Volume 1 Issue 1 October 1998

ISSUES AND INFORMATION ON CURRENT TOPICS

Editor: Howard Lederman, MD, PhD Of The Medical Advisory Committee Immunocompromised Jerry Winkelstein, MD Chairman Johns Hopkins University School of Baltimore, MD William Moss, MD, MPH and terminal complement deficiencies are at increased Douglas J. Barrett, MD Division of Pediatric Infectious risk of with encapsulated . They may University of Florida, Gainesville, FL R. Michael Blaese, MD Department of have even more benefit from pneumococcal and National Center for Human Genome Research Bethesda, MD Johns Hopkins University meningococcal than healthy children who do Rebecca H. Buckley, MD Baltimore, MD not have the same susceptibility to those . Duke University School of Medicine Durham, NC Information on safety and in Mary Ellen Conley, MD Howard Lederman, MD, PhD St. Jude Children's Research Hospital patients with specific diseases fre- Memphis, TN Division of Pediatric and quently is not available. Most of this information has Max Cooper, MD Department of Pediatrics University of Alabama School of Medicine been extrapolated from studies on persons with HIV Birmingham, AL Johns Hopkins University Charlotte Cunningham-Rundles, MD, PhD infection, and renal failure. Assessment of vac- Mt. Sinai Medical Center Baltimore, MD New York, NY cine efficacy in immunocompromised patients is fur- Erwin W. Gelfand, MD National Jewish Center For Immune and Respiratory Medicine ther complicated because efficacy is often assessed indi- Denver, CO rectly by measuring responses rather than Robert Good, MD, PhD Immunocompromised persons vary in their degree of University of South Florida All Children's Hospital protection against infection and . In the normal St. Petersburg, FL , response to immunization, and Richard Hong, MD susceptibility to infection. These differences correspond population, there often appears to be a correlation University of Vermont School of Medicine Burlington, VT to three issues of importance in the of between antibody level and protection. Although this Richard B. Johnston, Jr., MD would imply that immunization of patients unable to Yale University immunocompromised persons: vaccine safety, vaccine White Plains, NY efficacy and the potential benefit of particular vaccines mount an antibody response would have no benefit, this Alexander R. Lawton, III, MD Vanderbilt University School of Medicine in specific immunodeficiency disorders. Vaccine safety assumption has never been verified. D3237 Medical Center North, Nashville, TN 37232 Stephen Miles, MD correlates with the degree and type of immunosuppres- All Seasons Allergy, Asthma & Immunology Center Woodlands, TX sion, ranging from mild or limited deficits in immune Not All Hans D. Ochs, MD function to severe abnormalities in multiple arms of the Are Alike University of Washington School of Medicine Seattle, WA . In general, severely immunocompro- Primary disorders of the immune system can be Fred Rosen, MD The Center for Blood Research mised persons should not receive live, attenuated vac- divided into four categories: (1) disorders of humoral Boston, MA (antibody), (2) disorders of -mediated Andrew Saxon, MD cines because of the risk of disease caused by the vac- UCLA School of Medicine and humoral immunity, (3) disorders of phagocytes, Los Angeles, CA cine . Vaccine efficacy also is dependent upon the William T. Shearer, MD nature and degree of immunosuppression. For exam- and (4) disorders of complement. In addition, there Texas Children's Hospital Houston, TX ple, persons with X-linked agammaglobulinemia will are many causes of secondary immunodeficiency, such E. Richard Stiehm, MD UCLA School of Medicine not develop an antibody response following any immu- as treatment with immunosuppressive or chemothera- Los Angeles, CA nization. Vaccine benefit relates to the nature of the peutic agents, protein-losing enteropathy and HIV John L. Sullivan, MD University of Massachusetts Medical Center immunodeficiency and the risks of infection with spe- infection. Each group of diseases presents different Worcester, MA Diane W. Wara, MD cific . For example, persons with asplenia issues related to the risks and benefits of vaccines. UCSF Medical Center San Francisco, CA

Immune Deficiency Foundation, the national nonprofit organization devoted to research and education for Immune the primary immune deficiency diseases, publishes other materials for and healthcare professionals (eg. Deficiency ’s Primer and Guide for Nurses) and for patients (eg.Patient and Family Handbook, Our Immune System, and Foundation Newsletter). For Information about our programs, patient groups and publications, call 1-800-296-4433. 