Viral Infections

Treatment of Varicella Zoster Virus Infection

a report by

E n r i q u e B e r n a o l a I t u r b e 1 and F e d e r i c o M a r t i n n - T o r r e s 2
1. Head, Infectious Diseases and Pneumology Unit, Paediatric Department, Hospital Virgen del Camino, Pamplona; 2. Attending Physician, Paediatric Critical Care, Hospital Clnico Universitario, Santiago

Treatment of Varicella Zoster Virus Infection Chickenpox has traditionally been considered a benign illness typical of childhood. Initially, it was known as lesser smallpox because of its clinical similarity, apart from being much more benign, to smallpox. It was Heberden who, in 1767, first described the clinical differences between these two illnesses.1 Although herpes zoster (HZ) has been clinically described since the beginning of history, chickenpox was not identified as such until it had first been differentiated from smallpox. At the end of the 19th century, Von Bokay drew attention to the relationship that existed between HZ and chickenpox after realising that children in contact with adults afflicted with HZ developed smallpox. This finding was later confirmed by clinical and virological studies that demonstrated that both smallpox and HZ are produced by the same virus, a virus with identical morphological and serological characteristics. In 1958 the virus was isolated by Weller and named varicella zoster (VZ). Since then, greater knowledge of chickenpox has been built up in terms of its aetiological agent, its clinical manifestations and the complications that accompany it, especially in populations considered to be at high risk, such as newborns and the immunodeficient. Although VZ is considered to be benign, the morbimortality caused by infection with it is not negligible even in healthy children. The Varicella Zoster Virus The VZ virus is a single virus that causes two different illnesses: chickenpox, a very contagious disease that affects practically everybody, and HZ, a less contagious clinical form with unilateral lesions localised on a single metamere of the trunk. In HZ the virus remains in a latent form, stationed in the sensory ganglions of the dorsal roots of the spinal medulla, that can reawaken, generally at times when there is lowering of immunity. The virus is a member of the Herpesviridae family and has icosahedral symmetry, double-stranded DNA and a membrane coat containing lipids and glycoproteins, which play a very important role in the host immune response and in vaccination. Pathogeny Clinical Forms The virus enters the organism through the respiratory tract in the respiratory secretions or the fluid of cutaneous lesions of an infected patient. It replicates locally in the nasopharynx and in the regional lymphatic nodes. Later, between about four and six days after infection, a primary viraemia develops, which disseminates the virus to the liver, spleen and sensory ganglions. Between 10 and 14 days after infection, a second viraemia transports the virus to the skin, producing the cutaneous eruptions characteristic of the illness.2 Once an individual has had chickenpox (usually in childhood), the virus can remain stationed in between 1 and 7% of the neurons of the paravertebral sensory ganglions.3 After several decades, when the person is about 5060 years old, the virus can reactivate and

descend through the nerve roots to the epidermis, developing into the second illness produced by the VZ virus: HZ. There are several factors that unleash the reactivation of the VZ virus. The strongest factor is a decrease in cell immunity, whether part of the natural process of ageing or attributable to acquired factors that condition immunodepression: cancer, chronic illness or treatment with immunosuppressors. Other factors that can unleash reactivation of the virus are a lack of periodic exposure to the wild VZ virus (exogenous boosting, which periodically stimulates specific immunity) and the possibility of endogenous contacts (endogenous boosting, which involves subclinical reactivation of latent VZ virus).4 HZ is characterised by affecting a specific zone of skin, a metamere, in which, before the start of the exanthema, similar to that of chickenpox, intense pain is felt. This pain can sometimes continue for months after resolution of the acute symptoms, in which case it is referred to as post-herpes neuralgia (PHN). PHN is the most frequent complication of HZ. Chickenpox is a highly contagious childhood exanthemic illness that, when the virus disseminates in semi-closed communities such as schools or kindergartens, affects 90% of susceptible individuals. The illness is specific to the human species, and humans are the only reserve of the VZ virus. Transmission of the VZ virus occurs from person to person by direct contact with cutaneous vesicles that contain the virus. It is also possible to catch the virus from the lesions of both chickenpox and HZ. Infections by the Varicella Zoster Virus and Situations of Particular Risk Infection by the VZ virus can bring about complications in both immunocompetent children and adults (see Table 1).

