Passive Immunoprophylaxis for Tetanus, Varicella, HAV, HBV

and Uses of IVIG

Janet Wong, M.D.

1
 Immunoglobulin Preparations
• Immune Globulin (IG)
- Produced from pooled human plasma
Tetanus prophylaxis Globulin. The main product is tetanus immunoglobulin,
which is a human immunoglobulin with increased anti-tetanus antibody titers.
It is an immunoglobulin preparation. The indication for using tetanus
immunoglobulin is in an individual where they have received less than 3
doses of tetanus vaccine and have a serious dirty wound or puncture site, or
devitalized tissue, or it has been contaminated with soil or feces.
Immunocompromised patients, particularly AIDS patients with tetanus prone
wounds, should be immunized regardless of vaccine status because, in
immunocompromised patients, you may not be able to rely upon them having
mounted an adequate immune response.

- 16.5% protein; 95% IgG

- IM use only; Cohn Fraction two

• Intravenous Immune Globulin (IVIG)

- Produced from pooled human plasma

- 3-12% protein; >95% IgG

- IV use; further processing after fractionation

• Specific Immune Globulin

- Produced from specific donors

- Screened plasma or immunized donors

- Immunized animals (Equine)

- Both IG and IVIG

- Monoclonal antibodies

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 Use of Immunoglobulin in Tetanus Prophy-
laxis -- Tetanus Immune Globulin (TIG)
Type:
Generally it is given as a single dose, and, because it is an immunoglobulin
not IVIG, it must be given by IM injection, and you should infiltrate part of the
dose around the wound. Immunoglobulin is not indicated for minor clean
wounds. All wounds should be properly cleaned and débrided, and foreign
material Removed. Booster toxoid vaccines are still important in the proper
situations.

€ Human Immunoglobulin with increased anti-tetanus antibody titers.

€ Indications for TIG Trauma/Wound Prophylaxis:

• < 3 doses of tetanus vaccine
• Serious or dirty wound (puncture wounds, devitalized tissue; soil,
saliva, feces contamination)
• AIDS patients with tetanus-prone wounds (regardless of vaccine status)
• Unknown tetanus vaccine status

€ Dose:
• Single dose of 3,000 u to 6,000 u
• IM injection
• Infiltrate part of dose around the wound

TIG is not indicated for minor, clean wounds; all wounds should be
properly cleaned and derided and foreign material removed. Booster
toxoid vaccine may be indicated if < 3 previous tetanus toxoid doses or
>10 years since last tetanus toxoid (clean, minor wound) or >5 years
since last toxoid dose for more serious contaminated wounds.

3
 Varicella-zoster Immune Globulin (VZIG)
€ Type:
• Human Immune Globulin with increased levels of anti-VZV antibody.
€ Decision to use VZIG
• Likelihood the individual will develop complications if infected with
Varicella.
• Probability an exposure will result in a Varicella infection.
• Likelihood the exposed person is susceptible.
€ Indications after Varicella-Zoster exposure:
• Immunocompromised children without history of chickenpox.
Immunocompromised adolescents and adults are likely to be immune,
but if susceptible, they should also receive VZIG.
• Susceptible, pregnant women.
• Newborn infants whose mothers have the onset of chickenpox within 5
days before delivery or within 48 hours after delivery.
• Hospitalized premature infants (> 28 wk gestation) whose mothers
have no history of chickenpox.
• Hospitalized premature infants (<28 wk gestation or <1,000 g),
regardless of maternal history.
Varicella-zoster immunoglobulin is a human immunoglobulin that has
increased levels of anti-VZV antibodies. The decision to use varicella-zoster
immunoglobulin is based on the likelihood that the individual will develop
complications if infected with varicella and the probability that an exposure
will result in varicella infection, and the likelihood that the exposed person is
actually susceptible to varicella.
Indications for use after a varicella exposure. Immuno compromised children
without a history of chicken pox are definitely an indication, and
immunocompromised adolescents and adults are likely to be immune. Again,
if susceptible, they also should receive VZV, and age here is not limited to
children.
Susceptible pregnant woman should receive it, and this is because they are
at increased risk to disease themselves. Newborn infants whose mothers
have the onset of chicken pox within 5 days before delivery or within 48 hours
after delivery, will not have received from the mother: antibodies because that
mother was susceptible and, therefore, that newborn is at risk and should
receive VZV.
Hospitalized premature infants whose mothers have no history of chicken
pox, or hospitalized premature infants less than 28 weeks' gestation or less
than 1,000 grams, regardless of the term history, should receive it when
there is significant exposure. Well, we know that the majority of the
immunoglobulin IgG passes from the mother to the baby in the last 4 to 6
weeks of pregnancy. So, that even if the mother had a good level of
antivaricella antibodies, the baby would not have received it if it were at 28-
weeks' gestation or less.
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 Types of Exposure to Varicella or Zoster for
Which VZIG is Indicated*+ Types of exposure to varicella or zoster for which this is indicated. A
household contact where the individual is residing in that same household
or a playmate with face-to-face indoor play. Some people have said that 5
minutes or more exposure is significant. Some have said it needs to be
longer than that. Nobody knows exactly what the number is, but this is a very
• Household: Residing in the same household infectious virus, and one must consider even a reasonably brief exposure as
being significant.
• Playmate: Face-to-face- indoor play In the hospital, if you have in the same room an individual who is suscepti-
ble, that is in a 2- to 4-bed room or an adjacent bed in a larger ward, face-to-
• Hospital: face contact with an infectious staff member or patient. A visit by a person
being contagious.

