# Presentation: 730503

## Varicella-Zoster Virus:Clinical Manifestations& Options for Post-exposure Prophylaxis

- Philip LaRussa, M.D.
- Columbia University
- July 21, 2005

## Topics for Discussion

- Clinical Manifestations of Severe Varicella
- Epidemiology of Varicella in the Vaccine Era
- Correlates of Protection against Varicella
- Options for Post-exposure Prophylaxis

## Pathogenesis & Implications for Prophylaxis

-  Exposure/ mucosa of the oropharynx
****
-  Replication of Virus in Regional Lymph nodes (1-2 days)
****
**Small Primary Viremia**
****
-  Replication in Reticuloendothelial system
-  ****
**Large Secondary Viremia**
- (10-12 days post-exposure, 1-2 days before rash)
-  ****
- Rash (12-14 days post-exposure)

## Typical Varicella

## Varicella is highly contagious after household exposure

- Ross, 1962

## Zoster

- Limited to 1-3 dermatomes.
- May disseminate in immunocompromised hosts.

## Varicella in Healthy Children:How Serious Can It Be?

**Severe Complications**
- Cerebellar Ataxia, Encephalitis
- Arthritis, Hepatitis
- Hemorrhagic Varicella
- Invasive Group A Streptococcal Infections
**Pre-Vaccine era:**
- Hospitalizations: ≥ 10,000 per year
- Deaths: 50 - 100 per year

## Severe Varicella in a Healthy 9 Year Old Female

## Who is at Higher Risk for Serious Disease?

**Immunocompromised Patients**
**Leukemia, Lymphoma**:
- 60 children with cancer on Chemotherapy/Pre-Antiviral Era (Feldman, 1975):
- 19 (32%) severe disease, 4 (7%) fatal
- 288 children with cancer/antiviral Era (Feldman, 1987):
- 150 Received VZIG: attack rate = ***5% ?? w/50% ************ in pneumonia***
- 127 untreated: 7% mortality; 28% pneumonitis (25% mortality)
- 18 treated with ACV: no pneumonitis
- Bone Marrow, Heart, Kidney Transplants
- HIV
- Immunosuppressive Therapy
**Children with Asthma**
- Low dose steroids?

## Who is at Higher Risk for Serious Disease?

**Neonates:**
- 30% mortality with maternal varicella within 5 days before delivery
**Normal Adults:**
- Pregnant women
- Smokers
- Health Care Workers
- Parents

## Child with Leukemia and Severe Varicella

**Child with Leukemia and Severe Varicella**

## Fatal Varicella in a Child with

**Fatal Varicella in a Child with**
**Juvenile Rheumatoid Arthritis**
**Receiving High Dose Steroid Therapy**

## Varicella in Healthy Adults, Deaths

**23 year old parent**
- Pneumonia (day 4), IV acyclovir (day 5)
- Hemorrhagic rash, D.I.C. (day 13), death (day15)
**25 year old parent**
- Pneumonia (day 3), encephalitis (day 4), IV acyclovir
- Death (day 18)
**32 year old, Crohn’s Disease, prednisone 40 mg/day, 4 weeks**
- Varicella diagnosed on day 3 of rash, no antiviral therapy
- Hemorrhagic rash, D.I.C., death (day 4)

## Severe Varicella in a Healthy Adult

## Risks During Pregnancy

- Maternal risk probably highest in 3rd trimester:
- Reports of fatal pneumonia
- Many susceptible adults come from tropical countries

## Congenital Varicella

**Congenital Varicella**

## Fatal Neonatal Varicella

## Zoster in a 3 month old

## How Has Varicella Vaccine Changed the Epidemiology of Varicella

## Varicella Disease After Introduction of Varicella Vaccine in the United States, 1995 - 2000(Seward, JAMA, 287:606-611, 2002)

## Correlates of Protection

## Correlates of Protection

- Ross, NEJM, 1962: 452 secondary contacts: More ISG less varicella
- Gershon, et. al., J Clinical Microbiology, 1978:
- Immunocompromised children immunized within 3 days of exposure with either Zoster Immune Globulin (ZIG) or Immune Serum Globulin (ISG)
_**	**__**Preparation**__**	**__**	**__**FAMA>2 @48 hrs;  GMT**__**	**__**Varicella**_
- _	__ZIG__ (0.15 ml/kg)_
- 		1:1024		22/22 (4 - 32)	11.7 		10/22, all mild
- 		1:512		15/18 (<2 - 16)	5.2		<2:   2/3, severe								>2:   7/15, mild
- _	__ISG__ (1:128)_
- 		0.6 ml/kg	7/7 (4 - 16)	7.3		0/ 7
- 		1.2 ml/kg	13/ 13 (4 - 16 )	9.4		3/ 13, all mild

