Notifiable in Scotland and Northern Ireland
Varicella (chickenpox) is an acute highly infectious disease that is transmitted directly by personal contact or droplet spread, and indirectly via fomites. In the home, the secondary infection rate from a case of chickenpox can be as high as 90%. The infection is most common in children below the age of ten in whom it usually causes mild disease. Since chickenpox is so common in childhood, 90% of adults are immune. The incidence of varicella is seasonal and reaches a peak from March to May. The incubation period is between 2 and 3 weeks. Vesicles appear without prodromal illness on the face and scalp, spreading to the trunk and abdomen and eventually to the limbs; after 3 or 4 days they dry with a granular scab and are usually followed by further crops. Vesicles may be so few as to be missed or so numerous that they become confluent, covering most of the body. Virus is plentiful in the naso-pharynx in the first few days and in the vesicles before they dry up; the infectious period is therefore from 1 to 2 days before the rash appears until the vesicles are dry. This may be prolonged in immunosuppressed patients. Early treatment with oral/systemic aciclovir shortens the duration and severity of illness.
The disease can be more serious in adults, particularly pregnant women and those who smoke, as they are at risk of fulminating varicella pneumonia. Pregnant women appear to be at greatest risk late in the second or early third trimester; of the nine deaths due to varicella in pregnancy in England and Wales between 1985 and 1998, seven occurred between 27 and 32 weeks’ gestation.1 For neonates and immunosuppressed individuals the risk of disseminated or haemorrhagic varicella is greatly increased.
Herpes zoster is caused by the reactivation of the patient's varicella virus. It is transmissible to susceptible individuals as chickenpox but there is no evidence that it can be acquired from another individual with chickenpox. Although more common in the elderly, it can occur in children and is especially common in immunosuppressed individuals of any age. Vesicles appear in the dermatome representing cranial or spinal ganglia where the virus has been dormant. The affected area may be intensely painful with associated paraesthesia. Risks to the fetus and neonate from maternal chickenpox are related to the time of infection in the mother. 2,3
Varicella vaccine is a live attenuated vaccine derived from the Oka strain of varicella zoster virus. It is available from GlaxoSmith Kline (Varilrix™, Oka-RIT) as a lyophilised preparation which on reconstitution is given as a 0.5ml dose. It is stored at +2 to +8ºC and has a shelf life of 24 months. It is not affected by freezing.
Varicella vaccine (VARIVAX®, Oka/Merck) will be available from Aventis Pasteur MSD in spring 2004 as a lyophilised preparation, stored at +2 to +8º C, which on reconstitution is also given as a 0.5ml dose. The vaccine should be administered by subcutaneous injection.
The vaccination schedule varies with age: For individuals aged 13 and over, two doses 4-8 weeks apart; for children aged 1-12 years, a single dose. Up to 10% of adults and 5% of children develop a vaccine-associated rash, either localised at the injection site or generalised, within 1 month of immunisation.4 Varicella vaccine rashes may be papular or vesicular. Transmission of vaccine virus from immunocompetent vaccinees to susceptible close contacts has occasionally been documented but the risk is very low. Transmission in the absence of a post-vaccination rash has not been documented.4 The two-dose vaccination schedule in adolescents and adults provides about 75% protection and the single dose schedule in children about 90% protection [4]. In both age groups most of the breakthrough infections are modified and vaccinated individuals who contract varicella have fewer lesions and less systemic upset than unvaccinated individuals. The Oka strain can establish latency in immunocompetent individuals and result in herpes zoster but the risk is lower than with wild varicella infection. The Oka strain is sensitive to aciclovir.
Varicella vaccines are well tolerated. Extensive clinical and post-marketing safety surveillance data from the United States (for the Oka/Merck strain, VARIVAX®) shows the most commonly reported reactions are complaints at the injection site (pain, redness, rash). Generalised symptoms such as fever and rash can also occur but less frequently. Management of these reactions in health care workers (HCWs) is detailed below.