Enrique Bernaola Iturbe is Head of the Infectious Diseases and Pneumology Unit in the Paediatrics Department at Hospital Virgen del Camino in Pamplona. He is President of the Vaccine Advisory Board of the Spanish Society of Paediatrics and a member of the Vaccine Commission of the Health Service in Navarra. Dr Iturbe is an honorary member of the Spanish Society of Paediatrics and of the Societies of Spain Paediactric Infectious Diseases and Spain Paediatric Neurology. His research interests include vaccines and infectious pneumology. E: enrique.bernaola.iturbe@cfnavarra.es Federico Martinn-Torres is an Attending Physician in Paediatric Critical Care at the Hospital Clnico Universitario in Santiago, a Clinical Tutor in Paediatrics at the University of Santiago and an Academic of the Royal Academy of Medicine and Surgery of Galicia. His main research interests include vaccines, heliox therapy, meningococcal disease, bronchiolitis, non-invasive ventilation, HFOV and vasovagal syncope. E: federico.martinon.torres@sergas.es

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availability of specific treatment this chickenpox was associated with a mortality rate of up to 30%.5-8
Children Skin Bacterial secondary infection of cutaneous lesions (S. aureus /Str. pyogenes ) cellulitis; abscesses; necrotising fasciitis; septic shock syndrome Encephalitis; cerebellitis; transverse myelitis; cerebral ataxia Hepatitis; thrombopenia; nephrititis/arthritis myocarditis; pericarditis; orchitis; pancreatitis Varicella pneumonia (2/3 asymptomatic) Encephalitis; myelitis Scar formation Pneumonia <20 weeks: malformations 5th15th day post-partum: congenital varicella

Table 1: Varicella Complications

An expecting woman exposed to the VZ virus must be treated with varicella zoster immunoglobulin (VZIG) or, if that is not possible, with polyvalent immunoglobulin, in order to prevent the infection from leading to illness in the mother. The treatment must be given within 7296 hours after contact with the virus.6 Other therapies, such as acyclovir, have not been demonstrated to prevent vertical transmission of the infection. Other Situations of Particular Risk Other groups at risk of infection by the VZ virus are children or adults who are immunodepressed, have a chronic skin disease, are under treatment with salicylic acids or corticoids or have chronic pneumopathologies.9 Because treatment with salicylic acids in children with chickenpox has been discouraged, the serious complication of Reyes syndrome has diminished almost to the point of disappearance. Treatment of Varicella and Herpes Zoster Broadly speaking, nucleoside analogues (acyclovir, valaciclovir, famciclovir and brivudine) are the available antiviral treatments for VZ virus infections, with different degrees of indications and contraindications depending on the particular patient. In cases of resistance, foscarnet constitutes the alternative treatment.1017 To inhibit replication of human herpesviruses, including the VZ virus, a synthetic nucleoside analogue, acyclovir, is used. Acyclovir is an antiviral agent active in vitro and in vivo against types I and II of the herpes simplex virus and against the VZ virus. Its toxicity for infected human and mammalian cells is low. On penetration of a cell infected with herpes virus the agent becomes phosphorylated and is thus converted into the active compound acyclovir triphosphate. The first step in this process requires the presence of the enzyme thymidine kinase specific to the herpes simplex virus. Acyclovir triphosphate acts as a specific inhibitor of the DNA polymerase of herpesviruses, so prevents subsequent synthesis of viral DNA without affecting normal cell processes.10-17 Taken orally, acyclovir is absorbed only partially: about 20% of the administered dose. Its half-life in the blood plasma of individuals with normal renal function is about three hours, and 20 hours in patients in anuria. It is excreted by the kidney as a result of glomerular filtration and tubular secretion, passing into the urine where its only metabolite, 9-carboxymethoxymethylguanine, is eliminated. The oral use of acyclovir is usually reserved for immunocompetent children or adults looking for a shortening of the disease course.1017 On the other hand, oral valaciclovir can reach blood levels similar to those obtained with intravenous acyclovir. However, according to the existing data, its use is restricted to immunocompromised children with mild varicella or adults.18 Intravenous administration of acyclovir is indicated in the treatment of infections by herpes simplex and the VZ virus in the following groups:8 the immunodepressed; newborns with severe involvement;