Varicella:
a) in same 2- to 4-bed room, or adjacent beds in large ward,
b) Face-to-face- contact with an infectious staff member or patient, or
c) Visit by a person deemed contagious.
In the newborn infant, the onset of varicella from the mother, 5 days or less
before delivery or within 48 hours. Again, it is not indicated that the mother
have zoster and, again, many of these women have high antibody titers, and
if that baby is not born prematurely would have antibodies.
The important thing here is for maximal effectiveness, and these should be
given within 48 hours of exposure and not more than 96 hours after
exposure.

Zoster: Intimate contact (eg, touching or hugging) with a person deemed

contagious.
• Newborn infant: Onset of Varicella in the mother 5 days or less before
delivery or within 48 h after delivery. VZIG is not indicated if the mother
has Zoster.

* Patients should meet criteria of both significant exposure and candidacy

for receiving VZIG
+
VZIG should be administered within 96 h preferably sooner after
exposure.
- Experts differ in the duration of face-to-face contact that warrants the
administration of VZIG. However. the contact should be non-transient.
Some experts suggest a contact of 5 or more min as constituting
significant exposure for this purpose; others define close contact as more
than1 h.

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 VZIG Dose:
€ 125 u (one 1.25 mL vial) per/10 kg maximum dose is 5 vials (625 u),
minimum dose is 1 vial (125 u) (for maximal effectiveness VZIG should
be given within 48 hours of exposure and not more than 96 hrs after
exposure).
€ Avoid use in patients with bleeding disorders (VZIG cannot be given
IV).
€ IVIG (400 mg/kg) within 3 weeks should be protective and additional
VZIG is not required.
€ Exposed susceptible receiving VZIG should be considered exposure
risks for 28 days (normal 8-21 days).
€ If VZIG given > 3 weeks prior to a second exposure, a second VZIG
dose may be given if no infection after the first exposure.
You want to avoid use in patients with bleeding disorders and these things
cannot be given IV. So, the only alternative here again, is to use IVIG and
again 400 mg to 500 mg per kg within 3 weeks should be protective, and you
have some patients who are receiving IVIG prior to being exposed as part of
their normal immunoprophylaxis. The thing you need to be sure of in this
case is what is the dose of IVIG they are receiving, because not all patients
receive 400 mg to 500 mg per kg and secondly, is it within 3 weeks.
Exposed and susceptible children should be considered an exposure risk for
28 days. Normally, we talked about the incubation period being 8 to 21 days,
and that you have to watch individuals who have been exposed for 21 days
to ensure that they do not come down with varicella and then expose other
patients. If that individual again has received VZ, you may delay the onset of
clinical disease, and therefore you need to consider them a risk for 28 days.
If VZ is given greater than 3 weeks prior to a second exposure, and a second
VZ dose is being considered, if they did not develop clinical disease, and you
do not know that they developed varicella, then you must consider them
susceptible again. It often comes up where an individual has been reexposed
but received VZ previously. If it is greater than 3 weeks, they should received
a second course of VZ.
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Immunoglobulin for Hepatitis B Prophylaxis
€ Immune globulin-standard (IG)
• Immune globulin (human) 16.5% protein (165 mg/mL; 95% IgG)
€ Indications:
• Prevention of Perinatal HBV infection
• When mother is HBsAg positive
• Sexual contact (acute HBV case)
• Acute blood exposure (positive for HBsAg or potentially positive)
Immunoglobulins for hepatitis B prophylaxis. This hepatitis B immunoglobulin
