Open Access

Recurrent lymphocytic myocarditis in a young male with ulcerative colitis

  • Varnavas C Varnavas1Email author,
  • Nico Reinsch1,
  • Mareike Perrey1,
  • Felix Nensa2,
  • Thomas Schlosser2,
  • Hideo A Baba3,
  • Guido Gerken4,
  • Raimund Erbel1,
  • Rolf A Janosi1 and
  • Antonios Katsounas4
European Journal of Medical Research201419:11

DOI: 10.1186/2047-783X-19-11

Received: 17 October 2013

Accepted: 17 February 2014

Published: 27 February 2014

Abstract

Awareness of myocarditis in association with inflammatory bowel diseases is crucial as it bears a rare but serious risk for mortality. This report describes the case of a young Caucasian male, whose heart biopsy was tested negative for giant cells and bacterial or viral genomes or proteins. He was experiencing severe lymphocytic myocarditis (other than mesalamine-induced) along with cardiogenic shock during ulcerative colitis exacerbation. This is an extremely rare, if not unique, clinical constellation. We chose to study the epidemiologic grounds and all major aspects of differential pathogenesis and treatment of this serious health problem.

Keywords

Ulcerative colitis lymphocytic myocarditis heart failure

Background

Awareness of myocarditis, pericarditis or myopericarditis [1] in association with inflammatory bowel diseases (IBD), e.g. ulcerative colitis (UC) and Crohn’s disease, is crucial, as they convey a rare but serious risk for mortality. The onset of symptoms often occurs during IBD exacerbation and prognosis varies from a mild cardiac disorder to severe cardiogenic shock. To date, most of the cases reported in association with IBD (other than infectious or ‘giant cell’ myocarditis), consider the myocarditis as a side effect of mesalamine therapy [2]. Lymphocytic myocarditis as a pure extraintestinal manifestation of IBD is extraordinarily rare [3].

Case presentation

A 30-year-old Caucasian male with a one-year history of UC was admitted to our intensive care unit (ICU) due to acute heart failure from an external hospital, where he had presented with abdominal pain and bloody diarrhea two weeks previously. These symptoms were assumed to arise from UC exacerbation. Prednisone (1 mg/kg-body-weight/day) and azathioprine (2 mg/kg-body-weight/day) had been added to the standard therapy with mesalamine (4 g/day). Ten days later, the patient rapidly developed aggravated symptoms of left heart failure. A transthoracic cardiac echocardiogram (TTE) confirmed severe impairment of left ventricular (LV) function with the ejection fraction (EF) approaching 15%, before the patient was referred to our ICU.

On ICU admission, a 12-lead electrocardiogram (ECG) detected sinus tachycardia of 100/min and non-specific ST-T wave changes without any significant evidence of acute myocardial ischemia. A chest X-ray showed no pulmonary infection. TTE verified LV dysfunction with advanced hypokinesia to akinesia of the basal/middle-inferior/septal/anterior wall resulting in an EF of 13% and revealed pericardial effusion (PE) of 1.6 cm (Figure 1A,B). These findings were accompanied by abnormal laboratory tests including anemia (hemoglobin: 7.6 g/dl), leukocytosis (16.25/nl) and elevated levels of C-reactive protein (27.6 mg/dl), troponin-I (7.6 ng/ml), myoglobin (664 g/dl), brain natriuretic peptide (4744.7 pg/ml), creatinine (1.43 mg/dl), lactate dehydrogenase (565 U/l), aspartate aminotransferase (253 U/l), alanine aminotransferase (166 U/l) and gamma-glutamyl transpeptidase (119 U/l). Table 1 shows the initial as well as follow-up routine biochemistry parameters along with in-house-specific reference values.
Figure 1

Transthoracic cardiac echocardiogramms. At ICU admission: (A) long axis view, and (B) short axis view; both views show a pericardial effusion of 1.6 cm. At ICU discharge: (C) long axis view, and (D) short axis view; both views confirm significant reduction of pericardial effusion.

