Masoud Dadashi, Taher Azimi, Ebrahim Faghihloo?

1Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran

2Non Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran

3Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

4Students Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran 5Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

ABSTRACT Objective: To investigate the prevalence of viral myocarditis worldwide.Methods: We conducted a systematic search for the prevalence of the most common viruses in myocarditis and 75 studies were included for statistical analysis of the prevalence of adenovirus,hepatitis C virus, cytomegalovirus, Ebola virus, human herpesvirus 6, influenza virus, parvovirus, and non-polio enteroviruses.Results: The highest prevalence was related to B19 (25.0%)and non-polio enteroviruses (18%). The prevalence of human herpesvirus 6, cytomegalovirus, and Ebola virus was12.8%, 5.5%,and 3.1%, respectively. Hepatitis C virus accounted for 6.1% of the disease, the adenoviruses contributed to 5.2% of viral myocarditis.The lowest incidence was related to the influenza virus with 2.0%.Conclusions: Treatment of myocarditis is still problematic and may depend on the etiologic diagnosis. So it is important to know the commonly occurring viral factors in myocarditis and timely diagnosis and treatment are also imperative.

KEYWORDS: Virus; Myocarditis; Meta-analysis; B19; Non-polio enteroviruses

1. Introduction

Myocarditis is a multi-factorial disease of the myocardium with a large number of risk factors that are particularly attributed to multiple infectious and non-infectious agents[1,2]. Globally, the occurrence of myocarditis is around 1.5 million cases annually, and the incidence of myocarditis was 10 to 20 per 100 000 worldwide[3].Moreover, it is the main reason for the severe heart failure among all age groups, especially children and adults aged ＜40 years[4].The clinical symptoms of myocarditis are variable, including asymptomatic courses, chest pain, congestive heart failure, syncope,cardiogenic shock, cardiac arrest and even sudden death, and other severe illness with the necessity of intensive care therapy[2,5,6].According to the immunohistological evaluation of endomyocardial biopsies, clinicopathological and clinical criteria, the diagnosis and classification of myocarditis have been conducted[7-9]. Several autoimmune disorders such as Wegener’s granulomatosis, systemic lupus erythematosus, and giant cell arteritis belong to noninfectious causes of myocarditis[5,10]. However, among infectious causes, viral infections are the main reasons for inflammatory dilated cardiomyopathy and myocarditis. In the different parts of the world, especially in Europe and North America, myocarditis is caused predominantly by viral infections[1,4,11]. Moreover, it is predicted that 35% to 50% of dilated cardiomyopathy has been caused by viral myocarditis (VMC)[1,2,11]. The finding of several studies indicated that molecular pathological analyses, such as polymerase chain reaction and in situ hybridization, as well as serological analyses, could be applied for fast and comprehensive identification of viral myocardial infection[1,6,12,13]. Generally, the occurrence and prevalence of VMC is principally based on 3 types of evidence: (1) Detection rate of VMC at immunohistological evaluation of endomyocardial biopsies as the gold standard method; (2) High prevalence of myocarditis disease during the period of virus infection outbreaks; (3) Percentage of VMC out of all infection diseases in a definite province and a particular population[2]. Viral infections include adenovirus, enteroviruses,particularly coxsackievirus B, as well as parvovirus (B19) and human herpesvirus 6 (HHV-6) are related to VMC[4,11]. Previously published studies revealed that viral nucleic acids in the myocardium in patients with myocarditis were high[14,15], while information from distinct studies regarding the interaction between different viral family and myocarditis is not entirely consistent. For this purpose,we focused on the relationship of viral infection and myocarditis and we conducted a systematic review and meta-analysis with no language restriction.

2. Materials and methods

2.1. Literature search

We conducted a systematic search for the prevalence of the most common viruses in myocarditis including adenovirus, hepatitis C virus (HCV), herpesviruses including cytomegalovirus (CMV),Ebola virus (EBV), and human herpes virus (HHV) 6, influenza virus, B19 and non-polio enteroviruses based on scientific keywords“Myocarditis” or “Heart disease” and “Viral infection” or “Viral myocarditis” and their synonyms by using three main electronic databases of Medline (via PubMed), Embase, and Web of Science from October 1973 to September 2017. The search was limited to the original articles published in English that indicated the prevalence or incidence of mentioned viruses in different parts of the world.We also searched the bibliographies for any retrieved articles for additional references.

2.2. Inclusion and exclusion criteria

All of the original papers presenting cross-sectional studies on the prevalence of the most common viruses were evaluated perspicuously. The selected studies were analyzed based on titles,abstracts, and full texts. The entire recorded studies included in our analysis based on the following criteria: (1) Original articles that provided sufficient data; (2) With standard methods, including serology methods, immunohistochemistry assay, and molecular methods to detect adenovirus, HCV, CMV, EBC, HHV6, Influenza virus, B19, and non-polio enteroviruses. The exclusion criteria were:(1) Articles studying non-human samples; (2) Case reports; (3)reviews (4) Abstracts reported in conferences; (5) Duplicate articles for the same investigation.

2.3. Data extraction and definitions

The author’s first name, the date for the investigation, year of publication, country/continent, number of the most common viruses in myocarditis, detection method and the source of isolates were extracted from included studies. Deliberately, the information on the prevalence of adenovirus, HCV, CMV, EBC, HHV6, influenza virus,B19, and non-polio enteroviruses was extracted; concurrently, two people recorded the data from all articles independently without any bias.

2.4. Quality assessment

All reviewed studies were assessed based on the quality assessment checklist (designed by the Joanna Briggs Institute), and only highquality investigations were evaluated in the final analysis in this study based on mentioned including criteria.

