“Natural History of Neonatal Herpes Simplex Virus Infections in the Acyclovir Era”  (2001) by David W. Kimberlin, Chin-Yu Lin, Richard F. Jacobs, Dwight A. Powell, Lisa M. Frenkel, William C. Gruber, Mobeen Rathore, John S. Bradley, Pamela S. Diaz, et al.

In 2001, David Kimberlin and colleagues published “Natural History of Neonatal Herpes Simplex Virus Infections in Acyclovir Era,” hereafter, “Natural History of Herpes,” in the journal Pediatrics. In the article, the researchers explore the natural history of herpes, which entails asking how herpes simplex virus, or HSV, progresses in infants when treated with acyclovir, one of the first antiviral medications that effectively treated HSV in adults. HSV can cause painful lesions on the mouth or genitals. When infants contract HSV, it can cause life-threatening illness, including skin lesions, blindness, developmental delays, and often death. At the time of publication, researchers and physicians had evidence that acyclovir could effectively treat neonatal HSV, but physicians still struggled to address the condition quickly enough to improve treatment outcomes. “Natural History of Herpes” presents an updated picture, as of 2001, of how HSV progresses to provide physicians with quicker ways to identify the condition in neonates, who frequently contract the disease from their mothers in utero or during labor and delivery.

1. Background and Context
2. Article Roadmap
3. Detailed Contents
4. Study Impact

Background and Context

At the time of publication, most of the authors of “Natural History of Herpes” were a part of the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group, or CASG. CASG is a large research group that spans multiple institutions and that receives funding from the United States National Institutes of Health, or NIH. CASG has been studying treatments for viral diseases, such as those caused by HSV, since the 1970s and is still active as of 2024. Some of the authors of “Natural History of Herpes” were associated with other academic and medical institutions such as the University of Alabama-Birmingham or UAB, in Birmingham, Alabama, where the CASG headquarters are, the University of Arkansas in Little Rock, Arkansas, Ohio State University in Columbus, Ohio, and the University of Washington, in Seattle, Washington, and other institutions. Most of the researchers that published “Natural History of Herpes” were pediatric infectious disease physicians. Kimberlin, the leading author, was a pediatric infectious disease physician at UAB at the time of publication. As of 2024, Kimberlin is the Principal Investigator of the CASG and is also the Co-Director of Division of Pediatric Infectious Diseases at UAB.

“Natural History of Herpes” analyzes data previously collected from two clinical trials that CASG conducted in the 1980s and 1990s that sought to establish an effective treatment for neonatal HSV. At that time in the twentieth century, neonatal HSV had an extremely high death rate even when treated with antiviral medication. Researchers did know that beginning treatment in neonates as early as possible positively affected the outcomes. Kimberlin and colleagues use data from two clinical trials to understand how the disease progressed in neonates receiving antiviral treatments and identify ways that physicians could quickly identify HSV in neonates to initiate treatment.

The first clinical trial Kimberlin and colleagues review is a study CASG conducted in 1991 titled “A Controlled Trial Comparing Vidarabine with Acyclovir in Neonatal Herpes Simplex Virus Infections,” in the New England Journal of Medicine with Richard Whitley as the leading author. Whitley is a physician and researcher at UAB, conducting infectious disease research as a member of CASG since the 1970s, and is Co-Director of Division of Pediatric Infectious Diseases at UAB as of 2024. In that article, the researchers report that during a clinical trial from 1981 to 1988, there was no difference in the mortality and morbidity of neonates treated with acyclovir versus neonates treated with vidarabine, another antiviral medication that stops herpesviruses from synthesizing viral DNA and replicating. Mortality refers to the number of deaths caused by a disease, while morbidity denotes the state of being ill or experiencing symptoms of a disease.

The second study Kimberlin and colleagues review is a CASG trial from 2001 titled “Safety and Efficacy of High-Dose Intravenous Acyclovir in the Management of Neonatal Herpes Simplex Virus Infections,” which appeared in the journal Pediatrics with Kimberlin as the leading author. That article details the results of a clinical trial that ran from 1989 to 1997, in which researchers found that high dose acyclovir is safe to use to treat neonatal HSV and increases the survival rate of certain neonates with HSV. The findings of both Whitley and Kimberlin’s articles established the safety and efficacy of both vidarabine and acyclovir as treatments for neonatal HSV infections. The methods were largely the same. However, the researchers in Kimberlin’s trial provided the participants with intermediate or high doses of acyclovir, while in Whitley’s trial, researchers gave the participants only a standardized dose of either acyclovir or vidarabine. Also, in Kimberlin’s trial, the researchers specifically enrolled patients with certain types of HSV infections. Kimberlin and colleagues used the data from those trials to identify patterns in the progression of HSV in neonates enrolled in Whitley and Kimberlin’s prior trials in relation to the dose of acyclovir they received and how quickly they received it, among other factors. The authors then use those patterns to make conclusions about the natural history of HSV when treated with acyclovir, to aid in the development of medical strategies to care for neonates with HSV.

