Adverse reactions to vaccines practice parameter 2012 update.

Mild local reactions and fever after vaccinations are common and do not contraindicate future doses. Anaphylactic reactions to vaccines are rare and should be evaluated with skin tests to the vaccine and its components. If the skin test results are negative, subsequent doses can be administered in the usual manner but under observation. If the skin test results are positive and the patient requires subsequent doses, the vaccine can be administered in graded doses under observation. Some nonanaphylactic reactions to vaccines might also require evaluation, but only a few are contraindications to future doses. Pregnant women and persons who are immune compromised should generally not receive live vaccines. Purported long-term sequelae of vaccination, such as autism, are not supported by epidemiologic studies. Patients with egg allergy of any severity should receive annual influenza vaccinations because studies have demonstrated a very low rate of reactions. Studies to date have evaluated the injectable trivalent influenza vaccine (TIV), and thus TIV, rather than the live attenuated influenza vaccine (LAIV), should be used for recipients with egg allergy. All influenza vaccines available in the United States contain low amounts of ovalbumin. Neither skin testing with the vaccine nor dividing the dose is required; however, the vaccine should be administered in a setting in which anaphylaxis can be recognized and treated. EXECUTIVE SUMMARY Mild local reactions and constitutional symptoms, such as fever, after vaccinations are common and do not contraindicate future doses. Rarely, delayed-type hypersensitivity to a vaccine constituent can cause an injection-site nodule, but this is not a contraindication to subsequent vaccination. Anaphylactic reactions to vaccines are estimated to occur at a rate of approximately 1 per million doses. There are approximately 220million doses of vaccines distributed in the United States each year. All serious events occurring after vaccine administration should be reported to the Vaccine Adverse Event Reporting System (VAERS), even if it is not certain that the vaccine was the causal agent. Measuring levels of IgG antibodies to the immunizing agents in a vaccine suspected of causing a serious adverse reaction to determine whether they are at protective levels can help determine whether subsequent doses are required. All suspected anaphylactic reactions to vaccines should ideally be evaluated in an attempt to determine the culprit allergen. IgE-mediated reactions to vaccines are more often caused by additive or residual vaccine components, such as gelatin, rather than the microbial immunizing agent itself. Patients who have had an apparent anaphylactic reaction after immunization should undergo immediate-type allergy skin testing to help confirm that the reaction was IgE mediated and to determine the responsible component of the vaccine. If the intradermal skin test result is negative, the chance that the patient has IgE antibodies to any vaccine constituent is negligible, and the vaccine can be administered in the usual manner. Nonetheless, it is prudent in a patient with a history suggestive of an anaphylactic reaction to administer the vaccine under observation with epinephrine and other treatment available. In a patient with a history and skin test results consistent with an IgE-mediated reaction to a vaccine who requires additional doses of the suspect vaccine or other vaccines with common ingredients, consideration can be given to administering the vaccine in graded doses under observation. Some nonanaphylactic reactions to vaccines might also require evaluation, but only a few are absolute contraindications to future doses. Pregnant women should not be vaccinated with live vaccines. However, pregnant women should be given inactivated influenza vaccine, as well as tetanus and hepatitis B vaccine, if otherwise indicated. In general, live vaccines should not be given to persons who are immune compromised because of a risk of generalized infection with the immunizing agent. Specific vaccines or vaccination in general have been purported to have long-term consequences, including atopy, autism, and multiple sclerosis. Epidemiologic studies have not supported such associations. Patients with egg allergy should receive influenza vaccinations (TIV) because the risks of vaccinating are outweighed by the risks of not vaccinating. Persons with a history of suspected egg allergy should be evaluated by an allergist to determine the status of their egg allergy, but this should not delay their influenza vaccination. A growing number of studies suggest that influenza vaccines can be safely administered even to patients with a history of anaphylaxis to egg ingestion. Skin testing (prick, intradermal, or both) with the influenza vaccine itself in subjects with egg allergy (but without a history of reacting to the vaccine itself) does not reliably identify patients who are at increased risk of reacting to the vaccine and is not recommended. Influenza vaccine can be administered as a single dose to patients with egg allergy. Patients with egg allergy should receive influenza