PEDIATRICS Vol. 118 No. 2 August 2006, pp. 810-813 (doi:10.1542/peds.2006-0846)
COMMENTARY |
Immunization Recommendations for Children With Metabolic Disorders: More Data Would Help
Department of Pediatrics, Columbus Children's Hospital, Columbus, Ohio
Since Jenner's initial success with cowpox vaccination, active immunization with a wide variety of vaccines and toxoids has represented the most effective means of preventing infectious diseases and their disability and mortality. The benefits of successful immunization programs include not only a reduction in the disease burden associated with the infection (morbidity, pain, suffering, and even mortality) but also a significant savings of health care dollars in both developed and resource-poor countries. In the United States, declines of >95% have been noted for many infections for which universal vaccination has been implemented.1 For nearly all of the available vaccines given to children in the United States, there are significant health care dollars saved for every dollar invested. As one example, universal immunization with the measles-mumps-rubella vaccine saves $7.00 to $9.00 for every dollar spent.2 Currently recommended childhood vaccines have a significant beneficial public health impact. Despite the clear benefit to society, vaccines have a potential for reactions that might adversely affect the individual child. The actual risk/benefit of each vaccine for each individual child may vary.
The spectrum of clinical manifestations and severity of illness in children with metabolic disorders are as varied as the metabolic defects responsible for these conditions. Alterations in specific enzyme systems in children with inborn errors of metabolism can result in metabolic abnormalities that may be adversely affected by the metabolic changes that result from the inflammatory response associated with most infectious diseases. In addition, infections frequently result in temporary anorexia, vomiting, or diarrhea, which may further upset the metabolic homeostasis in the child with a metabolic disorder. Even minor infections have the potential of causing clinical decompensation in fragile children with metabolic disorders. There are also reports in the literature in which the initial clinical manifestations in children with inborn errors of metabolism have their onset temporarily associated with minor or severe infections.3 Clearly, it would be advantageous for the child with an inborn error of metabolism to avoid infectious diseases, particularly those that are preventable by available vaccines.
Vaccines may also cause metabolic changes that mimic, but typically less severely, the metabolic changes associated with inflammation and infection.4 It is necessary to understand the level of risk associated with receiving the vaccine, as compared with the risk potential of developing an even more devastating clinical deterioration associated with natural infection. As a general rule, vaccines licensed in the United States are safe and effective. However, not every vaccine is equally safe or equally effective in every person. Each of the available vaccines has the potential to cause minor, local, or even systemic adverse reactions. Most of the adverse reactions after vaccine administration in healthy children are trivial, inconvenient, and transient. Rarely, healthy children may experience severe and life-threatening events temporarily associated with vaccine administration. Fever, local swelling, redness, and pain at the injection site may be more than trivial in the child with an inborn error of metabolism. Transient metabolic changes associated with fever or anorexia may tip the balance in the child whose clinical status is fragile or not well controlled. In a few reports, the initial clinical presentation of children with inborn errors of metabolism occurred shortly after administration of a vaccine.3 Although it is clear that the vaccine was not responsible for the underlying metabolic disorder, the temporal association of the vaccine administration and onset of disease-related symptoms will make both parents and physicians concerned about the implications of future vaccine administration. Parents of children with chronic illnesses become more risk-averse as they try to minimize any possible additional harm to their child. There is reason to be concerned about established or potential adverse events associated with vaccine administration in some of our most vulnerable patients. Ironically, some of these fragile children are also the ones who would derive the greatest benefit from being protected from many of these vaccine-preventable conditions. Further complicating any risk/benefit analysis is the fact that as vaccines successfully reduce the incidence of many contagious diseases, there is a reduction in the risk of exposure and a diminished potential for benefit to the individual child of having protective immunity. Specific evidence defining the potential risk/benefit for individual vaccines in individual metabolic disorders is incomplete.
