Megan J. Troischt, MD

My 18-month-old son has had a diaper rash, with no other symptoms, within a few days of eating a poached egg on 3 separate occasions. I have not fed him eggs otherwise, but he is able to eat baked goods with eggs in them and doesn't get a rash. Can my son get a flu shot? 

With the current push to provide influenza vaccination to all children 6 months and older, pediatricians are likely to hear this question from many parents who are unsure whether their child has egg allergy. It is important to be able to identify whether a child's symptoms are consistent with a hypersensitivity reaction to egg and whether it is safe to administer influenza vaccine. In accordance with the American Academy of Pediatrics (AAP) guidelines, a child can be considered at low risk for anaphylaxis after influenza vaccination when his or her symptoms after egg exposure are not acute (eg, the findings do not clearly indicate an IgE-mediated process) and egg proteins are tolerated in other parts of the diet without reproduction of symptoms. For these children, a brief observation period postvaccination in the office or clinic, where a reaction could be treated with appropriate medications, would be reasonable, as would parental education about monitoring for specific developments at home. Allergy referral and testing may be sought to determine what the offending agent may be, and avoidance of more concentrated egg preparations, such as a poached egg, can be recommended until the follow-up evaluation is completed.

. Egg allergy is the most common food allergy in childhood after milk protein allergy. It affects an estimated 1% to 2% of young children and can cause severe hypersensitivity reactions, including anaphylaxis.

 Egg components are a leading cause of food-triggered atopic skin disease.

 Allergic sensitivity to egg can also be a future predictor of other atopic processes, such as asthma, and is associated with higher rates of sensitivities to other environmental agents, including aeroallergens.

 It may also influence vaccination decisions. Thus, child caregivers need to be aware of the prevalence, presentation, and management of egg allergy to avoid potential harm.

. There are misperceptions about what constitutes an adverse food reaction and what causes it. Many good references summarize the topic

; most of them differentiate between food allergy and food intolerance by the underlying immunological mechanism. Allergic reactions to foods can be divided into IgE-mediated (humoral) and nonIgE-mediated (nonhumoral, or cell-mediated).

 typically affect the GI tract, respiratory system, and skin. The corresponding signs and symptoms may include vomiting, facial swelling, difficulty in swallowing, trouble breathing, and widespread hives. Reactions resulting in anaphylaxis can affect multiple organ systems and lead to shock or death. Humoral-mediated reactions and anaphylaxis are typically associated with a rapid onset of symptoms, within minutes to hours after ingestion.

 predominantly cause GI disturbance, although localized skin manifestations can occur. The clinical features often include diarrhea or a blotchy, erythematous rash in places in direct contact with the allergen, such as the mouth or diaper area. These reactions are usually more insidious in onset, with hours to days being the norm, and can vary significantly in severity. Celiac disease and infantile milk protein colitis are well-known examples.

Food intolerances are abnormal reactions to food components that do not involve the immune system. Mechanisms may include altered metabolism of food components, such as specific sugars in lactose intolerance, or food-induced destabilization of mast cells and histamine release. A large percentage of intolerances can also be idiopathic. Although this form of food sensitivity may cause significant discomfort, it is generally considered benign.

Determining whether a child's symptoms are related to food ingestion and categorizing the type of reaction can be difficult. This is because of symptom overlap among the different reactions, combined reactions, and other variables (eg, illnesses) that may produce symptoms in coincidence with food intake. Although an elimination diet can help isolate the offending food, this may not be advisable for a child with a potential IgE-mediated food reaction. Allergy testing is helpful in determining whether presenting symptoms and history are linked biochemically to foods and the nature of the reaction. Some testing can be performed by general practitioners, such as blood tests for food-specific IgE antibodies. Alternatively, or additionally, an evaluation by an allergist can be prescribed.

Current recommendations for vaccination of egg-allergic patients

. Conventional wisdom and lack of scientific data have resulted in vaccination deferral for many infants and children, even those deemed at high risk for severe disease and complications from influenza. Although the feasibility and safety of vaccinating egg-allergic children with influenza vaccine has been studied, no guidelines have been established.

