search text   Advanced Search

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kingsley, J. D. Articles by Roth, K. S. Search for Related Content PubMed PubMed Citation Articles by Kingsley, J. D. Articles by Roth, K. S. Related Collections Infectious Disease & Immunity

Immunizations for Patients With Metabolic Disorders

^a Division of Pediatric Infectious Diseases
^d Combined Division of Metabolism, Creighton University Medical Center and University of Nebraska Medical Center, Omaha, Nebraska
^b Department of Pediatrics, Creighton University Medical Center, Omaha, Nebraska
^c Children's Hospital, Omaha, Nebraska

	ABSTRACT

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
Individuals with underlying metabolic disorders are a potential high-risk group for vaccine-preventable diseases. Newborn metabolic screening has provided a means of early identification and treatment for many of these disorders, whereas childhood immunization is one of the most effective means of decreasing the morbidity and mortality resulting from communicable diseases worldwide. There are very few contraindications to the routine administration of vaccines to the healthy, immunocompetent individual. In certain high-risk groups, such as immunocompromised patients, gravid females, and those with a history of previous anaphylactic reaction to a vaccine or its components, selective withholding of immunizations must be considered to decrease potential adverse events. A detailed analysis of the medical literature revealed few specific recommendations regarding appropriate immunization techniques for patients with metabolic disorders. In this review we detail the major metabolic disorder subtypes, elaborate on the available literature on immunizations for patients with these disorders, and provide suggested vaccine recommendations.

Key Words: immunizations • vaccines • metabolic diseases/disorders • public health

Abbreviations: DTaP—diphtheria-tetanus-acellular pertussis • PKU—phenylketonuria • NTBC—2-(2-nitro-4-trifluoromethyl benzoyl)-1,3-cyclohexanedione • Ig—immunoglobulin • SCID—severe combined immunodeficiency • MCAD—medium-chain acyl-CoA dehydrogenase • GSD—glycogen-storage disease • P5'N-1—pyrimidine 5'-nucleotidase deficiency

The practice of immunizing individuals against childhood illnesses has served 2 public health goals: (1) prevention of disease and (2) eradication of disease. In relation to children with inherited biochemical disease, achieving these 2 goals has had the salutary effect of diminishing dangers of infection and consequent metabolic decompensation. According to the 2003 Red Book,¹ there are very few contraindications to immunizations, but this highly respected source is often silent on the matter of immunizing infants and children with inborn errors. Another well-respected source of information on vaccine-related issues, published by the Centers for Disease Control and Prevention, also makes no reference to immunization of children with inborn errors of metabolism.²

There are many precautions (not contraindications) associated with immunizations, such as moderate-to-severe illness (all vaccines) or a history of seizure or shock-like state after a previous vaccine dose (diphtheria-tetanus-acellular pertussis [DTaP]). However, specific guidelines are often not readily available for administration of routine vaccines to this group of children with diseases that are often fulminant and life-threatening. The 2003 Red Book often recommends "a referral to a specialist for guidance."¹ Although published guidelines for recommendations are sometimes available to the specialist (eg, in the case of administration of pertussis-containing vaccines to children with evolving neurologic disorders³), for many vaccine-preventable diseases, potential risks and benefits of specific vaccines for patients with inborn errors of metabolism are not discussed. The Advisory Committee on Immunization Practices and the American Academy of Pediatrics do recommend that infants with evolving neurologic conditions not be vaccinated with DTaP until a treatment regimen has been established and the condition has stabilized. They further state that acetaminophen or ibuprofen may be administered to these children at the time of DTaP vaccination and every 4 hours for 24 hours thereafter to reduce the possibility of postvaccination fever. Another example for which guidelines are readily available is of patients with diabetes and/or kidney failure, for whom influenza and pneumococcal vaccines are routinely recommended. However, we could find no published guidelines for the use of vaccines in patients with inborn errors of metabolism that are organized by the metabolic disorders.

The recommendations regarding the withholding of immunizations are fairly straightforward and easy to implement in most instances. For example, some immunocompromised individuals and those with a previous history of anaphylaxis after a previous vaccine administration are at high risk for an adverse event after routine immunizations. Another possible high-risk group is that of individuals with metabolic disorders. However, a detailed analysis of the published English-language medical literature revealed little or no information regarding special considerations for immunization of patients with inborn errors. Hence, we have reviewed the available vaccine recommendations for the various types of metabolic disorders and, in several cases, discussed precautions based on specific aspects of the diseases. It would be an overwhelming task to include all diseases of inborn errors in this review; therefore, we have grouped families of metabolic diseases for discussion and attempted, where possible, to make general recommendations as a guide for generalists and specialists in their daily clinical duties. Our intention is to stimulate interest in what has been a neglected subject throughout the era of vaccine development.

