Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study
BMJ 1997; 314 doi: https://doi.org/10.1136/bmj.314.7097.1800 (Published 21 June 1997) Cite this as: BMJ 1997;314:1800
- Jacob Amir, director, day care unita,
- Liora Harel, senior physiciana,
- Zehava Smetana, directorb,
- Itzhak Varsano, directorc
- a Paediatric Ambulatory Care Unit, Golda Medical Centre, Hasharon Hospital, Petah Tiqva, Israel
- b Central Virology Laboratory, Chaim Sheba Medical Centre, Tel Hashomer, Israel
- c Department of Paediatrics C, Schneider Children's Medical Centre of Israel, Petah Tiqva, Israel
- Correspondence to: Dr J Amir Department of Paediatrics C, Schneider Children's Medical Centre of Israel, Petah Tiqva, Israel. hshmuely@post.tau.ac.il
- Accepted 10 April 1997
Abstract
Objectives: To examine the efficacy of aciclovir suspension for treating herpetic gingivostomatitis in young children.
Design: Randomised double blind placebo controlled study.
Setting: Day care unit of a tertiary paediatric hospital.
Subjects: 72 children aged 1-6 years with clinical manifestations of gingivostomatitis lasting less than 72 hours; 61 children with cultures positive for herpes simplex virus finished the study.
Main outcome measures: Duration of oral lesions, fever, eating and drinking difficulties, and viral shedding.
Intervention: Aciclovir suspension 15 mg/kg five times a day for seven days, or placebo.
Results: Children receiving aciclovir had oral lesions for a shorter period than children receiving placebo (median 4v 10 days (difference 6 days, 95% confidence interval 4.0 to 8.0)) and earlier disappearance of the following signs and symptoms: fever (1 v 3 days (2 days, 0.8 to 3.2)); extraoral lesions (lesions around the mouth but outside the oral cavity) (0 v 5.5 days (5.5 days, 1.3 to 4.7)); eating difficulties (4 v 7 days (3 days, 1.31 to 4.69)); and drinking difficulties (3 v 6 days (3 days, 1.1 to 4.9)). Viral shedding was significantly shorter in the group treated with aciclovir (1 v 5 days (4 days, 2.9 to 5.1)).
Conclusions: Oral aciclovir treatment for herpetic gingivostomatitis, started within the first three days of onset, shortens the duration of all clinical manifestations and the infectivity of affected children. Further studies are needed to evaluate the ideal dose and length of treatment.
Key messages
Herpetic gingivostomatitis is the most common clinical manifestation of primary herpes simplex virus infection in young children
The efficacy of oral aciclovir suspension was studied in a double blind placebo controlled study
All clinical symptoms and viral shedding were shorter in children receiving aciclovir than in those receiving placebo
Aciclovir was highly effective in treating children with herpetic gingivostomatitis
Introduction
Herpetic gingivostomatitis is the most common clinical manifestation of primary herpes simplex virus infection in young children. Although it is a self limiting disease, the general course is 10-14 days, and the children experience extreme discomfort and refuse to eat. If they also refuse to drink they often have to be admitted to hospital for rehydration.
Parenteral aciclovir has been shown to be effective in herpes simplex virus infections such as encephalitis,1 primary genital herpes,2 and herpes neonatorum.3 Oral aciclovir has been used successfully to treat genital herpes4 5 and recurrent herpes labialis.6 No study has shown definitively, however, that oral aciclovir is effective for primary herpes gingivostomatitis. Encouraging results have been reported in a few open studies,7 8 a small controlled study,9 and a prophylactic trial during an outbreak in a closed community.10
This randomised, double blind, placebo controlled study was designed to examine the efficacy of oral aciclovir suspension for treating herpetic gingivostomatitis in young children.
Subjects and methods
Subjects
All children aged 1-6 years of age with clinical manifestation of gingivostomatitis lasting less than 72 hours were identified by their primary pediatrician and referred to the paediatric day care unit of Hasharon Hospital, Petah Tiqva, Israel. Children seen in the emergency room of Hasharon Hospital and the Schneider Children's Medical Centre were also recruited.
After a swab from the oral lesions for viral cultures and blood for serological tests for herpes simplex virus were obtained, the children were assigned the next available study number by using a randomised number table with a block size of eight. The same numbers were on the study treatments–aciclovir suspension or placebo suspension. The placebo bottles were identical to the aciclovir bottles, and the suspension looked exactly the same with a similar smell. The aciclovir was given in a dose of 15 mg/kg (0.375 ml/kg), five times a day (up to a maximum of 200 mg per dose) for a period of seven days, and the placebo was given in the same volume, five times a day.
Written informed consent was obtained from the parents, and the study was approved by the hospital's ethics committee.