 Some studies suggest a role for skin prick and intradermal testing with influenza vaccine in egg-allergic persons and administration of the vaccine in a 2-dose or graded-dose protocol, even if the results of testing are positive. In addition, in children who had egg protein anaphylaxis after skin testing, influenza vaccine has been administered safely after appropriate desensitization. However, the AAP recommends that such egg-allergic children not be vaccinated because of their risk of reactions, the need for annual vaccination, and the availability of chemoprophylaxis and treatment against influenza infections.

 Localized manifestations or less severe (non–IgE-mediated) reactions to egg, such as this childs diaper rash, are not considered contraindications to influenza vaccines, and children with these reactions do not warrant vaccine skin testing before vaccination.

Articles

My 18-month-old son has had a diaper rash, with no other symptoms, within a few days of eating a poached egg on 3 separate occasions.

Influenza Vaccine for Egg-Allergic Patients-Safe?

Given the array of childhood disorders that can adversely affect the immune system, most pediatricians at some point will care for children who are immunodeficient. The well-child care of these patients, just like that for immunocompetent children, includes counseling parents about routine vaccines.

In this article, we discuss the basic principles (as articulated by the American Academy of Pediatrics [AAP]5,6 and other sources

) that guide decisions about how best to protect immunocompromised children against vaccine-preventable illnesses. Although we could not address every possible immunodeficiency state, we have included a variety of important and representative examples. Keep in mind that the unique medical circumstances of each immunocompromised child need to be considered to determine the optimal individual vaccination plan.

PREVALENCE OF CHILDHOOD IMMUNODEFICIENCY ON THE RISE


 Primary immunodeficiency diseases (inherited defects of humoral or cellular immunity and defects of phagocytes and the complement system) occur in an estimated 1 in 10,000 persons.

On the basis of telephone interviews, Boyle and Buckley

 report a calculated prevalence of primary immunodeficiency diseases (such as common variable immunodeficiency, IgA and IgG subclass deficiencies, and others) of 1 in 2000 in US children.

Data indicate that the number of children becoming immunocompromised as a result of secondary conditions (infections, cancer, use of medications, malnutrition, diabetes, kidney disease, and so forth) is increasing. Between the start of the AIDS epidemic and 2007, AIDS was diagnosed in approximately 10,000 children younger than 13 years in the United States.

The number of US children who received an organ transplant in a given year increased 13% from 1995 to 2004, such that in 2004, there were almost 2000 pediatric transplant recipients.

 The American Cancer Society predicts that in 2009, cancer will be diagnosed in about 10,730 US children younger than 15 years.

 In addition, for all childhood cancers combined, the 5- year relative survival has increased from less than 50% before the 1970s to nearly 80% today

; this markedly improved survival has further expanded the population of immunocompromised children. Some children in whom cancer develops may have already been vaccinated; however, because of medical procedures such as allogenic bone marrow transplantation, preexisting immunities may be attenuated or lost.

Eventually, vaccination regimens need to be established for all of these immunocompromised children.

VACCINATIONS AND IMMUNOCOMPROMISED CHILDREN: THE BASICS

 To clarify a given child's immune status, his or her underlying diagnoses need to be considered and the degree of immunosuppression must be determined. You may want to consult an immunologist to aid in the immunological evaluation and in development of the vaccination plan. Other medical specialists, such as a hematologist-oncologist, may also provide helpful suggestions.

Perform Careful Assessment of Risks Versus Benefits

 The risks and benefits of vaccinating an immunocompromised child have to be considered before any vaccines are administered.

 There have been many studies of vaccine safety and efficacy in immunocompromised children

; several representative studies involving secondary immunodeficiency conditions are listed in 

. However, because there is such diversity in the primary and secondary conditions that can lead to immunosuppression, each child will need to be considered individually in order to determine his actual risk of acquiring natural infection and of experiencing complications from such an infection-as well as the risk associated with vaccine administration.

Only then can the risks of vaccination be accurately weighed against those of not vaccinating.

) are generally safe in children with primary and secondary immunodeficiencies, although a modified schedule may be necessary. However, while they are safe, inactivated vaccines may not incite an effective immune response in these children.

All vaccines are probably ineffective in children with severe immunosuppression, such as those with severe combined immunodeficiency or complete DiGeorge syndrome.

In children who are unable to mount an antibody immune response, passive immunization with intravenous immunoglobulin (IVIG) is the main therapeutic intervention for preventing infections.