25 West Chesapeake Avenue Immune Deficiency Foundation - 25 West Chesapeake Avenue, Suite 206, Towson, MD 21204 • (800) 296-4433 • (410) 321-6647 • Fax: (410) 321-9165 Suite 206 Towson, MD 21204 supported by an educational grant from Centeon™ 2 Disorders of Humoral Immunity Disorders of Phagocytic Cells Patients with deficiencies of early complement There is a spectrum of disease within this The best known examples of these disor- components have a predisposition to develop category ranging from patients with an inability ders include chronic granulomatous disease bacterial caused by gram-positive encap- to make any type of antibody response to (CGD) - a disease of defective bactericidal func- sulated and a predisposition to patients whose only defect is making an IgA tion of phagocytes, and leukocyte adhesion defi- develop autoimmune diseases such as systemic antibody response. Patients with severe defi- ciency (LAD) - a disease of defective phagocytic erythematosis. Patients with deficiencies ciencies of humoral immunity (X-linked agam- cell locomotion. Patients with defective phago- of late complement components (C6 to C9) are maglobulinemia and common variable immun- cytic function are susceptible to bacterial and susceptible to infection caused by Neisseria odeficiency) have little or no ability to mount fungal infections. Intracellular bacterial species. antibody responses to vaccines or microbial pathogens such as mycobacteria and fungi can Vaccines Safe pathogens. They are highly susceptible to infec- cause of the and liver, lym- phadenitis and chronic granulomatous lesions for Use in tions caused by encapsulated bacteria and of the lung. Immunocompromised enteroviruses, including and coxsackie Another example of phagocytic deficiency Persons . Treatment with prophylactic intra- is asplenia, either anatomic or functional. In Vaccines that are not composed of live venous infusions of gamma globulin (IVIG) is either case, there is a predisposition to blood- viruses or bacteria are generally safe for admin- effective at preventing bacterial sepsis and borne infections because of a loss of the phago- istration to immunocompromised persons. meningitis, but may be less helpful for prevent- cytic filtering mass of the spleen. The “Safe vaccines” include vaccines, poly- ing sinusitis and bronchitis. Less severe forms of pneumococcal bacteremia is greatly saccharide vaccines, inactivated bacterial and of humoral immune deficiency include patients increased in persons with asplenia, and such viral vaccines, viral subunit vaccines and with selective inability to produce of infections can progress to fatal bacterial sepsis recombinant viral vaccines. Despite their safety, a specific class (IgA deficiency) or subclass (IgG within hours. persons with some immunodeficiencies will not subclass deficiency). They generally have less respond to these vaccines. Persons with severely severe problems with infection since some ele- impaired humoral immunity, such as X-linked ments of humoral immunity are intact. IgA Table 1: agammaglobulinemia and severe combined deficient patients typically develop infections Classification of Selected , will not develop an antibody Immunodeficiency Diseases along mucosal surfaces (otitis, sinusitis and response to these vaccines. However, persons with milder or more limited forms of impaired bronchitis) but rarely develop tissue invasive Deficiency of humoral immunity infections because they have normal ability to humoral immunity such as selective IgA defi- X-linked agammaglobulinemia ciency, and persons with defects of phagocytosis produce IgG and IgM antibodies. Common variable immunodeficiency and complement usually will respond adequate- Selective IgA deficiency ly to these vaccines. Persons with impaired Disorders of Cell-Mediated and humoral immunity should not be assumed to be Humoral Immunity Deficiency of cell-mediated and humoral protected against infection after vaccination. This group of disorders includes the vari- immunity Severe combined immunodeficiency Measurement of specific antibody titers follow- of severe combined immunodeficiency dis- ing vaccination is a reasonable way to assess ease (SCID). Patients are highly susceptible to Deficiency of phagocyte function vaccine efficacy and determine if additional all microbial pathogens including encapsulated Chronic granulomatous disease booster doses of vaccine are necessary. bacteria such as pneumococci, fungi such as Leukocyte adhesion deficiency Candida albicans, a wide variety of viruses Toxoid Vaccines and opportunistic infections such as Deficiency of complement are inactivated bacterial toxins Pneumocystis carinii. Patients with SCID do Deficiency of early components (C1-C5) that induce immunity against toxin-mediated not develop any antibody or cell-mediated Deficiency of late components (C6-C9) infections. Recommended toxoid vaccines are immune response to vaccines or natural infec- diphtheria and tetanus vaccines, which are safe tions. Although they have normal numbers of in immunocompromised children because they consist of non-infectious, inactivated toxins. phagocytic cells, bactericidal function is often The includes approxi- Although there is no greater risk for adverse impaired due to lack of cytokines. Serum mately two dozen proteins that can be activated reactions, persons with significantly impaired complement levels are normal, but antibody- by antibody- complexes or microbial humoral immunity may not have an adequate induced activation of complement depends products such as polysaccharides. When acti- immune response to toxoid vaccines to provide entirely on exogenously administered gamma vated, the complement system recruits phago- protection. Because the only adverse reactions globulin. for this group of patients is cytic cells to areas of infection, enhances the to these vaccines are local discomfort or low- supportive (passive immunization with intra- ability of B lymphocytes to produce antibody, grade fever, and these adverse reactions are no venous gamma globulin), unless marrow and causes the formation of lytic pores span- more likely in an immunodeficient patient than transplantation can be performed. ning the cell wall of gram-negative bacteria. 