	PATHOPHYSIOLOGIC IMPLICATIONS OF IMMUNIZATION

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
The effects of an infection on human metabolism are well known and extremely complex.⁴ After exposure to an infectious agent (incubation period), and usually coincident with onset of symptoms, the initial host response is activation of endogenous mediators, as well as cellular and humoral immunologic mechanisms. The liver enhances its uptake of amino acids and increases protein anabolism, reflected in a generalized hypoaminoacidemia, and retains essential minerals as well. The adrenal-hypothalamic-pituitary axis is stimulated with subsequent increased secretion of adrenocorticotrophic hormone, growth hormone, and glucocorticoids. Essential minerals and compounds are retained by the kidney.

The activation of endogenous and immunologic mediators provides the initiation of the inflammatory cascade of physiologic responses. Fever and other clinical symptoms of illness occur at this stage. Each degree Celsius of temperature increase creates an approximate 10% acceleration of basal metabolic rate,⁵ resulting in increased energy demands despite the typical decrease in oral intake accompanying acute febrile illness in infants and children. The production and use of metabolic energy is altered accordingly, requiring that the body draw on the stored energy sources located in fat depots, liver and muscle glycogen, and muscle protein. Onset of acute symptoms of a febrile illness results in rapid development of negative nitrogen balance in young adults, implying release of amino acids from muscle protein to maintain gluconeogenesis, as well as other metabolic needs.⁶ Similar studies in children who were vaccinated suggest that the decrease in nitrogen retention is directly related to severity of the response.⁷ It should be noted, however, that any decrease in nitrogen retention in a growing child who should always be in positive balance is a significant change from the normal. Use of the amino acids liberated as a consequence of the mobilization of endogenous protein varies; for example, branched-chain amino acids (leucine, isoleucine, and valine) are oxidized in situ in muscle, whereas alanine is released into plasma and carried to the liver for gluconeogenesis. Particularly noteworthy is the excess of phenylalanine released above what is usually required for either protein synthesis or conversion to tyrosine, thereby leading to a characteristic increase in serum phenylalanine during acute febrile illness.⁸

Early in the acute phase of febrile response, there is a mild carbohydrate intolerance and augmented insulin secretion with subsequent increased hepatic synthesis of glucose. The initial hyperglycemia characteristically seen at this stage is a result of the adjustment of the hypothalamic-pituitary-adrenal axis and derives from both glycogenolysis and enhanced gluconeogenesis. The alterations in glucose metabolism resulting from glucagon and catecholamine secretion elicited by the infectious process drive gluconeogenesis; combined with increased circulating glucocorticoids, there is a net increase in the circulating glucose pool and a mild insulin resistance. With time, the hyperglycemia wanes because catecholamine release slows and the liver cannot sustain the increase in gluconeogenesis sufficient to produce such glucose excesses; the increased rate of synthesis, however, must continue because of the increased energy demands of the body. This process clearly depends on continuous supply of gluconeogenic amino acids from endogenous protein stores; in more chronic infectious states, this is a major factor contributing to the muscle wasting that develops with time.

It is interesting to note that although lipids play a very large and important role in the host response to infection, there is relatively little change in lipid metabolism related to acute febrile reactions. Although catecholamine release would be expected to drive lipolysis and release of free fatty acids, the enhanced secretion of insulin, with its very potent antilipolytic action, tends to suppress fatty acid release. As a consequence, there is little to no detectable increase in ketogenesis. Given that most infants are somewhat anorectic in the febrile phase of infection, this is counterintuitive clinically until one understands that the enhanced insulin release blunts the normal fasting response. As the host mounts an immune response against the infection (convalescent period), the physiologic inflammatory cascade begins to slow down and correct itself via biological feedback loops. Metabolic deficits are replenished, and vitamin and mineral stores are returned to positive balances.

