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Rate and patient features associated with recurrence of acute myocarditis
European Journal of Internal Medicine 25 (2014) 946–950
Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Rate and patient features associated with recurrence of acute myocarditis Ville Kytö a,d,e,⁎, Jussi Sipilä b,f, Päivi Rautava c,g a
Heart Center, Turku University Hospital, Turku, Finland Clinical Neurosciences, Neurology, Turku University Hospital, Turku, Finland c Clinical Research Center, Turku University Hospital, Turku, Finland d PET Center, University of Turku, Turku, Finland e Medicine, University of Turku, Turku, Finland f Neurology, University of Turku, Turku, Finland g Public Health, University of Turku, Turku, Finland b
a r t i c l e
i n f o
Article history: Received 11 July 2014 Received in revised form 27 October 2014 Accepted 3 November 2014 Available online 7 November 2014 Keywords: Epidemiology Myocardial disease Myocarditis Recurrence
a b s t r a c t Background: Rate and patient features associated with recurrence after acute myocarditis are largely unknown. Methods and results: First recurrence of acute myocarditis was studied in 1662 patients aged 16–70 years using a registry data of 29 hospitals in Finland (median follow-up 4.5 years). Matched intoxication patients served as controls. Incidence rate of first time hospitalization due to acute myocarditis was 5.52 (CI 5.26–5.79) per 100,000 person-years during 2001–2008. During the first 30 days 5.5% (CI 3.5–4.4%) of patients were readmitted to hospital with acute myocarditis (p b 0.0001 vs. controls). After 30 days, recurrence rate was 7.0% (CI 5.7–8.6%; p b 0.0001 vs. controls). Acute myocarditis recurred after 365 days in 4.7% (CI 3.2–6.7%) of patients (p b 0.0001 vs. controls). During the whole follow-up, recurrence rate was 10.3% (CI 8.8–12.1%; p b 0.0001 vs. controls) with median recurrence time of 34.5 days. Prolonged (N7 days) initial admission was associated with recurrences during (HR 2.9; CI 1.6–5.2) and after first month (HR 1.8; CI 1.2–3.2), and overall (HR 2.0; CI 1.3– 3.2). Ventricular arrhythmia at initial occurrence was associated with recurrence after 30 days (HR 8.6; CI 2.5– 30.1), after 1 year (HR 22.6; CI 2.5–201.4) and overall (HR 6.7; CI 2.3–6.7). Other features associated with recurrence were younger age (N365 days), inflammatory bowel disease (during first month), and chronic pulmonary disease (≥30 days). Conclusions: Acute myocarditis reoccurs in a significant proportion of patients. Prolonged initial admission, ventricular arrhythmias, younger age, inflammatory bowel disease and chronic pulmonary disease are associated with recurrences at different phases after acute myocarditis. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Acute myocarditis is an inflammatory disease of myocardium. Myocarditis is commonly caused by viral infection, with entero-, adeno- and Parvovirus B19 recognized as the most common etiologies [1]. Clinical manifestation of acute myocarditis varies from chest pain to arrhythmias and heart failure [2,3]. Currently there are no effective treatments available for viral myocarditis as immunosuppression is found not be effective [1,2]. Both short and long-term outcomes of acute myocarditis are usually good [4], but development of heart failure or ventricular arrhythmias indicates poorer prognosis [5,6]. Acute pericarditis, inflammatory disease of pericardial sac, has similar causes and pathogenetical mechanisms with acute myocarditis [7]. Acute pericarditis is known to reoccur in 15–30% of patients [7]. Although recurrences of myocarditis have been reported in literature [8–10], the general recurrence rate of ⁎ Corresponding author at: Heart Center, Turku University Hospital, POB 52, FI-20521 Turku, Finland. Tel.: +358 23130000; fax: +358 23137206. E-mail address: ville.kyto@utu.fi (V. Kytö).
acute myocarditis has however remained unknown. We studied the recurrence of acute myocarditis by using a multihospital, nationwide registry follow-up data. 2. Methods 2.1. Study patients and data collection We studied 1662 consecutive patients aged 16–70 years hospitalized for acute myocarditis (primary discharge diagnosis code I40) during 2001–2008. Age- and sex-matched control population (n = 1662) was randomly selected from patients admitted due to drug intoxication (primary discharge diagnosis code T36). Discharge records of prior admissions were reviewed from May 1st 2000 and patients with any type of myocarditis, heart failure, cardiomyopathy, or heart transplant before index hospitalization were excluded (n = 49). Patients were followed for admission with acute myocarditis until October 31st 2009. Median follow-up was 4.5 years (IQR 2.2–6.6 years) after acute myocarditis and 4.7 years (IQR 2.6–6.8 years) for controls. Hospital
http://dx.doi.org/10.1016/j.ejim.2014.11.001 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
V. Kytö et al. / European Journal of Internal Medicine 25 (2014) 946–950
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transfers were joined as one admission. Readmissions with acute myocarditis (ICD-10 code I40) as primary, secondary or tertiary diagnosis were detected beginning from second day after initial discharge. Data was retrospectively collected from the Finnish Hospital Discharge Register (FHDR), a nationwide, obligatory registry maintained by the Finnish National Institute for Health and Welfare. Hospital discharge diagnoses from 29 hospitals (all university and central hospitals in addition to 8 regional hospitals) nationwide were studied. The study was conducted according to the National Institute for Health and Welfare permission (THL/1576/5.05.00/2010).
