The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention

Abstract

Introduction: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. Results: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3–12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and ‑negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. Conclusion: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

Safety and usefulness of left ventricular endomyocardial biopsy in new- onset acute heart failure requiring mechanical support by an Impella® device

“…Five of these patients without signs of viremia or sepsis had low cardiac viral DNA copies (B19V <400 copies/μg DNA), including three in combination with EBV, regarded as not being relevant for the pathogenesis of cardiac inflammation. These patients benefited from immunosuppressive therapy, as studied before in other cohorts [11,12]. We added a table (Table 1) as a supplement file for further details on histopathological and molecular findings.…”

Persistent viral infections and their role in heart disease

“…A higher percentage of heart tissue samples positive for HHV-6 was also detected by Kühl et al, where 23 out of 245 (9.4%) patients with presumptive DCM had HHV-6 genome in their hearts, but only 5 out of 245 (2%) were positive for EBV, and 2 out of 245 (0.8%) had HCMV genome ( Kühl et al, 2005b ). Low levels of HHV-6 DNA were detected in 79 out of 756 (10.4%) patients with unexplained heart failure (HF) and in 29 out of 354 (8%) patients without the disease in a study performed in Germany by Elsanhoury et al ( Elsanhoury et al, 2022 ). About 62% of patients with unexplained HF had myocardial inflammation, suggesting that the presence of HHV-6 is not always associated with an inflammatory state ( Elsanhoury et al, 2022 ).…”

“…Low levels of HHV-6 DNA were detected in 79 out of 756 (10.4%) patients with unexplained heart failure (HF) and in 29 out of 354 (8%) patients without the disease in a study performed in Germany by Elsanhoury et al ( Elsanhoury et al, 2022 ). About 62% of patients with unexplained HF had myocardial inflammation, suggesting that the presence of HHV-6 is not always associated with an inflammatory state ( Elsanhoury et al, 2022 ). A study by Mahrholdt et al conducted in Germany evaluated the potential correlation between myocardial damage and the presence of HHV-6 ( Mahrholdt et al, 2006 ).…”

DRESS syndrome with multiorgan involvement and HHV‐6 reactivation in the absence of a drug trigger

“…3 Human herpesvirus 6 (HHV-6) is a ubiquitous lymphotropic virus that can cause a range of end-organ manifestations, including myocarditis in adults and children. 4,5 HHV-6 infection and reactivation have been associated with DRESS, but whether HHV-6 plays an inciting or reactive role in the immunopathogenesis of DRESS remains unclear. 4,5 We present a case of a patient with typical manifestations of DRESS syndrome with HHV-6 reactivation and eosinophilic myocarditis, in the absence of a convincing drug trigger.…”