Guidelines for the Prevention & Treatment of Varicella-Zoster Virus Infection in Immunosuppressed Children & Young People with Cancer

• 
• Appendices

• Summary
• Aims
• Background
  • Definition of ‘significant contact’
• Prevention strategies
  • Persons at Risk
  • Universal strategies
  • Management of patients after significant contact DURING VZIG SHORTAGE
• Diagnosis of VZV infection
• Investigation of suspected VZV infection
• Management of VZV infection
• Audit
• Appendix 1 - Management of chicken pox contact (if not on PEPTalk2trail)
• Appendix 2 - Treatment of chicken-pox/shingles
• Appendix 3 - Doeses of intravenous antivirals: paediatric and adolescent oncology patients
• Appendix 4 - Treatment of herpes simplex/herpes zoster infections

Summary of Guideline

Children and young people who are immunosuppressed are at increased risk of complications if they are exposed to varicella zoster virus (VZV)

At-risk individuals should reduce their chance of exposure to people who have chickenpox/shingles infection

Non-immune siblings should be offered vaccination to improve protection

Post-exposure prophylaxis should be offered to non-immune, at-risk individuals following significant contact

Treatment of VZV infection in immunocompromised children and young people should be risk stratified on the basis of clinical appearance, fever and lymphopenia

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Aims

To improve the prevention and management of varicella zoster virus (VZV; chickenpox and shingles) infection in children and young people immunosuppressed through treatment of cancer.

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Background

Children who are immunosuppressed as a result of disease, chemotherapy and cranio-spinal radiotherapy are at increased risk of complications if they are exposed to varicella zoster virus (VZV) via significant contact with an infected person, presenting as chicken pox or shingles. If these patients have no evidence of immunity to VZV, they will need post-exposure prophylaxis which intends to reduce the chance developing a VZV infection, and ameliorate the severity of infection if one develops.

Chicken pox is the primary manifestation of VZV infection but following recovery the virus remains latent in nerve ganglia and if the body’s immunity becomes suppressed it may be reactivated as shingles. However direct contact with shingles lesions may cause chicken pox in individuals whose immunity is suppressed e.g. during chemotherapy.

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What Is Classed As Significant Contact?

Chicken Pox -
If the patient is in significant contact with a person with chicken pox during the infectious period he/she is at risk of developing the infection.

Significant contact is defined as play or direct contact for greater than 15 minutes on the ward, in a household, or in the same classroom at school.
The infectious period is from 2 days prior to onset of a rash until crusting of all the vesicles has occurred. (The incubation period for chicken pox is 10 - 21 days but the infectious period is only as above.)

Shingles (Herpes zoster) -
This is infectious when there is direct contact with the exposed lesions (if the person with shingles has normal immunity). Each case of contact with “shingles” needs to be judged individually and medical confirmation sought, if possible, of the index case.

Immunosuppressed patients with shingles may have more vesicles and shed virus for longer and more profusely than non immunosuppressed patients and (if on the ward/in clinic) will be in contact with patients who are in turn at risk of acquiring the virus if non-immune. They should be considered as infectious as patients with chickenpox.

This guideline covers the prevention and treatment of VZV infection in this population.

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Prevention Strategies

It is impossible, impractical and undesirable to attempt to protect children undergoing treatment for malignancy from every possible exposure to VZV infection other than by simple common sense precautions.

For the purposes of this guideline, the following are groups are considered ‘at risk’:

• Patients currently on chemotherapy treatment and for 6 months post treatment.
• Patients receiving cranio-spinal radiotherapy and for 6 months post treatment.
• All patients who have received an allogeneic or autologous haemopoetic stem cell transplant (HSCT) i.e. all bone marrow transplant and peripheral stem cell transplant patients. This continues until at least 1 year post HSCT (unless receiving treatment for graft-vs-host-disease) and at least 12 months after all immunosuppressive treatment has been withdrawn.

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UNIVERSAL STRATEGIES TO PREVENT CHICKEN POX / SHINGLES

Recommendation - Check Pre Treatment VZV IgG status
All new patients to the unit should have a varicella zoster virus antibody blood sample taken prior to any chemotherapy or blood product transfusions being administered. This baseline result (positive or negative) will be used to guide any future treatment regarding VZV exposure.

Routine retesting of patients is not recommended, as subsequent assays do not clearly provide useful information regarding protection (see Recommendation - Acutely test VZV status in very four specific circumstances).