again is a pooled fraction, and the indications for hepatitis B immunoglobulin
are the prevention of perinatal hepatitis B infection when the mother is
antigen positive, sexual contact of an acute hepatitis B case, and acute blood
exposure that is positive for hepatitis B or potentially positive. In the case of
hepatitis B immune globulin, the exposure needs to be one of an acute
nature. Notice that if it is a sexual contact with a chronic carrier or a
household contact with a chronic carrier, the prophylaxis of choice is
vaccination. However, if it is perinatal where there is an acute exposure
because of a mother being known to be antigen-positive, then HV must be
given in the first 12 hours after birth. If it is a primary household contact of an
acute case with identifiable blood exposure, HV is indicated. HV is indicated
in the infant less than 12 months of age if the acute case is in a primary
caregiver or in any patient where you have an accidental percutaneous
exposure.
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Post Exposure Immunoprophylaxis for Hepa-
titis B Infection
Type of Exposure
Perinatal
Sexual - acute infection
Sexual - chronic carrier
Household contact- chronic carrier
The indications for HV are very much based on susceptibility and known
vaccine history. If you know that they are unvaccinated and it is an exposed
individual, HV is important. If they have been previously vaccinated and is a
known responder, HV may not be used. If you have a known non-responder,
HV can be given and should be given and can either be given as 2 doses of
Immunoprophylaxis HV or HV plus 1 dose of hepatitis B vaccine. If you do not know the response,
HBIG + vaccination then if you test them, then if the exposed person is antibody negative for
HBIG + vaccination hepatitis B surface antigens, then they should receive HV.
Vaccination
Vaccination

Household contact - acute case

with identifiable blood exposure HBIG + vaccination
Infant (<12 mo) - acute case
in primary caregiver HBIG + vaccination
Accidental - percutaneous/
permucosal HBIG + vaccination

8
 Recommendations for Hepatitis B Prophy-
laxis after Percutaneous Exposure to Blood Now, the newborn has one other situation, and that is if you know the mother
is hepatitis B surface antigen positive, then HV is given immediately after

That Contains (Or Might Contain) HBsAg birth. If you know that you do not know that the mother is hepatitis B surface
antigen positive, if this is a high-risk individual should be tested, and if they
are positive, then the HV should be given, and it should be given in general
Treatment when source is found to be
within one week after birth.
Source
Exposed Source Source Unknown or
Person HBsAg-Positive HBsAg-Negative Not Tested

Unvaccinated Administer HBIG X I: and Initiate hepatitis B Initiate hepatitis B

initiate hepatitis B vaccine- vaccine vaccine'

Previously Test exposed person No treatment No treatment

vaccinated for anti-HBs
Known I. If adequate, no treatment
responder 2. If inadequate, hepatitis
B vaccine booster dose

Known HBIG X 2 or No treatment If known high-risk

nonresponder HBIG x I plus I dose source, may treat as
of hepatitis B vaccine as if source were
HBsAg-positive

Person for Test exposed person No treatment Test exposed person

whom response for anti-HBs for anti-HBs*
is unknown I. If inadequate, HBIG I. If inadequate,
x I, plus hepatitis B hepatitis B vaccine
vaccine booster dose- booster dose
2. If inadequate, 2. If adequate,
nn treatment no treatment

Hepatitis B immune globulin (HBIG dose 0.06 mL/kg, intramuscularly

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 Recommended Schedule of Hepatitis B
Immunoprophylaxis to Prevent Perinatal How is HV given? It is given 0.5 mL IM within 12 hours for newborns and at
a different site than the vaccine. As older children and adults, they should

Transmission received 0.06 mL which is smaller.

