Myocarditis, hepatitis, and pancreatitis in a patient with coxsackievirus A4 infection: a case report
© Akuzawa et al.; licensee BioMed Central Ltd. 2014
Received: 4 September 2013
Accepted: 9 January 2014
Published: 13 January 2014
Viral myocarditis presents with various symptoms, including fatal arrhythmia and cardiogenic shock, and may develop chronic myocarditis and dilated cardiomyopathy in some patients. We report here a case of viral myocarditis with liver dysfunction and pancreatitis. A 63-year-old man was admitted to our hospital with dyspnea. The initial investigation showed pulmonary congestion, complete atrioventricular block, left ventricular dysfunction, elevated serum troponin I, and elevated liver enzyme levels. He developed pancreatitis five days after admission. Further investigation revealed a high antibody titer against coxsackievirus A4. The patient’s left ventricular dysfunction, pancreatitis, and liver dysfunction had resolved by day 14, but his troponin I levels remained high, and an endomyocardial biopsy showed T-lymphocyte infiltration of the myocardium, confirming acute myocarditis. The patient underwent radical low anterior resection five weeks after admission for advanced rectal cancer found incidentally. His serum troponin I and plasma brain natriuretic peptide levels normalized six months after admission. He has now been followed-up for two years, and his left ventricular ejection fraction is stable.
This is the first report of an adult with myocarditis and pancreatitis attributed to coxsackievirus A4. Combined myocarditis and pancreatitis arising from coxsackievirus infection is rare. This patient’s clinical course suggests that changes in his immune response associated with his rectal cancer contributed to the amelioration of his viral myocarditis.
KeywordsCoxsackievirus Liver dysfunction Myocarditis Pancreatitis Rectal cancer
Myocarditis can present with a wide range of symptoms, ranging from mild dyspnea to chest pain, cardiogenic shock, and fatal arrhythmia. The main cause of myocarditis is current or recent viral infection . Enteroviruses, specifically Coxsackievirus (CV) group B serotypes, have traditionally been perceived as the predominant viral cause , although adenoviruses, parvovirus B19, and human herpesvirus 6 can also cause myocarditis [3–5].
The pathophysiological progression of viral myocarditis includes three distinct phases . The first phase is characterized by a nonspecific innate immune response, causing virus-mediated cell lysis and the indirect destruction of cardiomyocytes [3, 6]. During the second phase, a virus-specific immune response, including CD8+ lymphocytes, acts to eliminate the causative viruses, leading to heart failure with the destruction of the infected cardiomyocytes . In the third phase, commonly a few weeks after infection, the destroyed cardiomyocytes are replaced by diffuse fibrosis and progressive biventricular dilatation, resulting in cardiac failure [1, 3]. Approximately 50% of patients with viral myocarditis develop chronic myocarditis, and 21% develop dilated cardiomyopathy (DCM) . A longitudinal study reported that the immune clearance of viruses during or after the acute phase of myocarditis correlates with improvements in the left ventricular ejection fraction (LVEF) . In chronic myocarditis or DCM, a persistent viral presence on endomyocardial biopsy (EMB) specimens is associated with an increased mortality rate . However, viral genomic RNA and capsid protein are detectable in EMB specimens in no more than 35% and 10% of cases, respectively . Therefore, the relationship between persistent viral infection and progression from acute myocarditis to chronic irreversible cardiomyopathy is unclear.
We present here a rare case of CVA4 infection causing acute myocarditis with concomitant pancreatitis and liver dysfunction. The patient’s antibody titers against CVA4 were significantly elevated during the recovery period, and a pathological examination of an EMB specimen showed interstitial infiltration with CD3-positive lymphocytes, despite a normal LVEF on left ventriculography, confirming acute myocarditis. His plasma brain natriuretic peptide (BNP) and serum troponin I (TnI) levels remained elevated. Five weeks after admission, the patient underwent radical low anterior resection for advanced rectal cancer, found by chance. Interestingly, his plasma BNP and serum TnI levels returned to normal after surgery. The patient’s clinical course suggests that the immune modulation associated with his rectal cancer and surgery favorably affected his acute myocarditis, preventing its progression to chronic myocarditis or DCM.