3 in a normal host, toxoid vaccines can be with proteins such as the outer mem- influenzae type b vaccine. This vaccine may administered safely to test the function of a brane protein of Neisseria meningitidis and not be useful in patients with severe antibody patient’s immune system. Measurement of pre- diphtheria or tetanus toxoids. As with toxoid deficiency, but should be used for all immuno- and post-immunization antibody levels are use- vaccines, polysaccharide vaccines are non- deficient patients who are not receiving regular ful for this purpose. infectious and safe for use in immunocompro- prophylactic infusions of gamma globulin. mised persons. Available polysaccharide vac- Although ninety pneumococcal serotypes Polysaccharide Vaccines cines include vaccines for Haemophilus have been identified, a limited number of The polysaccharide capsules of bacteria influenzae type b, pneumococcus and serotypes most commonly cause invasive pneu- such as Haemophilus influenzae type b and meningococcus. mococcal disease. The available pneumococcal are fac- Haemophilus influenzae type b conju- vaccine contains capsular polysaccharide anti- tors which inhibit phagocytosis. Polysaccharide gate vaccine is recommended for all children gens of 23 pneumococcal serotypes, including vaccines provide protection against infection by and has greatly diminished the risk of invasive the majority of serotypes likely to cause infection inducing opsonic antibodies, enhancing the rate infections such as sepsis and meningitis. Older in children and adults. Pneumococcal immu- of phagocytosis. Polysaccharide vaccines are children and adults at high risk of nization is not recommended for all children, generally not immunogenic in children under Haemophilus influenzae type b infections who but is reserved for children two years of age or two years of age, but immunogenicity can be were not immunized previously should also be older who are at increased risk of acquiring improved by conjugation of polysaccharide considered candidates for Haemophilus pneumococcal infection or at increased risk of serious disease if infected. This includes per- Table 2: sons with complement deficiency, defects of Vaccine Safety and Efficacy in phagocytic function, asplenia, HIV-infected per- Immunocompromised Persons sons, those receiving immunosuppressive med- ications including long-term, systemic corticos- Vaccine Safety Efficacy teroid therapy, and persons with chronic lung or renal disease. The current 23-valent pneumo- Toxoid vaccines Safe for use. Not efficacious for persons with Tetanus toxoid coccal vaccine is not immunogenic in children Diphtheria toxoid severe defects of humoral immu- less than two years of age, but evaluation of nity (X-linked agammaglobu- protein conjugate vaccines is underway. Revaccination with is Polysaccharide vaccines linemia, common variable Haemophilus influenzae b recommended after 3 to 5 years in asplenic Pneumococcus immunodeficiency and severe children who are less than 10 years of age, and Meningococcus combined immunodeficiency). at 5-10 year intervals for high risk older chil- dren and adults. Inactivated bacterial vaccines Probably not necessary for The primary meningococcal serotypes Pertussis causing infection in the United States are patients receiving regular pro- serogroups B and C, but the licensed meningo- Inactivated and subunit viruses phylactic infusions of human coccal vaccine is a tetravalent polysaccharide Inactivated (IPV) immunoglobulin (IVIG). vaccine against serogroups A, C, Y and W-135. whole-cell Serogroup B is not a component of the current split-virus vaccine because of the poor immunogenicity of Of potential benefit in persons the group B polysaccharide. Serogroup A poly- Recombinant viral vaccines with selective IgA deficiency, saccharide is immunogenic in children 3 Hepatitis B asplenia, disorders of comple- months of age and older; however, the ment and impaired phagocytic immunogenicity of the other vaccine serogroups Live virus vaccines Not safe for use in persons with is poor under 2 years of age. Meningococcal function. Live poliovirus (OPV) severely impaired humoral or vaccine is recommended at 2 years of age or cellular immunity older for persons with asplenia and terminal complement deficiencies. Rubella Varicella Inactivated Bacterial Vaccines Live bacterial vaccines Not safe for use in persons with Inactivated bacterial vaccines resemble BCG disorders of cell mediated Rarely indicated in the United toxoid and polysaccharide vaccines in being immunity or phagocytic func- States. non-infectious and safe for administration in tion. immunocompromised persons, but differ in containing multiple, bacterial-derived antigens. 