Infant born to mother known to be HBsAg-positive:

Vaccine Dose and HBIG Age

First Birth (within 12 h)

HBIG Birth (within 12 h)
Second 1 mo
Third 6 mo

Infant born to mother not screened for HBsAg:

Vaccine Dose Age

First. Birth (within 12 h)
HBIG If mother is found to be
HBsAg positive, give 0.5 mL as soon as
possible, not later than 1 wk after birth

Second 1-2 mo
Third 6-18 mo^

Dose:

• Infants: HBIG 0.5 mL, IM within 12 hours after birth (at site
different from HBV vaccine)

• Older children/adults HBIG 0.06 mL/kg, IM

Due to plasma screening, the concentration of anti-HBs has declined in

standard immune globulins and thus only HBIG should be used for post-
exposure prophylaxis.

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 Use of Immunoglobulin in Hepatitis A Pro-
phylaxis
Immune globulin-standard (IG)
• Immune globulin (human) 16.5% protein (165 mg/mL; 95% IgG)
Indications:
• Household and sexual contacts of a Hepatitis A case
a. Identify exposed individuals
b. Administer IG as soon as possible
c. IG not indicated >2 weeks after exposure
• Newborn infants of infected mothers
a. May consider IG if material infections 2 weeks before
b. Efficacy not established
• Child care
a. HAV may survive on objects for weeks.
b. Facility with all children over 2 years or toilet trained: IG should be
given to all children in the same room and employees in contact
with patient.
c. Facility where children not yet toilet trained: IG should be given to
ALL employees and enrolled children (to include new employees
and children).
1. one case of HAV in child or employee
2. HAV infection in household contacts of two enrolled children
If child care outbreak is not recognized for >3 weeks from onset of index
case.
a. Disease is likely to have spread widely.
b. Consider IG use in:
1. all children enrolled
2. all staff
3. household contacts of enrolled children in diapers
Exclude children and adults with acute HAV infection from the child care
facility until one week after onset of illness or all appropriate children and
staff get IG. IG should not be given to those with HAV infection.
• Schools and Hospitals
a. IG generally not indicated.
b. IG may be given if close personal contact with a case.
c. IG should be given in outbreaks in custodial care institutions to all
staff and residents in close personal contact.
• Food or Waterborne Outbreaks
a. Source usually recognized late.
b. IG not indicated, unless <2 weeks from exposure.
• Foreign Travel
a. Travel to developing countries.
b. IG recommended short stay.
c. HAV vaccine for regular travelers or prolonged stay.
What about the use of immunoglobulins in hepatitis A prophylaxis? We are
using standard immunoglobulin that has antibody antigen to hepatitis A. The
indications for hepatitis A immunoglobulin use are a household and sexual
contact of an hepatitis A patient, and here you need to identify exposed
individuals and administer IG as soon as possible. What is very important
here is that this has to be delivered within two weeks to be very effective.
Indications of immunoglobulins for hepatitis A. For the newborn infants and
expectant mother, you may consider IG, if the maternal infection is two
weeks before. Again, what you are looking at is a mother who you know was
susceptible and did not transmit antibodies to that infant.
Child care is an area where this question comes up commonly. What do you
do in a setting of a child or even a childcare worker who comes in with
hepatitis A in that setting? HAV may survive on objects for weeks. We know
that hepatitis A is a very sturdy virus. You need to look at is the characteris-
tics of the facility. If the facility has all children two years of age or older and
they are all toilet trained, then you must determine where the exposure
occurred. So, you should give the immunoglobulin to all the children in the
same room and employees with direct contact with that patient. So, if they
are older and toilet trained, you focus on the case. On the other hand, if it is
a facility where the children are not yet toiled trained, where we know that
this virus can maintain itself on articles and toys for a long period of time, you
need to give the immunoglobulins to all employees enrolled and all enrolled
children, including new employees and children. The current guidelines are
triggered if one case of hepatitis A virus occurs in a child or employee of that
day care center or hepatitis A virus infection in household contacts of two
enrolled children. What they are saying there is that if just one household
member came down with hepatitis A virus, you cannot be sure that it was
from the daycare center. However if you have two instances, the likelihood
now is greatly increased that hepatitis A virus is in that daycare center and
you need to protect the rest of the people.
Now, one of the big problems in childcare, is identification of the outbreak.
If the childcare outbreak is not recognized for greater than 3 weeks from
onset, then this disease is likely to have already spread widely. You can
consider IG use in this setting, however; its overall effectiveness may be
decreased because you do not know how widely spread it is already. All