Varicella vaccine is not currently recommended for routine use in children. However, it may be given to healthy susceptible contacts of immunocompromised patients where continuing close contact is unavoidable (e.g. siblings of a leukaemic child).
Varicella vaccine can be given at the same time but at a different site from MMR vaccine. If the MMR and varicella vaccines are not given simultaneously they should be separated by at least 30 days.13
Note: Inadvertent vaccination in pregnancy. Surveillance of cases of inadvertent vaccination in pregnancy in the US has not identified any specific risk to the fetus. Follow up to March 2002 of 697 women in the US who have been vaccinated with Oka/Merck strain (VARIVAX®) while pregnant has identified no cases of congenital varicella in any liveborn infant. In addition, the rate of occurrence of congenital anomalies has been similar to that reported in the general population.11 However, it is nevertheless important to record such cases and to document the outcome of pregnancy. Surveillance of inadvertent vaccination in pregnancy is being established by the Immunisation Division of the Health Protection Agency to whom such cases should be reported (0208 200 6868 ext 4405). Any such cases in Scotland should be reported to the Scottish Centre for Infection and Environmental Health (SCIEH) by telephoning 0141-300-1191 and in Wales, cases should be reported to the National Public Health Service for Wales (tel. 01352 700227 ext 4055). These will, in turn, contribute to the UK figures via the Immunisation Division of the Health Protection Agency.
Two licensed VZIG preparations are available in the UK. VZIG distributed in England and Wales is made by the Bio Products Laboratory (BPL), Elstree; and in Scotland and Northern Ireland it is provided by the Protein Fractionation Centre (PFC), Edinburgh. VZIG is prepared from pooled plasma of non-UK donors with suitably high titres of V-Z antibody. The supply of VZIG is limited by the availability of suitable donors and its use is therefore restricted to those at greatest risk and for whom there is evidence that it is likely to be effective. VZIG is a clear, pale yellow fluid or light brown solution dispensed in vials containing 250 mg protein in a nominal 1.7ml of fluid (minimum potency 100 i ì of VZ antibody per ml) with added thiomersal and sodium chloride. On keeping, a slight turbidity or occasional particles may appear. VZIG should be stored in a refrigerator between +2 to +8oC. Under these conditions it has a nominal shelf life of 3 years. It can be stored for short periods at room temperature and is sufficiently heat stable to be despatched by post. VZIG must NOT be frozen.
All immunoglobulins are prepared from HIV, hepatitis B and hepatitis C negative donors.
VZIG prophylaxis is recommended for individuals who fulfil all of the following three criteria:
The post-exposure management algorithms for immunocompromised patients, neonates and pregnant women are summarised in figures 34.2, 34.3 and 34.4 respectively.
These are defined in Chapter 7 and include the following:
Patients with gammaglobulin deficiencies who are receiving replacement therapy with intravenous normal immunoglobulin, do not require VZIG (see below).
Whenever possible, immunosuppressed contacts should be tested irrespective of their history of chickenpox. However, VZIG administration should not be delayed past 7 days after initial contact while an antibody test is done. Under these circumstances VZIG should be given on the basis of a negative history of chickenpox. Those with a positive history in whom VZ antibody is not detected by a sensitive assay should be given VZIG.
VZIG is not indicated in immunosuppressed contacts with detectable antibody as the amount of antibody provided by VZIG will not significantly increase VZ antibody titres in those who are already positive. Second attacks of chickenpox can occasionally occur in immunosuppressed VZ antibody positive patients, but these are likely to be related to defects in cell-mediated immunity.
Effectiveness in immunocompromised patients : About half of susceptible immunosuppressed home contacts will develop clinical chickenpox despite VZIG prophylaxis and a further 15% will be infected subclinically.5 Severe or fatal varicella can occur despite VZIG prophylaxis. Immunocompromised contacts given VZIG should therefore still be monitored and aciclovir used at the first signs of illness.
