Myocarditis is an inflammatory cardiomyopathy that occurs in all age groups [1]. Most cases are thought to be sub-clinical, but myocarditis can manifest as fulminant or chronic heart failure [2]. The inflammation is presumed to most commonly start as an infectious process, although autoimmune and idiopathic forms also occur [1]. Bacterial or protozoal myocarditis is rare in the developed world, with the vast majority of cases being viral [3]. Although most viruses that are pathogenic for humans can cause myocarditis, common etiologic agents are enteroviruses and adenoviruses [4]. It remains unclear if the primary problem in severe disease is ongoing damage from a virus, a post-infectious inflammatory reaction, or a combination of both factors. If ongoing infection is the primary problem, IVGG could be efficacious if it contains antibodies to the microbe. IVGG also has anti-inflammatory properties that prevent the formation of and downregulate cytokines [5] so could be efficacious even if the primary problem is a post-infectious inflammatory reaction.

The objective of this study was to review the evidence evaluating the use of IVGG in the treatment of patients with acute myocarditis. A secondary objective was to determine if there is an identifiable group of acute myocarditis patients (based on age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virologic results, or the presence or absence of histologic evidence of acute myocarditis on cardiac biopsy in patients where a biopsy was performed) who would benefit from IVGG. The review of randomized controlled trials has been registered with the Cochrane Collaboration and regular updates will be available in the Cochrane Library.

Figure 1 presents a flow diagram of studies considered for inclusion in the review. Only one RCT evaluating IVGG for acute myocarditis has been reported to date [16]. The trial was of moderate methodological quality according to the Jadad scale (3 out of maximum 5 points, where 5 indicates highest quality); allocation concealment was unclear. The study enrolled 62 adults (mean age 43.0 +/- 12.3 years; 37 men), of which only ten had cellular inflammation on endomyocardial biopsy (four fulfilled the Dallas criteria for acute myocarditis, and three for borderline myocarditis). The authors reported that the given sample size would provide 80% power to detect a difference between groups of ≥ 8% in ejection fraction (EF) change scores. Patients were randomized to receive either 2 g/kg IVGG or an equivalent volume of 0.1% albumin in a blinded fashion. The incidence of death or requirement for cardiac transplant or placement of a left ventricular assist device was low in both groups. Event-free survival was not significantly different but favored the control group (OR 0.52, 95% CI 0.12, 2.30). Follow-up at 6 and 12 months showed no significant difference in improvement in left ventricular ejection fraction for cases and controls (mean difference 0.00, 95% CI -0.07, 0.07 at six months; 0.01, 95% CI -0.06, 0.08 at 12 months). Functional capacity as assessed by peak oxygen consumption was not significantly different in the two groups at 12 months (mean difference -0.80, 95% CI -4.57, 2.97). Infusion-related side effects occurred significantly more often in the treated group (RD 0.33, 95% CI 0.17, 0.50; number needed to harm = 3, 95% CI 2, 6), but all appeared to be mild.

Sixteen additional studies of various designs met the inclusion criteria [see Additional file 1]. These included a retrospective case series [17], an uncontrolled trial [18], two case series [5, 19], and twelve case reports [20‐31]. In a retrospective cohort study, Drucker compared children who were treated with IVGG (n = 21) to historic controls (n = 26); 65% of the sample was less than two years of age [17]. The treatment group showed improved cardiac function and a trend (though not statistically significant) towards improved survival. McNamara conducted an uncontrolled trial involving 10 adults (mean age 35.8 +/- 15 years) [18]. One patient with refractory arrhythmias and severe heart failure died during the infusion; the other nine patients showed an impressive improvement in cardiac function following administration of IVGG, with a significant increase in left ventricular ejection fraction at 12-month follow-up (p = 0.008). In ten case reports and both case series, improvement in cardiac function was described after use of IVGG in a total of 21 cases, although improvement was considered to be minimal in one case [26]. In the other two case reports, there was no benefit of IVGG in a patient presenting with hand, foot and mouth disease and acute myocarditis from coxsackievirus A16 [27] and in a patient with fulminant myocarditis of unclear etiology [28]. Hemolytic anemia was attributed to use of IVGG in one case report [26].