children enrolled, all staff enrolled, all household contacts of enrolled
children in diapers. If you have one that has spread widely, you have much
more difficulty controlling it.
Now, when you are looking at using immunoglobulins you should exclude
children and adults with acute hepatitis A virus infection because this is not
a treatment, this is a prevention. You should exclude the children who have
the disease from the onset of illness for one week. All appropriate children
and staff should get IG. You need to keep those who are infected out, protect
the people in, but you do not use it as a treatment. You want to make sure
you are not giving it to those who have hepatitis A virus.
Schools and hospitals. If somebody is at school ill the nurse calls and if
somebody has hepatis A in a classroom. In general, immunoglobulin is not
indicated. It may be indicated in a close personal contact, if somebody has
had a close personal contact with a case. IG should be given in outbreaks
in those medical institutional facilities where there is custodial care, and it
should then be given to staff and residents in close personal contacts. You
are looking more now at a daycare center where you do not expect wide-
spread dissemination, but there may be people exposed that are in very
close contact with the individual case, and hopefully it would not spread
beyond that. The single most important thing to keep from spreading this
from one patient to the other is still good hand washing. It is critical for all of
these agents, that the spread by people oral contamination and that it can
survive particularly for a long time on materials and articles.
The other indication is food- or waterborne outbreaks. The problem with
dealing with this is, by the time you get called by somebody that they have
actually recognized that they may have a food borne outbreak of hepatitis A,
it is usually so late that you cannot get within the two week window. If you get
fortunate enough to be in a situation where it is identified early and the
epidemiology is understood, then you may be able to give IG in that setting.
Most of the time, however, you just do not have all the information together
in that time period.
Foreign travel is one of the most common areas right now where people
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 Dose
• 0.02 mL/kg IG deep in large muscle as soon after exposure as possible
or pre-travel (max per dose site - 5 mL large child/adult or 1-3 mL small
child/ infant; max total dose in adult generally 20 mL).
have been getting immunoglobulin. If you go to developing countries where
hepatitis A may be a common exposure, IG is recommended. It is really now
only recommended for short stays, and I think what we are going to see is
that not only will hepatitis vaccine be used for those regular travelers and
people who are there for a prolonged stay, I think we are probably going to
see even a wider use for travelers in general for hepatitis A. Right now its
indications are for regular travelers and those who are going to be there a
long time. We have got such a mobile society that somebody will come into
you today and say, "I am going for my first trip someplace." So you give them
immune serum globulin. It is not unlikely that they are going to be back to see
you in the next year or two and say, "I am going again someplace." That this
vaccine is very effective and very good, and I think that it is going to become
an important part of the thought process for travelers. So, I think that for
regular travelers you have to think about and maybe do a better history to find
out if they are really thinking about going back and forth to places on a
regular basis. The dose of IG is .02 mL. Deep in large muscle as soon after
exposure as possible or pre-travel.
Now, you can see we are talking about reasonably good-size doses here,
particularly when you get into larger children. I much prefer getting two shots
of hepatitis A vaccine then even thinking about a second shot of immune
serum globulin. I think this alone will induce many people to get the vaccine
rather than sticking with immune serum globulin.
There are many things that antibodies. There are now many IVIG prepara-
tions, and there are different plasma pools and different production
techniques for each of these.
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 Comparison of IG and IVIG
Now, I think that when we think about how you use intravenous immunoglob-
ulin that it is helpful to categorize the use in three main categories. One is
IG IVIG replacement therapy, which is the one that we have been use to talking about
Pain on injection Minimal pain on infusion over the years. The second is specific uses which could become important
Rapid administration IM Slower infusion IV (several hours) for bacteria, as well as for viruses where there is no therapy. Then,
immunomodulation. This is an area where not everything is understood.
Limited amount of IgG Large amounts of IgG can be infused There are many diseases where affecting the up-regulation or down-
can be injected regulation of the immune system may play a major role in infectious disease
treatment.

