Immunoprophylaxis

Passive Immunoprophylaxis for Tetanus, Varicella, HAV, HBV and Uses of IVIG Janet Wong, M.D.

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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 Prophylaxis -- Tetanus Immune Globulin (TIG) Type: €

Human Immunoglobulin with increased anti-tetanus antibody titers.

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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

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

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.

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.

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Varicella-zoster Immune Globulin (VZIG) €

Type: • Human Immune Globulin with increased levels of anti-VZV antibody.

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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 28weeks' gestation or less.

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Types of Exposure to Varicella or Zoster for Which VZIG is Indicated*+ • Household: Residing in the same household • Playmate: Face-to-face- indoor play • Hospital: 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.

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 infectious virus, and one must consider even a reasonably brief exposure as being significant. In the hospital, if you have in the same room an individual who is susceptible, that is in a 2- to 4-bed room or an adjacent bed in a larger ward, face-toface contact with an infectious staff member or patient. A visit by a person being 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).

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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.

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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 Hepatitis B Infection Type of Exposure Perinatal Sexual - acute infection Sexual - chronic carrier Household contact- chronic carrier Household contact - acute case with identifiable blood exposure Infant (<12 mo) - acute case in primary caregiver Accidental - percutaneous/ permucosal

Immunoprophylaxis HBIG + vaccination HBIG + vaccination Vaccination Vaccination

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 HV or HV plus 1 dose of hepatitis B vaccine. If you do not know the response, then if you test them, then if the exposed person is antibody negative for hepatitis B surface antigens, then they should receive HV.

HBIG + vaccination HBIG + vaccination HBIG + vaccination

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Recommendations for Hepatitis B Prophylaxis after Percutaneous Exposure to Blood That Contains (Or Might Contain) HBsAg Treatment when source is found to be Source Unknown or Not Tested

Exposed Person

Source HBsAg-Positive

Source HBsAg-Negative

Unvaccinated

Administer HBIG X I: and initiate hepatitis B vaccine-

Initiate hepatitis B vaccine

Initiate hepatitis B vaccine'

Previously vaccinated Known responder

Test exposed person for anti-HBs I. If adequate, no treatment 2. If inadequate, hepatitis B vaccine booster dose

No treatment

No treatment

Known nonresponder

HBIG X 2 or HBIG x I plus I dose of hepatitis B vaccine

No treatment

If known high-risk source, may treat as as if source were HBsAg-positive

Person for whom response is unknown

Test exposed person for anti-HBs I. If inadequate, HBIG x I, plus hepatitis B vaccine booster dose2. If inadequate, nn treatment

No treatment

Test exposed person for anti-HBs* I. If inadequate, hepatitis B vaccine booster dose 2. If adequate, no treatment

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 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 within one week after birth.

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

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Recommended Schedule of Hepatitis B Immunoprophylaxis to Prevent Perinatal Transmission

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 received 0.06 mL which is smaller.

Infant born to mother known to be HBsAg-positive: Vaccine Dose and HBIG

Age

First HBIG Second Third

Birth (within 12 h) Birth (within 12 h) 1 mo 6 mo

Infant born to mother not screened for HBsAg: Vaccine Dose First. HBIG

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

Second Third

1-2 mo 6-18 mo^

Dose: •

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

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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 postexposure prophylaxis.

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Use of Immunoglobulin in Hepatitis A Prophylaxis 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.

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Food or Waterborne Outbreaks a. Source usually recognized late. b. IG not indicated, unless <2 weeks from exposure.

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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 characteristics 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 widespread 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 preparations, and there are different plasma pools and different production techniques for each of these.

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Comparison of IG and IVIG IG Pain on injection Rapid administration IM Limited amount of IgG can be injected

IVIG Minimal pain on infusion Slower infusion IV (several hours) Large amounts of IgG can be infused

Slow rise in serum IgG

Rapid peak serum IgG achieved

Modest elevation in total serum IgG

Marked increase in total serum IgG

Some degradation of IgG at inject site

IgG generally delivered to tissues intact

Now, I think that when we think about how you use intravenous immunoglobulin that it is helpful to categorize the use in three main categories. One is replacement therapy, which is the one that we have been use to talking about over the years. The second is specific uses which could become important for bacteria, as well as for viruses where there is no therapy. Then, immunomodulation. This is an area where not everything is understood. There are many diseases where affecting the up-regulation or downregulation of the immune system may play a major role in infectious disease treatment. Use of intravenous immunoglobulin therapy as replacement therapy. The standard one that we are all aware of is primary immunodeficiency disease. 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 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 to the serum IVG level for each individual.