2.2. Statistical analysis Proportion of patients with readmission was analyzed by Kaplan– Meier method. Association of acute myocarditis with sequential myocarditis admissions was studied using log-rank test stratified for study year. Patient features associated with recurrence were studied using exact Cox-regression models stratified by study year. Multivariate model included patient characteristics (Table 1) associated with readmission at the level of p b 0.05 in univariate analysis. Differences of dichotomous variables were analyzed with Fischer's exact test and differences in treatment times were analyzed with paired t-test. Incidence was calculated based on population data of whole Finland acquired from Statistics Finland, and standardized with European Standard Population 2013 with direct method. Scale variables are presented as mean ± standard deviation or median with interquartile range as appropriate. Categorical variables are presented as counts or percentages with 95% confidence intervals (CI) as appropriate. P-values b .05 were considered statistically significant. The SAS system version 9.3 (SAS Institute Inc, Cary, NC, USA) was used for statistical analyses.
3. Results 3.1. Patient features and incidence of acute myocarditis Majority (81%) of acute myocarditis patients were male. Mean age of patients at index hospitalization was 34.4 ± 14.7 years. Most common sites of co-infection in acute myocarditis were respiratory and otolaryngeal tracts (Table 1). Chronic co-morbidities were rare among study patients (Table 1). Standardized incidence rate of first time hospitalization due to acute myocarditis in participating hospitals was 5.52 (CI 5.26–5.79) per 100,000 person-years during the study period. Incidence was highest in population aged 16–19 years, followed by a linear decline to 40 years and a steady state in older population (Fig. 1).
Fig. 1. Age-specific incidence rates of first time hospitalization due to acute myocarditis in participating hospitals during 2001–2008. Error bars represent upper limits of 95% confidence intervals.
3.2. Recurrence rate During the first 30 days 5.5% (CI 3.5–4.4%) of patients with acute myocarditis were re-admitted to hospital with ongoing or recurrent acute myocarditis (p b 0.0001 vs. controls). Rate of re-admissions was highest during 10 first days after initial discharge and remained similar during following 20 days with median time of 10 (IQR 6–18) days to readmission (Fig. 2). After 30 days from acute myocarditis the cumulative recurrence rate was 7.0% (CI 5.7–8.6%; p b 0.0001 vs. controls) with 7.2 month (IQR 1.9–20.3) median time to recurrence (Fig. 3A). Acute myocarditis recurred late after onset (≥1 year after initial admission) in 4.7% (CI 3.2–6.7%) of patients (p b 0.0001 vs. controls). Median time to late onset recurrence was 2.3 (IQR 1.4–3.4) years (Fig. 3B). During the whole follow-up, the rate of readmission with acute myocarditis was 10.3% (CI 8.8–12.1%) with median time of 34.5 days (IRQ 11–257) to readmission (p b 0.0001 vs. controls). Twelve months after acute myocarditis 93% (CI 91–94%) of patients were free from recurrences (Fig. 4). None of the control patients had admissions with acute myocarditis during follow-up.
3.3. Features of recurrence admissions Acute myocarditis was the primary cause of readmission in 89.7% of recurrences. Ventricular arrhythmias were diagnosed in 3.9% (CI 1.4– 8.5%) of patients at readmission, which was significantly higher than
Table 1 Characteristics of acute myocarditis patients at index hospitalization.
Female sex Prolonged (N7 days) initial admission Hypertension Chronic pulmonary disease Diabetes Coronary artery disease Systemic connective tissue disease* Inflammatory bowel disease Malignant disease Heart failure Conduction abnormality Ventricular arrhyhtmia Otolaryngeal infection Lower respiratory tract infection Gastro-intestinal infection Septicemia
%
95% CI
19.0 9.1 3.7 1.1 0.8 0.8 0.7 0.6 0.2 1.4 0.7 0.5 3.4 3.2 0.4 0.1
17.0–21.2 7.7–10.7 2.5–4.4 0.6–1.7 0.4–1.3 0.4–1.3 0.4–1.3 0.3–1.1 0.1–0.6 0.9–2.1 0.4–1.3 0.2–0.9 2.6–4.4 2.4–4.2 0.2–0.9 0.01–0.4
Fig. 2. Readmission due to acute myocarditis during first 2–30 days after initial discharge. Short-dashed lines mark 95% confidence intervals. Please note origin of y-axis.