Attenuated immune responses following vaccination are likely in children with less severe disorders, such as selective IgA deficiency or IgG subclass deficiencies. However, because the immune response may not be adequate and immunity cannot be assumed, measurement of prevaccination and postvaccination antibody titers may be helpful.

 Consultation with an immunologist is helpful in such situations.

In patients with complement deficiencies or disorders of phagocyte numbers or function, all routine vaccines are probably effective.

Although all inactivated vaccines are important, some are especially so in children with certain primary deficiencies (for example, the meningococcal vaccine in patients with terminal complement deficiencies and the pneumococcal and meningococcal vaccines in patients with asplenia).

The effectiveness of inactivated vaccines in children with secondary immunodeficiency states varies; it is dependent on both the degree of immunosuppression and the underlying condition with which the immunosuppression is associated. Immunity to infection is not always guaranteed postvaccination. For example, administration of tetanus immunoglobulin is necessary if a child with HIV infection experiences a tetanus-prone wound, whether or not the child has been vaccinated.

Special rules govern vaccine administration in patients who are immunosuppressed as a result of medical interventions. In children who are receiving immunosuppressive agents or chemotherapy, the routine immunization schedule may need to be adjusted. In a child receiving immunosuppressive agents, vaccination should occur at least 3 months after the agents have been stopped; the amount of time required for an adequate immune response to occur varies depending on the specifics of the earlier treatment regimen. Various vaccination and revaccination strategies have been developed for patients who have had chemotherapy or a bone marrow transplant.

In patients with HIV infection, some vaccines (influenza, tetanus, and pneumococcal polysaccharide) have been associated with an increase in viremia. However, the exact clinical significance of this phenomenon is unknown.

For Certain Children, Consider Live Vaccines for Which Safety and Efficacy Data Are Available 

 The live vaccines routinely recommended in the United States are the measlesmumps- rubella (MMR) vaccine, the varicella vaccine, the live attenuated influenza vaccine (LAIV), and the rotavirus vaccine (

). The manufacturers of the rotavirus vaccine licensed for use in the United States warn that no safety  or efficacy data are available for its administration to infants who are potentially immunocompromised, including those receiving immunosuppressive therapy.

 However, safety and efficacy data are available for the MMR and varicella vaccines. Thus, these vaccines can be administered to some children with primary or secondary immunodeficiency states, depending on the patient's immune status.

All live vaccines are contraindicated in patients with severe immunodeficiency disorders or T-cell immunodeficiency disorders, such as severe combined immunodeficiency syndrome, DiGeorge syndrome, Wiskott-Aldrich syndrome, and ataxia telangectasia.

 It is important to emphasize that postvaccination immunity is not guaranteed in immunocompromised children. Thus, it is recommended that immunoglobulin be administered to children with HIV infection and those who are severely immunocompromised, regardless of immunization status, if they have been exposed to measles or varicella. 

 If a child has received immunoglobulin as a treatment for another disease, live vaccines must be delayed for 6 months.

. In children who have conditions associated with antibody deficiencies, such as X-linked agammaglobulinemia, measles vaccination can be considered.6 However, these children may not develop antibody responses to vaccines. Also, these patients are protected by the specific antibodies they receive through the IVIG they are given; thus, vaccination may be unnecessary.

. In children with HIV infection aged 1 to 8 years who are in CDC clinical category N, A, or B, the MMR vaccine is recommended. Varicella vaccine may be considered in children with HIV infection if their CD4+ T-lymphocyte percentage is 15% or greater. For children with HIV infection who are older than 9 years, consider the MMR and varicella vaccines if the CD4+ cell counts are greater than 200/µL. Although the MMR and varicella vaccines should not be given to infants with HIV infection, the rotavirus vaccine may be administered both to infants infected with HIV and to infants who have been exposed to HIV.

. In patients with complement and neutrophil dysfunction, live virus vaccines are considered safe. However, live bacteria vaccines, such as BCG and the live typhoid vaccine that contains Ty21a 

, are contraindicated in patients with neutrophil dysfunction.

. In patients with iatrogenic immunosuppression, immunization with live vaccines is most successful when vaccination is completed before initiation of the immune-modifying therapy or when the immunosuppressive agents have been temporarily discontinued.

