammation subsides) or the progression to cardiomyopathy.8 A mouse model has revealed that T cell–deprived mice (via thymectomy and bone marrow irradiation and transplant) or those given ATG have a significantly lower incidence of lethal myocarditis and a lesser extent of myocyte inflammation and necrosis.9 Other studies implicate CD4 and CD8 T cells in myocyte damage and reveal a protective role played by T regulatory cells.10
Bone marrow suppression resulting in thrombocytopenia and leukopenia is a known side effect of ATG.11 Our patient experienced both thrombocytopenia and lymphopenia. Thrombocytopenia, which can be a consequence of the ECMO circuit itself, can manifest as minor bleeding
PEDIATRICS Volume 142, number 5, November 2018 3
FIGURE 1ECG revealing low-voltage QRS complexes and diffuse ST elevations. Note that the scale is double standard. aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.
FIGURE 2A, Parasternal short-axis view on echocardiography at the level of the left ventricle. M-mode images obtained from this view reveal a cross-section over time. B, M-mode images on admission reveal almost no ventricular wall motion. C, M-mode images 1 week after discharge reveal improved ventricular wall motion and ejection fraction. LV, left ventricular.
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at cannula sites or the mucosa or as more serious bleeding, such as central nervous system bleeding. This had particular implications for our patient, and she required multiple platelet transfusions to maintain adequate platelet counts to prevent these complications. Leukopenia is usually dose dependent and reversible, as it was in this case. Our patient did not manifest any other side effects, which include urinary tract infection, abdominal pain, hypertension, nausea, shortness of breath, fever, anxiety, chills, and hyperkalemia. Less common side effects include anaphylaxis, infusion rate–related cytokine release, infections (in particular, reactivation of cytomegalovirus), and in rare cases, malignancy.11
Although the dramatic response to ATG in our patient was impressive, there are limitations to consider. There is no standard expected recovery time in cases of fulminant myocarditis. Rajagopal et al12 published retrospective outcomes in 255 children who required ECMO for acute myocarditis. They found no significant difference in the length of ECMO support between those who survived (168 hours) and those who did not survive (172 hours), and both groups demonstrated significant variability.12 Our patient began to improve on ECMO day 8 (>192 hours) and was decannulated on ECMO day 14, which was longer than the average for either group. It is impossible to know if myocardial function would have improved without receiving ATG, and it is difficult to assess the role played by the other immunomodulators.
Additionally, our patient had polymerase chain reaction secretions positive for influenza B, which was the presumed cause
of her myocarditis. However, an endomyocardial biopsy (the gold standard for diagnosis) was not performed. Our confidence in the diagnosis was high, and her fragile hemodynamic status made the risks of this procedure substantial. Furthermore, a biopsy result would not have altered management and thus was not pursued, leaving us without a definitive pathologic diagnosis.
Despite these limitations, this case reveals the potential safety and efficacy of ATG in a severe case of acute viral myocarditis in a pediatric patient. ATG was well tolerated with minimal reversible side effects, revealing that it may be used safely in this population. Future research in children with fulminant refractory myocarditis may further elucidate its benefits in these patients. After this past influenza season (with higher than usual morbidity and mortality), we want to highlight this case of severe influenza B myocarditis and the novel use of ATG as a contributor to dramatic improvement.
ABBREVIATIONS
ATG: antithymocyte globulinECG: electrocardiogramECMO: extracorporeal membrane
oxygenationIVIg: intravenous
immunoglobulin
REFERENCES
1. Rezkalla SH, Kloner RA. Influenza-related viral myocarditis. WMJ. 2010;109(4):209–213
2. Centers for Disease Control and Prevention. Weekly U.S. influenza surveillance report. 2018. Available at: https:// www. cdc. gov/ flu/ weekly/ index. htm. Accessed March 19, 2018
3. Frank H, Wittekind C, Liebert UG, et al. Lethal influenza B myocarditis in a child and review of the literature for pediatric age groups. Infection. 2010;38(3):231–235
4. Kleinert S, Weintraub RG, Wilkinson JL, Chow CW. Myocarditis in children with dilated cardiomyopathy: incidence and outcome after dual therapy immunosuppression. J Heart Lung Transplant. 1997;16(12):1248–1254
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6. Suarez-Barrientos A, Wong J, Bell A, Lyster H, Karagiannis G, Banner NR. Usefulness of rabbit anti-thymocyte globulin in patients with giant cell myocarditis. Am J Cardiol. 2015;116(3):447–451
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9. Woodruff JF, Woodruff JJ. Involvement of T lymphocytes in the pathogenesis of coxsackie virus B3 heart disease. J Immunol. 1974;113(6):1726–1734
10. Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM. T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation. Br J Pharmacol. 2017;174(22):3914–3925
11. Genzyme Corporation. Thymoglobulin [package insert]. Lyon, France: Genzyme Polyclonals S.A.S; 2017
12. Rajagopal SK, Almond CS, Laussen PC, Rycus PT, Wypij D, Thiagarajan RR. Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: a review of the Extracorporeal Life Support Organization registry. Crit Care Med. 2010;38(2):382–387
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DOI: 10.1542/peds.2018-0884 originally published online October 23, 2018; 2018;142;Pediatrics
Law, Linda J. Addonizio and Warren A. ZuckermanJenna A. Piccininni, Marc E. Richmond, Eva W. Cheung, Teresa M. Lee, Sabrina P.
Influenza Myocarditis Treated With Antithymocyte Globulin
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DOI: 10.1542/peds.2018-0884 originally published online October 23, 2018; 2018;142;Pediatrics
Law, Linda J. Addonizio and Warren A. ZuckermanJenna A. Piccininni, Marc E. Richmond, Eva W. Cheung, Teresa M. Lee, Sabrina P.
Influenza Myocarditis Treated With Antithymocyte Globulin
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