The metabolic homeostasis of individuals with inborn errors of metabolism is tenuously balanced and may be easily compromised by any degree of superimposed metabolic stress.^9–15 Inadequate food intake, depleted energy stores, and impaired or excess formation of metabolic components place considerable stress on these individuals' ability to achieve a metabolic balance. Febrile episodes caused by infections or other inflammatory processes further accentuate this stress and may result in a significantly amplified degree of morbidity and mortality in affected individuals. It seems obvious that measures to prevent such infections would be instrumental in decreasing morbidity and mortality, yet specific recommendations for the immunizations of patients with inborn errors of metabolism are often difficult to find. It is important to recognize that various types of vaccines may induce different types of reactions. For example, live attenuated viral vaccines differ from inactivated and subcomponent vaccines in terms of the types of inflammatory markers that are stimulated and their potential for causing fever and other potential metabolic stresses. Thus, individual vaccines may have differing potential to cause clinical deterioration in patients with metabolic disorders. However, although mild immunization-related reactions that are generally self-limited might cause some degree of metabolic stress and disequilibration, the reactions to wild-type infection would be expected to be far worse. Therefore, it is critical to offer recommendations that will provide this important patient population the most effective protection possible against vaccine-preventable infections.

	INBORN ERRORS OF AMINO ACID AND ORGANIC ACID METABOLISM

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
Inborn errors of metabolism are generally monogenic, autosomal recessive disorders caused by mutations that enable the synthesis of abnormal enzyme proteins. In turn, these abnormal products may result in disease states that can range from inconsequential to lethal in nature. Clinical manifestations may range from catastrophic to chronic and can include developmental delay, persistent emesis, elevated blood levels of ammonia, hepatomegaly, abnormal body or urine odors, and a variety of other symptoms. Early diagnosis, appropriate intervention, and monitoring for newborns with an inborn error are critically important for minimizing the possible devastating consequences. Proactive interventions can offer many of these patients the opportunity to live a relatively normal life. Table 1 provides immunization recommendations for selected examples of amino acid metabolic disorders that, if challenged by wild-type infection, may result in significant morbidity and/or mortality.

Hereditary infantile tyrosinemia is a relatively uncommon autosomal recessive disease with devastating consequences for the affected infant, including failure to thrive, biochemical changes of hepatic porphyria, hepatic cirrhosis, and renal tubular sclerosis. There is eventual hepatic failure, severe hyperammonemia, massive coagulopathy, and diminished renal function, with death a certainty if untreated. The enzyme defect (fumarylacetoacetate hydrolase), the gene for which is located on chromosome 15, impairs conversion of fumarylacetoacetic acid to fumaric and acetoacetic acids for further metabolism. The resultant accumulated metabolic byproduct, succinylacetone, has been shown to cause renal tubular dysfunction and inhibition of hepatic enzymes involved in heme biosynthesis in experimental animals.^17,18 A relatively common occurrence in affected children is the so-called paralytic neurologic crisis, which may result in fatality. It has been proposed that this manifestation is likely a result of deficient fumarylacetoacetase within brain tissue itself and a consequent autointoxication.¹⁹ A frequent precipitating cause of these crises is known to be intercurrent infection, most likely because of the superimposed metabolic stress.

Use of a compound called 2-(2-nitro-4-trifluoromethyl benzoyl)-1,3-cyclohexanedione (NTBC) has revolutionized the treatment of hereditary tyrosinemia. The underlying principle is that if catabolism of tyrosine can be blocked before the formation of fumarylacetoacetase, then the toxicity of succinylacetone and other metabolites that accumulate can be eliminated. Although still an experimental treatment, NTBC has proven itself to be enormously effective; thus, affected infants on NTBC therapy should not be subject to metabolic decompensation with intercurrent infections. For this reason, patients with tyrosinemia who are receiving NTBC treatment are able to receive all scheduled immunizations.

The result of an impaired process by which free ammonia is converted to urea in hepatocytes is the so-called urea-cycle defects, which are characterized by episodic and potentially fatal hyperammonemia. Essentially, the catabolic process of turning amino acids into energy is the only source of free ammonia in human metabolism. There are 6 known enzyme deficiencies, each of which affects an intermediate step by which urea is synthesized and ornithine regenerated, with incorporation of 2 mol of free ammonia per mol of urea synthesized. Free ammonia is a potent neurotoxin, with the central nervous system an especially sensitive target. Hence, brain damage and mental retardation are seen with fair regularity among children affected by these diseases.

Intercurrent illness, accompanied by anorexia, generally provokes an acute hyperammonemic episode because of the breakdown of muscle tissue to supply critically essential amino acids, as described above ("Pathophysiologic Implications of Immunization"). Clinical manifestations of hyperammonemia include further enhanced anorexia, vomiting, and lethargy, which are all characteristic of intercurrent illnesses as well. Thus, it is often very difficult to clinically distinguish an intercurrent illness from a hyperammonemic episode or a combination of the two. That being said, it is likely that any live-vaccine administration might provoke a minor degree of hyperammonemic response in an affected child. Although this is less than desirable, the alternative, such as a child with a urea-cycle disorder contracting rubeola, is likely to be a challenge in terms of management and outcomes. Thus, prudence dictates that all infants with urea-cycle disorders should receive scheduled immunizations and be followed closely for any ensuing hyperammonemia.