Recommendation - Awareness
Ensure that family, friends and those with whom the patients are likely to be in contact, particularly very young children or those that have not had the diseases or been vaccinated against them, are aware of the risk to the patient. Word of mouth is probably enough for family and friends. A written letter is advisable for circulation to the parents or groups where possibility of contact may occur, such as playgroups, school, dance classes, brownies, scouts, etc.

It is felt that the advantages of normalisation outweigh the medical risks of infection. Except for the immunocompromised, it is not possible for anyone who has already had a medically documented case of chicken pox or measles to have it again or “carry” it. However, it is possible for someone who has had chicken pox to develop shingles. It is possible for immunosuppressed patients to have any of these infections more than once.

Recommendation - Ring-fence vaccination
Siblings of patients who are varicella antibody negative should have their own antibodies measured if they have not had chickenpox or shingles, as described for new patients (see below) and subsequently vaccinated with varicella vaccine if negative. Guidelines for vaccination can be found on the Department of Health website :

https://www.gov.uk/government/publications/varicella-the-green-book-chapter-34

If required, vaccination of siblings should be organized through the family GP.

Recommendation - Isolate Immunocompromised Patients with VZV infection
Patients who are immunocompromised with chickenpox, or shingles, regardless of the extent of the shingles may shed virus from the respiratory tract and may be potentially infectious for up to two days before the onset of these lesions. It is therefore appropriate to nurse these patients away from immunocompromised patients.

Recommendation - Contact Principal Treatment Centre for advice following a significant contact
Parents should contact the paediatric oncology unit as soon as possible if their child has contact with chicken pox, shingles or measles to ascertain if any treatment is required.

Ideally, exposed children need to be isolated for 3 weeks post contact, from other immunosuppressed children, regardless of if they have lesions or not.

PREVENTATIVE MANAGEMENT OF CHICKEN POX / SHINGLES CONTACT
See also flowsheet Appendix 1

Patients who are not at risk as determined above should be observed only.

Recommendation - Give post-exposure prophylaxis to all HSCT recipients
Significant contact with another individual who has varicella zoster virus infection requires preventative treatment regardless of antibody status prior to HSCT in the 12 months after stopping immunosuppression after transplant and if no graft versus host disease..

Recommendation - Give post-exposure prophylaxis to others based on pre-treatment VZV IgG result
Patients whose pre treatment VZV antibody level was positive, (this indicates previous infection) require no further preventative treatment. There is no need to retest unless the patient undergoes allogeneic stem cell transplantation. However the family must immediately report the appearance of any suspicious spots and if chickenpox / shingles is confirmed, be managed according to the treatment section of this guideline.

Patients whose pre treatment VZV antibody level was negative have no evidence of previous infection and the child will need prophylactic treatment.

The following recommendation details the limited circumstances where the above recommendation does NOT apply:

Recommendation - Acutely test VZV status in very four specific circumstances
Retesting is only necessary where a previous test has been done if:

• The result was positive, but the patient had received blood or blood products at the time the sample was tested, or was less than 12 months of age.
• The result was negative but the patient had received VZV-prophylaxis with VZIG or aciclovir due to contact during the intervening period.
• The result was negative but the parents think that the child has had chicken pox during the period between starting chemotherapy and current exposure
• Patients with no pre treatment VZV antibody result

These patients will need VZV testing DURING NORMAL WORKING HOURS as soon as possible after the contact (within 7 days). In exceptional conditions, for example if the contact is only known about very close to the 7 day window, out-of-hours testing can be done. The “current” result will then drive treatment choices as above. In the rare situation of the results being not conclusive (as being positive or negative) it will usually be suggested to treat the patient as negative but this should be discussed with the consultant.

Recommendation - Choice of post-exposure prophylaxis
Due to a national shortage of ZIG, oral aciclovir should be given as prophylaxis except in cases where this is impossible, e.g. allergies, previous failure of ACV. These cases need discussion with the Consultant Virologist and Consultant Paediatric Haem/Onc on-call. See Appendix 3 for dosing in these rare cases,

Prophylactic High Dose Oral Aciclovir
Prescribe for 7 days from day 7 to 14 after contact
Dose: Under 2 years age 200mg four times daily
2 – 6 years age 400mg four times daily
over 6 years age 800mg four times daily

Administration of ZIG
If indicated, supplies of vials of ZIG are obtained in Leeds from the Virology department after discussion with the Consultant Virologist (via Switchboard)..

Zoster immunoglobulin (ZIG)
If less than 10 days from contact, given ZIG intramuscularly. This may attenuate infection if administered up to 10 days post exposure. Protection lasts 4 weeks.
ZIG dose: Under 5 years age 250mg
5 – 10 years age 500mg
Over 10 years age 750mg

The period of protection following ZIG administration is considered to be 4 weeks.