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Indications and Rationale • Indications for IVIG are rapidly expanding. • Rational for IVIG Use: 1. 2.

Opsonize bacteria or neutralize viruses or toxins Immune modulation (ie, phagocyte Fc Receptor blockade, antiidiotypic 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 determined. 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.

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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.

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Uses of Intravenous Immune Globulin Therapy Replacement Therapy

Indications

Dosage

Efficacy

Comments

10 Immunodeficiency

100-400 mg/kg q 4 weeks

AI*

Adjust dose according to serum IgG levels

CLL

400 mg/kg q 3-4 weeks

AI

Cost effectiveness is is questioned

Premature Infants

500-750 mg/kg q 2 weeks

CT

Variable antibody titers to neonatal pathogens

Bone Marrow Transplant

500 mg/kg 1 wk before and weekly for 90 days

CT

Reduces infections and graft vs. host disease

HIV Infection

200-400 mg/kg q 2-4 weeks

CT

Selected symptomatic HIV patients

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.

*AI - Approved Indication; CT - Clinical Trials

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Uses of Intravenous Immune Globulin Therapy Pathogen Specific Uses Indications

Dosage

Efficacy

Comments

Cytomegalovirus Prophylaxis

500 mg/kg wkly for 90 days

CT/AI*

Specific CMV IVIG and IVIG both efficacious

Therapy

400-500 mg/kg with ganciclovir

CT/AI

Specific CMV IVIG only

Group B Streptococcus Prophylaxis

500 -750 mg/kg q 2 weeks

CT

During hospitalization

Therapy

500-1000 mg/kg

CT

One or two doses

Respiratory Syncytial Virus Prophylaxis

750 mg/kg q 4 weeks during RSV season

CT

Specific RSV-IVIG in high-risk infants

Therapy

750-1000 mg/kg

CT

Specific RSV-IVIG; reduces shedding

Parvovirus

400 mg/kg daily for 5-10 days

CR

Relapses responded to retreatment

*AI - Approved Indication; CT - Clinical Trials

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 therapeutic strategies.

Group B strep prophylaxis and therapy with IVIG has been used. It generally has not been as effective in prophylaxis because we do not know what is in 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 prevent group B strep infections with IVIG, and that they did have antibodies in the group B streptococci and in their preparation. So, that prophylaxis is possible, but because you do not know what is in the preparation, it is not routine. 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 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. In those instances, we often think about what other things could we do to 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 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.

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Uses of Intravenous Immune Globulin Therapy Immune Modulation Indications

Dosage

Efficacy

Comments

Kawasaki disease

2 gm/kg, single dose

AI*

Treatment before 10 days

Guillain-Barre

400 mg/kg/d for 5 d

CT

Treatment early after dx

Immune Thrombocytopenia

400 mg/kg/d for 5 d

AI

Also up to 2 gm/kg in a single dose or divided into 2 doses given over 2 days

Staphylococcal and Streptococcal Toxic Shock

500-1000 mg/kg

CR

Selected, severely ill patients

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 from IVIG. When the IVIG antibodies to that organism attach to the bacteria and cause 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 broken off, they will go to the bone marrow and will cause decrease depletion 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 increase neutrophil movement into the blood and to decrease neutrophil storage pools.

Respiratory syncytial virus is an area where we do not have a good prophylaxis or therapy at this point, and the use of a high titer selected RSV immunoglobulin has been shown to reduce both hospitalizations, hospital 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.

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

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

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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.

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111 cases had received Gammagard (1 Polygam).

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Cases occurred between October. 1993 and June 1994.

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IGIV was the only risk factor in 92%.

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Age ranged from 2-84 years.

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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).

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

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Specific virucidal steps are important to minimize the opportunity for infectious agents such as HCV to persist in IVIG preparations.

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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 Reaction

Approximate Incidence

Response

Minor Systemic Reactions: headache, myalgia, fever light headedness

<5 %

Stop or slow infusion

Pyrogenic Reactions: high fever and systemic symptoms

<5 %

Stop or slow infusion and treat symptoms

Vasomotor/cardiovascular Manifestations: changes in BP & HR

<5 %

Stop or slow infusion

Aseptic Meningitis

<1%

Stop or slow infusion and treat symptoms

Hypersensitivity and Anaphylactic Anaphylactic Reactions: shock, collapse, airway compromise

<1%

Stop infusion and treat systematic manifestations

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