Hyperlysinuric protein intolerance is an autosomal recessive disorder associated with impaired transport of dibasic amino acids (lysine, arginine, and ornithine) out of renal tubules, intestinal epithelium, hepatocytes, and fibroblasts. Because of inability to transfer them across the basal membrane into blood, these dibasic amino acids are excessively excreted into the urine, thereby decreasing systemic levels. It is thought that the specific deficiency of the dibasic amino acid ornithine to join in the urea cycle causes hyperammonemia, failure to thrive, protein intake aversion, nausea/vomiting, diarrhea, and decreased cognitive ability. Another possible association of this disorder is B- and T- cell abnormalities. Nagata et al²⁰ reported delayed cutaneous hypersensitivity response to purified protein derivative and Candida in an 8-year-old affected female. They also demonstrated elevated immunoglobulin G (IgG), IgA, IgD, and serum immune complex, as well as decreased activity of antibody-dependent cell-mediated cytotoxicity, mild leukopenia and thrombocytopenia, and decreased numbers of bone marrow megakaryocytes.²⁰ Rheumatologic markers were also abnormal (elevated antinuclear antibody and positive lupus test).²⁰ Lukkarinen et al²¹ observed that some patients had a mild deficiency in B-cell function (IgG3 and IgG4), whereas some had diminished response to the conjugated Haemophilus influenzae type b vaccine and the pneumococcal polysaccharide vaccine. It was speculated that perhaps the protein malnutrition associated with this disorder leads to impaired T-lymphocyte maturation and function, decreased immunoglobulin availability, poor response to polysaccharide antigens, ineffective complement activity, and impaired phagocytic cells. Although it is possible that protective effects can be achieved despite suboptimal antibody concentrations, verification of immunologic status before vaccination, particularly when live-vaccine administration is under consideration, and documentation of adequate immune response after vaccination may be prudent for these patients. Additional studies documenting the serologic response to various vaccines in this patient population would be useful in making more specific recommendations.

The family of organic acid disorders actually derives from enzyme defects within individual amino acid catabolic pathways at points where the blocked substrate cannot be reversibly metabolized. Hence, there is accumulation of an organic intermediate (eg, propionic, methylmalonic acids) as well as products of alternative metabolic pathways, an example of which might be methylcitrate in the case of propionic acidemia. Therapy for the organic acidemias most often relies on a strict dietary regimen that limits intake of the affected amino acid(s) combined, in some instances, with administration of megadoses of a specific vitamin. Patients with many types of organic acidemias face 2 major challenges when ill: (1) the accumulation of organic acid(s) impairs formation of the compound N-acetylglutamate, which activates the urea cycle, leading to a mild-to-moderate hyperammonemia, and (2) in the slightly longer term (7–10 days), there is frequently a manifestation of a toxic bone marrow effect, with pancytopenia and increased susceptibility to sepsis. Given the pathophysiologic implications of immunization, it can be seen that the febrile response, the anorexia, or both may contribute to a metabolic decompensation in these patients with potentially serious consequences.

Methylmalonic acidemia is an autosomal recessive inborn error affecting branched-chain amino acid metabolism. Deficiencies of methylmalonyl CoA mutase or adenosylcobalamin lead to the accumulation of methylmalonic acid in tissues.²² In one type of genetic mutation, the enzyme defect is treatable with massive doses of vitamin B₁₂. Children with this form of the disease who are diagnosed and treated early may have a very good prognosis. The clinical symptoms of this disorder include various manifestations of psychomotor retardation, with intermittent attacks of ketoacidosis, hyperammonemia, and neutropenia associated with infections.²³ Patients with this disorder need attentive health care maintenance to optimize their clinical status. The full schedule of immunizations and yearly influenza vaccinations to provide protection against vaccine-preventable infections should be given.

Glutaric aciduria type I is an autosomal recessive disorder caused by deficiency of gluteryl CoA dehydrogenase activity. The enzyme defect results in impaired breakdown of lysine, hydroxylysine, and tryptophan, leading to elevated systemic levels of glutaric acid. If undiagnosed and untreated, mortality within the first decade of life is high. The available literature indicates that this particular inborn error of metabolism may have an acute presentation, coincident with a mild viral infection.²⁴ Clinical onset of underlying glutaric aciduria type I after administration of poliovirus vaccine has been reported.^25,26 Alkan et al²⁶ suggested that immunization-related encephalopathies induced the clinical manifestations of latent glutaric aciduria type I, although any such association between poliovirus and disease onset would be more likely to be triggered through exposure to asymptomatic shedding of virus by 60% to 70% of healthy cohort members. Because live poliovirus vaccines are no longer used in the United States, this potential problem has been eliminated, and patients with glutaric aciduria type I should receive all recommended immunizations.

