To our knowledge, this study is the first to provide a broad overview of all HHV infections in patients with severe COVID-19. Interestingly, we observed the detection of one more types of herpesviruses in patients. Coinfection by two or more viruseswas observed in 39 patients, whereas some patients showed the detection of up to four types of herpesviruses concurrently. These data indicate that the state of immunosuppression in SARS-CoV-2 infection, characterized by symptoms such as lymphocytopenia, may possibly trigger a cycle of opportunistic virus reactivations, which makes it necessary to monitor the influence of these viruses on the course of COVID-19 [35, 10]. These findings reiterate the importance of further studies on family Herpesviridae that investigate their reactivation frequency in the population and interference with other pathogens . Interestingly, we detected HHV-8 in 17% of patients. Previous studies have observed the low prevalence of HHV-8 in the Brazilian population compared to other herpesviruses . However, a considerable detection rate of HHV-8 in our study cohort suggests that the prevalence of HV-8 may be underestimated by serological detection methods curreent.
Herpesviruses are considered pathogens of importance in immunocompromised individuals. This state of immunodeficiency plays a potential role in viral reactivation. Some studies have shown the high incidence of herpetic reactivation in patients with COVID-19, reporting a significantly longer duration of mechanical ventilation in patients with CMV and HSV-1 reactivation, and showing that EBV reactivation is associated with aprolonged ICU stay [35, 38]. However, despite the high level of herpesvirus detection in our study, only HSV-1 showed a viral load correlation with SARS CoV-2 (p = 0.037) (Table 2), indicating that patients with a high viral load of SARS-CoV-2 tend to show HSV-1 reactivation. These data represent an important finding. According to some reported cases, patients coinfected with SARS-CoV-2 and HSV-1 can develop complications such as acute liver failure, neurological symptoms, and septic shock [39, 9, 10]. This information highlights the importance of the early screening of HSV-1 reactivation in patients with COVID-19-related complications and the necessity of appropriate treatment and avoidance of worse outcomes. We did not find any significant association between the detection of other herpesviruses and worse outcomes, as reported in previous studies [40, 38, 35].
In hospitalized patients with COVID-19, a high prevalence of some viral subtypes of Herpesviridae, such as HSV-1 and EBV, has been reported [ 41, 35]. In our study, both HSV-1 and EBV showed detected in 17% and 28.3% of the patients, respectively; however, the gammaherpesviruses HHV-6, CMV, and HHV-7 showed the highest DNA loads.
HSV-1, HSV-2, VZV, and EBV are important pathogens associated with neurological manifestations and have a prevalence of more than 60% in adults. HSV can reactivate in the peripheral ganglion with axonal transport to the temporal lobe, and it is estimated that 70% of HSV encephalitis cases are caused by reactivation, which is also the most common cause of encephalitis [42, 20]. With respect to the effects on the CNS, HSV-1 and SARS-COV-2 share the potential for acting as viral triggersfor NMDA receptor encephalitis [22, 23]. VZV, which also establishes latency in the ganglia upon reactivation, can cause several neurological symptoms, such as encephalitis and ischemic stroke . Conversely, EBV reactivation has been associated with several potentially long-term neurological complications, such as psychoneurosis/brain fog and headaches .
Although our study population showed a high rate of herpesvirus detection, a limitation of the study was the lack of information about the exact date of symptom onset and the time of sample collection. Seeßle et al. (2021) recently showed that the HSV-1 reactivation rate increased 11 days after the onset of symptoms in patients with COVID-19; therefore, possibly, there activation rate of some herpesviruses may be higher than that observed in our study, because the time between symptom onset and sample collection may vary.
In 26.4% of the patients, we observed CNS-associated neurological symptoms, such as impaired consciousness, headache, dizziness, acute cerebrovascular disease, and seizure. Similarly, a recent study confirmed SARS-CoV-2/HSV-1 coinfection in a patient with loss of consciousness, disorientation, and dizziness , which are symptoms suggestive of herpetic infection. EBV reactivation has also been associated with persistent symptoms observed in patients with COVID or long COVID,including some neurological manifestations, such as confusion and headache, which were observed in our patient group as well . The most commonly detected herpesviruses in patients with neurological changes were HHV-6, CMV, and HHV-7. Although a statistically significant association between neurological changes and herpesvirus detection was only observed for HHV-6, CMV also showed detection in several patients, and the reactivation of this virus is also associated with neurological changes in immunocompromised patients. The immunosuppressive condition triggered by SARS-CoV-2 infection may play a role in CMV reactivation, which may cause diffuse encephalitisand myelitis . This is similar to how HHV-7 reactivation can trigger CNS-related manifestations . In addition, our findings also suggested an association between neurological changes and HSV-1 detection in patients with a high SARS-CoV-2 load. In this group of patients, 33.3% (3/9) showed changes in the CNS and 22.2% (2/9) in the PNS. Given the strong association between HSV-1 reactivation and neurological changes, further investigation of this association is necessary.
A case of SARS-CoV-2/HHV-6 coinfection associated with myelitis has also been reported previously, with the presence of HHV-6 in the CSF. The findings of this case provided evidence of HHV-6 reactivation in the CNS associated with the immunocompromised status acquired during SARS-CoV-2 infection . Although neurological disorders are commonly associated with human alphaherpesvirus infection, the two viral species, HHV-6A and B, are neurotropic and cause neurological disorders such as dizziness, epilepsy, and encephalitis . HHV-6 has a high prevalence in the population and can infect neuronal cells and disrupt cellular functions and metabolic processes essential for maintaining a healthy environment in the CNS . Increasing evidence has indicated the association of HHV-6 infection with various neurological alterations in immunocompromised and immunocompetent individuals [48, 49]. Based on our findings and the ability of HSV-1 and HHV-6 to cause neurological disorders during reactivation, we suggest that this viral subtype should be investigated as a possible cause of neurological changes in SARS-CoV-2-infected individuals. However, although the detection of herpesvirus in body fluids of patients in an immunosuppressed state is strongly suggestive of a reactivation, we cannot determine ifthat it is a reactivation or a primary infection. A limitation of the study that should be considered, is the size of the study cohort, and the inability of examining the CSF for viral DNA because of the clinical status of the patients, and the overload on the public health system during the peak of the pandemic.
Another limitation of this study was that the size of the study population may have interfered with the result of the association between lymphocytopenia and the use of corticosteroids, since corticosteroids, such as steroids and immunomodulatory drugs, have been identified as triggers for the reactivation of latent herpesviruses in the host [50, 7].