Table 1

Initial and follow-up biochemistry values based on routine diagnostic tests

Parameter

Initial admission

Initial discharge

Readmission

Final discharge

Reference

Unit

Leucocytes (WBCs)

16.25

9.11

8.71

6.78

3.6–9.2

/nl

Red Blood Cells (RBCs)

2.63

4.14

4.97

5.08

4.5–5.6

/pl

Hemoglobin (Hb)

7.60

12.00

14.30

14.6

13.7–17

g/dl

Hematocrit (Hct)

0.22

0.37

0.42

0.421

0.4–0.5

l/l

Mean Corpuscular Volume (MCV)

82.90

89.40

83.70

82.9

83–98

fl

Mean Corpuscular Hemoglobin (MCH)

28.90

29.00

28.80

28.7

28–33

pg

Mean Corpuscular Hemoglobin Concentration (MCHC)

34.90

32.40

34.40

34.7

32–36

g/dl

Platelets

499

321

263

224

140–320

/nl

Mean Platelet Volumen (MPV)

9.00

9.20

9.70

10.2

9.4–12.2

fl

Prothrombin Time (PT or Quick)

48

96

98

97

70–130

%

International Normalized Ratio (INR)

1.45

1.04

1.02

1.02

  

Activated Partial Thromboplastin Time (aPTT)

28.60

26.30

27.10

26.8

24.4–32

sec

Fibrinogen

557

448

566

386

210–400

mg/dl

Sodium

127

138

142

142

136–145

mmol/l

Potassium

5.60

4.80

4.60

4.7

3.5–5.1

mmol/l

Calcium

1.94

2.29

2.38

2.48

2.08–2.6

mmol/l

Magnesium

0.78

0.83

0.79

0.81

0.66–1.0

mmol/l

Phosphate

4.40

4.40

2.80

3.2

2.7–4.5

mg/dl

Creatinine

1.43

0.84

1.24

1.32

0.9–1.3

mg/dl

Blood Urea Nitrogen (BUN)

42.00

21.00

22.00

22

6–19.8

mg/dl

Creatinine Kinase (CK)

418

13

45

59

38–174

U/l

Creatinine Kinase –MB (CK-MB)

61

   

<25

U/l

Creatinine Kinase –MB% (CK-MB %)

15

    

%

Troponin I

7.60

0.04

0.42

0.08

0–0.1

ng/ml

Myoglobin

664

21

30

20

10–67

μg/l

Aspartat Aminotransferase (ASAT)

253

19

15

21

0– < 50

U/l

Alanine Aminotranseferase (ALAT)

166

40

28

42

<50

U/l

Gamma-glutamyl transpeptidase (GGT)

119

79

33

84

<55

U/l

Lactate dehydrogenase (LDH)

565

183

142

138

100–247

U/l

C-reactive protein (CRP)

27.60

0.70

4.10

0.6

<0.5

mg/dl

Brain natriuretic peptide (BNP)

4744.70

462.30

108.60

60.5

0–100

pg/ml

Glomerular Filtration Rate (GFR) (MDRD)

62

114

73

68

 

ml/min/1.73 q

Invasive blood pressure monitoring and pulmonary artery catheterization (via a Swan-Ganz catheter) were used to record hemodynamic variables. Subsequently, dobutamine (15 μg/kg body weight/minute) was administered because of deranged cardiac output (1.8 l/min) and cardiac index (0.8 l/min/m2). However, due to undesirable tachycardia, the dobutamine was switched to milrinone (0.75 μg/kg-body-weight/minute). On grounds of insufficient inotropic drug efficacy in line with unchanged cardiac output and cardiac index measurements and echocardiographic findings, as well as lack of clinical improvement, the use of an intra-aortic balloon pump (ECG-triggered) was considered mandatory.

While no evidence of myocardial infarction or coronary artery disease was found in the left heart, right cardiac catheterization revealed an elevated mean pulmonary artery pressure of 33 mmHg (a mean value of 15 mmHg is considered normal) and multiple myocardial biopsies were acquired.