When it comes to vaccinating the child who will need to begin aggressive therapy with immune-modifying medication, forethought is crucial. Levin

 states that the ideal window of opportunity for vaccinating children who will be receiving immunosuppressive therapy varies depending on the immune-modifying treatment regimen that they will receive.

. Children who have been receiving systemic corticosteroids for more than 14 days (at a dosage of more than 2 mg/kg/d or with a total daily dose of more than 20 mg of prednisone in a child who weighs more than 10 kg) are considered immunosuppressed. 6 In a child who has received corticosteroids for 2 weeks or longer, live vaccines can be administered no earlier than 3 months after discontinuation of the corticosteroids. 

 lists other corticosteroid treatment settings.

 All close contacts who are eligible for vaccinations should be maximally vaccinated; they should receive all routine recommended vaccines, including the live attenuated MMR, varicella, and rotavirus vaccines. 

Good hand washing is always essential, but particularly so when the rotavirus vaccine has been administered. Viral shedding in recipients of the rotavirus vaccine occurs as early as 1 day after vaccination and as late as 15 days after a dose

; thus, good hand washing is essential for anyone who cares for infants who have received the rotavirus vaccine. With respect to LAIV, limited data are available regarding transmission of the virus from vaccinated persons to immunocompromised patients; however, transmission is thought to occur rarely. It is very important to administer the influenza vaccine annually to all contacts of immunocompromised patients.

 The pediatric health care provider is referred to the AAP and the CDC for the most up-to-date recommendations on vaccinations in all patients. Recommendations concerning the immunization of immunocompromised children change frequently as more studies about safety and efficacy and new vaccines become available.


1. Pirofski LA, Casadevall A. Use of licensedvaccines for active immunization of the immunocompromisedhost. 

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2. American Academy of Pediatrics. 

 infections. In: Pickering LK, Baker CJ,Kimberlin DW, Long SS, eds. Red Book: 2009Report of the Committee on Infectious Diseases. 28thed. Elk Grove Village, IL: 

; 2009:314-321.
3. Markowitz LE, Dunne EF, Saraiya M, et al;Centers for Disease Control and Prevention (CDC),Advisory Committee on Immunization Practices(ACIP). Quadrivalent human papillomavirus vaccine:recommendations of the Advisory Committeeon Immunization Practices (ACIP). 

. 2007;56(RR-2):1-24.
4. Centers for Disease Control and Prevention(CDC). Preventing pneumococcal disease amonginfants and young children: recommendations of theAdvisory Committee on Immunization Practices(ACIP). 

. 2000;49(RR-9):1-38.
5. American Academy of Pediatrics. Human immunodeficiencyvirus infections. In: Pickering LK,Baker CJ, Kimberlin DW, Long SS, eds. 

Red Book:2009 Report of the Committee on Infectious Diseases

; 2009:380-400.
6. American Academy of Pediatrics. Immunocompromisedchildren. In: Pickering LK, Baker CJ,Kimberlin DW, Long SS, eds. 

Red Book: 2009 Reportof the Committee on Infectious Diseases

 2009:72-87.
7. Centers for Disease Control and Prevention(CDC). Guidelines for the prevention and treatmentof opportunistic infections among HIV-exposedand HIV-infected children. Recommendations fromCDC, the National Institutes of Health, the HIVMedicine Association of the Infectious DiseasesSociety of America, the Pediatric Infectious DiseasesSociety, and the American Academy of Pediatrics.MMWR. 2009;58:161-164. 

http://aidsinfo.nih.gov/contentfiles/Pediatrics_OI.pdf

. Accessed September2, 2009.
8. Rotateq [package insert]. Whitehouse Station,NJ: Merck and Co, Inc; 2007.
9. Marin M, GÃ¼ris D, Chaves SS, et al; Centers forDisease Control and Prevention. Prevention ofvaricella: recommendations of the Advisory Committeeon Immunization Practices (ACIP).

.2007;56(RR-4):3.
10. Bliss SJ, O'Brien KL, Janoff EN, et al. The evidencefor using conjugate vaccines to protect HIVinfectedchildren against pneumococcal disease.