Slow rise in serum IgG Rapid peak serum IgG achieved Use of intravenous immunoglobulin therapy as replacement therapy. The
standard one that we are all aware of is primary immunodeficiency disease.
Modest elevation in total Marked increase in total serum IgG Here we now use closer to 400 mg/kg for replacement. The idea being that
you need to get the serum antibody level in a high enough range to get at the
serum IgG
tissues to maintain prevention of respiratory disease, sinusitis, and so forth.
This generally means that what you need to do is adjust the dose according
Some degradation of IgG IgG generally delivered to tissues intact to the serum IVG level for each individual.
at inject site

13
 Indications and Rationale
• Indications for IVIG are rapidly expanding.
• Rational for IVIG Use:
1. Opsonize bacteria or neutralize viruses or toxins
2. Immune modulation (ie, phagocyte Fc Receptor blockade, anti-
idiotypic antibodies, clearance of immune complexes, etc.)
• Many IVIG preparations; plasma pools and production techniques vary.
In cancer there is one indication and that is in primary lymphocytic leukemia,
which is primarily in adults. Here, while it was shown to effectively prevent
bacterial infection, it really was shown not to be cost effective, and that is
being questioned in how useful it is in that setting and is yet to be deter-
mined.
One of the big concerns about the treatment or the use of IVIG for the
prevention of infection is that one delivers the specific antibodies that may be
needed to be protected from the infection that the patient is exposed to. The
IVIG preparation and losses very significant antibody titers to the pathogens
such as Staph aureus. If a baby is exposed to a particular pathogen and the
preparation does not have this, then he will not be protected. So, you can
only provide protection if the immunoglobulin preparation has antibodies to
the origin. Prophylaxis is not standard, but it has been used in some patients.
14
 IVIG Administration
In bone marrow transplant, IVIG has been used. It is often given one week
before and weekly for 90 days, and it has been shown to reduce infections.

• Replacement Therapy
• Pathogen Specific Uses
• Immune Modulation
HIV infection is another area where if one gets selected HIV patients,
particularly those who are symptomatic, that have humoral immune
dysfunction, particularly those who have recurrent bacterial infections, those
who do not respond to vaccines, and those individuals who are
hypergammaglobulinemic. They should be treated with IVIG, and again one
needs to be at this 200 mg/kg to 400 mg/kg range. This is now an approved
indication, but I think the key is being selective for those patients who have
evidence of a humoral immunodeficiency, either demonstrated clinically or
from a laboratory.

15
 Uses of Intravenous Immune Globulin Ther-
apy Replacement Therapy One of these areas that is rapidly being explored is the use of intravenous
immunoglobulin therapy for pathogens. Cytomegalovirus has been used both
as a prophylaxis in cytomegalovirus, this has been used as a prophylaxis and
a therapy. Here we have both specific CMV immunoglobulin and there is a
standardized IVIG. For prophylaxis, both the standard IVIG and the
hyperimmune preparations have been shown to have a good result.
Indications Dosage Efficacy Comments