4 Whole-cell is a suspension of compromised persons. “Split-virus” vaccines Potentially Harmful inactivated Bordetella pertussis cells contain- contain either purified surface antigens or Vaccines in ing multiple antigens, including endotoxin. subvirions prepared by disrupting the lipid Immunocompromised The latter is responsible for many of the adverse membrane. Only “split-virus” vaccines should Hosts reactions following pertussis immunization. be administered to children younger than 13 Live, attenuated viral and bacterial vac- Acellular pertussis vaccine contains a limited years because of the high rate of local and cines induce immunity by causing a limited number of Bordetella pertussis antigens, febrile reactions with whole-virus vaccines. infection. Persons with some immuno- including pertussis toxin, but little or no endo- Protection against influenza in healthy chil- deficiency disorders, generally those with toxin. Diphtheria and tetanus toxoid vaccines dren and adults following vaccination ranges impaired humoral or cellular immunity, may are administered in combination with whole from 50% to 95%, but the duration of protec- not be able to contain infection with live, cell pertussis vaccine (DTP) and acellular per- tion is short lived, usually less than one year. strains. Severe disease can tussis vaccine (DTaP). There is no data related Persons receiving or high-dose result. However, persons with selective IgA to risk for adverse reactions to either of these have a diminished antibody deficiency, asplenia, disorders of complement, vaccines among substantial numbers of patients response to , as do HIV- and impaired phagocytic function do not with primary immunodeficiencies, but there are infected persons with low CD4+ T-lymphocyte appear to be at higher risk of complications no theoretical reasons to believe that adverse cell counts. However, because of the potential than the general population. Clinicians should reactions would be more severe or more fre- severity of influenza in immunocompromised weigh the risks and benefits of live, attenuated quent than in immunocompetent individuals. persons and the small risk of adverse effects, vaccines in the care of individual immuno- influenza vaccine is recommended except in compromised patients. Inactivated and Subunit Viral patients with severe Vaccines who are receiving IVIG therapy. Booster vacci- Live Viral Vaccines Inactivated and subunit viral vaccines are nations may be necessary to sustain protective Live, attenuated oral poliovirus vaccine not infectious and are safe for administration immunity through the influenza season. (OPV) can cause vaccine-associated paralytic in immunocompromised persons. Inactivated poliomyelitis (VAPP), particularly in persons poliovirus vaccine (IPV) contains poliovirus with severely impaired humoral or cellular types 1, 2 and 3 grown in monkey kidney or Recombinant Viral Vaccines immunity. For example, the risk of VAPP is ten human diploid cell lines and inactivated with The available is a thousand times greater in patients with formaldehyde. IPV is safe for use in recombinant DNA vaccine consisting of hepati- hypogammaglobulinemia than in healthy per- immunocompromised persons and must be tis B surface antigen (HBsAg) expressed in the sons. VAPP can be the initial presentation of used in place of the live, attenuated oral yeast Saccharomyces cerevisiae. Because the congenital or acquired immunodeficiencies, poliovirus vaccine (OPV) in persons with pro- protein is not normally glycosylated, the warranting caution in the administration of found defects of humoral and cellular immu- recombinant vaccine is less immunogenic than OPV to siblings of children with a known nity, and in infants born to HIV-infected moth- the plasma-derived HBsAg vaccine, but high- immunodeficiency. The risk of VAPP in HIV- ers. Since there can be person-to-person level antibody response to hepatitis B recombi- of the attenuated poliovirus, OPV nant vaccine occurs in 90-95% of healthy Table 3: should not be used in any member of a house- adults. Many nonresponders develop sufficient hold with an immunodeficient patient. In Immunization of Household antibody titers after a second complete course Contacts of Immunocompromised fact, because many patients with primary of vaccination, but persons with severely Persons immune deficiency diseases are not diag- impaired humoral immunity will not develop nosed in the first year of life and have a an antibody response to hepatitis B vaccine. Vaccines recommended for household negative family history, the Centers for Adults and children receiving chemotherapy contacts Disease Control and Prevention (CDC), have a 75% response rate to hepatitis B vaccine, Advisory Committee on Immunization whereas HIV-infected persons have only a 25- Influenza vaccine Practices (ACIP) recommends that IPV be 50% response rate. Additional or larger doses used exclusively for immunization of all of hepatitis B