Our study details the clinical characteristics of hospitalized adults with HSV DNA detected in the peripheral blood by PCR. Our series, derived from nearly 1000 clinical tests performed over 5 years, was notable for several features. First, the identification of 13 adult patients with HSV DNA in the peripheral blood over the span of 4 years within one group of hospitals in Seattle suggests that hospitalized patients with HSV viremia may be encountered by many practicing health care providers. Second, detection of HSV by PCR in the peripheral blood is associated with both primary HSV infection and reactivation disease. Third, approximately 1/4 of patients with HSV detected in the peripheral blood were immunocompetent. Fourth, we found detection of HSV in the peripheral blood to be accompanied by a myriad of clinical signs and symptoms, but the minority of patients had mucocutaneous lesions identified.
Our series relied on the detection of HSV DNA in the peripheral blood by PCR. None of the study patients had viral cultures of the peripheral blood performed to verify that the detection of HSV DNA represented the presence of HSV virions in the peripheral blood. However, members of our research group have recently shown that 60% of persons with high quantities of HSV DNA by PCR in peripheral blood in the setting of primary genital herpes likely had DNA contained within virions, as the samples were resistant to DNAase digestion [21
The presence of HSV in the bloodstream of individuals with no previously identified immunodeficiency suggests that there may be unidentified genetic predispositions to more severe HSV disease. Previous studies of neonates with disseminated HSV have hypothesized that variation in Toll-like receptor 2 and human leukocyte antigens may influence severity and frequency of HSV infections [25
], and recent work on HSV-2 in adults supports the role of TLR-1 polymorphisms in determining the virologic severity of disease [27
]. There is evidence that other immunodeficiencies with Mendelian inheritance (STAT-1, NEMO, UNC-93b, CD40L and CD16a) in the adult can also predispose to severe and recurrent HSV infection [28
]. Genetic factors related to the innate immune system play a critical role in the protection from HSV-1 infection and may be important in preventing dissemination of the disease beyond initial sites on infection.
The most frequent clinical signs and symptoms were fever and CNS symptoms, and the most frequent laboratory abnormality was hepatitis. Sepsis syndrome was seen in 4 patients. Aseptic meningitis is a common clinical manifestation of primary genital herpes and occurs more frequently in women than men [33
]. In our study, only 2 (15%) of these patients had detectable HSV by PCR in spinal fluid after peripheral blood detection, but 6 (46%) presented with altered mental status; the true incidence of detectable HSV in the CSF remains uncertain as only three out of six patients with altered mental status had CSF sent for PCR.
Approximately 60% of immunosuppressed and 33% of immunocompetent individuals died after HSV was detected in the peripheral blood. The most common cause of death was sepsis followed by multi-organ failure. The high mortality seen in this study raises a number of questions. Is HSV the primary cause of sepsis and multi-organ failure, or does detectable HSV in the blood stream represent viral reactivation in an individual whose immune system is impaired by ongoing sepsis syndrome by another causative organism or other underlying disease? Others have shown that another herpes virus, CMV, can be detected in critically ill immunocompetent patients and is associated with prolonged hospital stay and death [34
]. In our series, the high mortality rate despite treatment could be due to multiple causes. First, study patients may have been diagnosed too late in the course of illness to have clinical improvement with aggressive therapy. Second, another organism (such as S. pneumonia
in Patient #7) may have caused the patients’ sepsis. Third, the patient may have suffered from a significant and terminal co-morbid illness (such as large B cell lymphoma in patient #10). Ultimately, however, our study design precluded making definite conclusions as to whether there was a causal association between HSV viremia and mortality.
While we found the detection of HSV by PCR in the peripheral blood to be present in patients with high mortality, treatment was at least partially effective. The reasons for treatment failure despite administration of an effective antiviral should be investigated further but may include delay in diagnosis, inability to halt a “cytokine storm” or “sepsis syndrome,” or emergence of acyclovir-resistant virus (as was discovered in post-mortem viral cultures in Patient #6) [5
]. The length of treatment varied and some responded well to relatively short courses of therapy (as little as 3 weeks), while others were treated with longer courses (from 6 months to life-long suppression). Recurrence of HSV was not uncommon, occurring in 2 of the 13 patients (patients 6 and 12).
Our study was limited by its observational and retrospective design. We are clearly not able to describe the true prevalence of HSV viremia, as only patients in whom the diagnosis was entertained had samples sent to the laboratory for analysis. Accurate estimation of the frequency and clinical consequence of HSV viremia in hospitalized patients would require a larger prospective study. PCR is an extraordinarily sensitive tool for the detection of viral DNA, and observations based on PCR must be careful to avoid laboratory contamination. In our study, we feel this is extremely unlikely given our stringent negative controls and quality assurance. A recent analysis of the performance of our PCR assay for detecting genital HSV shedding found that misclassification (false positive and negative test results) occurred less than 1% of the time when a cutoff for positive test results was set at > 50 copies per mL[9
In summary, HSV DNA may be detected by PCR in the peripheral blood of some hospitalized inpatients with unexplained sepsis syndrome, evidence of hepatitis, and/or CNS infection with fever. Prospective studies are needed to determine the true prevalence, and clinical significance of HSV DNA detection in the peripheral blood, and to establish whether the HSV viremia is causality related to the concurrent acute illness.