varicella vaccine efficacy is not compromised. However, if varicella vaccine is given after but within 30 days of MMR the relative risk for later development of breakthrough varicella, defined as cases of varicella that occur following exposure to wild-type virus >42 days after varicella vaccine administration, is 2.5 (1.3–4.9). The risk for breakthrough varicella is not increased when varicella vaccine is given within 30 days after DTP, Hib, OPV, IPV, or hepatitis B vaccines. These findings parallel those in earlier reports that had shown a reduction in responsiveness to smallpox vaccine following measles vaccine (MMWR, 2001c).

The committee concludes that there is strong evidence for the existence of biological mechanisms by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk for heterologous infections.

SIGNIFICANCE ASSESSMENT

The charge to the Immunization Safety Review committee includes consideration of the public health response to the immunization safety concerns it examines. Most previous IOM immunization-safety studies by contrast, were limited to conclusions from causality assessments and to recommendations for future research. The public health response to an immunization safety concern potentially encompasses a broad range of activities, including policy reviews, new research directions, and changes in communication to the public and health care providers about issues of immunization safety. In formulating the breadth and direction of the recommended public health response, the committee considers not only its conclusions regarding causality and biological mechanisms, but also the significance of the immunization safety issues for society—the context in which policy decisions must be made.

Public concerns about immunization safety must be examined carefully because most vaccines are given to healthy children not only for their direct protection but also to help protect others in the population. In fact, to achieve this broader level of protection, certain vaccines are mandatory in all 50 states for school and day-care entry. Exemptions on medical grounds (contraindications) are allowed, although they are considered too limited by some (Fisher, 2001a). Exemptions are also allowed on religious grounds in 48 states and on philosophic grounds in 15 states (Evans, 1999). Such exemptions are rare, however, and it is argued that these public health mandates, because they are imposed on healthy children, place a special responsibility on the government for rigorous attention to safety issues, even for rare adverse outcomes.

In the present case, the committee considers the possibility that the exposure of infants to multiple immunizations might increase risks of immune dysfunction. This issue has gained attention because of indications that autoimmune and allergic diseases are increasingly common in children and because of the likelihood that yet more vaccines will be added to the recommended schedule of childhood immunizations. As part of the committee’s assessment of the



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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction varicella vaccine efficacy is not compromised. However, if varicella vaccine is given after but within 30 days of MMR the relative risk for later development of breakthrough varicella, defined as cases of varicella that occur following exposure to wild-type virus >42 days after varicella vaccine administration, is 2.5 (1.3–4.9). The risk for breakthrough varicella is not increased when varicella vaccine is given within 30 days after DTP, Hib, OPV, IPV, or hepatitis B vaccines. These findings parallel those in earlier reports that had shown a reduction in responsiveness to smallpox vaccine following measles vaccine (MMWR, 2001c). The committee concludes that there is strong evidence for the existence of biological mechanisms by which multiple immunizations under the U.S. infant immunization schedule could possibly influence an individual’s risk for heterologous infections. SIGNIFICANCE ASSESSMENT The charge to the Immunization Safety Review committee includes consideration of the public health response to the immunization safety concerns it examines. Most previous IOM immunization-safety studies by contrast, were limited to conclusions from causality assessments and to recommendations for future research. The public health response to an immunization safety concern potentially encompasses a broad range of activities, including policy reviews, new research directions, and changes in communication to the public and health care providers about issues of immunization safety. In formulating the breadth and direction of the recommended public health response, the committee considers not only its conclusions regarding causality and biological mechanisms, but also the significance of the immunization safety issues for society—the context in which policy decisions must be made. Public concerns about immunization safety must be examined carefully because most vaccines are given to healthy children not only for their direct protection but also to help protect others in the population. In fact, to achieve this broader level of protection, certain vaccines are mandatory in all 50 states for school and day-care entry. Exemptions on medical grounds (contraindications) are allowed, although they are considered too limited by some (Fisher, 2001a). Exemptions are also allowed on religious grounds in 48 states and on philosophic grounds in 15 states (Evans, 1999). Such exemptions are rare, however, and it is argued that these public health mandates, because they are imposed on healthy children, place a special responsibility on the government for rigorous attention to safety issues, even for rare adverse outcomes. In the present case, the committee considers the possibility that the exposure of infants to multiple immunizations might increase risks of immune dysfunction. This issue has gained attention because of indications that autoimmune and allergic diseases are increasingly common in children and because of the likelihood that yet more vaccines will be added to the recommended schedule of childhood immunizations. As part of the committee’s assessment of the