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V. Kytö et al. / European Journal of Internal Medicine 25 (2014) 946–950
2.2–10.2%) of readmitted patients comparably to findings at the initial admission (7.6%: CI 6.3–9.2%; p = NS). Readmissions for acute myocarditis were shorter than initial admissions (6.3 ± 6.9 vs. 4.2 ± 3.5 days, p = 0.001). 3.4. Patient features associated with recurrence Prolonged initial admission (N 7 days) was associated with readmissions of acute myocarditis during first month after initial discharge, and recurrences after 30 days and overall (Table 2). Association of chronic conditions with recurrence varied as inflammatory bowel disease was an independent predictor of readmissions at early stage, while chronic pulmonary disease was associated with recurrences after 30 days and systemic connective tissue disease with any recurrence in univariate analyses (Table 2). Younger age was associated with late recurrence of acute myocarditis (Table 2). Ventricular tachyarrhythmia at initial admission was associated with recurrence at all stages after acute myocarditis (Table 2). Heart failure was associated with early readmission in univariate analysis, but not with later recurrences (Table 2). 4. Discussion
Fig. 3. Kaplan–Meier plot of first recurrence of acute myocarditis 30 days (A) and one year (B) after initial discharge. Short-dashed lines mark 95% confidence intervals. Please note origin of y-axis.
rate at the initial admission (0.5%: CI 0.2–0.9%, p b 0.0001). Proportion of patients with diagnosed heart failure was similar at both readmission (2.6%: CI 0.7–6.7%) and the initial admission (1.4%: CI 0.9–2.1%: p = NS). Infection site other than myocardium was detected in 5.2% (CI
Fig. 4. Recurrence of acute myocarditis at any time (after second day from discharge) after initial occurrence. Short-dashed lines mark 95% confidence intervals. Please note origin of y-axis.
This multi-hospital study describes rates and patient features associated with recurrence after acute myocarditis. The main finding of our study is that recurrences occur in a significant proportion of patients after acute myocarditis, and that these recurrences may occur late after initial disease onset. Recurrences of myocarditis have been previously reported in case reports [8–10], but have not, to our knowledge, been systematically studied. We found 5.5% of patients to be readmitted with acute myocarditis during first month after initial discharge. This may include both true early recurrences, but also worsening of ongoing acute myocarditis. Acute myocarditis recurred in 7.0% of patients after one month and in 4.7% after one year from initial disease onset. The overall readmission/ recurrence rate during a 4.5 year follow-up was 10.3%. Acute pericarditis is an inflammatory disease of pericardial sac with similar etiologies and pathogenetical pathways with acute myocarditis [11]. Recurrences of acute pericarditis have, however, been reported in higher proportion (15–30%) of patients [12–15] than found in the current study. Most common causes of myocarditis are enteroviruses, especially coxsackieviruses, adenoviruses and parvovirus B19 [5,16,17]. Susceptibility to viral myocarditis varies significantly between different murine strains [18] and genetic predispositions to myocarditis [19] and its sequel dilated cardiomyopathy [20], have also been detected in humans, suggesting that patients with recurrence may be genetically susceptible for acquiring myocarditis during common viral infections. Development of autoimmunity is considered to be the major mechanism for recurrence of acute pericarditis [21]. In majority of patients with acute myocarditis, viral infection is cleared after acute phase and myocarditis resolves [1]. Viral infection may, however, trigger autoimmune myocarditis [1] as demonstrated by the development of heart specific antibodies [22] and autoreactive T-cells [23], implying that similar mechanisms as in pericarditis are likely also to contribute for recurrence of acute myocarditis. Our finding of association of inflammatory bowel disease with recurrence of acute myocarditis is in agreement with this possibility. Reactivation of latent or persistent viral infection is another potential mechanism of recurrence. Persistent infection has been found in patients with chronic myocarditis and dilated cardiomyopathy [24], and latent coxsackievirus infection of myocardium is detectable after resolution of acute experimental myocarditis [25]. It is also possible that persons with repetitive myocarditis encounter causative agents more commonly than normal population, but this is highly unlikely to be the sole mechanism of recurrence.
