IMMUNOGLOBULINS

5 Jun

Antibodies that occur  in  mucosal secretions play  two  major roles  in antiviral immunity. One mechanism is to prevent the virus from  reaching host  target cells,  thus providing immu- nity  by exclusion. Usually the  presence of a mucosal barrier prevents the  virus from  establishing an  infection. A second mechanism is  to  neutralize viral infectivity by  binding an antibody to a virus particle (Figure 4.2). Neutralization can occur  via  mucosal antibodies and  within the  cell. Antibodies may  bind  to virus particles rendering them unable to infect the  cell.  Neutralizing antibodies not  only  prevent infection but  may  aid  in clearing already established infection. Other factors also  may  protect the  host, such  as  innate immunity, specific  antibody in mucosal fluids, antibody-dependent cellu- lar  cytotoxicity, and  cytolytic T cells  (321).  IgA and  IgG  are present in high  concentrations and  contribute to intracellular neutralization and   cell  lysis.  The  antibodies can  move through interstitial fluid  and  may  enter through breaks in the  epithelium.

One  mechanism for administering immunoglobulins has been the nasal spray/respiratory inhaler as antibody in the res- piratory tract prevents or lessens the  viral infection and  may even  cure  some  viral infections. A number of human studies have been  conducted to test the  efficacy  of intranasal antibody treatment to  prevent viral respiratory tract infection. Treat- ments were  by nose  drops, aerosol application, or nasal spray.

Generally, various treatments of coxsackie virus, influenza, and rhinovirus infections were  effective in  decreasing viral shed- ding.  Human IgA treatments tended to decrease rhinitis and upper respiratory tract infection. The  treatment of RSV with IgG  (aerosol) and  monoclonal antibody IgA  (nose  drops) was deemed safe  with a trend for decreased illness (321).

Intravenous applications of immunoglobulin therapy as  a treatment adjuvant or as  immunoprophylaxis protect against RSV.  Prophylactic use  of immunoglobulins has  significantly reduced morbidity and mortality of infectious diseases (Table 4.7).

Table 4.7 Immunoglobulin Systems Currently Utilized

Immunoglobulins are  proteins made by B lymphocytes and  plasma cells as part of the humoral portion of the immune system. Commercial sterile preparations  are   made from pooled human plasma of several thousand donors, and  consist of purified IgG with small amounts of other globulins. These preparations were  first used to treat  immune deficiency dis- eases in  1952,  following the  discovery of Bruton’s agamma- globulinemia (328).  Early preparations were  associated with frequent side  effects   when given  intravenously, and   thus required frequent and  painful intramuscular administration. In  1981,  an  improved preparation  of immunoglobulin was licensed for  intravenous use  (IVIG).  FDA-approved indica- tions include the  following six conditions: 1) primary immun- odeficiencies; 2)  immune-mediated  thrombocytopenia; 3) Kawasaki syndrome; 4) recent bone  marrow transplantation (in persons at least 20 years of age); 5) chronic B-cell lympho- cytic leukemia; and  6) pediatric HIV-1  infection (329). IVIG is also  used in  clinical practice for numerous other conditions, such  as multiple sclerosis. Intravenous preparations are  man- ufactured by several different companies and, due  to  differ- ences  in  the  production process and  donor  populations, the products available may  vary  considerably (330).

The intramuscular form of immunoglobulin is still  avail- able  and  is  approved for  the  prophylaxis of hepatitis A and measles. Several immunoglobulin preparations  with high titers to individual viruses are  also  available for the  prophy- laxis  of specific  viral infections. These hyperimmune globulins are  available for rabies, varicella, CMV, respiratory syncytial virus, and  hepatitis B. For  the  immunotherapy of viral infec- tions, IVIG  is  predominantly used for  cytomegalovirus pro- phylaxis in  transplant  recipients. Prophylactic treatment in bone  marrow transplant  recipients does  not  prevent CMV infection, but  does  lessen the  risk of symptomatic disease, interstitial pneumonia, and  death due  to CMV (331,332). On comparing the  use  of IVIG and  CMV hyperimmune globulin, there were  no differences in clinical outcome to suggest the preferential use  of CMV-IG  (332,333). For  bone  marrow recipients with established CMV pneumonia, a combination treatment of IVIG and  ganciclovir has  been  shown to improve survival (334,335). However, studies of IVIG alone for this sit- uation have shown minimal efficacy  (336,337). Studies  of CMV  prophylaxis with IVIG  in  renal transplant recipients have also  shown favorable results, with either a decrease in the  risk of infection and/or attenuation  of clinical disease (338,339).