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction significance of this issue, the disease burden (e.g., seriousness, treatment, complications) associated with autoimmune and allergic diseases, especially type 1 diabetes and asthma, is reviewed here. Also discussed are indications of public concern about the safety of multiple immunizations and ideas that have been put forward about alternative approaches to the formulation of immunization policy. Disease Burden Autoimmune Disorders: Type 1 Diabetes As noted, diseases of autoimmunity affect 3 to 5 percent of the U.S. population (Jacobson et al., 1997), which translates into as many as 14 million people in 2001. From 500,000 to 1,000,000 people in the United States are thought to have type 1 diabetes, based on estimates that this form of the disease accounts for 5 to 10 percent of the roughly 10 million diagnosed diabetes cases (NIH, 1999). No national surveillance system exists to provide data on the incidence of type 1 diabetes. Rates from local diabetes registries and research projects suggest that about 30,000 new cases develop each year in the United States (LaPorte et al., 1995). Internationally, various registries indicate an average incidence increase of 3% per year (Onkamo et al., 1999). The disease can develop at any age, but incidence rates are higher in children and young adults. Moreover, among children under age 16, the incidence of type 1 diabetes is higher than that of other chronic illnesses, including all forms of cancer combined (Libman et al., 1993). In type 1 diabetes, the destruction of insulin-producing beta cells in the pancreas prevents proper metabolism of glucose. If not treated, the disease is fatal. Administration of insulin one or more times each day helps compensate for the loss of the beta cells, but the dosage must be calibrated to account for food intake and exercise levels. Children and adults with type 1 diabetes must monitor their blood sugar levels regularly. If blood sugar is not maintained at appropriate levels, there is risk of acute complications, particularly coma. Ketoacidotic coma occurs if insulin administration is inadequate, resulting in hyperglycemia and ketone production. Hypoglycemic coma results if insulin administration is excessive for the blood glucose level. Type 1 diabetes is associated with many serious long-term complications (Harris, 1995). Mortality rates are elevated at all ages, especially for women and girls, and life expectancy may be reduced by as much as 15 years. Acute coma is the greatest mortality risk during the first years with the disease, replaced over time by renal disease. Among persons who have had Type 1 diabetes for 30 years or more, cardiovascular disease accounts for most deaths. Several chronic complications are also common, and they are more likely to occur if blood sugar levels are poorly controlled. One such complication, diabetic retinopathy, is a leading cause of blindness in the United States. People with diabetes are also at risk of kidney damage that can progress to end-stage renal disease. Neuropathies