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Table 2 Patient features associated with recurrence of acute myocarditis at different timepoints after initial admission. Results of both univariate and multivariate Cox-models are given. See methods for details. Hazard ratio for recurrence of acute myocarditis (95% CI) N 30 days
Early (2–30 days)
Prolonged initial admissiona Age (/10 year increase) Chronic pulmonary disease Inflammatory bowel disease Systemic connective tissue diseaseb Heart failurec Ventricular arrhyhtmiac
Univariate
Multivariate
3.3 (1.9–5.6)⁎⁎⁎
2.9 (1.6–5.2)⁎⁎⁎
Univariate 2.2 (1.3–3.7)⁎⁎
Late (≥1 year) Multivariate
Univariate
Multivariate
1.8 (1.1–3.2)⁎ 0.7 (0.6–1.0)⁎
4.0 (1.5–10.9)⁎
Any Univariate
Multivariate
2.3 (1.5–3.5)⁎⁎⁎
2.0 (1.3–3.2)⁎⁎⁎
3.4 (1.1–10.5)⁎
3.1 (1.0–9.8)
0.7 (0.6–0.9)⁎
3.7 (1.4–10.3)⁎
7.4 (1.7–29.6) ⁎⁎ 7.2 (1.7–30.6)⁎⁎
3.2 (1.0–10.4)⁎ 6.6 (1.6–27.2)⁎
1.8 (0.5–6.3) 2.7 (0.6–12.8)
12.2 (3.7–40.0)⁎⁎⁎ 8.6 (2.5–30.1)⁎⁎ 18.1 (2.1–153.1)⁎⁎ 22.6 (2.5–201.4)⁎ 10.0 (3.6–27.7)⁎⁎⁎
6.7 (2.3–18.9)⁎⁎⁎
a
Duration N7 days. Including rheumatoid arthritis. At initial admission. ⁎ p b 0.05. ⁎⁎ p b 0.005. ⁎⁎⁎ p b 0.0005. b c
Ventricular arrhythmias during acute myocarditis are associated with poorer outcome during follow-up [5,6]. In agreement, we found ventricular arrhythmias to be associated with recurrence at all stages except during first month after acute myocarditis. Furthermore, ventricular arrhythmias were more common at recurrences than at index admission. Prolonged (N7 days) initial admission reflecting more severe or complicated disease course in acute phase predicted recurrences at all stages but one year after acute myocarditis. Although women with myocarditis have longer admissions times and appear to have ventricular arrhythmias more commonly than men [26], sex was not associated with recurrences in the current study. This study has some limitations. Major limitation is the retrospective nature of observational discharge registry data in which the diagnoses were made by the treating physicians. This limits the precision of diagnosis and therefore also the conclusions that can be drawn. The accuracy of nationwide, obligatory registry we used is however good [27]. Reliable diagnosis of myocarditis may be difficult and definitive diagnosis requires histological or immunohistological confirmation on endomyocardial biopsy or autopsy sample [1,2]. However, due to risk of complications and beneficence to only small patient subgroup, biopsy is currently indicated only when the course of acute myocarditis differs from typical benign type [28]. Furthermore, due to commonly patchy nature of myocarditis, sensitivity of biopsy is limited [28,29]. This poses a dilemma in myocarditis studies: including only patients with biopsy confirmation represents only small fragment of patients with severe disease, while studies without biopsy confirmation are prone to diagnostic inaccuracies and are unable to differentiate patients based on histological type of myocarditis (e.g. lymphocytic vs. giant cell). Recent expert opinion classifies myocarditis as clinically suspected if cardiac symptoms are associated with changes in ECG, troponin, or cardiac imaging studies in the absence of other reasons, namely acute coronary syndrome [2]. This classification most likely applies to the majority of our study patients. Magnetic resonance imaging is a developing modality for detection of myocarditis [30,31], but its use in clinical reality is still limited mainly to patients with uncommon disease course. In order to optimize the balance between diagnostic accuracy and representative population of all-comer real-life acute myocarditis patients, we included only patients that were studied and diagnosed in a hospital ward. Our data does not allow reporting on exact diagnostic tests or treatments used in individual patients. It is therefore possible that patients with worsening clinical course of initial acute myocarditis episode are included in study population, especially during the first
month after index admissions. It is also possible that knowledge of a previous episode of myocarditis may have affected the threshold used for diagnosis of new episode of myocarditis. We were able to follow patients for 4.5 years (median) after acute myocarditis. Usage of obligatory nationwide registry allows detection of recurrences occurring at any part of country during follow-up. Internal migration is notable among younger adults in Finland [32], but emigration is limited [33]. As all hospitals that treat acute cardiovascular patients in Finland are included in FHDR registry, the coverage of our follow-up is likely to be good. In conclusion, acute myocarditis reoccurs in significant proportion of patients after initial disease onset. Prolonged initial admission, ventricular arrhythmias, younger age, and the presence of inflammatory bowel disease or chronic pulmonary disease are associated with recurrences at different phases after acute myocarditis. Learning points • Acute myocarditis reoccurs often early in a significant proportion of patients • Prolonged initial admission and ventricular arrhythmias are associated with recurrence Disclosures None. Conflict of interests Ville Kytö: No conflicts of interest Jussi Sipilä: No conflicts of interest Päivi Rautava: No conflicts of interest Acknowledgments This study was funded by the Clinical Research Foundation of Turku University Hospital. References [1] Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, et al. Update on myocarditis. J Am Coll Cardiol 2012;59:779–92.