vaccine can induce immunity in children less than 12 months old. Trivalent influenza vaccines are prepared some patients. For example, patients receiving annually based on the anticipated viral sub- hemodialysis treatment should receive two to types for the coming season, and four times the standard dose of hepatitis B vac- cine, depending upon the vaccine manufactur- Vaccines contraindicated in household contain antigens from two influenza A sub- contacts types and one influenza B subtype. Influenza er. In addition, annual anti-HBsAg testing is vaccines are either formalin-inactivated, recommended for hemodialysis patients, and Live, attenuated poliovirus vaccine whole-virus vaccines or “split-virus” vaccines, booster doses should be administered if the and are safe for administration in immuno- antibody concentration is less than 10 mIU/ml. 5 infected children who have received OPV defective cell-mediated immunity. Measles in adverse effects were noted, and measles immu- appears to be low; nevertheless, HIV-infected HIV-infected adults and children frequently nization of HIV-infected children became rou- children should receive IPV. In fact, since the results in giant cell pneumonitis and has a high tine. However, in 1996, the CDC reported the newer generation IPV vaccine has increased case-fatality rate. Use of measles vaccine in first known death due to measles vaccine virus immunogenicity, there is no need to incur the patients with deficiencies of humoral and/or in a 20 year old HIV-infected man. He had a risk of OPV in a patient with any immunodefi- cell-mediated immunity is controversial. Early very low CD4 count but no HIV-related symp- ciency or in a household contact of such a in the HIV epidemic, measles vaccine was not toms, and was not receiving antiretroviral ther- patient. recommended for symptomatic HIV-infected apy at the time of vaccination. Ten months after Measles vaccination is generally con- patients in the United States. Measles immunization he developed fatal giant cell traindicated in immunocompromised persons from 1989 to 1991 resulted in severe and fatal due to measles vaccine virus. because of the risk of infection with vaccine measles in HIV-infected children and adults, Because of this case, the ACIP recommends virus. However, infection with wild-type prompting the use of measles vaccine in symp- measles vaccine not be administered to HIV- measles virus can be severe in persons with tomatic HIV-infected persons. No serious infected persons with severe immuno- suppression based on age-specific CD4+ T- Table 4: lymphocyte counts. Guidelines for Immunization in Specific Mumps and rubella vaccines are usually Immunodeficiency Disorders administered with measles vaccine (MMR); all are live, attenuated virus vaccines. Vaccination Immunodeficiency Vaccine Efficacy Vaccine Safety Vaccines of Special with mumps and rubella vaccines is generally Benefit contraindicated in persons with severe defects of X- Linked Doubtful efficacy Live viral vaccines humoral or cellular immunity and in those Agammaglobulinemia of vaccines are contraindicated. receiving immunosuppressive therapy, although Common Variable for which antibody reports of adverse events are uncommon. Immunodeficiency provides protection. Symptomatic HIV-infected persons who are not severely immunocompromised may receive mumps and rubella vaccines. The immuno- IgA Deficiency Killed and live Inactivated viral Patients may benefit genicity of mumps and rubella vaccines in vaccines are probably vaccines are preferred. from pneumococcal immunocompromised persons has not been well efficacious. Live viral and and influenza vaccines. studied. Antibody responses to mumps and bacterial vaccines rubella vaccines were decreased in HIV-infected are probably safe. children and bone marrow transplant recipi- ents. Severe Combined Doubtful efficacy of Live viral and Immunodeficiency vaccines for which bacterial vaccines are Varicella can be severe in immunocom- humoral or cellular contraindicated. promised persons, particularly those with defec- immunity important tive cellular immunity. In addition, children for protection. with varicella have an increased risk of invasive group A streptococcal infection. Both of these Chronic Killed and live Live viral Influenza and problems can be reduced by use of varicella Granulomatous viral vaccines are vaccines are safe. varicella vaccines vaccine. The immunogenicity and safety of this Disease probably efficacious. Live bacterial may decrease the live, attenuated viral vaccine has been exten- vaccines (BCG) are risk of secondary sively studied in children with acute lympho- contraindicated. bacterial infections. cytic leukemia (ALL). In spite of extensive experience in children with ALL, varicella vac- Asplenia Killed and live Live viral Polysaccharide vaccines cine is not recommended for other immuno- viral vaccines are vaccines are safe. against pneumococcus probably efficacious. and meningococcus compromised persons, including those with are recommended. “congenital immunodeficiencies.” However, as stated previously, not all immunodeficient Complement Killed and live Live