vaccines in a setting in which clinicians experienced in recognizing and treating anaphylaxis and equipment to manage anaphylaxis are immediately available and should be observed for 30minutes after vaccination. Patients with egg allergy with a history of only hives after egg ingestion can receive influenza vaccine in a primary care provider’s office provided the appropriate personnel and equipment are available, whereas those with a history of more severe reactions to egg ingestion should receive their vaccine in an allergist’s office. All influenza vaccines available in the United States contain low amounts of ovalbumin. Although the intranasally administered LAIV contains a low amount of ovalbumin, all published studies to date have evaluated the injectable TIV, and thus TIV rather than LAIV should be used for recipients with egg J ALLERGY CLIN IMMUNOL JULY 2012 28 KELSO ET AL allergy. Only for patients with a history of allergic reaction to influenza vaccine itself is additional evaluation appropriate, including skin testing with the vaccine and vaccine ingredients. For patients with positive skin test results, the vaccine can be administered in multiple divided doses or can be withheld. PREFACE This practice parameter provides a practical, peer-reviewed, evidence-based guide for evaluation and management of patients with suspected allergic or other adverse reactions to vaccines. It also addresses patients with preexisting allergies or other health conditions that might preclude or alter vaccination. It contains updates since the first publication in 2009. The practice parameter offers both general and vaccine-specific recommendations for (1) skin testing to vaccines and components, (2) serum specific IgE antibody testing, (3) serologic testing for protective antibody responses to vaccines, (4) vaccine administration, and (5) avoidance. The guidelines should prove useful for not only specialists in allergy and immunology but also other physicians. Most patients who avoid vaccination because of allergy concerns will be able to receive their appropriate vaccinations if this practice parameter is followed. This parameter emphasizes that (1) patients with suspected allergy to vaccines or vaccine components should be evaluated by an allergist/immunologist and (2) most patients with suspected allergy to vaccines can receive vaccination safely.Recommendations regarding the administration of influenza vaccine to recipients with egg allergy are specifically addressed in an addendum at the end of this practice parameter. Immunization is perhaps the greatest public health achievement of all time, having significantly reduced the morbidity and mortality of many infectious diseases. Routine immunization of children, adolescents, and adults provides substantial protection from a large number of infectious diseases. The current vaccination schedules for children and adults are available at www.cdc. gov/vaccines/recs/schedules. Patients who have experienced adverse reactions to vaccines might unnecessarily be advised to avoid subsequent immunization, which could have important adverse personal and population health consequences. Although there are some adverse reactions to vaccines that constitute absolute contraindications to administration of future doses, most such reactions do not preclude subsequent immunization. Patients who have experienced an apparent allergic or other serious adverse reaction after receiving a vaccine warrant evaluation by an allergist/immunologist. Also, patients with preexisting health conditions that might predispose to adverse reactions to vaccines could benefit from such an evaluation. In most cases, a riskbenefit analysis will favor subsequent immunization (Fig 1). SUMMARY STATEMENTS Summary Statement 1: Mild local reactions and constitutional symptoms, such as fever, after vaccinations are common and do not contraindicate future doses. Rarely, delayed-type hypersensitivity to a vaccine constituent can cause an injection-site nodule, but this is not a contraindication to subsequent vaccination. (C) Local injection-site reactions (swelling, redness, and/or soreness) and constitutional symptoms, especially fever, are common after the administration of most vaccines and are not contraindications to subsequent vaccination. Neomycin is contained in several vaccines. For those reporting a delayed-type hypersensitivity contact dermatitis to neomycin, the only anticipated reaction is a small temporary papule at the injection site, and this is not a contraindication to subsequent vaccination. Delayedtype hypersensitivity to thimerosal has also been reported. Although patients with a positive patch test result for thimerosal can have large local reactions to vaccination with thimerosalcontaining vaccines, most such patients do not. Neither a history of such reactions nor a positive patch test result to thimerosal is a contraindication to future vaccination. There is a single case report of a generalized pruritic maculopapular rash attributed to thimerosal in an influenza vaccine. Aluminum-containing vaccines rarely cause persistent nodules at the injection site, possibly because of delayed hypersensitivity or other immune responses to