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Contents lists available at ScienceDirect
European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim
Original Article
Rate and patient features associated with recurrence of acute myocarditis Ville Kytö a,d,e,⁎, Jussi Sipilä b,f, Päivi Rautava c,g a
Heart Center, Turku University Hospital, Turku, Finland Clinical Neurosciences, Neurology, Turku University Hospital, Turku, Finland c Clinical Research Center, Turku University Hospital, Turku, Finland d PET Center, University of Turku, Turku, Finland e Medicine, University of Turku, Turku, Finland f Neurology, University of Turku, Turku, Finland g Public Health, University of Turku, Turku, Finland b
a r t i c l e
i n f o
Article history: Received 11 July 2014 Received in revised form 27 October 2014 Accepted 3 November 2014 Available online 7 November 2014 Keywords: Epidemiology Myocardial disease Myocarditis Recurrence
a b s t r a c t Background: Rate and patient features associated with recurrence after acute myocarditis are largely unknown. Methods and results: First recurrence of acute myocarditis was studied in 1662 patients aged 16–70 years using a registry data of 29 hospitals in Finland (median follow-up 4.5 years). Matched intoxication patients served as controls. Incidence rate of first time hospitalization due to acute myocarditis was 5.52 (CI 5.26–5.79) per 100,000 person-years during 2001–2008. During the first 30 days 5.5% (CI 3.5–4.4%) of patients were readmitted to hospital with acute myocarditis (p b 0.0001 vs. controls). After 30 days, recurrence rate was 7.0% (CI 5.7–8.6%; p b 0.0001 vs. controls). Acute myocarditis recurred after 365 days in 4.7% (CI 3.2–6.7%) of patients (p b 0.0001 vs. controls). During the whole follow-up, recurrence rate was 10.3% (CI 8.8–12.1%; p b 0.0001 vs. controls) with median recurrence time of 34.5 days. Prolonged (N7 days) initial admission was associated with recurrences during (HR 2.9; CI 1.6–5.2) and after first month (HR 1.8; CI 1.2–3.2), and overall (HR 2.0; CI 1.3– 3.2). Ventricular arrhythmia at initial occurrence was associated with recurrence after 30 days (HR 8.6; CI 2.5– 30.1), after 1 year (HR 22.6; CI 2.5–201.4) and overall (HR 6.7; CI 2.3–6.7). Other features associated with recurrence were younger age (N365 days), inflammatory bowel disease (during first month), and chronic pulmonary disease (≥30 days). Conclusions: Acute myocarditis reoccurs in a significant proportion of patients. Prolonged initial admission, ventricular arrhythmias, younger age, inflammatory bowel disease and chronic pulmonary disease are associated with recurrences at different phases after acute myocarditis. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
1. Introduction Acute myocarditis is an inflammatory disease of myocardium. Myocarditis is commonly caused by viral infection, with entero-, adeno- and Parvovirus B19 recognized as the most common etiologies [1]. Clinical manifestation of acute myocarditis varies from chest pain to arrhythmias and heart failure [2,3]. Currently there are no effective treatments available for viral myocarditis as immunosuppression is found not be effective [1,2]. Both short and long-term outcomes of acute myocarditis are usually good [4], but development of heart failure or ventricular arrhythmias indicates poorer prognosis [5,6]. Acute pericarditis, inflammatory disease of pericardial sac, has similar causes and pathogenetical mechanisms with acute myocarditis [7]. Acute pericarditis is known to reoccur in 15–30% of patients [7]. Although recurrences of myocarditis have been reported in literature [8–10], the general recurrence rate of ⁎ Corresponding author at: Heart Center, Turku University Hospital, POB 52, FI-20521 Turku, Finland. Tel.: +358 23130000; fax: +358 23137206. E-mail address: ville.kyto@utu.fi (V. Kytö).
acute myocarditis has however remained unknown. We studied the recurrence of acute myocarditis by using a multihospital, nationwide registry follow-up data. 2. Methods 2.1. Study patients and data collection We studied 1662 consecutive patients aged 16–70 years hospitalized for acute myocarditis (primary discharge diagnosis code I40) during 2001–2008. Age- and sex-matched control population (n = 1662) was randomly selected from patients admitted due to drug intoxication (primary discharge diagnosis code T36). Discharge records of prior admissions were reviewed from May 1st 2000 and patients with any type of myocarditis, heart failure, cardiomyopathy, or heart transplant before index hospitalization were excluded (n = 49). Patients were followed for admission with acute myocarditis until October 31st 2009. Median follow-up was 4.5 years (IQR 2.2–6.6 years) after acute myocarditis and 4.7 years (IQR 2.6–6.8 years) for controls. Hospital
http://dx.doi.org/10.1016/j.ejim.2014.11.001 0953-6205/© 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
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transfers were joined as one admission. Readmissions with acute myocarditis (ICD-10 code I40) as primary, secondary or tertiary diagnosis were detected beginning from second day after initial discharge. Data was retrospectively collected from the Finnish Hospital Discharge Register (FHDR), a nationwide, obligatory registry maintained by the Finnish National Institute for Health and Welfare. Hospital discharge diagnoses from 29 hospitals (all university and central hospitals in addition to 8 regional hospitals) nationwide were studied. The study was conducted according to the National Institute for Health and Welfare permission (THL/1576/5.05.00/2010).