Neurological Other Adults Respiratory Neurological Other Mother Foetus Neonate

Pregnancy

Table 2: Antiviral Therapy of Varicella from Pregnancy to Adults

Pregnancy Neonate Children Aciclovir 3x10mg/kg/day IV, 7 days (in severe or complicated cases) Aciclovir 3x20mg/kg/day IV (if severe exanthema or systemic involvement) Immunocompetent Immunocompromised Aciclovir (optional) Aciclovir 3x20mg/kg/day IV, 100mg/kg/day po, 510 days 510 days Immunocompetent Immunocompromised Aciclovir Aciclovir 5x800mg/day po, 5x500mg/m2 day IV, 510 days 714 days 3x10mg/kg/day IV, 10mg/kg/day IV, 714 days 510 days (in severe cases) Valaciclovir Valaciclovir 3x1000mg/day po, 3x1000mg/day po, 7 days 710 days Famciclovir Famciclovir 3x500mg/day po, 3x500mg/day po, 7 days 710 days

Adults

Chickenpox During Pregnancy Infection by the VZ virus can be serious in pregnant women, frequently leading to the complication of pneumonia. It is important to achieve early diagnosis and treatment of varicella pneumonia, which is the most serious of the forms that usually arise in the third trimester.58 Infection by the VZ virus during pregnancy can have various consequences for the foetus and the neonate according to the timing of the maternal infection. If the mother is infected in the first 20 weeks of pregnancy, the result can be foetal death or so-called congenital varicella syndrome with malformations of the extremities (hypoplasia of limbs), central nervous system (mental retardation) and eyes (chorioretinitis, cataracts). If the chickenpox occurs in the first 12 weeks of pregnancy, the risk of the foetus suffering from congenital varicella syndrome is 0.4%. The frequency rises to 2% if the maternal infection occurs between weeks 13 and 20 of pregnancy.58 If infection in the mother occurs after 20 weeks, an involvement of the foetus does not result in lesions as in the earlier weeks. This later maternal varicella leads, with relative frequency, to the child having a form of HZ in his or her first few months or years of life.58 If the maternal infection occurs around the time of giving birth, five days before birth or two days after, within two weeks of life the newborn will develop a varicella that can be very serious. Before the

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Treatment of Varicella Zoster Virus Infection

patients with serious clinical forms, such as encephalitis, of infections by either virus; and patients with serious complications of the VZ virus (see Table 1). The dosages of antiviral agents (in particular acyclovir) used in children are indicated in Table 2. The dosages differ depending on whether they refer to children or adults with or without immunocompromise. The age threshold for adulthood in this setting is considered to be above 12 years of age. The dosage for children between three months and 12 years of age is usually calculated on the basis of body surface area or weight (see Table 2). In those patients with altered renal function, appropriate modifications to the dosage in accordance with their creatinine clearance are required. Acyclovir has not been demonstrated to be harmless during pregnancy.7,8 In fact, acyclovir is classified as a category B drug in the US Food and Drug Administration (FDA) use-in-pregnancy rating, so its use is not recommended during that time.7,8 It is used only in cases in which a previous riskbenefit evaluation suggests that its use is advisable. With regard to endovenous acyclovir in mothers in the first trimester of pregnancy, the rates of malformations have not been found to be higher than those in the general population. Use of acyclovir is not routinely recommended in pregnant women except in cases of complicated varicella (pneumonias), in which the risks of disease for the mother and for the foetus are high. In these cases, administration should be intravenous.7,8 There is no information available about the levels of acyclovir in human milk after oral or intravenous administration of the drug. Breast-feeding is not contraindicated if the mother is receiving or has received treatment with acyclovir.7,8