## Correlates of Protection

- Orenstein, et. al., J Pediatrics, 1981:
- High risk recipients of ZIG who had a 4 fold-rise in CF antibody titer at 48 hours compared to pre-ZIG titers were less likely to develop varicella than those who did not show a 4-fold rise:
- 22.4% (n=49) vs. 44.7% (n=85)
- 45 of the 48 4-fold rises were from <2 to 4
- Recipients of higher titer ZIG(1:2,560-5,120) were more likely to have a 4 fold-rise in CF antibody titer than those receiving Low titer ZIG (1:1280)
- Complications were more frequent in recipients of low-titered ZIG
- Zaia, et. al., JID, 1983:
- Antibody titers 48 hours post-VZIG/ZIG did not correlate with infection rate or severity of disease

## Correlates of Protection

- Healthy Individuals
- Susceptible:
- FAMA <2
- Immune:
- Adults with a history of varicella:
- FAMA > 4 or a positive VZV skin test
- Children in Vaccine trials: 6 week post-immunization gpELISA > 5 units
- How do we separate out the role of the cell-mediated immune response ?

## Immunity to Varicella in Vaccinated Leukemic ChildrenAttack Rate at Household Exposure (n=39)

- _Ab/CMI_	_Varicella/ Exposed_ 	_Attack Rate(%)_
-    +/+			3/ 27				  10
-    +/ -			 2/ 6				  33
-    -/+			 0/ 3				    0
-    -/ -			  3/3				100

- Gershon, et. al. Infectious Disease Clinics of North America, 1996

## Options for Post-Exposure Prophylaxis in At-Risk Individuals

-  IGIV
-  Vaccine
-  Antivirals
-  VZIG
-  (ISG or therapeutic antivirals)

## IGIV

**Advantages:**
-  Some data to support it’s use
- Currently has good anti-varicella titers
- Will need 300 - 400mg/kg (3 - 8ml/ kg)
-  _Usually_ in ample supply
**Disadvantages:**
- Cost and difficulty of administration:
-  Intravenous line needed
-  2 - 4 hours for administration
-  Volume of administration in Newborns?
-  Not titered for VZV antibodies
- Waning Anti-varicella titers in the post-vaccine era?

## Comparison of VZV Antibody Titers in Patients Given IGIV or VZIG  

- Pediatric oncology patients susceptible to varicella, but not exposed
- 4 patients - VZIG 1 vial/10 kg
- 4 patients - IGIV 4 ml/kg at 4-week intervals
- 5 patients – IGIV 6 ml/kg at 6-week intervals
- VZV IgG antibody titers for a period of 4 to 6 weeks after IGIV (4 ml/kg or 6 ml/kg) were equivalent to the titers measured 3 to 4 weeks after VZIG
- Maximum VZV IgG antibody titers similar in all three groups:
-  achieved within 24 h after IGIV and 1 week after VZIG

- Paryani, et al., J Pediatr, 1984

## IGIV Prophylaxis in High Risk Children 

**Shu-Huey, et. al., Pediatr Hematol and Oncology, 1992:**
- 5 VZV susceptible leukemic children
- IGIV (200mg/kg) within 3 days of a household exposure
- No varicella developed in any of the five (7 exposures)
**Kavaliotis et. al., Med and Pediatr Oncol, 1998:**
- 52 pediatric oncology patients (79 exposures)
- Prophlylaxis within 6-24 hours after exposure
- 11 VZIG – 0 infected
- 30 IGIV – 3 infected
- 38 VZIG+IGIV – 3 infected
- Varicella was mild, recovered after ACV (IV 7 days + PO 7 days)
- Only 11% of patients developed varicella
_**Ferdman**_**, et. al., PID, 2000:**
- 3 patients who developed varicella despite IGIV therapy (7, 11, 30 days before exposure)
- Varicella was mild (IGIV, CD4 count, acyclovir therapy)
- IGIV-treated individuals with profound T cell deficiency or dysfunction may not respond as well and VZIG prophylaxis should be considered

## Vaccine for Post-exposure Prophylaxis

** ****Advantages:**
-  Data in healthy individuals
-   < 13 years of age at ≤ 36 hours post-exposure:
-  0/42 vaccinated vs. 1/1 unvaccinated developed varicella
-  Long-lasting protection
-  Easy to administer
** ****Disadvantages:**
-  Not appropriate for immunocompromised hosts, Pregnant women or Newborns
-  Efficacy of one dose for post-exposure prophylaxis in Healthy Adults?