 Infect Dis. 2008;8:67-80.
11. Calaminus G, Hense B, Laws HJ, et al. Diphtheria(D) and tetanus (T) antibody values inchildren with acute lymphoblastic leukaemia (ALL)after treatment according to Co-ALL 05/92. 

. 2007;219:355-360.
12. Patel SR, Ortin M, Cohen BJ, et al. Revaccinationof children after completion of standard chemotherapyfor acute leukemia. 

. 2007;44:635-642.
13. Emir S, BÃ¼yÃ¼kpamukÃ§u M, KÃ¶seoglu V, et al.Varicella vaccination in children with lymphoma andsolid tumors. 

. 2006;82:760-762.
14. Masten B, McWilliams B, Lipscomb M, et al.Immune response to hepatitis B vaccine in asthmaticchildren. 

. 2003;36:522-528.
15. Clarke P, Powell PJ, Goldblatt D, Robinson MJ.Effect of a fourth Haemophilus influenzae type bimmunisation in preterm infants who received dexamethasonefor chronic lung disease. Arch Dis Child

. 2003;88:F58-F61.
16. LaRussa P, Steinberg S, Gershon AA. Varicellavaccine for immunocompromised children: resultsof collaborative studies in the United States andCanada. 

. 1996;174(suppl 3):S320-S323.17. McLaughlin M, Thomas P, Onorato I, et al.Live virus vaccines in human immunodeficiencyvirus-infected children: a retrospective survey.

Given the array of childhood disorders that can adversely affect the immune system, most pediatricians at some point will care for children who are immunodeficient.

Vaccinating theImmunocompromised Child

A 13-year-old girl presented to her primary care pediatrician for continuing evaluation of intermittent right lower quadrant and right hip pain of 7 months' duration. As part of the workup, a pediatric orthopedist had ordered an MRI scan of her pelvis. The findings were normal except for the presence of multiple ovarian follicles bilaterally (Figures 1 and 2).

Figure 1 – This coronal T2-weighted MRI scan of the pelvis demonstrates innumerable Subcapsular follicles in the left ovary. The follicles replace most of the normal ovarian tissue and measure about 6 mm each.

Figure 2 – This axial T2-weighed MRI scan of the pelvis shows multiple subcapsular follicles in both ovaries. The ovaries measure 4.5 to 5 cm bilaterally.

 The patient's height was 161.8 cm (75th percentile), weight was 75 kg (above the 95th percentile), and body mass index was 28.6 kg/m

 (above the 95th percentile). Menarche began at age 10 years. She reported having amenorrhea for 4 months and mood swings.

She appeared well, had moderate acne on her forehead and chin, a few prominent hairs above her upper lip, a small linear patch of hyperpigmentation on her neck, and obvious abdominal obesity; there was no thyromegaly. Abdominal and musculoskeletal examinations, including evaluation of the hips, were normal.

Autoimmune thyroiditis (AIT) had been diagnosed about 1 year earlier during a workup for fatigue. Antithyroglobulin antibodies were detected at a level of 286 IU/mL (reference range, less than 40 IU/mL). Thyroid replacement therapy was unnecessary because the thyroid-stimulating hormone and free thyroxine levels were normal and have remained normal; the fatigue, which was probably caused by a self-limited viral infection, resolved.

Review of the patient's clinical symptoms and MRI findings pointed to a diagnosis of polycystic ovary syndrome (PCOS).

Daily hormonal therapy with combination estrogen and progesterone was prescribed, and lifestyle changes, which included increased physical activity and a more nutritious diet, were initiated. The patient's pain, menstrual irregularity, and mood swings abated within 3 months.

PCOS is characterized by chronic anovulation, hyperandrogenism, and polycystic-appearing ovaries. The PCOS diagnosis is determined by a constellation of clinical, laboratory, and radiological findings in a female patient of reproductive age.

In a review by Porter,1 the controversies involved in diagnosing PCOS are described, along with the criteria established in 1990 by the NIH and in 2003 by the Rotterdam workshop.

 The NIH diagnostic criteria for PCOS required all of the following:

Clinical or biochemical evidence of hyperandrogenism.

The Rotterdam criteria required 2 of 3 criteria:

Hyperandrogenism or polycystic ovaries on ultrasonogram.

The Rotterdam definition potentially includes more patients (ie, those without androgen excess).

