The primary objective of this review was to compare event-free (death, requirement for a cardiac transplant, or placement of a left
ventricular assist device) or overall (death) survival of adults and children with presumed viral
myocarditis treated with
IVIG versus those who did not receive
IVIG. A secondary objective was to determine if a group of patients with presumed viral
myocarditis could be identified (on the basis of age, duration of symptoms, acuity of onset of symptoms, cardiac function at presentation, virological results, or the presence or absence of histological evidence of acute
myocarditis on cardiac biopsy in patients in whom a biopsy was performed) who would be the most likely to benefit from
IVIG.
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, DARE, CINAHL, Web of Science Core Collection, and LILACS in July 2019, and two trial registries in November 2019. We contacted authors of trials and checked reference lists of relevant papers. We applied no language restrictions.
SELECTION CRITERIA: We included studies if (1) participants had a clinical diagnosis of acute
myocarditis with a left ventricular ejection fraction (LVEF) ≤ 0.45, left ventricular end-diastolic diameter (LVEDD) > 2 standard deviations (SDs) above the norm, or a left ventricular shortening fraction (LVSF) > 2 SDs below the mean, with duration of cardiac symptoms < 6 months; (2) participants had no evidence of non-infectious or bacterial
cardiac disease; and (3) participants were randomly assigned to receive at least 1 g/kg of
IVIG versus no
IVIG or placebo. We excluded studies if (1) participants had received immunosuppression before outcome assessment; or (2) onset of
myocarditis was reported to have occurred < 6 months postpartum.
DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results and extracted data. We assessed risk of bias with the Cochrane 'Risk of bias' tool. We conducted meta-analysis for two outcomes (overall survival and improvement in LVEF) with two adult trials. Other meta-analyses were not possible because only three relevant trials were included, and researchers analysed markedly different populations and used different outcome measures.
MAIN RESULTS: In this update we added two trials to the two previously included trials. A quasi-randomised trial was previously included due to a paucity of evidence from randomised trials; however, with the addition of two new randomised trials, it was removed from this update. For two adult trials, the overall risk of bias was unclear with very low-certainty evidence for all outcomes. The first trial studied 62 adults with recent-onset
dilated cardiomyopathy randomly assigned to receive
IVIG or an equivalent volume of 0.1%
albumin in a blinded fashion. The effect on event-free survival between groups was uncertain (risk ratio (RR) of any event 1.76, 95% confidence interval (CI) 0.48 to 6.40). The second trial studied 41 adults with acute
myocarditis randomised to either high-dose
IVIG (1 to 2 g/kg over two days) or no treatment. The
IVIG group reported greater survival time after 60 days (no raw data, P < 0.01), but the evidence is uncertain. We pooled the reported number of deaths in both trials, with no evidence of a difference between groups (RR 0.91, 95% CI 0.23 to 3.62, I2 = 31%, very low-certainty evidence). The evidence on the effect of
IVIG treatment on LVEF (pooled mean difference (MD) -0.01, 95% CI -0.06 to 0.05) after 12 months and an unknown time frame is uncertain. The results for functional capacity, assessed by peak oxygen consumption at 12 months, were uncertain (MD -0.80, 95% CI -4.57 to 2.97). The results for infusion-related side effects were also uncertain due to a very large CI (RR 20.29, 95% CI 1.25 to 329.93). Lastly, there was uncertain evidence addressing failure to attain complete recovery (RR 0.46, 95% CI 0.19 to 1.14). Evidence for improvement in LVEDD, left ventricular shortening fraction, and hospitalisation status in adults was not reported. In the single included paediatric trial, the overall risk of bias was low with very low-certainty evidence for all outcomes. The trial included 86 children in Egypt presenting with acute
myocarditis. Children were randomly assigned to 1 g/kg
IVIG daily for two consecutive days or placebo followed by echocardiography one and six months post randomisation for recording of LVEDD and LVSF. The evidence for overall survival after six months was uncertain (risk of death RR 0.48, 95% CI 0.20 to 1.15). The evidence was also uncertain for improvement in LVEDD and LVSF after six months (LVEDD MD -4.00, 95% CI -9.52 to 1.52; LVSF no raw data). Evidence for improvement in LVEF, functional capacity, side effects, complete recovery, and hospitalisation status in children was not reported. AUTHORS' CONCLUSIONS: Evidence from two trials of very low certainty and with unclear risk of bias provides contradictory evidence on the use of
IVIG in the treatment of adults with presumed viral
myocarditis. One trial reported that use of
IVIG results in longer survival time after 60 days, whilst the other trial found that
IVIG does not provide an appreciable benefit. The evidence of a difference in event-free or overall survival, LVEDD, or LVSF is of very low certainty in a single paediatric trial with a low risk of bias. Until higher-quality studies with low risk of bias and larger sample sizes have demonstrated benefit in a particular group of patients, the evidence for treatment with
IVIG for presumed viral
myocarditis is uncertain. Further studies of the pathophysiology of
myocarditis would lead to improved diagnostic criteria, which would facilitate future research.