Article Roadmap

Kimberlin and colleagues divide “Natural History of Herpes” into four sections. In the first section, an unlabeled introduction, the researchers explain that understanding the natural history of HSV allows medical providers to quickly recognize signs of HSV infection in neonates to improve treatment outcomes, and they show that their study’s findings update the community’s knowledge of the natural history of the virus. Next, in “Methods,” the authors explain that the data they used came from the aforementioned CASG clinical trials, and the methods used in both clinical trials were the same except for medication dosages. After that, in “Results,” Kimberlin and colleagues share the results of their study in several tables and charts, noting that the average time it took physicians to notice physical symptoms of HSV in neonates did not change at all over the course of two decades from the beginning of Whitley’s trial to the end of Kimberlin’s trial. The authors of “Natural History of Herpes” conclude with the section “Discussion,” in which the authors state their sample size was too small for them to draw definitive conclusions about neonatal HSV, but they argue that the disease outcomes for neonates with HSV likely will not improve until physicians can quickly recognize and begin treatment in neonates, thus, they call for more research on the topic.

Detailed Contents

In the unlabeled introduction of “Natural History of Herpes,” the researchers begin by stating that the introduction of effective antiviral medications in late 1970s dramatically changed the way medical providers treat neonatal HSV infections. They explain that, historically, physicians used vidarabine and then transitioned to using acyclovir to treat neonatal HSV, and those antiviral medications improved the outcomes of neonates with herpes infections. Then the authors go on to explain that in the years leading up to the publication, other researchers had given patients higher doses of acyclovir given for longer periods of time, and that improved the outcomes of neonates with HSV. So, at the time of publication, more neonates were surviving than in decades prior, but researchers were still seeking to decrease the death rate among neonates with HSV.

Continuing in the introduction, Kimberlin and colleagues then go on to explain that in order to maximize the benefits of antiviral therapy, patients must receive treatment before the virus starts to replicate in the central nervous system, or CNS, and before it disseminates, or spreads systemically. The authors then emphasize that understanding the natural history of neonatal HSV allows for early initiation of treatment by providing the framework needed to quickly recognize HSV in a neonate. They further state that the data they present in their article provides an update to the body of knowledge regarding the natural history of HSV, such as how the disease progresses and outward signs of progression, which had not been updated since Whitley and team published an article about the natural history in the Journal of Infectious Disease in 1988. The introduction concludes with a list of the topics the authors will address in their study, including written descriptions of HSV presentation, associations with adverse outcomes, and shortcomings of the study.

The next section, “Methods,” describes the procedures that the authors used for their own research. First, Kimberlin and colleagues distinguish between the three clinical groupings used in both Whitley and Kimberlin’s prior clinical trials. They explain that researchers in both clinical trials classified the participants as having SEM disease, CNS disease, or disseminated infection. SEM disease describes cases of HSV infection limited to the skin, eyes, or mouth. CNS disease refers to the inflammation of the brain, and it may or may not also include skin infection. Disseminated disease describes cases where the virus has spread to multiple organ systems, which can include the CNS, skin, and all other organ systems.

Continuing in “Methods,” the authors note that they used the same standardized form to document information about the neonates participating in both the clinical trials. Researchers in the previous trials used the form to collect information about participant demographics, symptoms, disease progression, and follow-up visits. The authors also clarify that during follow-up visits, researchers categorized patients as either having normal development, being impaired but able to live at home, being institutionalized, or deceased. Kimberlin and colleagues also use the “Methods” to explain that in the previous trials, researchers collected throat swabs, cerebrospinal fluid, conjunctival samples, and fluid samples from skin lesions to diagnose patients with HSV and identify what type of HSV each patient had. Finally, they explain the mathematical models they used to calculate the statistical relationships discovered in the study.

In the following section, “Results,” the authors provide a description of the trials’ participants, and they include two tables that display the demographics of the participants and changes in the participants characteristics between Kimberlin’s and Whitley’s clinical trials. They describe 186 participants in total between the two trials, 107 participants in Whitley’s trial and 79 participants in Kimberlin’s trial. The authors take care to distinguish that during the earlier trial researchers gave all the neonates a standard dose of acyclovir but gave those in the later trial either an intermediate dose of acyclovir or a high dose of acyclovir. The results section also includes two figures where the authors organize participant demographics. Table 1 is a two-column chart with two categories, characteristic and number/percentage. Immediately following that figure is Table 2, a chart that denotes the number of premature newborns in each trial, mean age at enrollment in the trial, and mean time between first symptom and initiation of treatment. The researchers split those statistics by SEM, CNS, or disseminated type. They emphasize that thirty-five percent of the participants were born prematurely, and the average age of the neonates in the trials was 37.8 weeks. They also note that nine percent of the neonates in the trials began displaying signs and symptoms of herpes infection within twenty-four hours of birth, thus leading the researchers to believe that those neonates contracted HSV in utero. The researchers go on to point out that the average time between the development of symptoms and first dose of antiviral therapy did not change significantly between the two trials.

