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Three Part Question

In [immunocompromised children], what [methods] are the best way of preventing [varicella infection, before and after exposure]?

Clinical Scenario

You are phoned by the parent of a child with juvenile idiopathic arthritis on regular Etanercept (TNF alpha antagonist). A classmate has gone down with chickenpox.

Search Strategy

MEDLINE(R) 1950 to September Week 3 2008
EMBASE 1980 to 2009 Week 05


1 Chickenpox/ 5818
2 1 or varicella.mp. 10643
3 Steroids/ 24101
4 methotrexate.mp. 34515
5 infliximab.mp. 4211
6 etanercept.mp. 1853
7 Antirheumatic Agents/ 8184
8 3 or 4 or 5 or 6 or 7 66932
9 2 and 8 72

Search Outcome

72 papers from Medline
283 from Embase

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Kinder AJ. Hassell AB. Brand J. Brownfield A. Grove M. Shadforth MF. 2005 UK	673 patients on methotrexate, of whom 551 had a diagnosis of rheumatoid arthritis.	Drug safety report.	Cases of varicella	1 disseminated varicella (fatal)	No mention of seronegativity rate among group. No details of case management.
Lovell DJ, Giannini EH, Reiff A, Jones OY, Schneider R, Olson JC, Stein LD, Gedalia A et al 2003 USA	58 children with juvenile rheumatoid arthritis on Etanercept. Most cases followed up for at least 2 years.	Cohort. Drug safety report.	Cases of varicella	3 (1 with aseptic meningitis). None received VZIG prophylaxis.	Not prospective with regards VZV exposure
Feldman S. Lott L. 1987 USA	288 cases of varicella in children with cancer were reviewed. Acyclovir administered to 18 patients Passive immunisation received prior to onset of varicella in 45 patients	Cohort	Mortality rate (overall)	7%	Retrospective, not randomized
			Pneumonitis rate	28% of the untreated patients
			Mortality in pneumonitis (overall)	25%
			Pneumonitis rate	0% of aciclovir treated patients
			Pneumonitis rate	11% of passively immunised patients
Evans EB. Pollock TM. Cradock-Watson JE. Ridehalgh MK. 1980 UK	43 high-risk close contacts of chickenpox receiving VZIG	Cohort	Cases of varicella	29 infected, clinical disease in 24
Emir S. Buyukpamukcu M. Koseoglu V. Hascelik G. Akyuz C. Kutluk T. Varan A. 2006 Turkey	40 seronegative children receiving treatment for lymphoma or solid tumours vaccinated against VZV.	Cohort	Seroconversion rate	75% after 2 doses
			Cases of varicella	1 of 40
			Cases of varicella (post exposure)	0 of 7 confirmed seropositive
Goldstein SL. Somers MJ. Lande MB. Brewer ED. Jabs KL. 2000 USA	8 children (10 separate exposures) receiving corticosteroids for renal disease, given prophylactic aciclovir in addition to VZIG.	Case-control	Cases of varicella	0 of 8 patients (1 seroconverted)	Small study, even smaller control group (4 patients receiving VZIG alone)
Geiser CF, Bishop Y, Myers M, Jaffe N, Yankee R 1975 USA	58 children with neoplastic diseases following a close family contact	Case control study, some receiving zoster immune plasma	Cases of varicella (untreated group)	14 out of 14, 2 fatal pneumonitis, 1 encephalitis	Non-randomized
			Cases of varicella (zoster immune plasma group)	8 out of 27, all very mild
Judelsohn RG. Meyers JD. Ellis RJ. Thomas EK. 1974 USA	56 high risk children (with negative histories) after close contact with VZV who received ZIG	Cohort	Cases of varicella	7 of 56	Susceptibility was not confirmed serologically in all cases (40 were proven seronegative, 7 had "anticomplementary serum"). 7 cases were treated more than 72 hours after exposure, only 1 of whom developed clinical disease.
Kornhuber B. Kropp H. Ribeiro-Ayeh J. Hinderfeld L. Welte K. 1982 Germany	298 children on chemotherapy because of malignant diseases given Varicella immunoglobulin after VZV exposure.	Cohort	Cases of varicella	4 (3 very mild)	Susceptibility not given in abstract
Leung TF. Li CK. Hung EC. Chan PK. Mo CW. Wong RP. Chik KW. 2004 Hong Kong	17 seronegative children undergoing treatment for ALL or solid tumours vaccinated vs VZV	Cohort	Seroconversion rate	94% after 2 doses	VZV exposure not described
			Vaccine disease rate	1 of 17
			Cases of varicella	0 of 17 at median 27 months of follow up
Salzman MB. Garcia C. 1998 USA	13 child household contacts of cases of varicella were vaccinated vs VZV.	Cohort	Cases of varicella	5 of 10 (only 1 developed more than 20 lesions)	Serology not done before vaccination 3 of 13 cases lost to follow up
Ishida Y, Tauchi H, Higaki A et al. 1996	3 children with leukaemia receiving ZIG and aciclovir post exposure	Case report	Cases of varicella	2 mild, 1 subclinical (of 3)	Small numbers
Martin Hernandez E. 2000; Spain	2 children with nephrotic syndrome post-exposure - no VZIG offered	Case report	Cases of varicella	0 clinical, both seroconverted	Ethically dubious. Small numbers.
Boeckh, Michael. Kim, Hyung W. Flowers, Mary E D. Meyers, Joel D. Bowden, Raleigh A. 2006 USA	77 haematopoietic cell transplant recipients as risk for VZV reactivation randomized to long term aciclovir or placebo for 1 year.	RCT	Cases of varicella (untreated group)	10 of 39	Patients with a history of varicella. Exposure not discussed.
			Cases of varicella (treated)	2 of 38