VZIG is recommended for the following:
VZIG is also recommended for the following:
For infants in these two exposure groups who are born before 28 weeks gestation, weighed less than 1000g at birth, are more than 60 days old, or have had repeated blood sampling with replacement by packed red cell infusion, maternal antibody may not be present despite a positive maternal history of chickenpox 6,7. It is therefore recommended that where possible, such infants are tested to determine their VZ antibody status in the event of a contact. Other infants whose mothers have a positive history of chickenpox and/or a positive VZ antibody result will usually have maternal antibody and do not require VZIG.
Effectiveness in neonates: About half of neonates exposed to maternal varicella will become infected despite VZIG prophylaxis.3 in up to two-thirds of these infants infection is mild or asymptomatic, but rare fatal cases have been reported despite VZIG prophylaxis in those with onset of maternal chickenpox in the period 4 days before to 2 days after delivery. Early treatment with intravenous aciclovir is recommended for infants in this exposure category who develop varicella despite VZIG prophylaxis.
VZIG is recommended for VZ antibody negative pregnant contacts exposed at any stage of pregnancy, providing VZIG can be given within 10 days of contact (for household contacts count from day of onset of rash). However, when supplies of VZIG are short, issues to pregnant women may be restricted. Clinicians are advised to check availability of VZIG (see supplies section below) before offering it to pregnant women.
Pregnant contacts with a positive history of chickenpox do not require VZIG. Those with a negative history must be tested for VZ antibody before VZIG is given (see below). The outcome in pregnant women is not adversely affected if administration of VZIG is delayed up to 10 days after initial contact.1,8 There is, therefore, still time to test for VZ antibody even when the woman presents relatively late after contact.
Effectiveness in pregnant womenL: The rationale for the use of VZIG prophylaxis in pregnant women is two fold: reduction in severity of maternal disease and reduction of risk of fetal infection for women contracting varicella in the first 20 weeks of pregnancy. The risk of fatal varicella is estimated to be about five times higher in pregnant than non-pregnant adults with fatal cases concentrated late in the second or early third trimester.1 One study showed a significant reduction in the risk of congenital VZV infection in women who developed varicella after VZIG prophylaxis compared with women who developed varicella without VZIG prophylaxis; however, the study was too small to assess whether the risk of congenital varicella syndrome was reduced. 2 A case of congenital varicella syndrome has been reported in the infant of a woman exposed at the eleventh week of gestation and who developed clinical varicella despite post exposure prophylaxis with VZIG. 9
About 50% of susceptible pregnant women given VZIG after a household exposure to chickenpox will develop clinical varicella, although the disease may be attenuated; the clinical attack rates are similar whether VZIG is given within 72 hours or 4-10days after contact,1,8 A further quarter will be infected subclinically.8 Severe maternal varicella may still occur despite VZIG prophylaxis. Prompt treatment with aciclovir is indicated in such cases.
The majority of adults and a substantial proportion of children without a definite history of chickenpox will be VZ antibody positive. One UK study found that 11% of children aged 1 to 5 years, 37% aged 6 to 16 years and 89% of adults given VZIG on the basis of a negative history of chickenpox were VZ antibody positive. 5 To prevent wastage of VZIG, all individuals being considered for VZIG should have a serum sample tested for VZ antibody; only those without antibody require VZIG. Urgent VZ antibody testing is required; for patients presenting late, VZIG can be ordered (see below) at the same time that the blood is sent for testing and can be returned if the result is positive. VZ antibody testing should be available within 24 to 48 hours, seek advice from the local public health or hospital laboratory.
VZ antibody detected in patients who have been transfused or who have received intravenous immunoglobulin in the previous 3 months may have been passively acquired. Although VZIG is not indicated if antibody from other blood products is detectable, re-testing in the event of a subsequent exposure will be required as the patient may have become antibody negative.
About 15% of patients given VZIG who remain symptom-free after a home contact will have had a subclinical infection and seroconvert asymptom- atically .5,8 Patients who have received VZIG in the past following a close exposure should, therefore, be re-tested for VZ antibody in the event of another exposure.
