Prevalence and outcome of patients with acute myocarditis and positive viral search on nasopharyngeal swab

Abstract

Acute myocarditis (AM) is an acute-onset inflammatory heart disease with heterogeneous clinical presentation, varying from chest pain to cardiogenic shock.1 Viral infections are believed to be associated with AM and indeed typical prodromic symptoms/signs (i.e. fever, flu-like symptoms, sore throat) are frequently reported in AM patients.1, 2 Respiratory viruses, such as influenza and corona viruses, identified by real-time polymerase chain reaction (RT-PCR) from nasopharyngeal swabs, have been increasingly recognized as AM triggers.3, 4 Nevertheless, no systematic study ever investigated the presence of respiratory viruses in the upper respiratory airways in AM patients. We conducted a single-centre, prospective study to ascertain the prevalence of respiratory viruses in nasopharyngeal swabs in consecutive adult patients (≥16 years) with AM admitted to the Niguarda Hospital, Milan, Italy, between January 2018 and October 2020. We further evaluated differences in clinical presentation, management and prognosis between those who tested positive vs. negative. The Institutional Review Board (Milano Area 3) approved the study, and patients signed an informed consent. A control group of 36 consecutive patients admitted for other acute cardiac disorders was used as comparator to assess the prevalence of positive viral genome in nasopharyngeal swabs in patients without AM (online supplementary Table S1). Fifty consecutive patients with clinically suspected AM and symptom onset within 30 days were enrolled, including patients with all forms of clinical presentation from isolated chest pain to cardiogenic shock (i.e. fulminant myocarditis). All had high-sensitivity troponin T elevation upon admission (median 903 ng/L, normal value <14 ng/L) and final AM diagnosis was confirmed either by endomyocardial biopsy (EMB) or cardiac magnetic resonance imaging (CMRI). Median age at presentation was 34 years, female prevalence was 24.0% (Table 1). A total of 49 (98.0%) patients underwent CMRI during hospitalization. Right ventricular EMB was performed in 28 patients (56.0%) after a median time of 2 days following admission, and histologic evidence of myocarditis based on Dallas criteria was found in 19/28 (67.9%), whereas the diagnosis of myocarditis based on the European Society of Cardiology (ESC) criteria5 was confirmed in 26/28 cases (92.9%). Patients without histology or who did not reach Dallas/ESC criteria for AM had positive criteria on CMRI; one patient who did not perform CMRI had AM confirmed by histology. All 50 patients underwent nasopharyngeal swabbing within a median time of 1 day after hospitalization and the specimens were tested by RT-PCR for the following respiratory viruses: coronavirus [subtypes 229E, NL63, OC43 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from March 2020], influenza A and B, metapneumovirus, parainfluenza (subtypes 1 to 4), bocavirus (subtypes 1 to 4), rhinovirus A, B and C, syncytial respiratory virus (SRV) A and B, adenovirus and enterovirus. Nine (18.0%) patients tested positive for a virus on nasopharyngeal swab. The following viruses were identified: rhinovirus in four patients (in 1 case associated with influenza B), coronavirus in three patients (two subtype 0C43, and one subtype 229E associated with SRV A positivity), parainfluenza virus subtype 2 in one case and adenovirus in the other case. None of the 36 (0%) patients admitted with acute cardiac disorders other than AM tested positive for a virus on nasopharyngeal swab as opposed to 9/50 (18.0%) in the AM group (P = 0.009). In 12/28 patients with AM (42.9%) undergoing EMB, myocardium RT-PCR-based viral genome search was performed, yielding positive results in 5 (41.7%) patients, with parvovirus (PV) B-19 identified in all cases (two cases with a viral load >500 gEq/µg). Differences between patients who tested positive vs. negative on nasopharyngeal swab are reported in Table 1. Coherently with the presence of respiratory viruses in the nasopharyngeal mucosa, patients with positive nasopharyngeal swab had a higher prevalence of prodromal respiratory symptoms/signs compared with patients with negative nasopharyngeal swab (88.9% vs. 36.6%, P = 0.008). Positive patients were more likely to be female (55.6% vs. 17.1% in negative patients, P = 0.03) and to present with fulminant forms (55.6% vs. 17.1%, P = 0.03), defined as requiring temporary mechanical circulatory supports (t-MCS) and/or inotropes. Accordingly, positive patients were more likely to receive a t-MCS compared with negative patients (44.4% vs. 9.7%; P = 0.02). There were no significant differences when comparing other clinical characteristics including type of presentation, treatment, use of immunosuppressive therapy, and mortality. Lymphocytic AM was the most common histologic type in both groups. Of interest, all patients with a virus detected on nasopharyngeal swab had a lymphocytic AM, while detection of PVB-19 genome in the myocardium was not significantly different between the two groups. In conclusion, in the present cohort of AM patients, the prevalence of viral identification on nasopharyngeal swab was 18.0%, with rhinoviruses and coronaviruses detected in the majority of patients. Nevertheless, delays in swabbing relative to symptom onset could have potentially underestimated the proportion of patients with a viral-induced AM. Nasopharyngeal swab may thus be a valuable tool to identify viral triggers in AM. To reinforce the proposed association between viral findings on nasopharyngeal swab and AM, none of the patients with acute cardiac disorders other than AM tested positive for a virus. Our findings suggest that virus-triggered immune-mediated reactions can play a major role in determining cardiac injury in a susceptible host with a permissive genetic background. Acquired knowledge on myocardial injury in SARS-CoV-2 infection supports this hypothesis. SARS-CoV-2 may induce an immune-mediated systemic inflammatory response sustaining the associated cardiac injury and possibly explaining the benefits from corticosteroid therapy.6 Of note, immunosuppression was used in 66.6% of our cases who finally tested positive for a virus on nasopharyngeal swab and appeared safe. Furthermore, in line with another recent report,7 PVB-19 was the only detected virus in myocardial specimens, supporting the hypothesis that PVB-19 could be a bystander in the heart rather than the virus causing myocarditis.8 The absence of PVB-19 genome in the blood of all patients having a PVB-19 positive EMB ruled out a systemic PVB-19 infection. The identification of a specific trigger associated with AM may have an aetiological relevance. The presence of specific viruses, such as influenza virus, could lead to specific treatments (i.e. oseltamivir) to eradicate the virus. Respiratory viruses are not generally found in EMBs.9 Thus, it is more plausible that these viruses do not cause a direct cytolytic effect on the myocardium, although they might trigger an immune response against the heart in predisposed individuals. It should be acknowledged that the small sample size of the group with virus-positive nasopharyngeal swab (n = 9) is a limitation that might lead to potential statistical errors and thus this finding should be confirmed in larger studies. We further recognize that some patients could have a false-negative nasopharyngeal swab, or alternatively the virus could have disappeared by the nasopharyngeal mucosa at the time of swabbing. Furthermore, the case of AM triggered by gastrointestinal virus has not been explored and thus a proportion of virus-negative nasopharyngeal swab AM might have a viral aetiology/trigger that has not been assessed in the present study. Conflict of interest: none declared. Table S1. Characteristics of the control group based on a case mix of acute cardiac disorders vs. acute myocarditis who underwent nasopharyngeal swab. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Topics & Concepts