Clinical assessment revealed that 91% of iciHHV-6 cases and 33% of non-iciHHV-6 cases were incidental.
Traditionally, diagnostic testing in children with fever and possible neurologic abnormalities has involved culturing for bacterial, fungal and viral agents. Increasingly, multiplex PCR assay panels are being used, instead, because of their demonstrated accuracy. This is the case in children with possible central nervous system infections or sepsis.
The BioFire FilmArray meningitis/encephalitis panel (FAME) is used to aid in the diagnosis of patients with suspected meningitis or encephalitis. The panel detects 14 pathogens implicated in central nervous system (CNS) disease. It is less labor intensive than culturing for infectious agents, and provides results more rapidly.
FAME is a qualitative assay: it determines the presence or absence of a particular pathogen, but does not quantify the amount of the pathogen. With most of the pathogens in the panel, this is not a problem. However, with HHV-6, for reasons just below, it is a problem.
Interpreting HHV-6 positives identified by this panel, however, can be challenging in a pediatric population, for several reasons:
- Positive results for HHV-6 could indicate either primary infection or reactivated infection with exogenous virus;
- Such an infection with exogenous virus could either be the cause of the symptoms that led to the testing or an incidental and temporary infection—an epiphenomenon;
- A positive result could indicate a case of endogenous, inherited chromosomally integrated HHV-6 (iciHHV-6);
- While iciHHV-6 often is an incidental finding—an epiphenomenon—it now is clear that iciHHV-6 also can sometimes lead to reactivation of the endogenous virus, and the production of virions that could produce disease.
Investigators from Nationwide Children’s Hospital in Ohio systematically assessed all of these possibilities in children on whom cerebrospinal fluid (CSF) had been obtained according to care protocols because of suspected sepsis or CNS infection. They carefully examined clinical information in the patients’ medical records, and conducted testing for iciHHV-6 in each case of a positive FAME result for HHV-6.
Over four years, 2703 cerebrospinal fluid (CSF) samples were obtained. HHV-6, alone or in combination with other infectious agents, was detected in 65 (2.4%) of cases. Only enteroviruses (5.5%) were detected more often than HHV-6, and the other 12 pathogens were detected much less frequently.
Of the 65 detections of HHV-6, 42 were determined to be either primary or reactivated infection with exogenous virus. Of these 42, 17 were determined to have CNS disease caused by the virus (most had seizures); 9 were determined to have active HHV-6 infection that did not involve the CNS; and 33 were found to have active infection that was incidental, and not connected to the illness that had led to the testing.
Of the 65 detections of HHV-6, 23 (0.85% of all CSF specimens) were due to iciHHV-6. Most were identified in infants younger than 60 days. While 21 of these 23 cases were deemed to be epiphenomena, in two cases iciHHV-6 was considered to be causing the illness that led to the testing. One was a 14-day old baby with fever and rash, and the other a one-year-old child presenting with febrile seizure and rash.
The authors conclude that investigating iciHHV-6 is helpful in reaching an accurate diagnosis of active infection and the clinical significance of HHV-6 in CSF should be carefully interpreted. Since the BioFire assay is qualitative, follow-up quantitative testing is required to evaluate a positive HHV-6 result.
Read the full paper: Wang 2023