The associated clinical findings and symptoms of PCOS include menstrual irregularity, infertility, effects secondary to excess androgens (hirsuitism, male-pattern alopecia, acne), obesity, fatigue, and acanthosis nigricans. PCOS may affect up to 10% of premenopausal women. It may be on the rise in adolescents because of the increasing obesity epidemic in children.

Laboratory findings in a patient with PCOS may include hyperinsulinemia and elevated levels of luteinizing hormone (LH), testosterone,dehydroepiandrosterone sulfate (DHEAS), 17 hydroxyprogesterone (17-OHP), and estrone. Insulin resistance also goes hand-in-hand with PCOS.

Transvaginal ultrasonography is the radiological study of choice to evaluate the ovaries for the number of follicles, size, and stroma.

 polycystic ovaries are identified by the presence of 8 or more peripheral follicular cysts (10 mm or smaller) and increased central ovarian stroma. In most instances, an ultrasonogram is not needed for diagnosis and an MRI scan is typically not included in the workup of a patient with suspected PCOS; however, MRI can provide very clear images of polycystic ovaries, as shown in Figures 1 and 2.

 concluded that compared with ultrasonography, MRI provides greater delineation of the structural components of the ovary in obese girls with PCOS. On MRI, a functional cyst would appear as a single dominant cyst as opposed to multiple cysts involving both ovaries, which are seen in patients with PCOS.

Prompt recognition and treatment of PCOS in the young adolescent is essential for abatement of symptoms. The goal of therapy is to restore menstrual cycles and reduce signs of hyperandrogenism. Current interventions include lifestyle modifications (increased exercise, weight reduction), oral contraceptives, and metformin for those patients with insulin resistance.

The association of PCOS and AIT has been described mainly in women in the third decade of life or older.

 In a prospective multicenter study that included one 16-year-old patient, Janssen and colleagues

 revealed a 3-fold higher prevalence of AIT in patients with PCOS compared with age-matched controls. Elevated levels of thyroperoxidase or thyroglobulin antibodies were found in 47 (26.9%) of 175 patients with PCOS compared with only 14 (8.3%) of 168 controls.10 More than 40% of patients with PCOS also had hypoechoic tissue typical of AIT on ultrasonograms of the thyroid. The thyroid findings correlated to some degree with an increased estrogen to progesterone ratio.

suggest screening all patients with PCOS for thyroid dysfunction and thyroid-specific autoantibodies even when there is no evidence of overt thyroid dysfunction; however, this practice is not widely recommended.

The increased prevalence of AIT in PCOS is possibly explained by an imbalance of estrogen and progesterone. 

 Patients with PCOS have anovulatory cycles, which result in low to no progesterone levels and elevated estrogen levels. Lee and colleagues

 suggest that depletion of progesterone from anovulatory cycles in patients with PCOS may act as an immune system stimulant, which leads to AIT; likewise, restoration of ovulatory cycles may prevent AIT in patients with PCOS. They propose that the association between PCOS and AIT may be secondary to a common genetic defect, although the specific defect is still unknown.

Although disorders such as hypothyroidism and other endocrine abnormalities (congenital adrenal hyperplasia and hyperprolactinemia) can lead to polycystic ovaries, PCOS was the most likely diagnosis in this case. We believe the right lower quadrant pain and right hip pain in this patient was related to the PCOS/ menstrual irregularity; the pain resolved with adherent oral contraceptive treatment. Although the patient had a diagnosis of autoimmune thyroiditis, results of thyroid function tests were within the normal range. An evaluation of this patient by an endocrinologist, after hormonal therapy was initiated, revealed normal serum levels of 17-OHP, testosterone, prolactin, free thyroxine, and thyroid-stimulating hormone.

 The authors would like to acknowledge Stephany S. Swart, MD, associate professor of radiology, for her assistance with the figures and figure legends.

Porter MB. Polycystic ovary syndrome: the controversy of diagnosis by ultrasound. 

The Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). 

Hassan A, Gordon CM. Polycystic ovary syndrome update in adolescence. 

Bili H, Laven J, Imani B, et al. Age-related differences  in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years. 

Megan J. Troischt, MD

Articles

Influenza Vaccine for Egg-Allergic Patients-Safe?

Vaccinating theImmunocompromised Child

Polycystic Ovary Syndrome