It is not necessary for the patient to be absent from school when contact has occurred once protection has been given. Giving post-exposure prophylaxis (PEP) will not guarantee that the child will not develop chicken pox/shingles but reduces the risk and possibly the severity of the disease.

Recommendation - Advise family to monitor patient
The family must immediately report the appearance of any suspicious spots and seek review even following post-exposure prophylaxis. If chickenpox / shingles is confirmed, be managed according to the treatment section of this guideline.

Recommendation - Advise family to isolate from any sib with VZV infection
If the immunosuppressed child’s sibling develops chicken pox/shingles, ideally they should not have contact with each other until the disease is no longer infectious, even if post-exposure prophylaxis has been given to the immunosuppressed child. It may be possible for the sibling to stay with relatives.

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Treatment - Diagnosis

If a patient develops clinically identified chicken pox or shingles they should be seen by their GP for confirmation.

It should be remembered that unexplained hepatitis (ALT>500) in patients with a suspicious history should be treated as varicella infection until deemed unnecessary by a Consultant.

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Treatment - Investigation

In most cases, clinical confirmation of VZV infection is sufficient.

In rare, uncertain case, discussion with the Consultant Haematologist/Oncologist or Virologist should be undertaken.

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Treatment - Management

Recommendation - Consider altering chemotherapy
Chemotherapy may need to stopped during treatment of VZV, but please discuss with the child’s consultant.

Recommendation - Well, afebrile children - Outpatient oral aciclovir
If the child is well and does not have a fever or cough and is not then severely lymphopenic (<0.5) they should commence a course of oral acyclovir (total 10 days). (See appendices 3 & 4 for oral and IV drug doses).

A well, afebrile patient who has developed VZV infection and neutropenia does not need IV aciclovir.

The child must then be reviewed at 48 hours by their GP, POSCU, CCN, parent or if absolutely necessary, at the oncology unit. The review should focus on the clinical state of the child (no new lesions and they remain well). If these criteria are met, then they continue on the oral aciclovir for a total of 10 days. If after 48 hours of receiving oral aciclovir, the patient is still developing new chicken pox lesions and/or has developed a cough, fever or is unwell then the patient should be admitted for IV aciclovir.

Recommendation - Unwell, febrile or lymphopenic - Admission and IV aciclovir
If the patient is unwell, has a fever and/or cough at initial diagnosis or at any point during the infection they must be admitted to commence IV aciclovir. (See appendices 3 & 4 for oral and IV drug doses). Liver function should be evaluated as varicella hepatitis can be fatal.

If the patient is well, but severely lymphopenic (<0.5) then IV aciclovir should be considered.

IV aciclovir at high dose is nephrotoxic. The patient should be started on full maintenance fluids for the first 48 hours, but this can be reduced if good oral intake and stable renal function. Renal function must be checked daily whilst on IV acyclovir.

IV aciclovir should be administered until the patient is clinically improving and afebrile, and no new lesions have developed followed by oral aciclovir to complete a minimum total of ten days of treatment.

Recommendation - Treat fever and neutropenia additionally as usual unit policy
If the patient is also febrile and neutropenic, the usual course of antibiotics should also be given as directed by the antibiotic policy. The patient can still follow the usual febrile neutropenia protocol: the presence of chicken pox does not change their antibiotic management.

Recommendation - Isolate Immunocompromised Patients with VZV infection
Children who develop chicken pox/shingles must not have contact with other immunosuppressed children until they are no longer infectious, i.e. all the lesions have dried.

Appendix 1

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Appendix 2

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Appendix 3

DOSES OF INTRAVENOUS ANTIVIRALS: PAEDIATRIC AND ADOLESCENT ONCOLOGY PATIENTS

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Appendix 4

Treatment of Herpes Simplex/Herpes Zoster Infections

Herpes Simplex

1. Oral Aciclovir :
   Dose:
   >2 yrs 400mg 5 times a day for 5 days
   <2 yrs 200mg 5 times a day for 5 days
   
   
2. IV Aciclovir : (severe oral lesions)
   Dose:
   < 3 months 5mg/kg/tds
   3 months - 12 yrs 250mg/m2/tds
   >12 yrs 5mg/kg/tds

For 5 days. The course can be completed with oral therapy if symptoms resolve. The dose should be doubled if severe infection or if the child is very immunocompromised.

Herpes Simplex Encephalitis

IV Aciclovir should be used for FOURTEEN days.

Dose:

Herpes Zoster (Chicken Pox or Shingles) (Treatment)

Dose: IV Aciclovir

Dose: Oral Aciclovir