We could find no ongoing trials of the use of IVGG in acute myocarditis, although the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID) is evaluating hyperimmunoglobulin for patients with cytomegalovirus-positive myocarditis [32].

The small number of studies evaluating IVGG in the treatment of acute myocarditis reflects the immature state of this body of literature. We identified only one RCT (Level 1 evidence), which involved 62 adult patients with idiopathic cardiomyopathy (of which only 10 had histologic evidence of myocarditis) and showed no apparent benefit [9]. This is in contrast to an uncontrolled trial and numerous observational studies (Level 4 evidence), most of which suggested potential benefit. This indicates a possible bias towards publication of case reports or case series with positive results. The validity of evidence was generally poor, with the majority of included studies ranking low in terms of level of evidence. The most important threat to validity for fifteen of the seventeen included studies was the lack of controls, which could result in an overestimate of the benefit of IVGG. Spontaneous improvement in cardiac function is common with acute myocarditis and can be rapid or gradual, so it is possible that the improvement noted in these cases was part of the natural history of the disease. The retrospective cohort study demonstrated a greater improvement in cardiac function in patients given IVGG compared to historic controls [17]; this type of study is more susceptible to bias because of the inability to fully control for all potential confounders, such as other changes in patient management over the eight-year study period.

Acute myocarditis is a relatively non-specific entity, as the diagnosis is often clinical. Laboratory confirmation consists of microbiologic, histologic, and immunohistochemical methods. With regard to microbiologic confirmation, it is rare to isolate the etiologic agent from a myocardial biopsy (probably because the biopsy is usually done too late in the course of the illness), and identification of organisms by molecular techniques is in its infancy [4]. However, with the development of new effective antivirals, there should be increased efforts towards making a virologic diagnosis early in the course of myocarditis as it is possible that antivirals would improve the prognosis. Furthermore, there are case reports of hyperimmunoglobulin showing an apparent effect in cases of varicella [33], cytomegalovirus [34], and parvovirus [35] myocarditis. With regard to histologic confirmation, the Dallas criteria (lymphocyte infiltration with myocyte necrosis) [36] and more recently the World Heart Federation criteria (>14 leukocytes/mm² with necrosis or degeneration) [37] have been used for histologic diagnosis, but the sensitivity and specificity of these criteria are not known. There are no standardized values for immunohistochemical markers [38]. Our aim in this study was to analyze reports of use of IVGG for presumed viral myocarditis, but it is possible that many of the patients in the reports did not have viral myocarditis (only 10 of the 62 patients in the RTC had cellular inflammation on endomyocardial biopsy). Once our ability to accurately diagnose viral myocarditis improves, it may be possible to identify a subset of patients who will respond to IVGG. This might be patients whose disease was precipitated by a specific virus, or patients who are treated with IVGG early in the course of their illness when they have ongoing viral replication in the myocardium. Perhaps pediatric patients are more likely to respond. Children are thought to be more likely to present in the acute inflammatory stage of illness [16], and may have a worse prognosis than do adults when they present with fulminant myocarditis [39, 40]

In conclusion, the value of IVGG in patients with acute myocarditis is obscured by the poor quality of evidence. We were not able to identify a subgroup of patients who appear to be more likely to respond to IVGG. A large RCT is required to evaluate the efficacy of IVGG for acute myocarditis with emphasis on the etiology of the myocarditis. Until there are RCTs demonstrating benefit, use of IVGG for acute myocarditis should not be part of routine practice. Moreover, there is a great need for further studies of the pathophysiology of acute myocarditis, which would allow for a better understanding of the etiology and the natural history of the disease. This might allow for improved diagnostic criteria, which would make it much easier to design studies of treatment options. This may also assist in identifying sub-groups of patients where IVGG or other therapies have a greater potential to confer clinical benefit.