Three aspects of the exposure are relevant:
Management of health care workers exposed to VZV infection Vaccinated HCWs or those with a definite history of chickenpox or zoster and with a significant exposure to VZV (as above and including those dressing localised zoster lesions on non-exposed areas of the body) should be considered protected and allowed to continue working. As there is a remote risk that they may develop chickenpox, they should be advised to report to their occupational health department for assessment before having patient contact if they feel unwell or develop a fever or rash.
Unvaccinated HCWs without a definite history of chickenpox or zoster and with a significant exposure to VZ virus (see above), should either be excluded from contact with high risk patients from 8 to 21 days after exposure or be advised to report to their occupational health department before having patient contact if they feel unwell, or develop a fever or rash. There is some evidence that varicella vaccine administered within 3 days after exposure may be effective in preventing chickenpox12 (Varivax® is licensed for post-exposure prophylaxis.) In any case, irrespective of the interval since exposure, vaccine should be offered to reduce the risk of the HCW exposing patients to VZV in the future (see above).
HCWs with localised herpes zoster on a part of the body that can be covered with a bandage and/or clothing should be allowed to continue working unless in contact with high risk patients when an individual risk assessment should be made.
The dosage for both the BPL and PFC products are as follows:
| 0-5 years | 250 mg (1 vial) |
| 6-10 years | 500 mg (2 vials) |
| 11-14 years | 750 mg (3 vials) |
| 15 years and over | 1000 mg (4 vials) |
VZIG is given by intramuscular injection. It must not be given intravenously. If a second exposure occurs after 3 weeks, a further dose is required. Contacts with bleeding disorders who cannot be given an intramuscular injection should be given intravenous normal immunoglobulin at a dose of 0.2g per kg body weight (i.e. 4 ml/kg for a 5% solution) instead. This will produce serum VZ antibody levels equivalent to those achieved with VZIG.10
VZIG has no place in the treatment of severe disease.
England and Wales: Available from Public Health Laboratories and the Communicable Disease Surveillance Centre (CDSC) (Tel. 0208 200 6868). Northern Ireland : Available from the Public Health Laboratory, Belfast City Hospital, Lisburn Road, Belfast Tel. 01232 329241 Scotland: Available from Regional Transfusion Centres. Aberdeen & North East of Scotland Blood Transfusion Centre: Foresterhill Road, Foresterhill, ABERDEEN AB9 2ZW Tel: 01224 685685. North of Scotland Blood Transfusion Centre, Raigmore Hospital, Inverness IV2 3UJ Tel: 01463 704212. Dundee & East of Scotland Blood Transfusion Centre, Ninewells Hospital, Dundee DD1 9SY Tel: 01382 645166. The West of Scotland Blood Transfusion Centre, Gartnavel General Hospital, 25 Shelly Road, GLASGOW G12 0XB. Tel: 0141 357 7700. Edinburgh & South East of Scotland Blood Transfusion Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA. Tel: 0131 242 7520 (Irene McKechnie)
VZIG is issued free of charge to patients who meet the criteria given above. Clinicians who wish to issue VZIG for patients not meeting these criteria should approach the manufacturer directly to purchase a dose.
No other licensed VZIG preparations for intramuscular use apart from the BPL and PFC products are available in the UK.
VZIG is well tolerated. Very rarely anaphylactoid reactions occur in individuals with hypogammaglobulinaemia who have IgA antibodies, or those who have had an atypical reaction to blood transfusion. Severe reactions should be reported to the Committee on Safety of Medicines using the yellow card system. No cases of blood borne infection acquired through immunoglobulin preparations designed for intramuscular use have been documented in any country. The plasma used for the all the immunoglobulin preparations manufactured by BPL and PFC is sourced from non-UK donors. All donors are screened for HIV, hepatitis B and C, and all plasma pools are tested for presence of RNA from these viruses. A solvent detergent inactivation step for envelope viruses is included in the production process.