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction are common, and along with peripheral vascular disease, can result in damage to lower extremities (e.g., ulcers, infections) that necessitates amputations. Infection rates are higher, as are periodontal disease rates. Women with type 1 diabetes who become pregnant may see a worsening of any existing eye or kidney damage, and they are at increased risk of spontaneous abortion, preterm delivery, and birth defects. The financial cost of type 1 diabetes is high. People with this disease are more likely to experience work disability, and they make greater than average use of health care services. A 1988 paper estimated treatment cost for a patient through age 40 at $40,000 (LaPorte et al., 1995). Health expenses and office visits for diabetics exceed those of nondiabetics.7 For example, the estimated annual cost of physician visits for a diabetic was nearly twice that for a nondiabetic ($1,045 versus $554). Costs of prescriptions and medical supplies are over five times as expensive for diabetics as for nondiabetics ($1,056 versus $201). Increased costs in overall health expenses also affect diabetics far more than nondiabetics ($11,157 versus $2,604 annually) (Javitt and Chiang, 1995). Allergic Disorders: Asthma Allergic disorders—including asthma, rhinitis, and dermatitis—are the sixth most common chronic disease in the United States. Together, they result in $18 billion in health care costs annually (AAAAI, 2000). For this report the committee focused on asthma. A serious allergic disease, asthma was estimated to have affected 14.6 million adults in 2000 (CDC, 2001b) and about 4 million children in 1998 (CDC, 2001a). The prevalence rates of self-reported asthma appear to have increased overall by 74 percent between 1980 and 1994 (Mannino et al., 1998). For children age 0 to 4 years, rates increased by 159 percent during this period (from 22.0 per 1,000 to 57.4 per 1,000). Increases in asthma prevalence were seen in all race, sex, age, and regional groups. The reasons for the increasing prevalence are unclear, although changes in environmental or behavioral factors are considered likely (IOM, 2000). Symptoms of asthma include shortness of breath, coughing, wheezing, and chest tightness. Some people experience these symptoms only occasionally, but in the most severe cases, symptoms are continuous. Even when the general level of disease is mild or moderate, individual episodes can be severe and may require hospital or emergency department care. Without proper treatment, severe episodes can be life-threatening. Management of the disease includes limiting exposure to environmental triggers (e.g., allergens, tobacco smoke, exercise, viral infections) and appropriate use of medications in response to the underlying level of symptoms and any acute changes. Daily use of medications may be 7   Most estimates of treatment cost in the medical literature are for both type 1 and 2 diabetes.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction necessary. In addition to disease-related complications, children with asthma are more susceptible to comorbid upper and lower respiratory conditions (Weiss and Sullivan, 2001). The societal impact of asthma is reflected in over 10 million missed school days and 100 million days of restricted activity (AAAAI, 2000). In 1998, asthma was also responsible for almost 13.9 million office visits, 2.0 million emergency department visits, and 423,000 hospitalizations (CDC, 2001a). In 1998, asthma-related costs were estimated at $12.7 billion, attributable to medications and healthcare (Weiss and Sullivan, 2001). Disease severity affects the cost of treatment. Malone and colleagues (2000) found that fewer than 20 percent of asthma patients accounted for more than 80 percent of treatment costs. This high-cost minority was composed of individuals who reported their health as poor or fair, and used four or more different asthma medications. Attitudes Toward Multiple Immunizations and Vaccine Safety As this report reflects, there are concerns that the growing number of immunizations routinely given to young children could be a contributing factor to increases in rates of some allergic and autoimmune conditions. The extent of this concern among parents with young children is suggested by a national telephone survey conducted in spring 1999 (Gellin et al., 2000). Among these parents of children under age 6 or expectant parents, 87 percent of the respondents rated immunization as extremely important. But 25 percent agreed with the statement that they were concerned that the immune system could be weakened by too many immunizations, and 23 percent agreed with the statement that children receive more immunizations than are good for them. Gellin and colleagues (2000) note that levels of concern about immunization safety might now be even higher because of events following the survey. In July 1999, the American Academy of Pediatrics and the U.S. Public Health Service called for the removal of thimerosal, a mercury-based preservative, from vaccines (CDC, 1999a); and in October 1999, the rotavirus vaccine was withdrawn from the childhood immunization schedule because of its association with increased reports of intussusception.8 Most recently, the threat of bioterrorism has led to discussion of vaccines against smallpox and anthrax, focusing attention on the benefits as well as the risks of using those vaccines. Without direct evidence, however, it is hard to know what effect such events have on beliefs and perceptions regarding vaccine safety, including any concerns regarding administration of multiple vaccines. Moreover, interpretations of an event can vary. For example, some may view the withdrawal of rotavirus vaccine 8   Based on reports of intussusception to VAERS, the CDC recommended in July 1999 that rotavirus vaccination be postponed, and in October 1999, the ACIP recommended rotavirus vaccine not be given to infants (CDC, 1999b).

