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Acyclovir for treating primary herpetic gingivostomatitis (Review)

Primary herpetic gingivostomatitis is a highly contagious infection of the oral cavity which is caused by the herpes simplex virus. It is prevalent in children and young adolescents and sometimes can cause uncomfortable symptoms including eating and drinking difficulties and even life-threatening inflammation of the brain (encephalitis).

Background

Primary herpetic gingivostomatitis (PHG) is an infection of the oral cavity which is caused by the herpes simplex virus (HSV). It is highly contagious, typically affects children but can also occur in adults, and has a high rate of recurrence of infection (Chauvin 2002; Kolokotronis 2006). Symptoms may vary widely from mild discomfort to life-threatening encephalitis (Amir 2001). Only about 5% to 10% of patients initially infected with the herpes simplex virus develop clinical lesions. This is referred to as primary herpetic gingivostomatitis.

Aetiology and prevalence

Many patients may remain undiagnosed because they are either asymptomatic or have mild symptoms (Amir 2001). Ninety per cent of Americans are said to have HSV-1 serumantibodies (Siegel 2002). The herpes simplex virus is a double-strandedDNA virus of which the HSV-1 type is responsible for oral, facial and ocular infections including primary herpetic gingivostomatitis. Although HSV-2 is primarily responsible for most genital and cutaneous lower body herpetic lesions, it can also be the cause of primary herpetic gingivostomatitis. The peak periods of PHG incidence are between the ages of 6 months and 5 years, and in young adults who are in their early 20s (Amir 1997a). Although the virus is short lived on external surfaces it can readily disrupt the integrity of skin or mucous membranes and viral replication occurs as soon as it penetrates the epithelial cell. It is at a later stage that the virus travels along the sensory nerve endings to the corresponding nerve ganglion (i.e. trigeminal ganglion) where it enters a latent phase and can remain dormant until it is reactivated either spontaneously or by one or another of a number of stimulants (e.g. infection, ultraviolet light, fever, cold) (Chauvin Acyclovir for treating primary herpetic gingivostomatitis 
As the infection is highly contagious most patients acquire it through direct contact (e.g. skin or via infected secretions (e.g. saliva)). It can spread rapidly in a closed community setting such as a daycare nursery or orphanage. Therefore, factors such as location and socio-economic status can influence the rate of HSV- 1 infection and it has been noted that individuals in developing countries and from lower socio-economic groups become HSV-1 seropositive at an earlier age than individuals from developed countries (Amir 2001; Chauvin 2002; Kolokotronis 2006)

Symptoms

Primary herpetic gingivostomatitis is characterised by a sudden onset and with the severity of symptoms related to the virulence of the HSV and the host’s immune response (Chauvin 2002).
Non-specific symptoms may include cervical lymphadenopathy, malaise and low grade fever, and can occur in the absence of any discrete clinical lesions. The general course of PHG infection is 10 to 14 days which is usually preceded by an incubation period of 1 to 26 days (Faden 2006; Kolokotronis 2006).
Primary herpetic gingivostomatitis can include oral as well as extraoral lesions, swollen and bleeding gums, and symptoms such as pain, fever, irritability, malaise, headache and upper respiratory tract infection.
The oral lesions in PHG may start as vesicles on the tongue and the buccal and gingival mucosa, and which rapidly rupture to become ulcers. The ulcers, which are usually 1 to 3 mm in size,
may subsequently enlarge to form a large ulcerated area covered by a yellowish-greymembrane. In some patients, especially adults, the gingivae (gums) may also become swollen. Healing generally occurs without scarring.
During the acute phase of PHG many children may refuse to eat or drink because of the discomfort and pain from these lesions and consequently become rapidly dehydrated. Extraoral lesions (herpes labialis), which appear as erythematous papules on the vermilion border and adjacent skin of the lips, may accompany PHG (Kolokotronis 2006).
Complications are rare but do occur and usually as a result of viral shedding, and it is at this stage that HSV infection becomes readily transmittable. During this phase with its high risk of direct transmission, eye infections (ocular herpes or herpetic keratoconjunctivitis) and infections of the digits (herpetic whitlow) are not infrequent complications. After the primary infection, the virus may become dormant but can be readily reactivated producing episodic bouts of recurrent infection which are generally considered to be less severe than the primary infection.