2.2. Statistical analysis Proportion of patients with readmission was analyzed by Kaplan– Meier method. Association of acute myocarditis with sequential myocarditis admissions was studied using log-rank test stratified for study year. Patient features associated with recurrence were studied using exact Cox-regression models stratified by study year. Multivariate model included patient characteristics (Table 1) associated with readmission at the level of p b 0.05 in univariate analysis. Differences of dichotomous variables were analyzed with Fischer's exact test and differences in treatment times were analyzed with paired t-test. Incidence was calculated based on population data of whole Finland acquired from Statistics Finland, and standardized with European Standard Population 2013 with direct method. Scale variables are presented as mean ± standard deviation or median with interquartile range as appropriate. Categorical variables are presented as counts or percentages with 95% confidence intervals (CI) as appropriate. P-values b .05 were considered statistically significant. The SAS system version 9.3 (SAS Institute Inc, Cary, NC, USA) was used for statistical analyses.
3. Results 3.1. Patient features and incidence of acute myocarditis Majority (81%) of acute myocarditis patients were male. Mean age of patients at index hospitalization was 34.4 ± 14.7 years. Most common sites of co-infection in acute myocarditis were respiratory and otolaryngeal tracts (Table 1). Chronic co-morbidities were rare among study patients (Table 1). Standardized incidence rate of first time hospitalization due to acute myocarditis in participating hospitals was 5.52 (CI 5.26–5.79) per 100,000 person-years during the study period. Incidence was highest in population aged 16–19 years, followed by a linear decline to 40 years and a steady state in older population (Fig. 1).
Fig. 1. Age-specific incidence rates of first time hospitalization due to acute myocarditis in participating hospitals during 2001–2008. Error bars represent upper limits of 95% confidence intervals.
3.2. Recurrence rate During the first 30 days 5.5% (CI 3.5–4.4%) of patients with acute myocarditis were re-admitted to hospital with ongoing or recurrent acute myocarditis (p b 0.0001 vs. controls). Rate of re-admissions was highest during 10 first days after initial discharge and remained similar during following 20 days with median time of 10 (IQR 6–18) days to readmission (Fig. 2). After 30 days from acute myocarditis the cumulative recurrence rate was 7.0% (CI 5.7–8.6%; p b 0.0001 vs. controls) with 7.2 month (IQR 1.9–20.3) median time to recurrence (Fig. 3A). Acute myocarditis recurred late after onset (≥1 year after initial admission) in 4.7% (CI 3.2–6.7%) of patients (p b 0.0001 vs. controls). Median time to late onset recurrence was 2.3 (IQR 1.4–3.4) years (Fig. 3B). During the whole follow-up, the rate of readmission with acute myocarditis was 10.3% (CI 8.8–12.1%) with median time of 34.5 days (IRQ 11–257) to readmission (p b 0.0001 vs. controls). Twelve months after acute myocarditis 93% (CI 91–94%) of patients were free from recurrences (Fig. 4). None of the control patients had admissions with acute myocarditis during follow-up.
3.3. Features of recurrence admissions Acute myocarditis was the primary cause of readmission in 89.7% of recurrences. Ventricular arrhythmias were diagnosed in 3.9% (CI 1.4– 8.5%) of patients at readmission, which was significantly higher than
Table 1 Characteristics of acute myocarditis patients at index hospitalization.
Female sex Prolonged (N7 days) initial admission Hypertension Chronic pulmonary disease Diabetes Coronary artery disease Systemic connective tissue disease* Inflammatory bowel disease Malignant disease Heart failure Conduction abnormality Ventricular arrhyhtmia Otolaryngeal infection Lower respiratory tract infection Gastro-intestinal infection Septicemia
%
95% CI
19.0 9.1 3.7 1.1 0.8 0.8 0.7 0.6 0.2 1.4 0.7 0.5 3.4 3.2 0.4 0.1
17.0–21.2 7.7–10.7 2.5–4.4 0.6–1.7 0.4–1.3 0.4–1.3 0.4–1.3 0.3–1.1 0.1–0.6 0.9–2.1 0.4–1.3 0.2–0.9 2.6–4.4 2.4–4.2 0.2–0.9 0.01–0.4
Fig. 2. Readmission due to acute myocarditis during first 2–30 days after initial discharge. Short-dashed lines mark 95% confidence intervals. Please note origin of y-axis.
