Results from this study showed that fever remained the most common clinical symptom in children with PHGS. The duration of fever in children with other virus-induced diseases usually ranged from two to four days, while children with PHGS would suffer for a longer fever duration [16,17]. In this study, the average fever duration was 5 days and more than 20% of the patients even had a fever duration longer than 7 days.
In this series, only 35% of the cases were diagnosed with PHGS at the time of admission. Most of the cases not diagnosed early were considered to be herpangina/HFMD (due to enteroviral infection) initially. In general pediatric practice, it is believed that HSV-related infection would cause vesicles and/or ulcers in the perioral region and anterior oral cavity [18-20]. On the contrary, the oral lesions of herpangina and HFMD typically located at the posterior oral cavity region, such as the anterior pillars of the fauces, soft palate, tonsils, and uvula, presented as hyperemic vesicles and/or ulcers. However, coxsackievirus A6, a specific serotype of enterovirus, could result in so-called atypical HFMD with clinical manifestations of perioral vesicles and more devastating skin lesions such as onychomadesis and even Stevens-Johnson syndrome since 2008 [21,22]. In this series, we found the oral ulcers in PHGS could be equally resided in both the anterior and posterior parts of oral cavity. Compared with the patients in the Early Diagnosis group, the patients in both the Late and Other Diagnosis groups had a significantly lower rate of the presentation of both stomatitis lesions over the anterior oral cavity and gingivitis at the time of admission. The presentation of both lesions reached a comparable rate during hospitalization in the patients in the Late Diagnosis group while still significantly lower in the patients in Other Diagnosis group. These findings suggest that both the stomatitis lesions over the anterior part of the oral cavity and gingivitis are key features for a clinical diagnosis of PHGS. A case of PHGS may manifest stomatitis lesions over the posterior part of the oral cavity first, which may be misdiagnosed as herpangina caused by enterovirus, and then the stomatitis lesions may extend to the anterior part of oral cavity and the presentation of gingivitis may occur, which leads to the diagnosis of PHGS. For those without the presentation of both lesions, a clinical diagnosis of PHGS would be not considered and not made on most occasions. It is not impossible that some cases might indeed present both lesions but were missed by the clinicians and subsequently undiagnosed.
Only a few cases of PHGS in this series had complications such as CNS dysfunction, compared to certain serotype of enterovirus, such as enterovirus D68 and enterovirus A71, which may lead to fatal viral meningitis or encephalitis and result in limb paralysis or mortality [23,24].
C-reactive protein (CRP), a laboratory test, is often used as a reference biomarker to distinguish bacterial (higher level) from viral (lower level) infections, though inconclusively. Nevet et al  reported that a high value of CRP was commonly seen in pediatric patients with PHGS and the average value of 66 patients in their study was up to 74 mg/L, with more than one-third of the patients having a value > 70 mg/L. In the current study, along with leukocytosis, a higher serum CRP level > 40 mg/L (normal, < 5 mg/L) was found in around 30% of the cases. High values of CRP are prevalent in patients with primary herpetic gingivostomatitis, similar to adenoviral infections and some bacterial infections. In contrast, for enteroviral infection, a retrospective study including 3566 children with a diagnosis of either herpangina or HFMD in Taiwan revealed that three quarters of the cases had a CRP level < 40 mg/L while only 6% cases had a CRP level > 80 mg/L . CRP levels in patients infected with different serotypes of enteroviruses may vary from a normal level to a higher level. For example, an average CRP level was 9 mg/L for children with enterovirus-A71 infection while the average level was up to 77 mg/L for children infected with coxsackievirus A2 . Other studies also showed the different CRP levels in children infected with different enterovirus serotypes [21, 28-30]. These findings suggest that a CRP level is not reliable to distinguish PHGS from both bacterial and enteroviral pharyngitis.
Some studies indicated that administration of oral acyclovir within 72 to 96 hours after disease onset can effectively reduce the duration of fever, oral ulcers, and food intake difficulty in children with PHGS [31-33]. Half of the cases in this study received acyclovir treatment. However, the administration of acyclovir treatment, whether within 72 hours of fever onset or not, had no significant beneficial influence on either the duration of fever or the length of hospital stay. Since this was a retrospective study, the exact timing and dosing of acyclovir therapy as well as the healing of oral ulcers and the amount of food intake might not be meticulously evaluated and recorded and subsequently led to a negative result of the effect of acyclovir therapy.
In this series, 41 (22.2%) patients, especially those in the Other Diagnosis group, received antibiotic treatment for more than 3 days during hospitalization, though there was no evidence of bacterial infection. Again, judicious usage of antibiotics cannot be overemphasized. Recognizing that children with PHGS may manifest prolonged high fever, leukocytosis, and a high serum CRP level that mimics bacterial infections may help clinicians to avoid the unnecessary prescription of antibiotics.
There are several limitations in this study. First, as a retrospective study, there were “inherent” drawbacks. Not all clinical information and laboratory data could be collected by chart review and some confounding bias could not be avoided due to different judgments of clinical physicians. Second, we did not check serum IgG and IgM against HSV, which can distinguish primary infection from reactivation. However, in this study, we tried to identify and include PHGS cases for final analysis as possibly as we can. Because most primary HSV-1 infection presents with oral manifestations [34,35], we excluded 97 cases without oral manifestations, who accounted for more than one-third of the initial HSV-positive patients and might be probable HSV-reactivated cases, for final analysis. Third, we already excluded those co-infected with other bacteria and viruses; however, throat swab for group A streptococcus was not performed for each case to exclude the possibility of such infection and the possibility of co-infection with other viruses could not be totally excluded. Since only virus isolation using tissue culture was applied in this study, the viruses which cannot present CPE in the selected cell lines, such as coronavirus, human metapneumovirus, human bocavirus etc., would be missed. This could explain that there were still some cases present with symptoms of upper respiratory tract infection in this study.