Histological examination revealed acute myocarditis with lymphocytic infiltration. No neutrophile granulocytes or giant cells were found (Figure 2A). Furthermore, PCR analysis of the tissue did not detect any adenovirus DNA, parvovirus B19 DNA, human herpesvirus 6 DNA, Epstein-Barr virus DNA, varicella zoster virus DNA, herpes simplex virus DNA, cytomegalovirus DNA or enterovirus RNA including Coxsackie A virus and Coxsackie B (1-6) virus. In addition, immunohistochemical analysis did not detect any cytomegalovirus-associated proteins. The patient tested negative for HIV infection based on detection of specific antibodies (via ELISA) as well as RNA (via PCR) in serum.
Figure 2

Histology images revealed acute myocarditis with lymphocytic infiltration and moderate myocyte apoptosis at first onset (A) and relapse (B). These biopsies did not detect giant cells or significant neutrophile infiltrates.

In consideration of the patient’s critical condition and the persistently high levels of serum inflammatory markers, the patient was started on empiric antibiotic coverage consisting of intravenous piperacillin/tazobactam (3 × 4.5 g/day over 10 days).

While awaiting systemic infection (diagnostic) results, azathioprine was paused. Further immunological and infection parameters pertinent to myocarditis were measured: rheumatoid factor (negative, <10.3 IU/ml) and antinuclear and anti-centromere antibody levels (ANA negative, HEP2-IFT <1:80; c-ANCA and p-ANCA negative, ANCA-IFT <1:10). All blood cultures collected within 3 days of admission were negative for bacterial and fungal growth.

Nine days later, the intra-aortic balloon pump was removed after gradual tapering off of milrinone accompanied by normalization of hemodynamic parameters, e.g. cardiac output was 8 l/min and cardiac index was 3.7 l/min/m2. At day 15 of ICU treatment, a TTE confirmed improved LV function with an EF of 50% as well as elimination of the PE (Figure 1C, D) and the patient was discharged to a ward. At this point, cardiac magnetic resonance imaging (MRI) was performed, which confirmed myocarditis along with tissue edema and moderate PE (0.3 cm); however, no late enhancement was detected. Subsequently, the heart failure therapy, i.e. bisoprolol (10 mg/day), ramipril (2.5 mg/day) and spironolactone (25 mg/day), was adjusted in a stepwise fashion based on hemodynamic parameters and clinical improvement and the patient was discharged after full recovery to ambulant treatment. Of note, the systemic therapy with mesalamine was never interrupted. Because of the active colitis, additional systemic therapy with acetylsalicylic acid was not taken into consideration after discharge from the hospital.

Six months after the first incident, the patient presented to our hospital with mild dyspnea on exertion and slight abdominal pain without bloody diarrhea. On admission, medication consisted of mesalamine (4 g/day) and budesonide (rectal foam, 2 mg/day). His blood pressure levels and serial ECG reports were normal. An X-ray showed no pulmonary infection. A TTE revealed a stable LV function (EF 50%); however, moderate PE (0.8 cm) was observed (Figure 3). Laboratory tests demonstrated slight elevations of inflammatory parameters and brain natriuretic peptide (Table 1). Thus, we promptly assumed that the beginning of an UC re-exacerbation might have triggered recurrent myocarditis. Unfortunately, the patient declined colonoscopy. As expected, a follow-up cardiac MRI revealed anterior LV wall edema along with PE (1.2 cm) and lateral wall late enhancement, indicative of acute myocarditis (Figures 4, 5 and 6). Again, myocardial biopsies were obtained, which showed the same pattern of lymphocytic myocarditis (Figure 2B). This time, the patient’s clinical condition improved on administering prednisone (1 mg/kg-body-weight/day), bisoprolol (10 mg/day), ramipril (2.5 mg/day) and spironolactone (25 mg/day). After discharge, a 6-month follow-up TTE showed normal LV function and no PE.
Figure 3

Transthoracic cardiac echocardiogramms. (A) Long axis view. (B) Short axis view. These views show a pericardial effusion of 0.8 cm at readmission.