Defects in biotin-dependent enzyme pathways result in organic acidemias. Two biotin-responsive defects have been described: (1) multiple carboxylase (holocarboxylase) deficiency, which is an early-infant–onset disorder manifested as severe lactic acidosis, organic acidemia, erythematous papular skin rash, and coma,²⁷ and (2) biotinidase deficiency, which is an inborn error of metabolism that appears in later infancy and is associated with lactic acidosis, erythematous skin rash, and organic aciduria. Without holocarboxylase, the biotin-lysine covalent linkage with the enzyme apoprotein cannot be created, rendering the enzyme inactive. Without biotinidase, biotin is not liberated from the covalent linkages to carboxylases and, thus, cannot be recycled by the body, which eventually creates a systemic biotin deficiency. The associated clinical symptoms overlap with those of holocarboxylase synthase deficiency and include hypotonia, convulsions, ataxia, optic atrophy, hearing loss, alopecia, rash, conjunctivitis, cutaneous candidiasis, recurrent upper respiratory infections, and severe combined immunodeficiency (SCID). In many states presently, only biotinidase is being screened for in newborns, although an expanded newborn metabolic screen will detect holocarboxylase deficiency as well. Because of the miniscule dietary requirement, intercurrent illness and/or metabolic stress are highly unlikely to result in metabolic decompensation in a treated child with either form of biotin-dependent disease. Therefore, these patients may receive the full schedule of immunizations unless they are diagnosed with an associated SCID, in which case live vaccines would be contraindicated.

	INBORN ERRORS OF LIPID METABOLISM

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
Errors in the metabolism of lipids comprise a wide array of disorders that include mitochondrial fatty acid oxidation, long-chain fatty acid disorders, errors of lipoprotein metabolism and transport, lipid-storage disorders, and abnormal lysosomal or peroxisomal enzyme activity (Table 2). Of these, many are indolent disorders that may manifest clinical symptoms over many years and are not subject to acute metabolic decompensation. Several, however, show acute episodes that may become life-threatening and, therefore, require clarification regarding administration of immunizations.

Other, much less common lipid metabolic disorders include entities such as Zellweger syndrome,³² X-linked adrenoleukodystrophy,³³ GM₁ gangliosidosis,³⁴ Niemann-Pick disease,³⁵ metachromatic leukodystrophy,³⁶ and Krabbe disease.³⁷ Unlike the disorders of fatty acid catabolism discussed above, this group of widely disparate disorders has in common the fact that the metabolic defect results in intracellular storage of catabolic intermediates, with secondary, frequently structural adverse effects on the cell. In general, the onset of each is gradual and is not impacted by intercurrent illness except in later stages where pulmonary compromise may supervene. Hence, a routine immunization schedule should be applied for all such children.

	INBORN ERRORS OF CARBOHYDRATE METABOLISM

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
Under normal conditions, much of the energy required for metabolic activity is provided by the formation and breakdown of carbohydrates. The 4 carbohydrates that play a significant role in metabolic processes are glucose, galactose, fructose, and glycogen. Defects in the proper metabolic use of these carbohydrates can lead to varied clinical pictures ranging from asymptomatic to lethal presentations (Table 3).

Type 1 glycogen-storage disease (GSD) is an autosomal recessive disorder associated with the ineffective hepatic conversion of glucose-6-phosphate to glucose secondary to inadequate activity of glucose-6-phosphatse or glucose-6-phosphate translocase in the liver, kidney, and intestines.³⁹ These patients may present as neonates with hypoglycemia and lactic acidosis that are difficult to control but may also present at 3 months of age with significant hepatomegaly, impaired platelet function, hyperuricemia, hyperlipidemia, and hypoglycemia-induced seizure activity. A specific subtype of type 1 GSD, type 1b with associated deficiency of glucose-6-phosphate translocase, has additional complications of recurrent bacterial infections related to ineffective neutrophil and monocyte functions and neutropenia. The metabolic nature of this disorder is such that the infant completely depends on dietary sources of glucose and is highly intolerant of any significant fast. Thus, the normal and usually brief anorexia experienced by most infants after immunizations can have significant adverse effects on an infant affected by GSD I. This, however, should not be counted as a contraindication to immunizing such an infant; instead, it should raise awareness in providers and caregivers of the possibility of hypoglycemia occurring after immunization so that appropriate plans for evaluation and treatment can be made.