Diagnosis

This is usually made by clinical presentation and history. In addition, the diagnosis may be confirmed via laboratory tests: serological assays (anti-HSV IgM and IgG), the Tzanck test and immunofluorescence, but the culture of viral isolates is still considered to be the gold standard (Neville 2002).
The differential diagnosis of primary herpetic gingivostomatitis includes acute necrotizing ulcerative gingivitis, herpangina, aphthous stomatitis, candidiasis of the mouth, Steven-Johnson syndrome and hand, foot and mouth disease (Amir 2001; Chauvin 2002).

Treatment options

Individuals with symptoms such as pain, fever, and dehydration may seek treatment (Amir 2001) including rehydration, analgesics and oral lavage. Systemic analgesics (acetaminophen) may be adequate to manage the associated pain but topical applications of diphenhydramine and Maalox, Kaopectate, viscous lidocaine are
also frequently prescribed. 
Reduction of viral replication by using antivirals may shorten the acute phase of the illness, relieve symptoms, stop the virus from going into the latent phase and possibly prevent future recurrence (Siegel 2002). A known selective inhibitor of replicating HSV is acyclovir which is widely used for different forms of HSV infections.

Antiviral therapy and acyclovir

Acyclovir, in either oral or topical form, is used fairly routinely for HSV infections (e.g. herpes encephalitis, neonatal herpes, primary herpes genitalis and recurrent herpes labialis) (Amir 2001).One of the limitations of acyclovir is its poor gastrointestinal absorption and bioavailability and therefore derivatives (e.g. valacyclovir and famciclovir) have been developed with an apparently increased bioavailability but these are not currently available as paediatric suspensions.
A number of studies on the efficacy of acyclovir for treating primary herpetic gingivostomatitis have shown promising results and this systematic review sought to assess the available evidence.

Objectives

The objective of this review was to provide reliable evidence regarding the effectiveness of systemic acyclovir versus placebo or no treatment for primary herpetic gingivostomatitis.

The following null hypothesis was tested: there is no difference between acyclovir and placebo or no intervention for the treatment of primary herpetic gingivostomatitis against the alternative hypothesis of a difference.

Discussion

Primary herpetic gingivostomatitis (PHG) is the most commonly observed clinical manifestation of primary herpes simplex infection and can produce a range of symptoms (e.g. pain, drooling) in addition to difficulties with eating and drinking. Acyclovir is frequently prescribed for PHG and is presumed to be effective at decreasing symptoms as a result of its capability of reducing viral shedding.
This review sought high level evidence for the effectiveness of systemic acyclovir versus placebo or no treatment for primary herpetic gingivostomatitis but found only two eligible studies, one of which (Ducoulombier 1988) provided very limited data on the outcomes of interest and was not consistent in the reporting of its results. It was also unclear to what extent the participants adhered to the treatment reported in the study.
Although some of the limitations and side effects of acyclovir (i.e. poor gastrointestinal absorption and bioavailability), have been previously reported, none of the included studies in this review illustrated any significant side effects.Mild gastrointestinal symptoms were reported in one of the included studies (Amir 1997b) but these resolved spontaneously after 48 hours.
Whilst recognising the clinical heterogeneity, the methodological limitations, the incompleteness of data and the likelihood of bias and uncertainties in respect of outcomes assessment in both of these studies, we have nevertheless chosen to include them but advise caution in the interpretation of their results.

Author's Conclusions

Implications for practice

Out of the two trials in this systematic review, only one was able to provide some weak evidence that acyclovir is an effective treatment in reducing the number of oral lesions, preventing the development of new extraoral lesions, decreasing the number of individuals with difficulties experienced in eating and drinking and of those who are admitted to hospital for children under the age of 6 with primary herpetic gingivostomatitis.

Implications for research

The results of this systematic review confirm the necessity for further larger sample, methodologically sound trials that are reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement (www.consort-statement.org/) and provide means and standard deviations for important outcomes measurements.

To helpminimise the effects of systematic bias in outcomes assessment, it would be prudent if in future trials the trialists are not included as evaluators of outcomes and that appropriate training is given to independent assessors to ensure standardisation of criteria to be used in any outcomes assessments.