viral and patients are alike. The risk of complications Deficiencies viral vaccines are bacterial vaccines is recommended in from varicella vaccine is probably greatest in probably efficacious. are safe. persons with persons with defective cell-mediated immunity, deficiencies of and minimal in persons with selective IgA defi- terminal complement ciency, asplenia, complement deficiencies and components. disorders of phagocytic function. Children with ALL in remission for at least one year can 6 receive varicella vaccine as part of a study pro- require the production of -specific and measles/mumps/rubella vaccines as a safer tocol. Our usual practice is to administer this antibodies (BCG vaccine is an exception), the alternative to natural infection. There is no need vaccine even to immunodeficient patients if they value of immunization in these patients is to use OPV since IPV is highly immunogenic have documented normal cell-mediated immu- doubtful. Other than the issues of cost and the and carries no risk for to wild-type nity and ability to produce normal IgG antibody discomfort of an injection, there is no contra- virus. responses to a “test vaccine” such as tetanus indication to immunization with killed vaccines. toxoid. Varicella vaccine virus can be transmit- However, there is a serious risk of harm from the Severe Combined ted to household contacts. The varicelliform use of live, viral vaccines in this patient group. Immunodeficiency rash is usually mild, transmission to household Due to the inability to produce neutralizing anti- Infants with any of this group of disorders contacts is infrequent, and those household bodies, immunization with live vaccines such have no humoral or cell-mediated immune contacts usually have very mild illness. as oral (OPV) may lead to a pro- function and are highly susceptible to the com- Therefore, the risk of administering varicella longed state of viral colonization. This can plications of all live vaccines. They suffer from vaccine to the household contacts of an occur in the absence of direct immunization, as the same high risk of chronic or severe infection immunodeficient patient may be smaller than person-to-person transmission of vaccine caused by live poliovirus, varicella or the risks associated with natural infection. poliovirus has been documented. An immuno- measles/mumps/rubella vaccines as patients Thorough investigation of the nature of the logically normal infant immunized with live, with severe humoral immune deficiency. In immune deficiency is warranted before making oral polio vaccine can transmit vaccine virus to addition, the lack of T cell function leads to defi- the decision to immunize an individual patient an agammaglobulinemic adult through fecal- ciencies in -gamma production and with varicella vaccine. oral contamination. Within the hypogamma- secondary deficiencies of bactericidal function of globulinemic host, attenuated poliovirus can phagocytic cells. These patients can develop Live Bacterial Vaccines mutate and revert to a wild type virus that is disseminated infection with the attenuated BCG No live bacterial vaccines are recommend- capable of causing acute paralytic polio and/or strain of mycobacteria that can be difficult if not ed for routine use in the United States. The chronic meningoencephalitis. For these rea- impossible to treat. In addition to the prohibi- bacillus Calmette-Guerin (BCG) vaccine, sons, OPV and all other live viral vaccines are tion of direct immunization with live viral or derived from an attenuated strain of absolutely contraindicated in patients with bacterial vaccines, patients with severe combined Mycobacterium bovis, is used in many other severe deficiencies of humoral immunity. In immunodeficiency should be isolated from countries to prevent meningeal and miliary fact, largely because of OPV complications in immunologically normal individuals who have in infants and young children. this patient population, expanded use of the recently been immunized with any of these vac- Indications for the use of BCG in the United inactivated polio vaccine (IPV) is recommended cines. States include health care workers in high-risk in the United States. settings and children with intimate and pro- Chronic Granulomatous Disease longed exposure to a person with contagious Selective IgA Deficiency Patients with disorders such as chronic tuberculosis, particularly if the isolate is resis- Patients with selective IgA deficiency have granulomatous disease have normal ability to tant to isoniazid and rifampin. BCG should an inability to produce antibodies of the IgA mount humoral and cell-mediated lymphocyte never be given to persons with impaired cellular class, but have normal ability to produce IgG responses to vaccines, and phagocytic cells such immunity or defective phagocytic function and IgM antibodies in response to vaccines and as and polymorphonuclear neu- because of the risk of severe local or disseminat- natural infection. There is no contraindication trophils appear to have little or no role in host ed mycobacterial infection. to the use of any killed vaccine in persons with defense against