Aspartylglucosaminuria is an autosomal recessive lysosomal storage disorder that leads to an accumulation of uncleaved metabolites in lysosomes of almost all cells.⁴⁰ Onset of clinical manifestations usually occurs within the first year of life; as the patients become older, there is progression toward profound mental retardation, minimal motor ability, and seizure activity. However, early deaths do occur as a result of respiratory infections and complications. In an effort to provide protection from vaccine-preventable infections, adhering to all scheduled immunizations for these children is recommended.

	INBORN ERRORS OF PURINE AND PYRIMIDINE METABOLISM

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
Purines and pyrimidines are essential components of all biological processes, providing necessary components of RNA and DNA, acting as coenzymes for metabolic regulation, and serving as substrates for cellular signal transduction. Disruptions in their metabolism can cause a varied symptom complex often involving psychomotor delay and respiratory compromise (Table 4). Scheduled immunizations should be an essential component of affected infants' health care maintenance.

Also deserving of mention is hereditary orotic aciduria, an autosomal recessive inborn error of pyrimidine metabolism that results in excessive accumulation of orotic acid with the clinical manifestations of psychomotor retardation, anemia, megaloblastic bone marrow, leukopenia, and abnormalities of cell-mediated immunity.⁴² Because of these associated symptoms, this patient population should receive the full schedule of immunizations and yearly influenza vaccinations to provide protection from vaccine-preventable infections. These patients may need to have follow-up serum antibody concentration tests performed after vaccinations to determine if appropriate immune responses have occurred.

	INACTIVATED INFLUENZA VACCINATION

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
Although annual influenza vaccination has not been addressed separately under each category of metabolic disorders, virtually all patients with these underlying disorders would be expected to benefit from prevention of wild-type influenza infection. Live-attenuated influenza vaccines, as with all other live vaccines, would be contraindicated in those with metabolic disorders that are associated with significant immunodeficiency such as lysinuric protein intolerance or biotinidase deficiency.

	DISCUSSION

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 
The purpose of this review is twofold: (1) to search the literature for pertinent case reports and peer-reviewed articles concerning possible vaccine precautions and contraindications in an attempt to provide vaccination guidelines for patients with inborn errors of metabolism and (2) to garner discussion among metabolic and infectious disease experts regarding the appropriate immunization recommendations for this patient population. As we clearly show, the available literature regarding immunization recommendations for patients with inborn errors is sparse. Contraindications against immunizations were not found in the available infectious disease and metabolic disease databases for inborn errors of metabolism. However, there are some inborn errors with associated impaired immune functions or tendency for rapid decompensation that may require caution and close follow-up after administration of immunizations. The purpose of these follow-up evaluations is to not only monitor for metabolic decompensation but also assess for suboptimal immune responses to the vaccinations that could potentially leave these patients susceptible to major vaccine-preventable diseases.

There may be unwritten and anecdotal immunization guidelines and protocols for patients with metabolic disorders, but there are no stated recommendations found in available published English-language literature. This review is meant to be the initial step in promoting a dialogue among medical professionals to remedy this deficiency. One option to consider would be for the National Organization for Rare Diseases to implement and promulgate a vaccine registry for children with these diseases. Over time, such a registry could significantly shed light on the safety and/or risks of vaccines in this population.

It is our full understanding and expectation that aspects of the stated immunization recommendations will most likely change in time as further discussion and possible research ensue. Regardless, health care providers will now be able to incorporate the recommendations of this review into their daily comprehensive care of patients with inborn errors of metabolism.

	FOOTNOTES

 
Accepted Feb 17, 2006.

Address correspondence to Karl S. Roth, MD, Department of Pediatrics, Creighton University Medical Center, Omaha, NE 68131. E-mail: ksroth{at}creighton.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT PATHOPHYSIOLOGIC IMPLICATIONS OF... INBORN ERRORS OF AMINO... INBORN ERRORS OF LIPID... INBORN ERRORS OF CARBOHYDRATE... INBORN ERRORS OF PURINE... INACTIVATED INFLUENZA... DISCUSSION REFERENCES

 