IVIG  has  also  been  shown to be of potential benefit for HIV-infected children. This population frequently suffers from bacterial  infections with common encapsulated  bacteria, whereas infected adults more  frequently develop opportunis- tic infections (340). Several small studies have demonstrated decreased bacterial infections and  sepsis as well as improved survival in  HIV-positive children (341–343). Another study of HIV-infected children  on  zidovudine showed a  benefit with the  use  of IVIG, but  only in those subjects not  receiving trimethoprim-sulfamethoxazole as antibiotic prophylaxis (344). The exact role of IVIG in this situation remains unclear.

Intramuscular immunoglobulin can  be given  for the  pre- vention of measles in  susceptible individuals (those with no previous infection or immunization). It is indicated for exposed persons with an  increased risk of complications from  disease, such  as  immunocompromised patients  or children less  than 1 year old. This  treatment should be given  within 6 days  of exposure. The  second indication for  intramuscular  immuno- globulin is the  prophylaxis of hepatitis A. The protective effect is of most  value if given prior to or immediately after exposure, and  within 2 weeks of exposure. If given  within several days of  exposure, the   immunoglobulin prevents  infection i 80–95%  of patients (345,346). This  treatment was  also  indi- cated for travelers who planned to stay in areas with poor san- itation, but  the  HAV vaccine is now the  preferred method for HAV prevention in travelers (347).

Rabies immune globulin is given  once  locally  as  well  as systemically at the  initiation of postexposure prophylaxis. It provides immediate antibodies to previously unvaccinated per- sons.  Seven days  after vaccination, recipients begin  actively producing antibodies.

Hepatitis B immune globulin is given  with hepatitis  B vaccine in  certain situations as  part of the  recommended post-exposure prophylaxis regimen. The following susceptible persons who were  exposed to hepatitis B virus should receive hepatitis B hyperimmune globulin in  addition to immuniza- tion:  persons with acute exposure to  HBsAg-positive blood; infants with perinatal exposure to  HBsAg-positive mothers; persons with sexual exposure to HBsAg-positive partners; and infants with an  HBsAg-positive primary care-giver. Hepatitis hyperimmune globulin has  been  evaluated for the  prophylac- tic  treatment of HBsAg-positive liver  transplant recipients. High-dose, long-term treatment has  led to increased survival and  decreased serological recurrence in  a number of studies (348,349). However, maintenance treatment is required for the prevention of recurrence and  long-term treatment is  expen- sive (350).

Varicella-zoster immune globulin should be administered to susceptible persons exposed to varicella virus who have an increased risk for  complications (i.e.,  immunocompromised individuals). The  postexposure prophylaxis should be admin- istered as  soon  as  possible and  no later than 96 hours after exposure (351). The duration of protection lasts at least 3 weeks after the  injection.

RSV  immune globulin is  indicated for  prophylaxis in high-risk infants. A clinical trial by Groothuis et al. (352) eval- uated monthly RSV-IG  prophylaxis in  at-risk infants with bronchopulmonary dysplasia, congenital heart disease, or pre- maturity. Results showed that the  RSV-IG  prophylaxis led to a reduction in the number of hospitalizations, hospital days, and  intensive care  unit days. These results were  confirmed by a second clinical trial (353). Adverse reactions with any  of the immunoglobulin preparations are  rare. The  incidence of sys- temic side  effects  is generally less  than 5%, and  these reac- tions are   typically mild   and   self-limited. Fever, chills, headache, backache, nausea, vomiting, chest tightness, myal- gias,  and  dyspnea have all  been  reported. With  intravenous preparations, slowing of the  infusion rate can  be of benefit in alleviating the  side  effects. Hydrocortisone and  antihista- mines are  also  useful. Anaphylactic reactions may  also  occur in IgA-deficient patients receiving IVIG, but this is a rare com- plication (354). From 1985–1998, acute renal failure has  been described in 120 IVIG recipients worldwide (330). Acute  renal failure appears most  closely  associated with IVIG  prepara- tions with high  sucrose content. The  majority of affected patients developed renal failure within 7 days  of IVIG admin- istration, and  40% required dialysis due  to the  degree of fail- ure.  Although this complication remains infrequent, it is associated with significant morbidity and  mortality.

Because these biological products are  derived from human plasma, viral contamination poses  a potential, though small, risk. In 1994, two different IVIG preparations were  associated with hepatitis C contamination, leading to numerous cases of acute hepatitis C infection (more  than 100 cases in the  United States). The  manufacturers added a solvent-detergent treat- ment for  viral inactivation, and  the  products no  longer are considered to be at risk for hepatitis C (355). All current IVIG preparations come from  donors who are  screened for hepatitis B and  C, HIV,  and  elevated liver  enzymes. Also, the  majority of manufacturers include a viral inactivation step in the  pro- duction process. No  cases of HIV  transmission have been reported with IVIG.

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