Figure 4

Cardiac magnetic resonance imaging (MRI), turbo inversion recovery magnitude (TIRM) sequence. (A) Edema in anterior wall. (B) Pericardial effusion of 1.2 cm.

Figure 5

Cardiac magnetic resonance imaging (MRI), balanced steady-state free precesion (bSSFP) sequence. (A-C) These images show pericardial effusion of 1.2 cm.

Figure 6

Cardiac magnetic resonance imaging (MRI), inversion recovery (IR) turbo fast low-angle shot (FLASH) sequence. (A) Beginning enhancement in lateral wall. (B-C) Intramural late-enhancement in lateral wall.

Conclusions

An association of cardiac disease with IBD has rarely been found [2]. In a large nationwide study of IBD patients (N = 15,572) conducted from 1977 to 1992 in Denmark, the incidence of myocarditis was 0.03% [2]. In these cases, the most frightening scenario is finding giant cells in a biopsy. Giant cell myocarditis, which often coincides with autoimmune diseases, has been reported as inevitably fatal with a fulminate course resulting in death, usually within 3 months [46]. To date, less than five cases have been reported in the literature of IBD-related myocarditis (other than giant cell myocarditis) that rapidly ends in severe heart failure during UC exacerbation for either new onset or relapse cases. This convinced us of the need to report this case of a young male experiencing severe lymphocytic myocarditis along with left heart failure during UC exacerbation.

Lymphocytic myocarditis emerges through an interstitial influx of lymphocytes followed by consecutive myocyte apoptosis [4]. Apparently, lymphocytic infiltrates have been observed in most cases of biopsy-verified myocarditis. Of these, the positive detection of circulating cardiac auto-antibodies and/or viral genomes in myocardial biopsy specimens or bacterial or fungal systemic infections represent the most trivial findings in patients experiencing active IBD-related lymphocytic myocarditis (reviewed in [3, 4, 7]). Biopsy results for our patient were negative for viral genomes or proteins. No bacterial or fungal infections were found in peripheral blood during all stays or follow-up visits in our hospital. Azathioprine was paused on first admission to the ICU as it is of unproven benefit for myocarditis other than for giant cell myocarditis [4]. Therefore, both times acute phase immunosuppressive therapy was confined to systemic therapy with prednisone [79]. Because of the symptoms of co-emergent severe colitis, systemic therapy with prednisone was considered mandatory. In any other case, intrapericardial treatment with triamcinolone, especially in patients with perimyocarditis, would be an equally effective local therapy option [10]. Interestingly, 6 months after the first incident, the patient’s cardiac function deteriorated after discontinuation of prednisone [7] (Figure 7). This event had clinical, TTE, MRI and histological evidence of recurrent myocarditis, which improved after recontinuation of immunosuppressive therapy and is consistent with data published elsewhere [7].
Figure 7

Medication curves. The graph illustrates dose and application time of systemic treatment with prednisone, azathioprine and mesalamine and local therapy with budesonide during the entire observation period. This graph also indicates the time points of clinical exacerbation of ulcerative colitis along with emergence of myocarditis symptoms.

IBD-related cardiac disease may also occur as mesalamine-induced myocarditis. This form of myocarditis, where eosinophilic infiltration can be observed on a biopsy, has previously been described as a mechanism of drug hypersensitivity, and the symptoms are milder [11]. Here, mesalamine-induced myocarditis is unlikely since mesalamine administration was never interrupted. Moreover, according to the Naranjo Nomogram, it is doubtful that these episodes of myocarditis were due to mesalamine [12].

Consent

Written informed consent was obtained from the patient for publication of this case report and the accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.