1. American Academy of Pediatrics. Immunization in special clinical circumstances. In: Pickering LK, ed. 2003 Red Book Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:82
2. Atkinson W, ed. Epidemiology and Prevention of Vaccine-Preventable Diseases. 8th ed. Washington, DC: Department of Health and Human Services, Centers for Disease Control and Prevention; 2004
3. American Academy of Pediatrics. Pertussis. In: Pickering LK, ed. 2003 Red Book Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003:484 –485
4. Beisel WR. Metabolic response of the host to infections. In: Feigin RD, Cherry JD, eds. Textbook of Pediatric Infectious Diseases. 5th ed. Philadelphia, PA: Saunders Publishing; 2004:62 –77
5. Scrimshaw NS. Rhoades lecture: effect of infection on nutrient requirements. JPEN J Parenter Enteral Nutr. 1991;15 :589 –600[Abstract]
6. Beisel WR, Sawyer WD, Ryll ED, Crozier D. Metabolic effects of intracellular infections in man. Ann Intern Med. 1967;67 :744 –779[ISI][Medline]
7. Wilson D, Bressani R, Scrimshaw NS. Infection and nutritional status. I. The effect of chicken pox on nitrogen metabolism in children. Am J Clin Nutr. 1961;9 :154 –158[Abstract/Free Full Text]
8. Wannemacher RW Jr, Klainer AS, Dinterman RE, Beisel WR. The significance and mechanism of an increased serum phenylalanine-tyrosine ratio during infection. Am J Clin Nutr. 1976;29 :997 –1006[Abstract/Free Full Text]
9. Dierdorf SF, McNiece WL. Anaesthesia and pyruvate dehydrogenase deficiency. Can Anaesth Soc J. 1983;30 :413 –416[ISI][Medline]
10. Walter JH. Inborn errors of metabolism and pregnancy. J Inherit Metab Dis. 2000;23 :229 –236[CrossRef][ISI][Medline]
11. Leonard JV. The nutritional management of urea cycle disorders. J Pediatr. 2001;138(1 suppl) :S40 –S44; discussion S44–S45
12. Steiner LA, Studer W, Baumgartner ER, Frei FJ. Perioperative management of a child with very-long-chain acyl-coenzyme A dehydrogenase deficiency. Paediatr Anaesth. 2002;12 :187 –191[CrossRef][ISI][Medline]
13. Wilcken B. An introduction to nutritional treatment in inborn errors of metabolism: different disorders, different approaches. Southeast Asian J Trop Med Public Health. 2003;34(suppl 3) :198 –201
14. Wiese M, Mehlinger SL, Drinkard B, et al. Patients with classic congenital adrenal hyperplasia have decreased epinephrine reserve and defective glucose elevation in response to high-intensity exercise. J Clin Endocrinol Metab. 2004;89 :591 –597[Abstract/Free Full Text]
15. Lindholm H, Lofberg M, Somer H, Naveri H, Sovijarvi A. Abnormal blood lactate accumulation after exercise in patients with multiple mitochondrial DNA deletions and minor muscular symptoms. Clin Physiol Funct Imaging. 2004;24 :109 –115[CrossRef][ISI][Medline]
16. Phenylketonuria (PKU): screening and management. NIH Consens Statement. 2000;17(3) :1 –27
17. Wyss PA, Carter BE, Boynton SB, Connor E, Fowler B, Roth KS. Renal heme metabolism in hereditary tyrosinemia: use of succinylacetone in rat renal tubules. Biochim Biophys Acta. 1991;1070 :300 –304[Medline]
18. Wyss PA, Boynton SB, Chu J, Roth KS. The physiologic basis for an animal model of the renal Fanconi syndrome: use of succinylacetone in the rat. Clin Sci (Lond). 1992;83 :81 –87[Medline]
19. Wyss PA, Boynton SB, Chu J, Roth KS. Tissue distribution of succinylacetone in the rat in vivo: a possible basis for neurotoxicity in hereditary infantile tyrosinemia. Biochim Biophys Acta. 1993;1182 :323 –328[Medline]
20. Nagata M, Suzuki M, Kawamura G, et al. Immunological abnormalities in a patient with lysinuric protein intolerance. Eur J Pediatr. 1987;146 :427 –428[CrossRef][ISI][Medline]
21. Lukkarinen M, Parto K, Ruuskanen O, Vainio O, Kayhty H, Olander RM. B and T cell immunity in patients with lysinuric protein intolerance. Clin Exp Immunol. 1999;116 :430 –434[CrossRef][ISI][Medline]