Comment(s)

There have been many case reports of severe varicella disease in the immunosuppressed (Rice, Leung),(but most varicella deaths actually occur in the immuncompetent. Few prospective studies so the incidence of varicella in these patients remains unclear (Lovell, Diez-Domingo). Given the potential for serious disease, patients starting immunosuppressive therapy should have their immunity to VZV checked, so that they and their families are aware whether or not VZV exposure is a risk. A positive history is usually but not invariably reliable (87-100% correct), whereas a negative history is not very reliable, especially in older age groups (as low as 26% correct),(Diez-Domingo, Heininger).

VZIG is not particularly effective at preventing disease. 3-50% will develop clinical varicella, depending on type of contact and how early it is given, but it tends to be less severe. Nonetheless, fatal cases have occurred (Feldman, Evans, Geiser, Judelsohn, Kornhuber). The Royal College of Paediatrics and Child Health recommends that “if circumstances permit, VZV antibody status should be checked prior to starting immunosuppressive treatment; where appropriate, varicella-zoster vaccine should be given at this time” (RCPCH, Best Practice Statement). In the immunosuppressed, it does appear be effective although it may take 2 doses (Emir, Leung). However, there is a risk of vaccine strain disease, hence the recommendation to vaccinate prior to immunosuppressive treatment.

Varicella vaccine can also be used as post-exposure prophylaxis. In immunocompetent children vaccinated within 3 days of exposure, it has protective efficacy of up to 90% (Ferson). But it is unclear whether such high rates are achievable with modern, lower dose vaccines; and again, the use of a live vaccine in this context is probably inappropriate for the immunosuppressed (Salzman).

Aciclovir post-exposure is 80-93% protective when given to healthy young household contacts, but it is not clear what dose is appropriate, what time period it is effective in or how long it should be continued (Huang). There are a few reports of its use post-exposure in the immunosuppressed where it does appear to prevent clinical disease, or at least modify it, either alone or together with immunoglobulin (Goldstein, Ishida, Martin). Bone marrow transplant recipients are usually on routine antiviral prophylaxis against herpesviruses, and this appears to be protective against varicella reactivation (Boeckh). Whether aciclovir in combination with VZIG is better than either alone is likely but unproven; an extended course of aciclovir would be indicated since VZIG prolongs the incubation period (Ogilvie). The possibility of inducing resistance with long term or frequent treatment must be considered. Since the use of live vaccines in the immunosuppressed is controversial, an alternative strategy for protecting those at risk would be to immunize potential contacts eg siblings. Varicella vaccine is licensed for this purpose, and could be considered for post-exposure prophylaxis. Vaccine strain disease does occur however, and can be transmitted between individuals, although symptoms are usually mild (Sharrar).

Clinical Bottom Line

Need for more studies to establish real level of risk. Status should be checked. Ideally varicella vaccine should be used before commencement of immunosuppression, and susceptible siblings should be immunised. VZIG is useful but not very effective as prophylaxis. Aciclovir and varicella vaccine can also be used prophylactically, but data is limited.