10 Immunodeficiency 100-400 mg/kg AI* Adjust dose according

q 4 weeks to serum IgG levels

CLL 400 mg/kg AI Cost effectiveness is

q 3-4 weeks is questioned

Premature Infants 500-750 mg/kg CT Variable antibody titers

q 2 weeks to neonatal pathogens

Bone Marrow 500 mg/kg CT Reduces infections and

Transplant 1 wk before and graft vs. host disease
weekly for 90 days

HIV Infection 200-400 mg/kg CT Selected symptomatic

q 2-4 weeks HIV patients

*AI - Approved Indication; CT - Clinical Trials

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 Uses of Intravenous Immune Globulin Ther-
apy Pathogen Specific Uses One area where therapy has been particularly moving towards is combined
IVIG for specific CMV therapy and ganciclovir in the bone marrow transplant
group. Here, using a specific CMV-IVIG plus ganciclovir, increases the
survival in a CMV pneumonia bone marrow transplant patient up to as much
as an 80% survival, and that is a great improvement from previous therapeu-
Indications Dosage Efficacy Comments tic strategies.
Cytomegalovirus 500 mg/kg wkly CT/AI* Specific CMV IVIG and
Prophylaxis for 90 days IVIG both efficacious
Group B strep prophylaxis and therapy with IVIG has been used. It generally
Therapy 400-500 mg/kg with CT/AI Specific CMV IVIG only has not been as effective in prophylaxis because we do not know what is in
ganciclovir the preparation that you use and some of the large studies, particularly the
study where they looked at prophylaxis of late onset, they found that they did
Group B Streptococcus 500 -750 mg/kg CT During hospitalization
prevent group B strep infections with IVIG, and that they did have antibodies
Prophylaxis q 2 weeks
in the group B streptococci and in their preparation. So, that prophylaxis is
Therapy 500-1000 mg/kg CT One or two doses possible, but because you do not know what is in the preparation, it is not
routine.
Respiratory Syncytial 750 mg/kg q 4 weeks CT Specific RSV-IVIG in
Virus Prophylaxis during RSV season high-risk infants For therapy, it is again not standard to treat group B streptococcus with IVIG
as adjunctive therapy. However, there are those patients who, when they
Therapy 750-1000 mg/kg CT Specific RSV-IVIG;
reduces shedding become septic have a particularly severe and pulmonic course, these may
get into profound shock, and it would be very difficult to get them stabilized.
Parvovirus 400 mg/kg daily for CR Relapses responded to In those instances, we often think about what other things could we do to
5-10 days retreatment help stabilize them, to help the immune system clear the organism. When
you have a patient that is not responding well one of the things that can be
*AI - Approved Indication; CT - Clinical Trials
done is to give IVIG and to give it in the range of 500 mg to 1,000 mg/kg.
Two things have been identified to occur if there are antibodies to the
organisms they are being invaded with in that preparation. One of them is
that when the antibody attaches to the bacteria, it causes the deposition of
complement, and those organisms are then more rapidly cleared from
circulation, and bacteremia can then be reduced. That has been shown in
both in vitro studies and animal studies.

17
 Uses of Intravenous Immune Globulin Ther-
apy Immune Modulation The second thing that has been shown very nicely, and this has been in both
animals and in human studies, is that the white blood cell count, which often
in these stages is dropping during the acute stage of their illness, will
respond rather quickly. That will generally occur over 6 to 12 to 24 hours, so
even a rapidly dropping peripheral white blood cell count may well benefit
Indications Dosage Efficacy Comments
from IVIG.

Kawasaki disease 2 gm/kg, single dose AI* Treatment before 10

When the IVIG antibodies to that organism attach to the bacteria and cause
days
the deposition of compliment, there are fragments that are broken off. It has
been shown in studies that using just the compliment fragments that are
Guillain-Barre 400 mg/kg/d for 5 d CT Treatment early after
broken off, they will go to the bone marrow and will cause decrease depletion
dx
of bone marrow storage pool cells and will increase the release of cells to
the peripheral blood. So that in this setting you actually have the ability to
Immune 400 mg/kg/d for 5 d AI Also up to 2 gm/kg in
increase neutrophil movement into the blood and to decrease neutrophil
Thrombocytopenia a single dose or divided
storage pools.
into 2 doses given over
2 days
Respiratory syncytial virus is an area where we do not have a good
Staphylococcal and 500-1000 mg/kg CR Selected, severely ill
prophylaxis or therapy at this point, and the use of a high titer selected RSV
Streptococcal Toxic patients
immunoglobulin has been shown to reduce both hospitalizations, hospital
Shock
days, and intensive care days for individuals with RSV. Prophylaxis should
be limited to high-risk individuals, and that is individuals who are premature,
less than six months of age in the season of disease, or those individuals
who have bronchopulmonary dysplasia and have oxygen requirements. I think
that the issue here is having to give an IV infusion several times during the
winter season, and the cost of it, and which patient should receive it. In the
near future, you may have a preparation that can be given quickly by
intramuscular use at a small volume and delivered in the clinics.