## Antivirals for Prophylaxis

** ****Advantages**
-  Some data in healthy children
-  Available (Acyclovir, Famciclovir, Valacyclovir)
-  **Effective after the window for use of VZIG has passed**
** ****Disadvantages:**
-  Limited data in immunocompromised patients
-  Class C drugs in pregnancy
-  Use as P.O. prophylaxis in newborns?
-  Most of the data is with Acyclovir
-  Poor adsorption of P.O. Acyclovir
-  No liquid formulations of Famciclovir or Valacyclovir
-  Limits use in young children & infants
- Multiple day regimen/ compliance will effect efficacy

## Oral ACV During The Incubation Period (1)  

- Suga, et. al., Arch Dis Child, 1993:
- 				_ACV post-household exposure_
- 				_0-3 days_ 	_6-10 days_	_No ACV_
- Participants		  13	 	  14		  19
- Infection rate:		85%		79%		100%
- Clinical attack rate:	91%		27%		100%
- Severity:				milder

## VZIG

** ****Advantages:**
-  Benefits and Limitations are well understood
-  Long-standing experience
-  Utility in those who can not be vaccinated or when antivirals are not appropriate
-  Small volume for newborns
** ****Disadvantages:**
-  Cost of continuing production/ new source
-  Limited period of protection
-  May be more expensive to make in the vaccine era

## What Are Our Options for Prophylaxis in VZV-Susceptible High Risk, Exposed Patients?

- Immunocompromised Patients
- Leukemia, Lymphoma, Transplants, Immunosuppressive Therapy, HIV :
**VZIG**, or IGIV? or Antiviral ??

## What Are Our Options in VZV-Susceptible High Risk, Exposed patients?

- Neonates:
**VZIG**, or IGIV? or Antiviral ??
- Normal Adults:
- Pregnant women:
**VZIG**, or IGIV? or Antiviral ??
- Other Adults:
- VZIG or IGIV? or Antiviral ?? or Vaccine ??

## Summary

-  There probably is still a need for VZIG
-  IGIV is probably equivalent to VZIG in the appropriate dose
-  Antivirals may be useful, especially if the window for VZIG/ IGIV is missed, but should be tested in populations other than healthy children
-  Vaccine will be of limited utility as a substitute for VZIG

## Postexposure Prophylaxis of Varicella in HH Contacts by Oral ACV (1)

- Asano et al (Pediatrics, 1993), Lin et al (PID, 1997), Huang et al (PID, 1997)
- Oral ACV given to 69 healthy children, starting 7, 9, or 11 days after HH exposure
- Clinical features were compared with those among 51 controls who did not receive ACV
- The infection rate (seroconversion, ELISA) was similar in the two groups
- The clinical attack rate and severity of varicella were significantly lower in the ACV group

## Postexposure Prophylaxis with Oral ACV in High Risk Children (1)  

- Hayakawa et al (J Hosp Infect, 2003)
- Oral ACV administered to 6 preterm infants in cribs in the NCU, starting 7 days post-exposure
- None of them developed clinical varicella or had any adverse effects associated with ACV
- Seroconversion was not observed in any infant
- VZV DNA was not detected in 6 preterm infants on the expected day of onset of varicella (oral ACV completely inhibit replication or no transmission)

## Postexposure Prophylaxis with Oral ACV in High Risk Children (2)  

- Hernandez Martin (Pediatr Nephrol, 2000)
- 2 children (3 and 5 yo) with nephrotic syndrome receiving steroids
- Oral ACV given on the 9th day post-exposure (used twice the usual dose)
- Both patients developed humoral immunity (ELISA 2, 6, 9 months postexposure) without evidence of clinical infection

## Postexposure Prophylaxis with Oral ACV in High Risk Children (3)  

- Ishida et al (Pediatrics, 1996)
- 3 children (1-2 yo) with ALL
- Oral ACV administered within 48 h post-exposure
- Varicella was completely prevented in one child, 2 and 3 lesions were present in the other two (these 2 children also received gamma globulin )
- Seroconversion (ELISA) was observed in all children, but VZV antibodies disappeared 6 months later in the case who did not have symptoms

## IGIV and ACV Prophylaxis in High Risk Children

- Huang et al (Eur J Pediatr, 2001)
- High risk: 15 newborns whose mother’s rash was within 7 days before and 5 days after delivery
- 4 received IGIV soon after birth – 2 developed varicella
- 10 received IGIV and ACV (IV, 7 days after maternal rash onset) – none developed varicella
- 1 received ACV – no symptoms
- Not high risk: 9 newborns without prophylaxis
- 7 born >7 days after mother’s rash onset, 2 IgG – developed varicella
- 2 whose mothers had rash >5 days after delivery developed varicella