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2.2–10.2%) of readmitted patients comparably to findings at the initial admission (7.6%: CI 6.3–9.2%; p = NS). Readmissions for acute myocarditis were shorter than initial admissions (6.3 ± 6.9 vs. 4.2 ± 3.5 days, p = 0.001). 3.4. Patient features associated with recurrence Prolonged initial admission (N 7 days) was associated with readmissions of acute myocarditis during first month after initial discharge, and recurrences after 30 days and overall (Table 2). Association of chronic conditions with recurrence varied as inflammatory bowel disease was an independent predictor of readmissions at early stage, while chronic pulmonary disease was associated with recurrences after 30 days and systemic connective tissue disease with any recurrence in univariate analyses (Table 2). Younger age was associated with late recurrence of acute myocarditis (Table 2). Ventricular tachyarrhythmia at initial admission was associated with recurrence at all stages after acute myocarditis (Table 2). Heart failure was associated with early readmission in univariate analysis, but not with later recurrences (Table 2). 4. Discussion
Fig. 3. Kaplan–Meier plot of first recurrence of acute myocarditis 30 days (A) and one year (B) after initial discharge. Short-dashed lines mark 95% confidence intervals. Please note origin of y-axis.
rate at the initial admission (0.5%: CI 0.2–0.9%, p b 0.0001). Proportion of patients with diagnosed heart failure was similar at both readmission (2.6%: CI 0.7–6.7%) and the initial admission (1.4%: CI 0.9–2.1%: p = NS). Infection site other than myocardium was detected in 5.2% (CI
Fig. 4. Recurrence of acute myocarditis at any time (after second day from discharge) after initial occurrence. Short-dashed lines mark 95% confidence intervals. Please note origin of y-axis.
This multi-hospital study describes rates and patient features associated with recurrence after acute myocarditis. The main finding of our study is that recurrences occur in a significant proportion of patients after acute myocarditis, and that these recurrences may occur late after initial disease onset. Recurrences of myocarditis have been previously reported in case reports [8–10], but have not, to our knowledge, been systematically studied. We found 5.5% of patients to be readmitted with acute myocarditis during first month after initial discharge. This may include both true early recurrences, but also worsening of ongoing acute myocarditis. Acute myocarditis recurred in 7.0% of patients after one month and in 4.7% after one year from initial disease onset. The overall readmission/ recurrence rate during a 4.5 year follow-up was 10.3%. Acute pericarditis is an inflammatory disease of pericardial sac with similar etiologies and pathogenetical pathways with acute myocarditis [11]. Recurrences of acute pericarditis have, however, been reported in higher proportion (15–30%) of patients [12–15] than found in the current study. Most common causes of myocarditis are enteroviruses, especially coxsackieviruses, adenoviruses and parvovirus B19 [5,16,17]. Susceptibility to viral myocarditis varies significantly between different murine strains [18] and genetic predispositions to myocarditis [19] and its sequel dilated cardiomyopathy [20], have also been detected in humans, suggesting that patients with recurrence may be genetically susceptible for acquiring myocarditis during common viral infections. Development of autoimmunity is considered to be the major mechanism for recurrence of acute pericarditis [21]. In majority of patients with acute myocarditis, viral infection is cleared after acute phase and myocarditis resolves [1]. Viral infection may, however, trigger autoimmune myocarditis [1] as demonstrated by the development of heart specific antibodies [22] and autoreactive T-cells [23], implying that similar mechanisms as in pericarditis are likely also to contribute for recurrence of acute myocarditis. Our finding of association of inflammatory bowel disease with recurrence of acute myocarditis is in agreement with this possibility. Reactivation of latent or persistent viral infection is another potential mechanism of recurrence. Persistent infection has been found in patients with chronic myocarditis and dilated cardiomyopathy [24], and latent coxsackievirus infection of myocardium is detectable after resolution of acute experimental myocarditis [25]. It is also possible that persons with repetitive myocarditis encounter causative agents more commonly than normal population, but this is highly unlikely to be the sole mechanism of recurrence.