Table 3: Antiviral Therapy of Herpes Zoster from Pregnancy to Adults

Pregnancy Children Adults Either topical or systemic antiviral therapy not recommended Aciclovir 500mg/m2 or 10mg/kg every 8 hours IV, 710 days Immunocompetent Immunocompromised Aciclovir Aciclovir 5x800mg/day po, 7 days 500mg/m2 or 10mg/kg every 8 hours IV, 710 days 5x800mg/day po, 710 days (without visceral involvement, moderate immunocompromise) Valaciclovir Valaciclovir 3x1,000mg/day po, 7 days 3x1,000mg/day po, 7 days (without visceral involvement, moderate immunocompromise) Famciclovir Famciclovir 23x250mg/day po, 3x500mg/day po, 7 days 7 days (without visceral involvement, moderate immunocompromise) Brivudine Foscarnet 1x125mg/day po, 7 days 23x60mg/kg per day IV (contraindicated for 714 days, until complete patients treated healing of lesions with 5-fluorouracil or other 5-fluoropyrimidines, because of drug interaction associated with severe and potentially fatal bone marrow suppression)

children are treated with acyclovir. This is the case despite the fact that Treatment of Immunocompetent Children and Adults The effectiveness of acyclovir in the treatment of varicella in otherwise healthy, immunocompetent children is not clear. Due to the drugs limited clinical effectiveness, several studies have investigated the possible induction of resistance and the increase in the pharmaceutical cost supposed by acyclovir.
11

disappearance of the virus from cutaneous lesions is usually faster in treated individuals.16 Treatment with acyclovir is given to children and adults who have a particular risk of suffering a complicated varicella. It has not been demonstrated that acyclovir treatment in healthy children yields sufficient benefits to indicate its use universally in all the young with varicella.8,17 Following the above analysis, it is clear that acyclovir treatment in the immunocompetent, bearing in mind the increased costs, can be indicated in adolescents over 12 years of age, in adults (see Table 2) and in children less than 12 years of age who have intrafamily contact with the virus and are consequently potential victims of a more severe and complicated varicella. Treatment in Immunodepressed Children and Adults The use of nucleoside analogues is customary for the treatment of varicella in the immunodepressed, aciclovir being the standard therapy for those more severely affected. When acyclovir is administered intravenously at the start of the illness, it is effective in reducing the seriousness of the illness and in preventing death in both immunodepressed children and adults (see Table 2).1017 It is necessary to administer antiviral agents in their full doses and for sufficient time in order to prevent visceral dissemination of the infection. If the patient is not too affected by the illness, oral treatment with high-dose oral acyclovir, famciclovir or valacyclovir can be useful. The latter two agents, as stated in their technical data sheets, are not authorised for children under 12 years of age. In order to avoid varicella complications it is critical to start treatment within the first few hours after exanthema appears.16

In the paediatric literature there are

12,13

placebo-controlled tests in children.

In all of these the acyclovir

treatment was initiated early, within 24 hours of the onset of exanthema, and the drug was administered orally. From the data obtained from studies in healthy children, it is concluded that when acyclovir is given early, within the first few hours of the illness (exanthema),14 the duration of the illness is reduced slightly;15 the time before apparition of new lesions is reduced by a little more than a day;
12,13

the total number of lesions diminishes significantly;

13

and the

days of fever are reduced by 11.4 days.12,13 These conclusions are also extrapolable to healthy adults. No clear reduction in the number of complications or their seriousness is apparent in healthy children. This lack of data may also be related to the scarcity of varicella complications in these cases. In immunodepressed children treated with acyclovir, the appearance of resistance has been demonstrated. In healthy children this aspect has not been tested but, in a scenario of general treatment with acyclovir for all children with chickenpox, one might speculate that resistance would increase noticeably.16 There is no evidence that dissemination in group situations, such as the family, kindergarten or classroom, diminishes when the affected

