In October 1939, the world was on fire. Nazi Germany had invaded Poland on September 1, and 2 days later Great Britain and France declared war on Germany. The war on the western front was hot, but, initially at least, all was quiet on the eastern front. During those tumultuous first months of the Second World War, it was unclear what Russia’s involvement would be. On October 1, 1939, British Prime Minister Winston Churchill delivered one of his most famous quotations during a radio broadcast on the BBC: “I cannot forecast to you the action of Russia. It is a riddle, wrapped in a mystery, inside an enigma.” Although obviously very different from global war, herpes simplex virus (HSV) also is a riddle, wrapped in a mystery, inside an enigma. The virus can be devastatingly brutal to the body of a neonate who acquires the virus at the time of delivery, but it also is exceedingly rare, occurring in only 1 in roughly 2000 deliveries.1 We have powerful molecular testing tools that can identify minute amounts of HSV DNA, technologies that have revolutionized our diagnostic capabilities for neonatal HSV2 but that also can be prone to false-positive results given how commonly HSV-1 is shed in the oral cavity (including among people who work in molecular diagnostic laboratories).3 Neonatal HSV cases require 2 to 3 weeks of hospitalization for their initial treatment,4 so it is critical that the appropriate neonates at higher actual risk for this rare infection are evaluated, thereby improving the likelihood that a positive test reflects a true-positive result.
Over the 9 decades since neonatal HSV was first described,5,6 risk factors for acquisition of neonatal disease have been explored extensively.7–11 What has been missing until now, however, was a risk assessment tool with which this information could be applied to the assessment of neonates in the pediatrician’s office or the emergency department. This is the gap that Cruz et al have made a substantial contribution toward narrowing in their article in this issue of the journal.12 By conducting a case-control study across 23 medical centers over 9 years, this dedicated study group identified essentially the same risk factors as previously recognized but then did something novel and potentially groundbreaking: they assigned points to the risk factors on the basis of the estimated effect size from their regression modeling and then probed the resulting risk score for breakpoints that could predict which neonates were more likely or less likely to have what they termed “invasive neonatal HSV infection,” meaning neonatal HSV central nervous system (CNS) disease or disseminated disease but not including neonatal HSV skin, eye, and mouth (SEM) disease, which is the largest category of neonatal herpes infection. By using a risk score breakpoint of ≥3, 2 of 41 (4.9%) of infants with invasive HSV infection were misclassified as low risk, whereas 401 of 689 (58%) of infants without invasive HSV infection were misclassified as high risk. The most important application of this tool, however, is likely to be its inverse: in this study, a score of 0, 1, or 2 correlates with a very low risk for invasive neonatal HSV infection and hence identifies patients who do not need to be assessed for HSV infection.
Despite this likely significant advance that this research provides, the authors are correct to note that external validation of the scoring system is required before it should be used clinically. Subsequent assessment of how or when to use this tool should include consideration of 2 main weaknesses of the current scoring system. First, the risk score is only for young infants with neonatal HSV CNS disease and disseminated disease. This completely leaves out the largest group of infected neonates who are classified as having SEM disease. In the Cruz data set, 40% of neonates with HSV infection were classified as having SEM disease.12 This is remarkably similar to the 40% to 45% proportion that has previously been reported.13 Importantly, however, when neonatal HSV SEM disease is missed it oftentimes will progress to disseminated disease,13 so any scoring system to determine who should be evaluated for neonatal HSV disease must be comprehensive in scope and include all 3 manifestations of neonatal HSV infection, namely disseminated disease, CNS disease, and SEM disease. Second, the risk score as currently developed is likely to be too sensitive: that is, to trigger an assessment for neonatal HSV too easily. Assuming that the risk score is used for neonates presenting to emergency departments, consider that all neonates presenting to an ED at <14 days of age will receive 3 points in the current risk score and therefore be considered at high risk for neonatal HSV invasive disease. This includes a 3-day-old with previously unrecognized congenital heart disease presenting as the patent ductus arteriosus closes, a 5-day-old with neonatal jaundice, and an 8-day-old with colic. Given the rarity of neonatal HSV, as reflected in the fact that it took this group of 23 large international study sites almost a decade to identify 90 patients who actually had neonatal HSV CNS or disseminated disease, committing every neonate <14 days of age to a workup for neonatal HSV infection is excessive.
So where does this leave us? The work of Cruz et al undoubtedly is an advance. We now have a risk score that can identify neonates who are at extremely low risk of neonatal HSV invasive disease, albeit one that is incomplete (leaves out SEM patients) and too sensitive (considers every infant <2 weeks of age as being at high risk of neonatal HSV invasive disease). Undoubtedly, revisions to this will be needed, and it most certainly is not ready for routine clinical use at this time. But Cruz et al are to be commended for accomplishing what those of us in the field have been unable to do for decades. They have significantly advanced the field, and although neonatal HSV is still an enigma, it now is perhaps a bit less of a mystery.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2021-050052.
POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.