A 63-year-old man was admitted to our hospital with a three-day history of dyspnea and fatigue, which had gradually increased until he experienced dyspnea and fatigue at rest. He had taken amlodipine (5 mg/day) for hypertension for the preceding five years, but had no other remarkable past history or family history. He was a nonsmoker and did not consume alcohol. Two weeks previously, he had presented with flu-like symptoms, including fever, sore throat, cough, and diarrhea, which had completely resolved within a week.
Laboratory findings on admission
White blood cells*
3300 – 9000/mm3
Red blood cells
467 × 104/mm3
430 – 570 × 104/mm3 (Male)
13.5 – 17.5 g/dl (Male)
39.7 – 52.4% (Male)
29.3 × 104/mm3
14.0 – 34.0 × 104/mm3
Differential white blood cell count
34.0 – 70.0%
Band cells, stab cells*
1.0 – 7.0%
0 - 8.0%
2.0 – 10.0%
18.0 – 49.0%
6.7 – 8.3 g/dl
3.8 – 5.2 g/dl
10 – 40 IU/l
5 – 45 IU/l
120 – 240 IU/l
100 – 325 IU/l
10 – 50 IU/l
0.2 – 1.2 mg/dl
0 – 0.4 mg/dl
60 – 270 IU/l
< 5.2 ng/ml
Blood urea nitrogen*
8.0 – 20.0 mg/dl
0.61 - 1.04 mg/dl
135 – 145 mEq/l
3.5 – 5.0 mEq/l
98 – 108 mEq/l
8.4 – 10.4 mg/dl
2.5 – 4.5 mg/dl
70 – 109 mg/dl
< 0.30 mg/dl
< 18.4 pg/ml
< 0.04 ng/ml
Blood coagulation test
IgM anti-HAV Ab
The intravenous administration of dopamine (10 μg/kg/min), unfractionated heparin (15,000 units/day), and furosemide (20 mg/day) was begun on the day of admission. The patient’s systolic blood pressure increased to about 120 mmHg and stabilized. The low-dose intravenous administration of human atrial natriuretic peptide (0.025 μg/kg/min) was begun on day 2. Nonsustained monomorphic ventricular tachycardia lasting for about 1 min was observed several times on day 2, but had no significant hemodynamic impact, and was effectively treated with an intravenous bolus injection of amiodarone (150 mg). On day 3, the patient’s atrioventricular conduction returned to normal and his daily urine output increased to 3500 mL/day. On day 4, echocardiography showed an improvement in LVEF to 55.2% and the temporary pacing wire was removed. His serum CPK levels peaked on day 4 at 3229 IU/L. On day 7, a chest X-ray showed resolution of the right pleural effusion and his serum creatinine level returned to normal (0.98 mg/dL). The intravenous administration of human atrial natriuretic peptide was stopped, and the patient commenced a regimen of oral losartan (25 mg/day), spironolactone (12.5 mg/day), azosemide (30 mg/day), and warfarin (3.0 mg/day). Supplemental oxygen was no longer needed.
A colonoscopy on day 18 showed a protruding rectal lesion above the level of the peritoneal reflection. The plasma carcinoembryonic antigen level was 4.7 ng/mL (normal: 0–4.9 ng/mL) and the cancer antigen 19–9 level was 434.6 U/mL (normal: 0–36.9 U/mL). A pathological examination of a biopsy specimen of the rectal lesion showed a moderately differentiated tubular adenocarcinoma invading the muscularis propria. Transesophageal echocardiography on day 27 showed no signs of left atrial thrombus, and the administration of warfarin was stopped in preparation for surgery. The patient was transferred to the Department of Surgery on day 28, and underwent a low anterior resection on day 35. The postoperative diagnosis was stage II rectal cancer (T3N0M0, Union for International Cancer Control Classification). His postoperative recovery was uneventful, with no complications such as heart failure or arrhythmia. He was discharged on day 45. A histological examination of the surgical specimen showed lymphovascular invasion, and adjuvant chemotherapy with folinic acid, fluorouracil, and oxaliplatin was commenced a month after discharge. Interestingly, his plasma BNP level decreased to less than half the preoperative value (78 pg/mL) and his serum TnI level returned to normal (< 0.04 ng/mL) three weeks after surgery. His plasma BNP level returned to normal (18 pg/mL) four months after surgery. Oral medications for heart failure were stopped five months after discharge. The patient underwent a partial hepatectomy six months after discharge for a solitary metastasis in the liver, but his myocarditis did not recur. Adjuvant chemotherapy was continued until 12 months after surgery. The patient has now been followed-up for two years, with stable LVEF and no recurrence of myocarditis or rectal cancer.