Biochemical changes that are present in children with inborn errors of metabolism may affect their immune response system and not only increase risk for infection but also diminish their ability to develop protective immunity after immunization. Understanding the immunogenicity and ability of vaccines to provide protective immunity in each of the specific metabolic disorders will be critical to understanding the child's risk/benefit equation. Immunogenicity of vaccines and protection have not been well characterized in children with most metabolic disorders. A recent review5 of immune deficiencies in children with genetic syndromes identified at least 13 syndromes with inborn errors of metabolism with some level of immunodeficiency (adenosine deaminase deficiency; purine nucleoside phosphorylase deficiency; 5'-nucleotidase elevation; glycogen storage disease Ib/Ic; galactosemia; Barth syndrome; methylmalonic aciduria; propionic acidemia; isovaleric acidemia; lysinuric protein intolerance; orotic aciduria; 
-mannosidosis; and biotinidase deficiency). The mechanism for the immunodeficiency is presumed to be a block of a metabolic process necessary for immune function or the deleterious effect of the buildup of toxic metabolites on immune function. This same review identified additional genetic or metabolic syndromes with immunodeficiency including (1) 21 associated with syndromes of growth deficiency, (2) 4 associated gastrointestinal dysfunction syndromes, (3) 17 associated with syndromes that primarily exhibit cutaneous manifestations, (4) 11 associated with neurologic dysfunction syndromes, (5) 9 associated with hematologic dysfunction syndromes, and (6) 35 associated with miscellaneous genetic or chromosomal abnormalities.
For the hepatitis B vaccine, a larger antigen dose is required for patients undergoing dialysis and for immunosuppressed adults.6 Also, the response to the hepatitis B vaccine is better earlier in the course of renal failure.7 HIV-infected children with a CD4+ cell percentage of >25% may receive the live varicella vaccine, but they require any extra dose given at least 3 months after the first dose.8(p685) These specific examples provide evidence that metabolic or immunologic abnormalities in other clinical conditions diminish the effectiveness of routine vaccine doses/schedules and may require an altered dose/schedule to ensure adequate protection in children with inborn errors of metabolism.
The American Academy of Pediatrics Committee on Infectious Diseases recommends that children with metabolic disorders receive immunizations recommended for healthy children unless there is a contraindication to specific components of the vaccines.8(p82) A clear contraindication would be the administration of live-virus vaccines to children with immunodeficiency disorders. However, as previously noted, the frequency and severity of immunodeficiency in most metabolic disorders is not clearly defined. The diphtheria-tetanus-acellular pertussis vaccine should be withheld in children with evolving neurologic conditions until they are receiving appropriate therapy and the neurologic condition is stabilized. This is very relevant for many children with metabolic disorders, because neurologic abnormalities are not infrequent. For children whose chronic metabolic condition results in an increased risk of complications from infection with influenza or pneumococcus, it is recommended that they receive the influenza and/or pneumococcal conjugate and/or polysaccharide vaccines. Those with metabolic diseases are included as a specific risk group that should receive the influenza vaccine.8(p388) However, only children with renal insufficiency, diabetes mellitus, and immunodeficiency are specifically identified as those with an increased risk for invasive pneumococcal infection.8(p492) The hepatitis A vaccine is recommended for children whose metabolic disease may result in chronic liver disease. These recommendations are made despite an acknowledgment that experience with immunization in children with many of the metabolic disorders is minimal or nonexistent. A final recommendation is that the child's physician seek guidance from a specialist before administering the vaccine to their patients with metabolic conditions. It is not clear from where the specialist will derive the required information to recommend vaccines that are safe and given at the appropriate dose. It is this lack of literature-based evidence or expert consensus that prompted the authors of "Immunization for Patients With Metabolic Disorders"9 in this issue of Pediatrics Electronic Pages to stimulate interest and initiate a dialogue that may lead to more informed recommendations.
