Biofire multiplex PCR assay accurately detects HHV-6 meningitis/encephalitis in immunocompromised adults

Utility of the assay in immunocompetent patients requires further study.

Multiple viral, bacterial and fungal agents can cause meningitis and encephalitis. Over the past decade, multiplex PCR assays of multiple microbial pathogens increasingly have been used to make a rapid diagnosis of the responsible pathogen in cerebrospinal fluid of people with meningitis and/or encephalitis. The Biofire FilmArray Meningitis / Encephalitis PCR panel is one example. Unfortunately, several studies have reported that the assay may not be very accurate, in part because it often is used when the pre-test probability of a microbial infection is low. When used in such circumstances, the expense associated with the test is wasteful.

Investigators at the University Hospital Basel examined clinical and laboratory data in 1,236 adult patients in whom the Biofire assay was used in people with suspected meningitis or encephalitis. The assay includes 14 different pathogens that can cause meningitis or encephalitis.

Results were positive for at least one pathogen in 106 (8.6%) of patients tested: detection rates were varicella zoster virus (VZV, 27%), Streptococcus pneumoniae (19%), enteroviruses (16%), Herpes simplex virus 1/2 (16%), and human herpesvirus 6 (HHV-6, 13%). The symptoms most commonly present in test-positive patients were fever, vomiting, headache, and photophobia; CSF leukocyte counts and protein concentrations also were higher in test-positive patients, including people with just viral infections.

No systematic assessment of the accuracy of the Biofire assay was conducted: no confirmatory PCR or culture evidence in test-positive patients, and no systematic PCR and culture studies in test-negative patients to identify falsely negative results.

Among HHV-6 patients who were immunocompromised, the results regarding HHV-6 proved useful: when a test was positive for HHV-6, clinicians generally judged the patient was experiencing HHV-6-related meningitis or encephalitis, and prescribed antivirals.  In the few patients who were not immunocompromised, a “positive” result for HHV-6 often was judged falsely positive, for the most part due to inherited chromosomally integrated HHV-6 (iciHHV6), which occurs in approximately 1% of the population. The best way to determine if a positive result is due to iciHHV6 would be to order a whole blood qPCR test for HHV-6, but this is not recommended by Biofire and not routinely performed in hospitals. Therefore, in the absence of a rigorous assessment of test accuracy, and of whether a positive result may reflect iciHHV6, one cannot know if the clinicians’ judgment was correct.

This report is consistent with other reports that find that a positive result for HHV-6 in the spinal fluid of an immunocompromised patient likely is truly positive more often than falsely positive.  The value of a positive result for HHV-6 in patients who are not immunocompromised, however, remains uncertain unless rigorous testing is performed to rule out iciHHV-6 and to evaluate other markers of active infection such as HHV-6 IgM or a four-fold increase in IgG antibody titers. So far none of the studies analyzing Biofire results have studied this question adequately.

Read the full article: Erba 2024