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Treatment in Newborns To treat neonates whose mothers have had varicella at the end of pregnancy or in the immediate post-partum period, treatment with acyclovir together with specific VZIG is indicated.8 In the case that exanthema develops in the mother in the days just before giving birth or in the two days after, the transplacental passage of virus during viraemia is very important. Maternal antibodies have not been formed and therefore cannot, after passing through the placenta, control the pathogenicity of the virus in the newborn. In such situations the illness produced in the neonate is very serious and can lead to death if not treated correctly and quickly. Treatment with intravenous aciclovir should be added to VZIG at dosages of 3x20mg/kg/day over a period of no less than five to 10 days. The approach should be the same as if one was dealing with an immunodeficient patient.8 In cases of contact between hospitalised neonates and hospitalised cases of chickenpox, the following prophylactic treatments should be carried out:8 a premature newborn of a susceptible mother should be treated as for serious infection by administration of VZIG (if the mother has varicella antibodies, this VZIG prophylaxis is not necessary); and a premature baby of less than 28 weeks gestation who has been exposed to nosocomial VZ should be treated with VZIG irrespective of the susceptibility of the mother. Treatment of Herpes Zoster The indications for antiviral therapy for HZ are summarised in Table 3. Acyclovir, famciclovir and valacyclovir, all of which are nucleoside analogues, are approved for the treatment of HZ in healthy individuals. When administered early, i.e. within the first three days from the start of exanthema, the agents are effective in shortening the duration of the illness and reducing the symptomatology and the associated pain.19 The agents also reduce the incidence of PHN.20 Despite the above indications there are many otherwise healthy sufferers of HZ who are not treated with antiviral agents, and in only a minority of those that are thus Acknowledgements This work has been partly funded by Consellera de Sanidade-Xunta de Galicia (RHI07/2, Intensificacin de la actividad investigadora, F Martinn-Torres). Even if the risk of developing PHN is not reduced by combining antiviral therapy with analgesic or corticosteroid treatment in patients with HZ, effective relief of acute pain is a very desirable treatment goal.2427 Corticosteroids should be administered in the acute phase of the illness and always together with antiviral agents. The standard dosage of prednisone is 60mg/day for seven days, reducing the dosage by half each week for two weeks until discontinuation. The effectiveness of topical application has not been demonstrated. Corticosteroids are principally indicated in patients over 50 years of age.24,25 Treatment of pain should be started early and decisively,23,26 with paracetamol, non-steroidal anti-inflammatory drugs, opiates, codeine or morphine. On occasion it is necessary to add to the pain treatment with antidepressant and anticonvulsant drugs.22,27 Tricyclic antidepressants (especially nortriptyline, at 25mg daily with a gradual increase by 25mg/daily every two to three days, as tolerated, and up to a maximum of 150mg daily) have been used extensively in this setting. 26,27 Of the anticonvulsant drugs, the gabapentinoids (gabapentin and pregabalin) are prescribed most often.26,27 patients over 50 years of age; immunocompromised patients; patients with an ophthalmic or cervical localisation of HZ; and patients with moderate to severe pain before or at the start of the rash.22,23 The specific indications for treatment with antiviral agents are especially important in the following groups: treated is the treatment begun within the first three days of illness.21 In the event that antiviral treatment is not started early, it should still be given if lesions continue to appear or in the case of PHN.22