aluminum. Summary Statement 2: Anaphylactic reactions to vaccines are estimated to occur at a rate of approximately 1 per million doses. There are approximately 220 million doses of vaccines distributed in the United States each year. (B) Anaphylaxis after vaccination is rare. The Vaccine Safety Datalink reviewed the diagnostic codes from medical encounters after the administration ofmore than 7.5million doses of vaccines and estimated the risk of anaphylaxis to be 0.65 to 1.53 permillion doses. The US Centers for Disease Control and Prevention (CDC) estimates that there were 220,717,119 doses of all vaccines distributed in the United States in 2009, although not all doses are administered (John Iskander, CDC, written communication, July 20, 2011). Thus there are calculated to be approximately 140 to 340 cases of vaccine-induced anaphylaxis in the United States annually. Fatalities from vaccine-induced anaphylaxis are exceedingly rare. Summary Statement 3: All serious events occurring after vaccine administration should be reported to the Vaccine Adverse Event Reporting System, even if it is not certain that the vaccine was causal. (C) In 1990, the VAERS was established by the CDC and the US Food and Drug Administration. The VAERS relies on reporting by health care professionals and parents or patients, and all serious events after vaccination should be reported. These reports of suspected associations between vaccine administration and adverse events can then be evaluated for strength of potential causality. Summary Statement 4: Measuring levels of IgG antibodies to the immunizing agents in a vaccine suspected of causing a serious adverse reaction to determinewhether they are at protective levels can help determine whether subsequent doses are required. (B) In a patient who has experienced an apparent adverse reaction to a vaccine yet has received fewer than the recommended number of doses, the level of IgG antibodies to the immunizing agent can be measured to see whether it is at a level associated with protection from disease. Such levels have been established for some but not all vaccines (Table I), and many are available from diagnostic laboratories. If serologic evidence of immunity is documented, consideration can be given to withholding additional doses, although the magnitude and duration of immunity might be less than if all doses were received. Even if the recommended number of doses has already been received or if protective antibody levels have already been achieved, evaluation of the reaction, including skin testing, if indicated, should be undertaken, as discussed herein. FIG 1. Suggested approach to suspected adverse reactions to a vaccine. J ALLERGY CLIN IMMUNOL VOLUME 130, NUMBER 1 KELSO ET AL 29 Summary Statement 5: All suspected anaphylactic reactions to vaccines should ideally be evaluated in an attempt to determine the culprit allergen. (B) When a patient experiences an apparently IgE-mediated reaction after an immunization, the patient is often labeled as being ‘‘allergic’’ to the vaccine and advised against receiving future doses without further investigation. However, this approach should be avoided because it might leave patients inadequately immunized if they unnecessarily avoid vaccines to which they are not allergic or if the vaccine could be administered safely despite the allergy. In addition, not knowing the particular constituent of a vaccine to which the patient is allergic might pose a risk with future doses of other vaccines that contain the same ingredient. Summary Statement 6: IgE-mediated reactions to vaccines are more often caused by additive or residual vaccine components, such as gelatin, rather than the microbial immunizing agent itself. (B) Gelatin is added to many vaccines (Table II) as a stabilizer and has been shown to be responsible for many anaphylactic reactions to measles, mumps, and rubella vaccine (MMR), varicella vaccine, and Japanese encephalitis vaccine. Although MMR and varicella vaccines in the United States still contain gelatin, vaccine manufacturers in Japan and Germany removed gelatin or changed to a less allergenic gelatin, with a resultant decrease in allergic reactions. A new Japanese encephalitis vaccine does not contain gelatin. A history of allergy to the ingestion of gelatin should be sought before the administration of any gelatin-containing vaccine. A negative history, however, might not exclude an allergic reaction to gelatin injected with the vaccine. Gelatin used in vaccines is of either bovine or porcine origin, which are extensively cross-reactive. Some patients sensitized to beef or pork meat are also sensitized to beef or pork gelatin, which might place them at risk for reactions to gelatin-containing vaccines. Measles and mumps vaccines and one type of rabies vaccine are grown in chick embryo fibroblast cultures and contain negligible or no egg protein. Measles or MMR vaccines can be administered to children with egg allergy without adverse reactions and can be given to such patients without skin TABLE I. Levels of antibody associated with protection from vaccine-preventable diseases Vaccine Protective level of IgG antibody >_ Diphtheria 0.1 IU/mL Haemophilus influenzae b 0.15 