22. Aikoh H, Sasaki M, Sugai K, Yoshida Y, Sakuragawa N. Effective immunoglobulin therapy for brief tonic seizures in methylmalonic acidemia. Brain Dev. 1997;19 :502 –505[CrossRef][ISI][Medline]
23. Guerra-Moreno J, Barrios N, Santiago-Borrero PJ. Severe neutropenia in an infant with methylmalonic acidemia. Bol Asoc Med P R. 2003;95(1) :17 –20
24. Martinez-Lage JF, Casas C, Fernandez MA, Puche A, Rodriguez Costa T, Poza M. Macrocephaly, dystonia, and bilateral temporal arachnoid cysts: glutaric aciduria type 1. Childs Nerv Syst. 1994;10 :198 –203[CrossRef][ISI][Medline]
25. Nagasawa H, Yamaguchi S, Suzuki Y, et al. Neuroradiological findings in glutaric aciduria type I: report of four Japanese patients. Acta Paediatr Jpn. 1992;34 :409 –415[Medline]
26. Alkan A, Baysal T, Yakinci C, Sigirci A, Kutlu R. Glutaric aciduria type I diagnosed after poliovirus immunization: magnetic resonance findings. Pediatr Neurol. 2002;26 :405 –407[CrossRef][ISI][Medline]
27. Roth KS, Yang W, Foremann JW, Rothman R, Segal S. Holocarboxylase synthetase deficiency: a biotin-responsive acidemia. J Pediatr. 1980;96 :845 –849[CrossRef][ISI][Medline]
28. Andresen BS, Dobrowolski SF, O'Reilly L, et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001;68 :1408 –1418[CrossRef][ISI][Medline]
29. Amendt BA, Greene C, Sweetman L, et al. Short-chain acyl-coenzyme A dehydrogenase deficiency: clinical and biochemical studies in two patients. J Clin Invest. 1987;79 :1303 –1309[ISI][Medline]
30. Hale DE, Batshaw ML, Coates PM, et al. Long-chain coenzyme A dehydrogenase deficiency: an inherited cause of nonketotic hypoglycemia. Pediatr Res. 1985;19 :666 –671[ISI][Medline]
31. Wanders RJA, Duran M, Ijilst L, et al. Sudden infant death and long-chain 3-hydroxyacyl-CoA dehydrogenase [letter]. Lancet. 1989;2 :52 –53[ISI][Medline]
32. Kelley RI. The cerebrohepatorenal syndrome of Zellweger, morphologic and metabolic aspects. Am J Med Genet. 1983;16 :503 –517[CrossRef][ISI][Medline]
33. Moser HW. Adrenoleukodystrophy: phenotype, genetics, pathogenesis and therapy. Brain. 1997;120 :1485 –1508[Abstract/Free Full Text]
34. Okada S, O'Brien JS. Generalized gangliosidosis: beta-galactosidase deficiency. Science. 1968;160 :1002 –1004[Abstract/Free Full Text]
35. Brady RO. The sphingolipidoses. N Engl J Med. 1966;275 :312 –318[ISI][Medline]
36. Kappler J, Leinekugel P, Conzelmann E, et al. Genotype-phenotype relationship in various degrees of arylsulfatase A deficiency. Hum Genet. 1991;86 :463 –470[ISI][Medline]
37. Wenger DA, Rafi MA, Luzi P, Datto J, Costantino-Ceccarini E. Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70 :1 –9[CrossRef][ISI][Medline]
38. Suzuki M, West C, Beutler E. Large-scale molecular screening for galactosemia alleles in a pan-ethnic population. Hum Genet. 2001;109 :210 –215.[CrossRef][ISI][Medline]
39. Chou JY, Mansfield BC. Molecular genetics of type I glycogen storage diseases. Trends Endocrinol Metab. 1999;10 :104 –113[CrossRef][ISI][Medline]
40. Rapola J. Lysosomal storage diseases in adults. Pathol Res Pract. 1994;190(8) :759 –766
41. Rees DC, Duley JA, Marinaki AM. Pyrimidine 5' nucleotidase deficiency. Br J Haematol. 2003;120 :375 –383[CrossRef][ISI][Medline]
42. Girot R, Durandy A, Perignon JL, Griscelli C. Hereditary orotic aciduria: a defect of pyrimidine metabolism with cellular immunodeficiency. Birth Defects Orig Artic Ser. 1983;19 :313 –316[Medline]

This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kingsley, J. D. Articles by Roth, K. S. Search for Related Content PubMed PubMed Citation Articles by Kingsley, J. D. Articles by Roth, K. S. Related Collections Infectious Disease & Immunity

	Home | My Pediatrics | Journal Information | Current Issue | Past Issues | Subscriptions & Services | Contact Us Click here for faster international access © 2006 American Academy of Pediatrics. All rights reserved.