Assessment
On enrolment (day 0), a medical history was taken and physical examination performed. On clinical evaluation, fever, severity of the oral lesions, presence of extraoral skin lesions (lesions around the mouth but outside the oral cavity), drooling, and drinking and eating difficulties were noted. The oral lesions were categorised as mild (up to 10 lesions on the tongue or oral mucous membrane), moderate (11 to 20 lesions with swelling of the gums), or severe (more than 20 tongue or oral lesions and gum lesions). Drinking and eating abilities were categorised as normal, less than normal, and total inability to drink or eat.
The clinical examination was repeated on days 3, 6, and 8, the day after ending the treatment, and thereafter every two to three days if symptoms persisted. The parents recorded the child's symptoms, and the rectal temperature was measured daily until a normal reading (<38.0°C) was obtained for more than 24 hours. Compliance was measured by the volume of suspension left in the bottle. A single investigator (JA) carried out the follow up evaluation of all the children.
Laboratory investigations
On day 0, in addition to the culture and serological tests, a full blood count was performed. The viral cultures were repeated at each visit until the complete disappearance of all oral or extraoral lesions. A second sample for serological testing for herpes simplex virus was obtained between day 12 and day 16.
Culture of herpes simplex virus–The culture swabs were placed into 2 ml of transport medium,11 and the specimens were either sent immediately on ice to the Central Virology Laboratory, Tel Hashomer, or kept refrigerated overnight and sent the next day. The herpes simplex virus was isolated as described previously.12
Serotyping of herpes simplex virus with monoclonal antibodies–All isolates of herpes simplex virus were typed by fluorescence conjugate monoclonal antibodies (Syva Microtak HSV-1, HSV-2; Palo Alto, CA), according to the manufacturer's instructions.12
Serology assays–An indirect immunofluorescence antibody test was performed as described previously.13
Statistical analysis
The sample size was calculated on the assumption that the clinical symptoms of herpes simplex virus gingivostomatitis may last 5-15 days with a standard deviation of five days. On the basis of these data, we estimated that a sample size of 60 children with proved herpes simplex virus would be needed to detect a difference of 2.5-3.0 days between the treatment groups with a power of 0.80 and a significance level of 0.05. The times of disappearance of symptoms (mouth lesions, fever, external lesions, drooling, and eating and drinking difficulties) were compared by the Mann-Whitney non-parametric test. The severity scores of eating and drinking difficulties were compared by the χ2 test.
The t test was applied to compare the groups with respect to the continuous variables–that is, the difference in maximal temperature, the laboratory results (haemoglobin, polymorphonuclear cells, and lymphocytes), and the number of days to the last positive culture and to the first negative culture. Finally, Fisher's exact test was used to determine differences in the level of compliance and admission between the groups. Only children with laboratory evidence of herpes simplex virus infection (positive culture or serological result) were included in the statistical analysis for efficacy outcome, according to the protocol.
Results
Altogether, 72 children were enrolled between December 1993 and February 1995. Thirty six children were randomly allocated to receive aciclovir and 36 to receive the placebo. Ten children whose viral cultures were negative for herpes simplex virus and whose serological results remained negative during convalescence were excluded from the clinical evaluation, as was one child whose parents refused to continue with the follow up after day 2. Thus, the final study population comprised 61 children with positive cultures for herpes simplex virus; 31 children were in the group receiving aciclovir and 30 were in the placebo group.
On enrolment both groups were similar regarding demographic variables and severity of clinical symptomatology (table 1). Two children in the aciclovir group and three in the placebo group were admitted for rehydration at enrolment.
Demographic, clinical, and haematological variables at admission in 61 children in ambulatory care unit of a tertiary paediatric hospital
The children in the aciclovir group had significantly more blood lymphocytes than those in the placebo group (table 1). The other haematological variables were similar.
Efficacy outcome
Oral lesions–The oral lesions persisted for a significantly shorter time in the children receiving aciclovir than in those receiving placebo (median 4 (range 2-12) days v 10 (3-15) (table 2). At the end of treatment on day 8, two out of 31 children in the aciclovir group had oral lesions compared with 21 out of 30 in the placebo group.
Median (range) duration (in days) of clinical variables in 61 children with confirmed herpes simplex virus gingivostomatitis
Fever–The fever disappeared significantly earlier in the children in the aciclovir group than in those in the placebo group (median 1 day v 3 days (table 2).
Extraoral lesions–On day 0 about one third of the children in each group had extraoral herpetic lesions (table 1). Children in the aciclovir group did not develop new lesions after treatment had been started. Twelve of those in the placebo group, however, continued to develop extraoral lesions after the treatment had been started. The duration of the lesion was significantly shorter in the aciclovir group (median 0.0 v 5.5 days (table 2).
Eating and drinking ability–On enrolment all the children had eating and drinking difficulties. On day 8 of the treatment, in the aciclovir group two children had eating difficulties and one child had drinking difficulties, compared with 14 and 9 children respectively in the placebo group. The median duration of the eating difficulties was 4 v 7 days respectively and of drinking difficulties was 3 v 6 days respectively (table 2).