Therapy with RSV immunoglobulin has not been shown to be as effective as

a therapeutic agent at this time. It has shown to reduce shedding, but it is not
indicated as therapy at this time.

Now what about the use of IVIG for immune modulation. Probably the one
place that IVIG is our most standard therapy is in the treatment of Kawasaki's
disease. We have now come down to a single 2 gm/kg dose, and what you
would like to do is treat those patients as early as possible.

Guillain Barre is a postinfectious problem in many cases, and at this stage

IVIG has been shown to be equal to the plasma phoresis. So that it is
something that can be considered in progressive Guillain Barre as one is
considering other types of treatment for it, and it has been used and studied
in a controlled fashion.

Thrombocytopenia. That occurs with a number of infectious diseases, and

again one can use high dose IVIG and actually get responses in many cases.
Unfortunately, not every case will respond to this, and they are not all going
to respond repeatedly. So, one must take into consideration that this is not
going to be universally effective, but it is an indication that is there.

Something that we have clinical reports on, and you will read more about this
because control trials are currently underway, is the use of IVIG in both
staphylococcal and streptococci toxic shock. There are actually two methods
of action to this. One of them is that we know that there are
antistaphylococcal and streptococcal antitoxins in the IVIG preparations, in
many of them, so you may be neutralizing and removing toxins. The other is
that we know that these toxins have super antigen properties and may be in
fact producing a major part of their disease through a super antigen affect.
It has been shown that the high-dose IVIG can alter that super antigen affect.
For those individuals who are doing poorly on standard therapy with toxic
staph or strep, IVIG is something that can be considered.

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 IVIG Safety Issues
€ RES Blockade: Antibiotic therapy was less effective in neonatal GBS
model treated with 2 gm/kg IVIG.
€ Infection Transmission
a. HIV not transmitted
b. Hepatitic C has been reported in commercial preparations

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 Hepatitis Summary (HCV)

• Hepatitis C (HCV) now accounts for approximately 80% of transfusion

or blood product associated hepatitis.

• HCV may cause mild illness, but often leads to chronic liver disease
associated with cirrhosis and hepatic carcinoma.

• The virus may be in the blood for several months prior to antibody
detection.

• Since antibody screening will not predict viremia with HCV, some
blood/plasma donors will have HCV in their blood.

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Outbreak of Hepatitis C Associated with IVIG
• CDC has received 112 reports from 24 states and Puerto Rico.

• 111 cases had received Gammagard (1 Polygam).

• Cases occurred between October. 1993 and June 1994.

• IGIV was the only risk factor in 92%.

• Age ranged from 2-84 years.

• Anti-HCV was detected in 53% of primary immunodeficiency patients

and in 95 % of other groups (no cases found among 55 patients who
only received other IVIG products).

• IVIG without a viral inactivating process is capable of transmitting HCV.

• Specific virucidal steps are important to minimize the opportunity for

infectious agents such as HCV to persist in IVIG preparations.

• Many patients receiving IVIG are immunosuppressed and may be

highly susceptible to infection and severe disease.

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 Adverse Effects of IVIG Therapy
Approximate
Reaction Incidence Response

Minor Systemic Reactions: headache, <5 % Stop or slow

myalgia, fever light headedness infusion

Pyrogenic Reactions: high fever and <5 % Stop or slow

systemic symptoms infusion and treat symp-
toms

Vasomotor/cardiovascular <5 % Stop or slow

Manifestations: changes in BP & HR infusion

Aseptic Meningitis <1% Stop or slow infusion and

treat symptoms

Hypersensitivity and Anaphylactic <1% Stop infusion and

Anaphylactic Reactions: shock, treat systematic
collapse, airway compromise manifestations

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