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.