Kingsley et al9 divide the inborn errors of metabolism into 4 "families of metabolic diseases" on the basis of the toxic metabolite resulting from the deficient enzyme system: (1) amino acid and organic acids; (2) lipids; (3) carbohydrates; and (4) purines and pyrimidines. The list of metabolic conditions provided by the authors represents a logical starting point. It clearly does not include all of the potential metabolic disorders for which immunization decisions need to be made. However, they are representative and provide an exceptional opportunity to begin the dialogue desired by the authors. With few exceptions, which will be discussed later, they recommend that children with these inborn errors of metabolism should proceed with the routine childhood schedule of immunization with the caveat that there be close observation and, at times, close monitoring of specific serum levels of toxic metabolites (eg, phenylalanine, ammonia, etc). In some cases, such as hereditary infantile tyrosinemia, they recommend a full schedule of immunizations after the child receives effective therapy with 2-(2-nitro-4-trifloromethyl benzoyl)-1,3-cyclohexanedione. For those with a select group of inborn errors of metabolism, they recommend administering the 23-valent pneumococcal polysaccharide vaccine at 
24 months, as would be recommended for children with a high risk of invasive pneumococcal disease such as sickle cell disease or splenectomy. This recommendation may be appropriate. However, it is not entirely clear why only certain children with inborn errors of metabolism should receive the 23-valent pneumococcal polysaccharide vaccine and others should not. In many of the disorders for which the pneumococcal polysaccharide vaccine is recommended, respiratory compromise is listed under cardinal features. However, this is not universal. For some children with pyrimidine 5'-nucleotidase deficiency, a splenectomy may be needed. For these children, they added a recommendation for the recently licensed quadrivalent meningococcal conjugant vaccine, as would be recommended for other children postsplenectomy.10 For children who have metabolic disorders for which there is clear documentation of immune compromise (eg, biotinidase deficiency), they state that a contraindication for the use of live vaccines occurs when a child has evidence of an immunodeficiency, in this case severe combined immunodeficiency. The recommendations found in this article serve as a good basis on which to begin the dialogue but, as the authors have pointed out already, are limited by a lack of supporting evidence.
Clearly, in most children with metabolic diseases, the risks associated with vaccine administration are outweighed by the benefits of vaccine-associated immunity, which protect them from the more devastating consequences of natural infection. The American Academy of Pediatrics Committee on Infectious Diseases8(p82) and Kingsley et al8(p82) came to the same conclusion that children with metabolic disorders should receive the same immunizations recommended for healthy children with only a few exceptions. It would be valuable if data were available to help determine the risks and immunogenicity of individual vaccines for each of these unique children to help define these exceptions. This requires a better understanding of the correct dose and schedule for administration of each of the immunizations in each of the specific patient populations. Rigorous investigation of the safety and immunogenicity of each individual vaccine in all metabolic diseases would be a daunting task. Because comprehensive investigations to define the safety and protective efficacy for each vaccine and dose schedule in each metabolic disorder is not likely to occur, the authors suggest the creation of a vaccine registry for children with metabolic diseases. This would provide a more evaluable information source to inform physicians and parents as they attempt to make decisions about the relative safety and benefit for specific vaccines in medically fragile children with metabolic disorders. Registries are less than perfect because they rely on passive surveillance. However, one would hope that as the value of the registry became apparent to pediatricians who care for these complex patients that it would encourage levels of participation in the registry that would make the data meaningful. The registry might also point investigators toward specific metabolic disorders and/or vaccines that deserve closer scrutiny, because registry findings suggest an unanticipated risk or a concern that protection after routine vaccine schedules is not adequate for certain infections. Because earlier diagnosis and increasing availability of therapies prolong the lives of children with metabolic disorders, it is important that we constantly reevaluate what we can do for these children to also ensure that their quality of life is maintained at the highest levels possible. Prevention of infections through the judicious use of vaccines and avoiding circumstances that might adversely affect the fragile metabolic balance in these children would be helpful.
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FOOTNOTES |
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Accepted Mar 29, 2006.
Address correspondence to Michael T. Brady, MD, Columbus Children's Hospital, 700 Children's Dr, AB 7048, Columbus, OH 43205. E-mail: mbrady{at}chi.osu.edu
The author has indicated he has no financial relationships relevant to this article to disclose.
Opinions expressed in this commentary are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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