The authors also include a third table in the results section that details the types of symptoms that trial participants had and how long the symptoms lasted, and highlights that skin lesions were the most common symptom among neonates with SEM, CNS, and disseminated HSV alike. From that table, the authors highlight that the presence of skin lesions in neonates with SEM, CNS, or disseminated HSV is the most frequent indicator of herpes infection in neonates. Though researchers knew that starting treatment early improves the neonate’s outcomes when “Natural History of Herpes” was published, Kimberlin and colleagues found that over the course of almost twenty years when Whitley and Kimberlin’s clinical trials took place, physicians were not able to begin treatment any quicker after neonates first showed physical symptoms of HSV.

Using a fourth chart, the authors describe the number of trial participants who experienced skin vesicles before and during antiviral treatment. They pay special attention to the skin vesicle symptom given that it is the most easily observed symptom. Almost all neonates with SEM developed lesions before enrollment or during enrollment and treatment. The authors are careful to note that most patients with lesions had observable vesicles before trial enrollment and developed new lesions during treatment. However, the authors also stated that seventeen to thirty-nine percent of all participants never experienced lesions at any point in their illness.

Next, the research team discusses the mortality rates of neonates twelve months after being enrolled in the trials. They state that no participants with SEM died in either trial, so researchers came to their conclusions about mortality using data from patients with CNS or disseminated disease. Six participants, or fifteen percent, with CNS died during the trials, as well as nine participants, or sixty-nine percent, with disseminated HSV caused by HSV-1. Sixteen participants, or forty-seven percent, with disseminated HSV caused by HSV-2 died during the trials. HSV-1 and HSV-2 are the two types of HSV, which cause lesions on the mouth and genitals, respectively. The authors then go on to explain that mortality in neonates with CNS is associated with premature birth and seizures at the beginning of treatment. Mortality among neonates with disseminated HSV treated with the standard dose of acyclovir is associated with lethargy at the beginning of treatment and increased levels of a liver enzyme.

The researchers finish the results section by examining participants’ morbidity at twelve months of age to understand how HSV had impacted the participants’ development, especially as it related to when the participant began treatment and the symptoms they had. They note that in the surviving participants, researchers documented ninety-eight percent of those who had SEM as having normal development at twelve months old. The authors then compared that to neonates with CNS, among whom only thirty percent had normal development at twelve months old, and seventy-five percent of neonates with disseminated HSV had normal development at twelve months. Then the authors clarify how the participants’ clinical presentations of HSV were associated with their likelihood of having normal development at their twelve month follow up. Kimberlin and colleagues found that for those neonates with CNS and disseminated HSV, having experienced seizures when beginning antiviral therapy increased their likelihood of having abnormal development at twelve months. 

Finally, the researchers conclude the article with the section “Discussion” in which they declare that the morbidity and mortality of neonatal HSV will likely not improve until more research is done. The authors begin the section by pointing out that the physicians in the trials were not able to identify neonatal HSV and initiate treatment quicker in the twenty years that passed during Whitley and Kimberlin’s trials. That led the authors to conclude that there will be no reduction in the morbidity and mortality of neonatal HSV until the researchers are able to uncover a way to reduce the time between first symptoms and initiation of treatment. After that statement, the authors recommend that clinicians should consider HSV as a possible diagnosis for sick infants younger that one month old. They elaborate, stating that as soon as neonates demonstrate signs and symptoms of HSV, such as skin lesions, providers should order appropriate diagnostic tests and begin treatment with acyclovir. The authors do not recommend adding acyclovir to the list of standard antibiotics to avoid sepsis until doctors can confirm that the newborn has HSV.

Kimberlin and colleagues also present the shortcomings of the study in the discussion section and argue that there is a need for further research to determine easily identifiable symptoms of neonatal herpes so physicians can diagnose the condition more rapidly. The researchers explain that the small sample size of the trial population means that they cannot state there is a definite relationship between virus type and disease outcome. They then state that there needs to be more research into neonatal herpes to find a method to quickly identify HSV infections in neonates and initiate treatment. Finally, the research team concludes by stating that increasing awareness of HSV among clinicians and utilizing diagnostic tests can improve neonatal HSV outcomes presently.

Study Impact

As of 2024, “Natural History of Herpes” has been cited 562 times according to Google Scholar. The findings of “Natural History of Herpes” helped CASG advance their understanding of neonatal herpes interventions and the natural history of HSV. Kimberlin cited “Natural History of Herpes” in numerous publications about the clinical treatment of neonatal HSV. For example, in 2018, Kimberlin and fellow physician Swetha Pinninti published a review article in the journal Seminars in Pathology, where they explain that HSV can be transmitted from mother to child. They cite “Natural History of Herpes” as a source to explain that approximately forty percent of neonates with HSV do not present with skin lesions, the most easily identifiable symptom. In 2003, a group of researchers published an article in the Journal of the American Medical Association in which they note that performing C-sections in women with HSV reduces neonatal HSV infection rates. The authors of that article referenced “Natural History of Herpes” to explain that despite the existence of antiviral medication, neonatal HSV is still extremely deadly and there has been little scientific progress to reduce the amount of time to diagnosis and treatment initiation. “Natural History of Herpes” documented the natural history of neonatal HSV during a time period when researchers and physicians had made little progress to improve patient outcomes, and it raised awareness of the condition, encouraging future research.