most viruses. Therefore, there selective IgA deficiency. In fact, those IgA defi- Guidelines for does not appear to be a contraindication to live cient patients who suffer from recurrent viral vaccines in this patient population. In fact, Immunization of Patients sinopulmonary infections may derive benefit with Selected immunization with varicella vaccine may pre- from immunization with pneumococcal poly- vent a more severe cutaneous infection with the Immunodeficiency saccharide and influenza virus vaccines. No Diseases wild-type virus and protect patients with phago- formal studies of live viral vaccines have been Severe Deficiency of Humoral cytic defects from secondary skin infections. performed in this group, but the lack of case Immunity The live, bacterial vaccine BCG poses the same reports of vaccine complications suggests that Patients with severe deficiency of humoral risk to CGD patients as it does to patients with immunity, for example X-linked agammaglobu- immunization with varicella and defects of cell-mediated immunity. An interac- linemia and common variable immuno- measles/mumps/rubella vaccines is safe. After tion between T lymphocytes and monocytes is deficiency, generally have no ability to mount an documenting that a child with IgA deficiency required for successful control and eradication antibody response to any vaccine, and are treat- has normal serum antibody responses to killed of intracellular pathogens such as mycobacteria. ed with prophylactic doses of pooled human vaccines such as tetanus toxoid or one of the If either the T cell or phagocytic compartment is gamma globulin. Since the efficacy of most of Haemophilus influenzae type b conjugate vac- defective, there is significant risk for chronic and the currently licensed vaccines appears to cines, we recommend live attenuated varicella sometimes fatal infection with BCG. 7 Asplenia ers. Therefore, it is reasonable to consider mission of vaccine viruses does not occur. Individuals may have anatomic asplenia (congen- vaccination of household contacts and health Vaccines Contraindicated in ital asplenia or splenectomy following abdominal care workers against contagious and pathogen- Household Contacts trauma) or functional asplenia (sickle cell dis- ic organisms to provide an additional means of Due to the potential transmission of live vac- ease). In either case, they have an increased risk protecting immunocompromised persons from cine virus from vaccinated household contacts to of bloodstream infections due to lack of phagocyte infection. immunocompromised persons, vaccination of the mass within the circulation. The pneumococcus Varicella vaccine is recommended for all household contact is sometimes contraindicated. is the most important pathogen in asplenic indi- children and susceptible young adults. Household contacts of persons with severe impair- viduals, and it is well documented that immu- Varicella vaccine is specifically recommended ment of humoral or cellular immunity should not nization with pneumococcal polysaccharide vac- for susceptible health care workers and house- receive live, oral polio vaccine (OPV) because of cines can elicit levels of anti-pneumococcal anti- hold contacts of immunocompromised persons. the risk of transmitting virulent poliovirus and bodies that can compensate in part for the lack of Because varicella vaccine is a live viral vaccine, development of vaccine-associated paralytic splenic tissue. Anti-pneumococcal antibodies are transmission of vaccine virus can occur. poliomyelitis (VAPP). Instead, inactivated opsonins which enhance the phagocytosis of the However, the risk of transmission of vaccine poliovirus vaccine should be used. If live, oral organisms by other phagocytes such as Kuppfer virus is very low and disease caused by vaccine polio vaccine is inadvertently given to a household cells in the liver. Asplenic individuals do not have virus in immunocompromised persons is mild. member, close contact should be limited for 4 to 6 difficulty with immune responses to viruses, so Recipients of varicella vaccine who develop a weeks after vaccination, the duration of poliovirus live attenuated viral vaccines are not contraindi- rash should avoid direct contact with immuno- shedding. Increased attention to good hygiene, cated. compromised persons for the duration of the particularly hand washing, may also reduce the rash. Varicella-zoster immune globulin is not risk of poliovirus transmission. The risk of VAPP Complement deficiency indicated should contact occur between an from household transmission of poliovirus in per- Complement, as demonstrated in the lab- immunocompromised person and a varicella sons with selective IgA deficiency, asplenia, com- oratory, functions as an opsonin for host vaccine recipient with a varicelliform rash. plement deficiencies and phagocytic defects is defense against viral pathogens. In addition, Immunization of household contacts probably no greater than the general population patients with C3 deficiency have impaired anti- against other contagious and potentially serious although no studies have been done to assess this. body responses