Duration of clinical variables–Table 3) represents the clinical data of all the children randomised in the study except the one child who left the study on day 2. Ten of the 71 children showed no evidence of herpes simplex virus infection. In the intention to treat analysis, the duration of all measured clinical variables was still significantly shorter in the aciclovir group than in the placebo group (table 3).
Median (range) duration (in days) of clinical variables of all enrolled children (n=72)
Hospital admission–Five children were admitted before inclusion in the study (table 1). Among the children not admitted, none treated with aciclovir was admitted after treatment was started, while three children in the placebo group were admitted for two to three days for rehydration (P=0.11).
Recurrences–Telephone screening of the enrolled children 16 months after the start of the study showed only one case of herpes labialis (in a child in the placebo group).
Viral cultures–All the cultures (positive for herpes simplex virus in all the children included in the study) were identified as type 1. The cultures were obtained every two to three days, so if a child had a positive culture on day 0 and on day 3, we assumed that he or she was positive also on days 1 and 2. According to this evaluation, the children in the aciclovir group had a significantly shorter period of positive viral culture than those in the placebo group (median (range 1-3) 1 v 5 (1-10) days) respectively (difference 4 days, 95% confidence interval 2.9 to 5.1) (table 2).
Serological examination–Serology samples were taken during the acute and convalescence phases of the infection were available for 41 children. In those with culture negative for herpes simplex virus (10 cases), the serological findings for the convalescence samples were negative. Of those included in the efficacy calculation, 18 were from the aciclovir group and 13 from the placebo group. No differences between groups in seroconversion or maximal titres of immunofluorescence antibody were observed. All children had seroconversion with titres of >64.
Compliance–Compliance was good in both groups: 29 children in the aciclovir group and 24 in the placebo group received >80% of the prescribed treatment, and the rest used 50-80% (P=0.117).
Side effects–No significant side effects were recorded in either group. Two children in each group had mild gastrointestinal symptoms that resolved spontaneously after 24 to 48 hours without a change in the study treatment.
Discussion
Treatment with oral aciclovir suspension–started during the first three days of the appearance of herpetic gingivostomatitis and continued for seven days–was shown to be significantly more effective than placebo in reducing the severity of the clinical symptoms and shortening the period of infectivity as a result of viral shedding. The beneficial effect of aciclovir was evident in all clinical variables evaluated, the healing rate of the oral and extraoral lesions, duration of the fever, and the duration of the eating and drinking difficulties. In an intention to treat analysis of all enrolled children, including those without proved herpes simplex virus infection, the difference between the treatment groups remained highly significant (table 3). No child in the aciclovir group was admitted after treatment had been started, compared with three children in the placebo group who were admitted for rehydration.
The beneficial effect of aciclovir treatment has been previously reported in an open study.7 The study showed that in children with herpetic gingivostomatitis who were treated with aciclovir, fever disappeared after the third day of treatment in all cases, concomitant with marked improvement in the oral lesions. Of the 33 children, only about 10% had oral or extraoral lesions after six days of treatment.
Herpes gingivostomatitis is a contagious disease, especially among children in closed communities or day care centres.14 15 Data regarding intrafamilial transmission are unclear.
In young children herpes simplex virus is transmitted primarily by contact with infected oral secretions. In the children treated with aciclovir, the period of viral shedding was significantly shorter than in those receiving placebo. After three days of aciclovir treatment all viral cultures became negative, compared with almost 50% positive cultures on day 6 in the placebo group, probably indicating a decrease in the infectivity of the treated children.
Recurrences of gingivostomatitis are unusual in normal hosts and are most probably related to immunity after infections. One important question is the effect of aciclovir treatment on long term immunity against herpes simplex virus. The serological data in this study, although available for only half the children, showed no difference between the aciclovir and placebo groups in the humoral immune response to the virus. The influence of the treatment on local recurrences needs long term follow up.
Concern has been expressed over the possible selection of resistant strains once aciclovir is being used for such relatively common disorders as herpetic gingivostomatitis. Most clinical isolates resistant to aciclovir have been recovered from immunocompromised patients receiving multiple treatment courses. A seven day treatment of aciclovir in normal children is unlikely therefore to create a problem. Aciclovir has been used to prevent recurrent genital herpes for more than six years, and no resistant strains have been isolated.16
The clinical manifestation of herpetic gingivostomatitis varies from a mild illness to a severe course with admission to hospital. In the placebo group (n=30), which represented the natural course of herpetic gingivostomatitis, oral lesions were found in 25 children for seven days or more, and eating and drinking difficulties in 16 (data not shown). During this period, the sick children were unable to attend day care or kindergarten. Although this study did not attempt to address the economic issue of aciclovir treatment in gingivostomatitis, the significant reduction in the duration of illness and the prevention of admission are likely to allow children and parents to return to their normal life earlier, a benefit that may balance the price of the treatment.
Acknowledgments
Funding: The study was partially funded by the Wellcome Foundation, London.
Conflict of interest: None.