Coxsackieviruses belong to the genus Enterovirus, in the family Picornaviridae, and are important viral pathogens, causing myocarditis and pancreatitis. CVs are subdivided according to their pathogenicity in suckling mice aged less than 48 h into CVA, which causes flaccid paralysis, and CVB, which causes spastic paralysis [10–12]. There are 23 CVA serotypes and six CVB serotypes . Although CVs are known to cause myocarditis, most cases are attributed to CVB serotypes . CVA infection can cause viral myocarditis, but it has a more benign course than CVB myocarditis . Serotypes A4 and A16 have been most frequently implicated in the rare cases of CVA-associated myocarditis reported . Combined myocarditis and pancreatitis arising from CV infection is very rare, with only three previously reported cases, which were all attributed to CVB infection [14, 15]. Ischemic pancreatitis was unlikely in our patient because of the late disease onset (day 5) and hemodynamic stability after admission. Moreover, although we did not stop any medications, including diuretics, the patient’s pancreatitis improved spontaneously. Therefore, it is more likely that his pancreatitis developed from his CV infection. To our knowledge, this is the first reported case of an adult patient with myocarditis and pancreatitis attributable to CVA infection. It is unclear why combined myocarditis and pancreatitis is uncommon in CV-infected humans. In a mouse model, the viral titer was higher in the pancreas than in the heart, liver, or spleen during the early stage of CVB infection . In humans, CVB3 capsid protein VP1 was detected in both the cardiomyocytes and islets of endocrine cells in patients who died of acute CVB myocarditis . These results suggest that the rate of latent or asymptomatic pancreatitis may be higher than previously thought in patients with myocarditis attributable to CV infection.
The course of our patient’s myocarditis is interesting. Although his LVEF on echocardiography improved soon after admission and normalized on left ventriculography by day 16, an EMB specimen on the same day still showed prominent T-lymphocyte infiltration with a slightly elevated serum TnI level. His serum TnI level had returned to normal three weeks after surgery, and his plasma BNP level had also decreased at this time. This suggests that resection of the rectal cancer may have resulted in the improvement of his myocarditis and inhibited any progression to chronic myocarditis or DCM. The patient’s normal LVEF during the two-year follow-up supports this conjecture. The relationship between persistent viral infection and the establishment of chronic myocarditis is controversial. A recent study reported that regulatory T cells (Tregs), which are positive for CD4, CD25, and Foxp3, reduced viral titers and suppress cardiac damage in CVB-infected mice . Furthermore, the myocardial Treg frequency was reduced during the course of CVB3 myocarditis in BALB/c mice and the adoptive transfer of Tregs resulted in the significant amelioration of cardiac fibrosis . Tregs maintain immunohomeostasis and limit autoimmunity, but there may be high levels of Tregs in the blood and tumor tissues of cancer patients, leading to the suppression of antitumor immunity . The proportion of Tregs is significantly higher in colon cancer patients than in healthy controls, and decreases significantly after the radical resection of the tumors . Increased Treg activity also suppresses CD8+ T-cell responses to specific antigens of various viruses . The limitations of our report include our inability to determine the myocardial frequency or activity of Tregs before and after surgery, but our findings suggest that the modulation of the immune response associated with rectal cancer and surgery, including a change in Treg activity, may have contributed to the amelioration of myocarditis in our patient. More specifically, the increased Treg activity associated with rectal cancer may have had an inhibitory effect on his cardiac fibrosis and CD8+ T-cell-associated myocardial damage during the acute or subacute period of myocarditis, leading to the benign clinical course of this patient, although the onset of myocarditis per se could not be prevented. However, a point of uncertainty persists because reduced Treg activity after surgery might have exacerbated his myocarditis. Despite this, the patient’s myocarditis improved. This suggests that components other than Tregs were involved in the improvement in his myocarditis, such as mesenchymal stromal cells (MSCs), which have been identified in the bone marrow and have unique immunoregulatory and regeneration properties . MSCs reduced myocardial inflammation by reducing the expression of proinflammatory cytokines and inducing an increase in Tregs and CD4+- and CD8+-T-cell apoptosis in CVB3-infected mice . However, it should be noted that no Treg or MSC activity has yet been reported in patients with chronic myocarditis or DCM. Although our patient’s clinical course after surgery included the resolution of his myocarditis, further research is required to clarify the mechanisms involved.