CTE, Jr, The first description of chickenpox as a disease, by william heberden the elder (1710-1801) in 1767, Pediatrics , 1970;45:588. 2. Hope-Simpson HE, Infectiousness on communicable diseases in the household measles, mumps and chickenpox, Lancet , 1952;2:54954. 3. Arvin AM, Varicella-zoster virus, Clin Microbiol Rev , 1996;9:36181. 4. Arvin AM, Cell-mediated immunity to varicell-zoster virus, J Infect Dis , 1992,166:S3541. 5. Chapman SJ, Varicella in pregnancy, Semin Perinatol , 1998;22:33946. 6. Enders G, Miller E, Cradock-Watson J, et al., Consequences of varicella and herpes zoster in pregnancy: prospective study of 1739 cases, Lancet , 1994;343:154851. 7. Daley AJ, Thorpe S, Garland SM, Varicella and the pregnant woman: prevention and management, Aust N Z J Obstet Gynaecol , 2008;48:2633. 8. Centers for Disease Control and Prevention CDC, Prevention of Varicella, MMWR , 2007;RR4:138. 9. Reusser P, Infections in the immunocompromised host: opportunistic viral infections, Cohen J, Powderly WG (eds), Infectious Diseases , 2004, London: Mosby:1169-81. 10. Rajan P, Rivers JK, Varicella zoster virus: recent advances in management, Can Fam Physician , 2001;47:22992304. 11. Levin MJ, Dahl KM, Weinberg A, et al., Development of resistance to acyclovir during chronic infection with the Oka vaccine strain of varicella-zoster virus, in an immunosuppressed

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child, J Infect Dis , 2003;188:9549. 12. Balfour Jr HH, Rotbart HA, Feldman S, et al., Acyclovir treatment of varicella in otherwise healthy adolescents. The 33 Collaborative Acyclovir Varicella Study Group, J Pediatr , 1992;120:62733. 13. Dunkle LM, Arvin AM, Whitley RJ, et al., A controlled trial of acyclovir for chickenpox in normal children, N Engl J Med , 1991;325:153944. 14. Klassen TP, Belseck EM, Wiebe N, et al., Acyclovir for treating varicella in otherwise healthy children and adolescents: a systematic review of randomised controlled trials, BMC Pediatr , 2002;2:914. 15. Wallace MR, Bowler WA, Murray NB, et al., Treatment of adult varicella with oral acyclovir A randomized, placebo-controlled trial, Ann Intern Med , 1992;117:35863. 16. Balfour Jr HH, Edelman CK, Anderson RS, et al., Controlled trial of acyclovir for chickenpox evaluating time of initiation and duration of therapy and viral resistance, Pediatr Infect Dis J , 2001;20:91926. 17. Commitee of Infectious Diseases American Academy of Pediatrics, The use of oral acyclovir in otherwise healthy children with varicella, Pediatrics , 1993;91:6746. 18. Hoglund M, Ljungman P, Weller S, Comparable acyclovir exposures produced by oral valaciclovir and intravenous acyclovir in immunocompromised cancer patients, J Antimicrob Chemother , 2001;47:85561. 19. Wood MJ, Shucla S, Fiddian AP, et al., Treatment of acute herpes zoster: effect of early <48h versus late 48-72 therapy

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with acyclovir and valaciclovir on prolonged pain, J Infect Dis , 1998;178:814. Wood M, Kay R, Dworkin RH, et al., Oral acyclovir therapy accelerates pain resolution in patients with herpes zoster: a meta-analysis of placebo-controlled trial, Clin Infect Dis , 1996;22:3417. Macintyre CR, Chu CP, Burgess MA, Use of hospitalisation and pharmaceutical prescribing data to compare the revaccination burden of varicella and herpes-zoster in Australia, Epidemiol Infect , 2003;131:67582. Centers for Disease Control and Prevention, Prevention of herpes zoster, Recomendation of the Advisory Committee on Immunization Practices (ACIP), MMWR , 2008;RR5:123. Dwyer DE, Cunningham AL, Herpes simplex and varicella virus infection, Med J Aust , 2002;177:26773. Whitley RJ, Weiss H, Gnann JW, et al., Aciclovir with an without prednisone for the treatment of herpes-zoster: a randomized, placebo controlled trial, Ann Intern Med , 1996;125:37683. Wodd MJ, Jhonson RW, McKendrick MW, et al, A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster, N Engl J Med , 1994;330:896-900. Dworkin RH, Johnson RW, Breuer J, et al., Recommendations for the management of herpes zoster, Clin Infect Dis , 2007;44:S126. Cunningham AL, Breier J, Dwyer DE, et al., The prevention and management of herpes zoster, MJA , 2008;188:1716.

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