The two included studies only provided data on children under 6 years of age and there is therefore a requirement for trials to be conducted on patients in other age groups. Moreover, to enable patients and carers to make better healthcare decisions it would be beneficial if patient-reported outcomes (i.e. quality of life and patient satisfaction) were included in future trials.

References

References to studies included in this review

Amir 1997b {published data only}
Amir J, Harel L, Smetana Z, Varsano I. Treatment of herpes simplex gingivostomatitis with aciclovir in children: a randomised double blind placebo controlled study. BMJ 1997;314(7097):1800–3.

Ducoulombier 1988 {published data only}
Ducoulombier H, Cousin J, Dewilde A, Lancrenon S, Renaudie M, Steru D, et al.Herpetic stomatitis-gingivitis in children: controlled trial of acyclovir versus placebo [La stomato–gingivite herpetique de l’enfant: essai controle aciclovir versus placebo]. Annales de Pédiatrie 1988;35(3):212–6.

References to studies excluded from this review

Amir 1997a {published data only}
Amir J, Harel L, Smetana H, Varsano I. Aciclovir for herpetic gingivostomatitis in children. New Zealand Medical Journal 1997; 110(1053):369.

Amir 2001 {published data only}
Amir J. Clinical aspects and antiviral therapy in primary herpetic gingivostomatitis. Paediatric Drugs 2001;3(8):593–7.

Amir 2002 {published data only}
Amir J. Primary herpetic gingivostomatitis--clinical aspects and anti-viral treatment. Harefuah 2002;141(1):81–4.

Jacobs 1998 {published data only}
Jacobs RF. Neonatal herpes simplex virus infections. Seminars in Perinatology 1998;22(1):64–71.

Madigosky 2004 {published data only}
Madigosky WS, Meadows S, McCormack O. Clinical inquiries. Does acyclovir help herpes simplex virus cold sores if treatment is delayed?. The Journal of Family Practice 2004;53(11):923–4.

Mennemeyer 1997 {published data only}
Mennemeyer ST, Cyr LP, Whitley RJ. Antiviral therapy for neonatal herpes simplex virus: a cost-effectiveness analysis. The American Journal of Managed Care 1997;3(10):1551–8.

Yarom 2006 {published data only}
Yarom N, Buchner A, Dayan D. Herpes simplex infection--Part II: Management of HSV infections. Refuat Hapeh Vehashinayim 2006; 23(2):6–13.

Zhilina 1976 {published data only}
Zhilina VV, Medvedeva II, Maksimova ZhI, Novikova NI. Effectiveness of the overall treatment of acute herpetic stomatitis in children. Stomatologiia 1976;55(5):78–82.

Additional references

Chauvin 2002
Chauvin PJ, Ajar AH. Acute herpetic gingivostomatitis in adults: a review of 13 cases, including diagnosis and management. Journal of the Canadian Dental Association 2002;68(4):247–51.

Egger 1997
Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315(7109): 629–34.

Faden 2006
Faden H. Management of primary herpetic gingivostomatitis in young children. Pediatric Emergency Care 2006;22(4):268–9.

Higgins 2008
Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions version 5.0.0 (updated February 2008). The Cochrane Collaboration 2008. Available
from www.cochrane–handbook.org.

Kolokotronis 2006
Kolokotronis A, Doumas S. Herpes simplex virus infection, with particular reference to the progression and complications of primary herpetic gingivostomatitis. Clinical Microbiology and
Infection 2006;12(3):202–11.

Neville 2002
Neville BW, Damm DD, Allen CM, Bouqout JE. Viral infections. Oral and maxillofacial pathology. 2nd Edition. Philadelphia: WB Saunders Co, 2002:213–20.

RevMan 2008
The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2008.

Siegel 2002
Siegel MA. Diagnosis and management of recurrent herpes simplex infections. Journal of the American Dental Association 2002;133(9): 1245–9.  Indicates the major publication for the study
 


Comments

good review

Posted by Christopher Cumming - 11.52am 27th December 2013

excellent review

Posted by Laleh Alim Marvasti - 11.19am 24th December 2013

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  • The objective of this review was to evaluate the effectiveness of systemic acyclovir for primary herpetic gingivostomatitis.

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  • Figure 1: In association with the Cochrane Collaboration