We have presented a rare case of myocarditis, liver dysfunction, and pancreatitis arising from CVA4 infection in a patient with undiagnosed advanced rectal cancer. His clinical course was good and his elevated serum TnI and plasma BNP levels returned to normal over four months after the radical resection of his rectal cancer. These features suggest that changes in the immune response to myocarditis that were associated with the patient’s rectal cancer may have had a favorable effect on his myocarditis, thereby preventing the progression of acute myocarditis to chronic cardiomyopathy.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of this written consent is available for review by the Editor-in-Chief of this journal.
Left ventricular ejection fraction
Brain natriuretic peptide
Mesenchymal stromal cell
Regulatory T cell.
The authors would like to thank Mr. Yousuke Kitadume for his assistance in preparing the pathological tissue specimen and Miss Hisae Kuribara for her secretarial assistance under the financial support provided by Social Insurance Gunma Chuo General Hospital.
- Cooper LT: Myocarditis. N Engl J Med 2009, 360: 1526-1538. 10.1056/NEJMra0800028PubMedView ArticleGoogle Scholar
- Magnani JW, Dec GW: Myocarditis: current trends in diagnosis and treatment. Circulation 2006, 113: 876-890. 10.1161/CIRCULATIONAHA.105.584532PubMedView ArticleGoogle Scholar
- Feldman AM, McNamara D: Myocarditis. N Engl J Med 2000, 343: 1388-1398. 10.1056/NEJM200011093431908PubMedView ArticleGoogle Scholar
- Dec GW Jr, Palacios IF, Fallon JT, Aretz HT, Mills J, Lee DC, Johnson RA: Active myocarditis in the spectrum of acute dilated cardiomyopathies: clinical features, histologic correlates, and clinical outcome. N Engl J Med 1985, 312: 885-890. 10.1056/NEJM198504043121404PubMedView ArticleGoogle Scholar
- Mahrhodlt H, Wagner A, Deluigi CC, Kispert E, Hager S, Meinhardt G, Sechtem U: Presentation, patterns of myocardial damage, and clinical course of viral myocarditis. Circulation 2006, 114: 1581-1590. 10.1161/CIRCULATIONAHA.105.606509View ArticleGoogle Scholar
- Andréoletti L, Lévêque N, Boulagnon C, Brasselet C, Fornes P: Viral causes of human myocarditis. Arch Cardiovasc Dis 2009, 102: 559-568. 10.1016/j.acvd.2009.04.010PubMedView ArticleGoogle Scholar
- Guglin M, Nallamshetty L: Myocarditis: diagnosis and treatment. Curr Treat Options Cardiovasc Med 2012, 14: 637-651. 10.1007/s11936-012-0204-7PubMedView ArticleGoogle Scholar
- Kühl U, Pauschinger M, Seeberg B, Lassner D, Noutsias M, Poller W, Schultheiss HP: Viral persistence in the myocardium is associated with progressive cardiac dysfunction. Circulation 2005, 112: 1965-1970. 10.1161/CIRCULATIONAHA.105.548156PubMedView ArticleGoogle Scholar
- Why HJ, Meany BT, Richardson PJ, Olsen EG, Bowles NE, Cunningham L, Freeke CA, Archard LC: Clinical and prognostic significance of detection of enteroviral RNA in the myocardium of patients with myocarditis or dilated cardiomyopathy. Circulation 1994, 89: 2582-2589. 10.1161/01.CIR.89.6.2582PubMedView ArticleGoogle Scholar
- Woodruff JF: Viral myocarditis: a review. Am J Pathol 1980, 101: 425-484.PubMedPubMed CentralGoogle Scholar
- See DM, Tilles JG: Pathogenesis of virus-induced diabetes in mice. J Infect Dis 1995, 171: 1131-1138. 10.1093/infdis/171.5.1131PubMedView ArticleGoogle Scholar