References

1. Rice P. Simmons K. Carr R. Banatvala J. Near fatal chickenpox during prednisolone treatment BMJ. 1994 ; 309(6961):1069-70
2. Leung,V.S.; Nguyen,M.T.; Bush,T.M. Disseminated primary varicella after initiation of infliximab for Crohn's disease. Am.J.Gastroenterol., 2004, 99, 12, 2503-2504
3. Kinder AJ. Hassell AB. Brand J. Brownfield A. Grove M. Shadforth MF. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology. 44(1):61-6, 2005 Jan.
4. Lovell DJ, Giannini EH, Reiff A, Jones OY, Schneider R, Olson JC, Stein LD, Gedalia A et al Pediatric Rheumatology Collaborative Study Group. Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multi Arthritis & Rheumatism. 48(1):218-26, 2003 Jan.
5. Feldman S. Lott L. Varicella in children with cancer: impact of antiviral therapy and prophylaxis. Pediatrics. 80(4):465-72, 1987 Oct.
6. Ogilvie MM. Antiviral prophylaxis and treatment in chickenpox. A review prepared for the UK Advisory Group on Chickenpox on behalf of the British Society for the Study of Infection. Journal of Infection. 36 Suppl 1:31-8, 1998 Jan.
7. Diez-Domingo J. Gil A. San-Martin M. Gonzalez A. Esteban J. Baldo JM. Planelles MV. Ubeda MI. Graullera M. Peris A. Martinez M. Anton V. Gallego D. Alvarez T. Villarroya JV. Jubert A. Casani C. Peidro Seroprevalence of varicella among children and adolescents in Valencia, Spain. Reliability of the parent's reported history and the medical file for identification of potential candidates for vaccinat Human Vaccines. 1(5):204-6, 2005 Sep-Oct.
8. Heininger U. Baer G. Bonhoeffer J. Schaad UB. Reliability of varicella history in children and adolescents. Swiss Medical Weekly. 135(17-18):252-5, 2005 Apr 30.
9. Evans EB. Pollock TM. Cradock-Watson JE. Ridehalgh MK. Human anti-chickenpox immunoglobulin in the prevention of chickenpox. Lancet. 1(8164):354-6, 1980 Feb 16.
10. Emir S. Buyukpamukcu M. Koseoglu V. Hascelik G. Akyuz C. Kutluk T. Varan A. Varicella vaccination in children with lymphoma and solid tumours. Postgraduate Medical Journal. 82(973):760-2, 2006 Nov.
11. Ferson MJ. Varicella vaccine in post-exposure prophylaxis. Communicable Diseases Intelligence. 25(1):13-5, 2001 Jan
12. Goldstein SL. Somers MJ. Lande MB. Brewer ED. Jabs KL. Acyclovir prophylaxis of varicella in children with renal disease receiving steroids. Pediatric Nephrology. 14(4):305-8, 2000 Apr.
13. Geiser CF, Bishop Y, Myers M, Jaffe N, Yankee R Prophylaxis of varicella in children with neoplastic disease: comparative results with zoster immune plasma and gamma globulin. Cancer. 1975 Apr. 35(4):1027-30
14. Judelsohn RG. Meyers JD. Ellis RJ. Thomas EK. Efficacy of zoster immune globulin. Pediatrics 1974 Apr. 53(4):476-80
15. Kornhuber B. Kropp H. Ribeiro-Ayeh J. Hinderfeld L. Welte K. [Varicella-zoster-immunoglobulin as a safe prophylaxis of varicella] [German] Monatsschrift Kinderheilkunde. Organ der Deutschen Gesellschaft fur Kinderheilkunde. 1982 Jan. 130(1):27-9
16. Leung TF. Li CK. Hung EC. Chan PK. Mo CW. Wong RP. Chik KW. Immunogenicity of a two-dose regime of varicella vaccine in children with cancers. European Journal of Haematology. 2004 May. 72(5):353-7
17. Salzman MB. Garcia C. Postexposure varicella vaccination in siblings of children with active varicella. Pediatric Infectious Disease Journal. 1998 Mar. 17(3):256-7
18. Ishida Y, Tauchi H, Higaki A et al. Postexposure prophylaxis of varicella in children with leukemia by oral acyclovir. Pediatrics 1996;97:150-1
19. Martin Hernandez E. Acyclovir prophylaxis of varicella in children with nephrotic syndrome. Pediatric Nephrology 2000;15(3-4):326-7
20. Boeckh, Michael. Kim, Hyung W. Flowers, Mary E D. Meyers, Joel D. Bowden, Raleigh A. Long-term acyclovir for prevention of varicella zoster virus disease after allogeneic hematopoietic cell transplantation--a randomized double-blind placebo-controlled study. Blood 2006 Mar. 107(5):1800-5
21. Sharrar RG, LaRussa P, Galea SA et al. The postmarketing safety profile of varicella vaccine. Vaccine 2000;19:916–923.
22. Huang YC, Lin TY, Chiu CH. Acyclovir prophylaxis of varicella after household exposure. Pediatr Infect Dis J 1995;14:152-4.
23. Royal College of Paediatricians and Child Health. Immunisation of the immunocompromised child. Best Practice Statement. February 2002