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction as an indication of inadequate pre-licensing testing. Others, however, may view the withdrawal as an indication of the successful use of VAERS as a warning system and appropriate responsiveness of immunization policymakers. A fundamental concern for immunization policymakers, discussed in previous reports from this committee (IOM, 2001a,b), is that apprehensions about the safety of vaccines will lead to lower rates of vaccination and increases in serious morbidity and mortality from vaccine-preventable disease, as experienced recently in the United Kingdom (Communicable Disease Report, 2001). Gellin and colleagues (2000) called for periodic assessments of parental attitudes toward vaccines and immunization policy so that clinicians, researchers, and policymakers will have a better understanding of concerns about immunization and can develop more effective responses. But a better understanding of how such concerns affect decisions about immunization will also be needed. Considering Alternative Approaches to Immunization Policy The increasing number of vaccines in the childhood immunization schedule—and the anticipated addition of still more vaccines—is raising questions not only about the safety of multiple immunizations but also about the adequacy of the current approach to immunization policy-making, which emphasizes national recommendations and state mandates for universal immunization. For example, the public may perceive new vaccines as less compelling if an assessment of these vaccines are based on their cost-benefit, not their public health benefit. Immunization policies must, implicitly or explicitly, make tradeoffs among a variety of factors, including disease risks, the efficacy and safety of vaccines, the financial costs of disease and vaccines, and the differing perspectives of individuals and society. A recent paper by Feudtner and Marcuse (2001) argued for greater attention to ethical considerations in developing immunization policies and explores some of the complexities that should be addressed in evaluating policy alternatives. The authors propose a policy framework that explicitly incorporates ethical considerations along with the epidemiological and economic considerations that dominate current decisionmaking. Such a framework should guide both the articulation of policy objectives and the evaluation of policy options to achieve those objectives. In particular, they emphasize the importance of considering matters of personal liberty and equity in the distribution of the benefits and burdens of immunization. For instance, there may be benefits to individuals who have philosophical reasons to refuse immunization. However, there also may be an increased burden on those individuals should they be affected by a vaccine-preventable illness, and the burden would extend to the caretakers of those individuals and to society at large.

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Immunization Safety Review: Multiple Immunizations and Immune Dysfunction Feudtner and Marcuse (2001) also proposed consideration of a broader range of policy options to accommodate a greater degree of autonomy in immunization decisions. The current emphasis on universal immunization recommendations and state mandates may not be appropriate or necessary. The experience of the 15 states that allow philosophic exemptions to required immunization illustrates that the availability of exemptions does not appear to be directly related to levels of immunization coverage. In 2000, although some states that allow philosophic exemptions had some of the lowest immunization rates, other states offering exemptions had some of the highest rates (Marcuse, 2001). An alternative approach might allow for a range of priorities (e.g., mandatory, recommended, or elective), based on an evaluation of the immunization objectives and tradeoffs associated with specific vaccines. Feudtner and Marcuse (2001) acknowledged the challenges of reaching consensus regarding immunization policies with their broader approach to these issues, but they argued that more explicit attention to a wider range of conflicting views and values is needed to maintain public trust in immunization and other public health programs. Conclusions The committee’s assessment of the significance of concerns about possible immune system dysfunctions as a result of multiple immunizations took several factors into account: the burden of the possible adverse outcomes of autoimmune diseases such as type 1 diabetes and allergic diseases such as asthma; indications of the extent of the concern about multiple immunizations; and views regarding the framework for immunization policy-making. Although parents appear to value immunization, a substantial minority believes that multiple immunizations could be harmful. Autoimmune and allergic diseases are common in the United States, after all, and the incidence of these conditions appears to be increasing. As represented by type 1 diabetes and asthma, these conditions are life-threatening if not adequately treated and are associated with substantial health care costs. Given also the prevalence of allergic diseases, specifically asthma, a relatively small increase in risk may lead to a significant public health impact. A better understanding of parents’ perceptions of risk and decision-making may be necessary to prevent decreases in immunization rates and increases in vaccine-preventable disease. Current approaches to immunization policy-making emphasize epidemiological and economic considerations, but may benefit from greater attention to ethical issues, including personal liberty and equity in allocation of the benefits and burdens of immunization. With new vaccines in development and discussions of the wider use of existing vaccines, more flexible approaches to immunization policies—especially regarding priorities—may be needed. Thus, the committee concludes that concern about multiple