- Baboonian C, Treasure T: Meta-analysis of the association of enteroviruses with human heart disease. Heart 1997, 78: 539-543.PubMedPubMed CentralView ArticleGoogle Scholar
- Bendig JW, O’Brien PS, Muir P, Porter HJ, Caul EO: Enterovirus sequences resembling coxsackievirus A2 detected in stool and spleen from a girl with fetal myocarditis. J Med Virol 2001, 64: 482-486. 10.1002/jmv.1075PubMedView ArticleGoogle Scholar
- Coplan NL, Atallah V, Mediratta S, Bruno MS, DePasquale NP: Cardiac, pancreatic, and liver abnormalities in a patient with coxsackie-B infection. Am J Med 1996, 101: 325-326. 10.1016/S0002-9343(97)89436-3PubMedView ArticleGoogle Scholar
- Lau G: Acute fulminant, fatal coxsackie B virus infection: a report of two cases. Ann Acad Med Singapore 1994, 23: 917-920.PubMedGoogle Scholar
- Gomez RM, Cui X, Castagnino CG, Berria MI: Differential behavior in pancreas and heart two coxsakievirus B3 variants. Intervirology 1993, 36: 153-160.PubMedGoogle Scholar
- Foulis AK, Farguharson MA, Cameron SO, McGill M, Schönke H, Kandolf R: A search for the presence of the enteroviral capsid protein VP1 in pancreases of patients with type 1 (insulin-dependent) diabetes and pancreases and hearts of infants who died of coxsackieviral myocarditis. Diabetologia 1990, 33: 290-298. 10.1007/BF00403323PubMedView ArticleGoogle Scholar
- Shi Y, Fukuoka M, Li G, Liu Y, Chen M, Konviser M, Chen X, Opavsky MA, Liu PP: Regulatory T cells protect mice against coxsackievirus-induced myocarditis through the transforming growth factor -coxsackie-adenovirus receptor pathway. Circulation 2010, 121: 2624-2634. 10.1161/CIRCULATIONAHA.109.893248PubMedView ArticleGoogle Scholar
- Cao Y, Xu W, Xiong S: Adoptive transfer of regulatory T cells protect against Coxsackievirus B3-induced cardiac fibrosis. PLoS One 2013, 6: e7455.Google Scholar
- Ondondo B, Jones E, Godkin A, Gallmore A: Home sweet home: the tumor microenviroment as a haven for regulatory T cells. Front Immunol 2013, 4: 197.PubMedPubMed CentralView ArticleGoogle Scholar
- Sellito A, Galizia G, De Fanis U, Lieto E, Zamboli A, Orditura M, De Vita F, Giunta R, Lucivero G, Romano C: Behavior of circulating CD4 + CD25 + Foxp3+ regulatory T cells in colon cancer patients undergoing surgery. J Clin Immunol 2011, 31: 1095-1104. 10.1007/s10875-011-9585-8View ArticleGoogle Scholar
- Li S, Gowans EJ, Chougnet C, Plebanski M, Dittmer U: Natural regulatory T cells and persistent viral infection. J Virol 2008, 82: 21-30. 10.1128/JVI.01768-07PubMedPubMed CentralView ArticleGoogle Scholar
- Miteva K, Van Linthout S, Volk HD, Tschöpe C: Immunomodulatory effects of mesenchymal stromal cells revisited in the context of inflammatory cardiomyopathy. Stem Cells Int 2013, 2013: 353097. doi:10.1155/2013/353097PubMedPubMed CentralView ArticleGoogle Scholar
- Savvatis K, Van Linthout S, Miteva K, Pappritz K, Westermann D, Schefold JC, Fusch G, Weithäuser A, Rauch U, Becher M, Klingel K, Ringe J, Kurtz A, Schultheiss HP, Tschöpe C: Mesenchymal stromal cells but not cardiac fibroblasts exert beneficial systemic immunomodulatory effects in experimental myocarditis. PLoS One 2012, 7: e41047. 10.1371/journal.pone.0041047PubMedPubMed CentralView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.