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Table 2 Patient features associated with recurrence of acute myocarditis at different timepoints after initial admission. Results of both univariate and multivariate Cox-models are given. See methods for details. Hazard ratio for recurrence of acute myocarditis (95% CI) N 30 days
Early (2–30 days)
Prolonged initial admissiona Age (/10 year increase) Chronic pulmonary disease Inflammatory bowel disease Systemic connective tissue diseaseb Heart failurec Ventricular arrhyhtmiac
Univariate
Multivariate
3.3 (1.9–5.6)⁎⁎⁎
2.9 (1.6–5.2)⁎⁎⁎
Univariate 2.2 (1.3–3.7)⁎⁎
Late (≥1 year) Multivariate
Univariate
Multivariate
1.8 (1.1–3.2)⁎ 0.7 (0.6–1.0)⁎
4.0 (1.5–10.9)⁎
Any Univariate
Multivariate
2.3 (1.5–3.5)⁎⁎⁎
2.0 (1.3–3.2)⁎⁎⁎
3.4 (1.1–10.5)⁎
3.1 (1.0–9.8)
0.7 (0.6–0.9)⁎
3.7 (1.4–10.3)⁎
7.4 (1.7–29.6) ⁎⁎ 7.2 (1.7–30.6)⁎⁎
3.2 (1.0–10.4)⁎ 6.6 (1.6–27.2)⁎
1.8 (0.5–6.3) 2.7 (0.6–12.8)
12.2 (3.7–40.0)⁎⁎⁎ 8.6 (2.5–30.1)⁎⁎ 18.1 (2.1–153.1)⁎⁎ 22.6 (2.5–201.4)⁎ 10.0 (3.6–27.7)⁎⁎⁎
6.7 (2.3–18.9)⁎⁎⁎
a
Duration N7 days. Including rheumatoid arthritis. At initial admission. ⁎ p b 0.05. ⁎⁎ p b 0.005. ⁎⁎⁎ p b 0.0005. b c
Ventricular arrhythmias during acute myocarditis are associated with poorer outcome during follow-up [5,6]. In agreement, we found ventricular arrhythmias to be associated with recurrence at all stages except during first month after acute myocarditis. Furthermore, ventricular arrhythmias were more common at recurrences than at index admission. Prolonged (N7 days) initial admission reflecting more severe or complicated disease course in acute phase predicted recurrences at all stages but one year after acute myocarditis. Although women with myocarditis have longer admissions times and appear to have ventricular arrhythmias more commonly than men [26], sex was not associated with recurrences in the current study. This study has some limitations. Major limitation is the retrospective nature of observational discharge registry data in which the diagnoses were made by the treating physicians. This limits the precision of diagnosis and therefore also the conclusions that can be drawn. The accuracy of nationwide, obligatory registry we used is however good [27]. Reliable diagnosis of myocarditis may be difficult and definitive diagnosis requires histological or immunohistological confirmation on endomyocardial biopsy or autopsy sample [1,2]. However, due to risk of complications and beneficence to only small patient subgroup, biopsy is currently indicated only when the course of acute myocarditis differs from typical benign type [28]. Furthermore, due to commonly patchy nature of myocarditis, sensitivity of biopsy is limited [28,29]. This poses a dilemma in myocarditis studies: including only patients with biopsy confirmation represents only small fragment of patients with severe disease, while studies without biopsy confirmation are prone to diagnostic inaccuracies and are unable to differentiate patients based on histological type of myocarditis (e.g. lymphocytic vs. giant cell). Recent expert opinion classifies myocarditis as clinically suspected if cardiac symptoms are associated with changes in ECG, troponin, or cardiac imaging studies in the absence of other reasons, namely acute coronary syndrome [2]. This classification most likely applies to the majority of our study patients. Magnetic resonance imaging is a developing modality for detection of myocarditis [30,31], but its use in clinical reality is still limited mainly to patients with uncommon disease course. In order to optimize the balance between diagnostic accuracy and representative population of all-comer real-life acute myocarditis patients, we included only patients that were studied and diagnosed in a hospital ward. Our data does not allow reporting on exact diagnostic tests or treatments used in individual patients. It is therefore possible that patients with worsening clinical course of initial acute myocarditis episode are included in study population, especially during the first
month after index admissions. It is also possible that knowledge of a previous episode of myocarditis may have affected the threshold used for diagnosis of new episode of myocarditis. We were able to follow patients for 4.5 years (median) after acute myocarditis. Usage of obligatory nationwide registry allows detection of recurrences occurring at any part of country during follow-up. Internal migration is notable among younger adults in Finland [32], but emigration is limited [33]. As all hospitals that treat acute cardiovascular patients in Finland are included in FHDR registry, the coverage of our follow-up is likely to be good. In conclusion, acute myocarditis reoccurs in significant proportion of patients after initial disease onset. Prolonged initial admission, ventricular arrhythmias, younger age, and the presence of inflammatory bowel disease or chronic pulmonary disease are associated with recurrences at different phases after acute myocarditis. Learning points • Acute myocarditis reoccurs often early in a significant proportion of patients • Prolonged initial admission and ventricular arrhythmias are associated with recurrence Disclosures None. Conflict of interests Ville Kytö: No conflicts of interest Jussi Sipilä: No conflicts of interest Päivi Rautava: No conflicts of interest Acknowledgments This study was funded by the Clinical Research Foundation of Turku University Hospital. References [1] Kindermann I, Barth C, Mahfoud F, Ukena C, Lenski M, Yilmaz A, et al. Update on myocarditis. J Am Coll Cardiol 2012;59:779–92.
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