compared to individuals with infections is important in protecting immuno- normal levels of C3. However, these contribu- compromised persons. Specific recommenda- Immunization of Siblings of tions of complement seem not to be clinically tions for household contacts include vaccina- Immunocompromised Children important because viral infections are not espe- tion against influenza, measles, mumps and Siblings of children with severe humoral or cially virulent in complement deficient patients. rubella (MMR). The latter vaccine, although cellular immunodeficiencies, or siblings of chil- We do not believe that there are any contraindi- consisting of attenuated, live viruses, is not dren with perinatally-acquired HIV infection, cations to live viral vaccines in complement contraindicated in household contacts of should not receive potentially harmful vaccines deficient patients. Patients with deficiencies of immunocompromised persons because trans- until their own immune status is established. the early complement components C2 and C3 are at increased risk for pneumococcal and to Special Considerations lesser extent meningococcal infections, and Immune Activation and HIV Immunosuppression Following should be immunized against these pathogens. Replication Measles Vaccine Similarly, patients with deficiencies of late com- plement components (C6 to C9) are at risk of Efficient replication of HIV in CD4+ T Measles virus infection is associated with a infection with Neisseria species. For this group lymphocytes and monocytes is dependent on prolonged suppression of cell-mediated immu- of patients, meningococcal vaccine can elicit cellular activation. The activation of CD4 lym- nity, manifested by loss of delayed type hyper- high titers of antibody against the meningococ- phocytes and / that sensitivity reaction to purified protein derivative cal capsule and help compensate for the prob- occurs as part of the immunologic response to (PPD) and increased risk of secondary bacteri- lem of complement deficiency. immunization has the potential for directly al infections. Transient immunosuppression enhancing HIV replication. Transient increases may also occur after measles vaccination. Loss Vaccination of Household in HIV plasma viremia have been documented of delayed type and Contacts following vaccination with tetanus toxoid, can occur after immunization with live, atten- Vaccines Recommended for influenza vaccine and pneumococcal polysac- uated measles vaccine. The clinical signifi- Household Contacts charide vaccine. At present, it is thought that cance of transient immunosuppression follow- Immunocompromised persons are at risk among patients receiving effective anti-retrovi- ing immunization with live, attenuated measles of acquiring infection through person-to-per- ral therapy, the transient increase in HIV plas- vaccine in unclear, but may be important in son transmission from household contacts and ma viremia is not of clinical significance and is persons whose immune function is compro- nosocomial acquisition from health care work- not a contraindication to immunization. mised. 8 This situation most frequently arises in the administration of the prima- Conclusions ry vaccine series to a young infant whose sibling has a severe immun- Vaccine safety, efficacy and potential benefit are critically dependent odeficiency or perinatally-acquired HIV infection. Live, attenuated upon the nature and degree of immunodeficiency in an individual patient. MMR vaccine should be withheld from the infant until his/her immune Not all immunodeficiencies are alike, and broad recommendations for the status is known. If the infant is determined to have no immunodefi- vaccination of immunocompromised persons may not be universally ciency, the MMR vaccine can be administered at the appropriate age. applicable. The risks and benefits of vaccination should be considered in Regardless of the infant’s immune status, inactivated poliovirus vac- the context of the specificity and magnitude of the immune deficits within cine, and not OPV, should be administered because the infant is the the individual patient. household contact of a person with severe immunodeficiency.

References Center for Disease Control. Recommendations of the Advisory Committee on Immunization Practices (ACIP): Use of vaccines and immune glob- ulins in persons with altered . MMWR 1993;42 (No. RR-4):1-18 American Academy of Pediatrics. Immunization in Special Clinical Circumstances. In: Peter G, ed. 1997 Red Book: Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics, 1997: 50-58. Pirofski LA, Casadevall A. Use of licensed vaccines for of the immunocompromised host. Clin Microbiol Rev 1998; 11:1-26. Puck JM. Primary immunodeficiency diseases. JAMA 1997;278:1835-1841. Stiehm ER, ed. Immunologic Disorder in Infants and Children. 4th ed. Philadelphia, PA: W. B. Saunders Company 1996. to receive your FREE subscription to Clinical Focus on Primary Immune Deficiencies, send your mailing address with your request to: Immune Deficiency Foundation 25 West Chesapeake Avenue Suite 206 Towson, Maryland 21204

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