Abbreviations

ANA: 

antinuclear antibody

ANCA: 

anti-centromere antibody

ECG: 

electrocardiogram

EF: 

ejection fraction

ELISA: 

enzyme-linked immunosorbent assay

IBD: 

inflammatory bowel disease

LV: 

left ventricle

MRI: 

magnetic resonance imaging

PCR: 

polymerase chain reaction

PE: 

pericardial effusion

TTE: 

transthoracic cardiac echocardiogram

UC: 

ulcerative colitis.

Declarations

Authors’ Affiliations

(1)
Department of Cardiology, University Hospital Essen
(2)
Institute of Diagnostic and Interventional Radiology, University Hospital Essen
(3)
Institute of Pathology and Neuropathology, University Hospital Essen
(4)
Department of Gastroenterology and Hepatology, University Hospital Essen

References

  1. Mowat NA, Bennett PN, Finlayson JK, Brunt PW, Lancaster WM: Myopericarditis complicating ulcerative colitis. Br Heart J 1974, 36: 724–727. 10.1136/hrt.36.7.724PubMedPubMed CentralView ArticleGoogle Scholar
  2. Sorensen HT, Fonager KM: Myocarditis and inflammatory bowel disease. A 16-year Danish nationwide cohort study. Dan Med Bull 1997, 44: 442–444.PubMedGoogle Scholar
  3. Freeman HJ, Salh B: Recurrent myopericarditis with extensive ulcerative colitis. Can J Cardiol 2010, 26: 549–550. 10.1016/S0828-282X(10)70470-0PubMedPubMed CentralView ArticleGoogle Scholar
  4. Davidoff R, Palacios I, Southern J, Fallon JT, Newell J, Dec GW: Giant cell versus lymphocytic myocarditis. A comparison of their clinical features and long-term outcomes. Circulation 1991, 83: 953–961. 10.1161/01.CIR.83.3.953PubMedView ArticleGoogle Scholar
  5. Cooper LT Jr, Berry GJ, Shabetai R: Idiopathic giant-cell myocarditis – natural history and treatment. N Engl J Med 1860–1866, 1997: 336.Google Scholar
  6. Davies MJ, Pomerance A, Teare RD: Idiopathic giant cell myocarditis – a distinctive clinico-pathological entity. Br Heart J 1975, 37: 192–195. 10.1136/hrt.37.2.192PubMedPubMed CentralView ArticleGoogle Scholar
  7. Frustaci A, Chimenti C, Calabrese F, Pieroni M, Thiene G, Maseri A: Immunosuppressive therapy for active lymphocytic myocarditis: virological and immunologic profile of responders versus nonresponders. Circulation 2003, 107: 857–863. 10.1161/01.CIR.0000048147.15962.31PubMedView ArticleGoogle Scholar
  8. Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE: A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995, 333: 269–275. 10.1056/NEJM199508033330501PubMedView ArticleGoogle Scholar
  9. Wojnicz R, Nowalany-Kozielska E, Wojciechowska C, Glanowska G, Wilczewski P, Niklewski T, Zembala M, Polonski L, Rozek MM, Wodniecki J: Randomized, placebo-controlled study for immunosuppressive treatment of inflammatory dilated cardiomyopathy: two-year follow-up results. Circulation 2001, 104: 39–45. 10.1161/01.CIR.104.1.39PubMedView ArticleGoogle Scholar
  10. Maisch B, Seferovic PM, Ristic AD, Erbel R, Rienmuller R, Adler Y, Tomkowski WZ, Thiene G, Yacoub MH: Guidelines on the diagnosis and management of pericardial diseases executive summary. Eur Heart J 2004, 25: 587–610.PubMedView ArticleGoogle Scholar
  11. Stelts S, Taylor MH, Nappi J, Van Bakel AB: Mesalamine-associated hypersensitivity myocarditis in ulcerative colitis. Ann Pharmacother 2008, 42: 904–905. 10.1345/aph.1K288PubMedView ArticleGoogle Scholar
  12. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ: A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981, 30: 239–245. 10.1038/clpt.1981.154PubMedView ArticleGoogle Scholar

Copyright

© Varnavas et al.; licensee BioMed Central Ltd. 2014

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 credited. 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.

Advertisement