2.5. Meta-analysis

The analysis was performed using STATA (version 14.0) software.The data were pooled using the fixed-effects model[16] and the random-effects model[17]. Statistical heterogeneity was assessed using Cochran Q and I2statistical methods[18].

3. Results

3.1. Characteristics of included studies

In total, we identified a total of 2 152 articles in the mentioned databases search. Based on the title and abstract evaluation, after the secondary screening, 1 992 articles were excluded. Upon a fulltext review, 84 out of 160 studies were excluded. Ultimately 75 studies were included for statistical analysis of the prevalence of adenovirus, HCV, CMV, EBC, HHV6, influenza virus, B19, and non-polio enteroviruses respectively, based on the inclusion and exclusion criteria (Supplementary Figure 1). These 75 articles that indicated the prevalence of the most common viruses is shown in Table 1. The majority of studies were from Germany (n=22),USA (n=14), Italy (n=10), Japan (n= 6), and England (n=5),respectively[19-83].

3.2. The prevalence of adenovirus, HCV, CMV, EBC, HHV6,influenza virus, B19, and non-polio enteroviruses

Eloquently, the pooled prevalence of adenovirus, HCV, CMV,EBV, HHV6, influenza virus, B19 and non-polio enteroviruses were 5.2% (95% CI: 3.3-7.0) among 1 355 patients, 6.1% (95%CI: 1.8-10.4) among 413 patients, 5.5% (95% CI: 3.3-7.7) among 1 648 patients, and 3.1% (95% CI: 1.7-4.6) among 1 952 patients,12.8% (95% CI: 8.8-16.7) among 3 003 isolate, 2.0% (95% CI:0.5-3.4) among 891 patients, 25.0% (95% CI: 20.0-29.0) among 3 840 patients and 18 % (95% CI: 4.7-11.1) among 599 patients respectively (Figure 1-8).

Table 1. Studies used in the meta-analysis.

able 1. Studies used in the meta-analysis (Continued).

Figure 1. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of B19 in patients with myocarditis.

Figure 2. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of human herpes virus 6 in patients with myocarditis.

Figure 3. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of influenza in patients with myocarditis.

Figure 4. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of hepatitis C virus in patients with myocarditis.

Figure 5. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of non-polio enteroviruses in patients with myocarditis.

Figure 6. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of cytomegalovirus in patients with myocarditis.

Figure 7. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of Ebola virus in patients with myocarditis.

Figure 8. Forest plot (A), funnel plot (B) and Galbraith (C) of the meta-analysis on prevalence of adeno in patients with myocarditis.

4. Discussion

VMC includes inflammatory cardiomyopathy caused by viruses,which is one of the common diseases of heart disease. The disease is on the rise and is now becoming a common cardiovascular disease after coronary heart disease. It can occur in all age groups,from infants to the elderly, but mainly in children and adults under the age of 40[84].

The clinical course of VMC manifests itself with various cardiac symptoms including breathing difficulty, fatigue, exercise intolerance, chest pain, severe heart failure and arrhythmia and maybe non-symptom[85]. It sometimes mimics myocardial infarction. Sixty percent of patients presented arthralgia, fever,sweating, respiratory or gastrointestinal symptoms 1-2 weeks before disease[86].

Since the 1970s, the incidence of VMC has been continuing to grow in China, Japan, and other countries, and a large amount of clinical information has been reported. However, its pathogenesis is still unclear. Considering the rapid development of molecular biology in recent years, great progress has been made in this field. Almost, all human virus infections can involve the heart.It has been found that more than 30 kinds of viruses can cause myocarditis.

Since the incidence of myocarditis is high in the 21st century,understanding the epidemiological characteristics of the viral causes of the disease is important[84].

The prevalence of adenovirus, HCV, CMV, EBV, HHV6,influenza virus, B19, and non-polio enteroviruses are calculated using 75 studies based on the inclusion and exclusion criteria. This meta-analysis shows that the highest prevalence is related to B19 and non-polio enteroviruses prevalence were 25.0% (95% CI: 20.0-29.0) and 18% (95% CI: 4.7-11.1) respectively. The prevalence of viruses belonging to the herpes virus family includes HHV6, CMV,EBV (12.8%, 95% CI: 8.8-16.7; 5.5%, 95% CI: 3.3-7.7; and 3.1%,95% CI: 1.7-4.6, respectively).

HCV accounted for 6.1% (95% CI: 1.8-10.4) of the disease,while the adenoviruses leded to 5.2% (95% CI: 3.3-7.0) VMC. The lowest incidence was related to influenza virus with 2.0% (95% CI:0.5-3.4).

Several studies have found that some viruses are the main cause of myocarditis. For example, most researchers believe that enteroviruses are the most common cause of VMC. Whereas Kühl et al. reported that the parvovirus B19 genome could be in about 51.4% of VMC cases[87]. However, Griffin et al. found that VMC patients were mostly infected with adenovirus[88].

The result of this meta-analysis shows that B19 is the most common cause of VMC and non-polio enteroviruses are the second.

In conclusion, whereas effective commercial medications are available for some viruses that cause myocarditis such as ganciclovir for CMV and oseltamivir for influenza, a rapid and correct diagnosis could lead to the prevention of further disorders and the treatment of this infections.

There were some limitations in this study that should be discussed. First, as with any systematic review and meta-analysis,the existence of publication bias must be taken into account.Second, heterogeneity was observed among the evaluated articles.Although the random-effects model allows for heterogeneity, there may still be differences of opinion regarding the composition of the studies.

Conflict of interest statement

The authors report no conflict of interest.

Authors’ contribution

M.D. and E.F. conceived and designed the study. T.A. and M.D.contributed in comprehensive research. M.D. and T.A. analyzed the data. M.D., T.A., and E.F. wrote the paper. M.D. and F.F. participated in data analysis and manuscript editing.