mg/mL Hepatitis A 10 mIU/mL Hepatitis B Surface Antibody 10 mIU/mL Measles (Rubeola) 120 PRN titer Polio types 1, 2, and 3 1:8 neutralizing antibody titer Rabies 0.5 IU VNA/mL Rubella 10 IU/mL Tetanus 0.1 IU/mL Yellow fever 0.7 IU/mL IU, International units; mIU, milli-international units; PRN, plaque reduction neutralization; VNA, virus-neutralizing antibodies. TABLE II. Gelatin content of vaccines, 2011 Vaccine Gelatin content Influenza (Fluzone, Sanofi Pasteur) 250 mg per 0.5 mL dose Influenza (FluMist, MedImmune Vaccines, Gaithersburg, Md) 2,000 mg per 0.2 mL dose Measles, mumps, rubella (ATTENUVAX, MERUVAXII, MMRII, MUMPSVAX; Merck, Whitehouse Station, NJ) 14,500 mg per 0.5 mL dose Measles, mumps, rubella, varicella (ProQuad, Merck) 11,000 mg per 0.5 mL dose Rabies (RabAvert; Novartis, Emeryville, Calif) 12,000 mg per 1.0 mL dose Typhoid vaccine live oral Ty21a (VIVOTIF, Berna, Coral Gables, Flo) Capsule Varicella (VARIVAX, Merck) 12,500 mg per 0.5 mL dose Yellow fever (YF-VAX, Sanofi Pasteur) 7,500 mg per 0.5 mL dose Zoster (ZOSTAVAX, Merck) 15,580 mg per 0.65 mL dose J ALLERGY CLIN IMMUNOL JULY 2012 30 KELSO ET AL testing. Egg protein is present in higher amounts in yellow fever and influenza vaccines and could, in theory, cause reactions in recipients with egg allergy. However, numerous studies have demonstrated that injectable influenza vaccine can be safely administered even to patients with severe egg allergy with appropriate precautions, likely because of the very low amount of egg protein (ovalbumin) contained in recent years’ vaccines.Recommendations regarding the administration of influenza vaccine to recipients with egg allergy are specifically addressed in an addendum at the end of this practice parameter. If patients have a history of reaction to the influenza vaccine itself, as opposed to a history of a reaction to the ingestion of eggs, evaluation as per Fig 1 is appropriate. Patients can be allergic to heat-labile egg proteins in raw egg and, because they tolerate the ingestion of cooked egg, do not think of themselves as having egg allergy. Thus the clinical history might not identify all persons allergic to egg proteins present in influenza or yellow fever vaccines. Chicken proteins other than those found in chicken eggmight be present in yellow fever vaccine and could be responsible for reactions in recipients with chicken allergy. Hepatitis B vaccines are grown in Saccharomyces cerevisiae (baker’s yeast or brewer’s yeast) and contain residual yeast protein, but adverse reactions to these, if any, appear to be rare. Quadrivalent human papillomavirus vaccine (HPV4) might also contain residual yeast protein. The ‘‘rubber’’ in vaccine vial stoppers or syringe plungers can be either dry natural rubber (DNR) latex or synthetic rubber. Those made with DNR pose a theoretic risk to the patient who is allergic to latex. There is one report of an anaphylactic reaction in a patient with latex allergy after hepatitis B vaccine, which was attributed to rubber in the stopper. A review of more than 160,000 VAERS reports found only 28 cases of possible immediate-type allergic reactions after receiving a DNRcontaining vaccine, and these might have been due to other components. The latex content of vaccine packaging is provided in Table III and is updated at www.cdc.gov/vaccines/pubs/ pinkbook/pink-appendx.htm. There is a single report of an immediate-type allergic reaction to a vaccination that was attributed to neomycin. However, the patient had a maculopapular (not urticarial) rash to the topical application of neomycin, and no testing for IgE to neomycin was performed. There is a single case report of an immediatetype reaction that might have been caused by thimerosal in a vaccine. However rare, if a patient provides a history of an immediatetype reaction to yeast, latex, neomycin, or thimerosal, it is appropriate to investigatewith immediate-type skin testing before immunization with a vaccine containing these constituents. A recent publication described 8 children with anaphylaxis within 1 hour of receiving diphtheria, tetanus, and pertussis vaccines (diphtheria and tetanus toxoids and acellular pertussis vaccine [DTaP] or tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis [Tdap]). Six had histories of past allergic reactions to cow’s milk, and all had very high levels of milk-specific serum IgE. These vaccines might contain trace (nanogram) quantities of residual casein from the medium in which they are produced. The results of this report require further investigation. Anaphylactic reactions to DTaP or Tdap vaccines are rare, and the majority of patients with cow’s milk allergy tolerate them without reaction. It is recommended that all patients, including those with milk allergy, continue to receive these vaccines on schedule but perhaps with some additional observation after vaccination in those with very high levels of milk sensitivity. Table IV lists vaccine excipients by vaccine. Updated lists of vaccine excipients by vaccine and by excipient are available at www.cdc.gov/vaccines/pubs/pinkbook/pink-appendx.htm. Summary Statement 7: Patients who have had an apparent anaphylactic reaction after immunization should undergo immediate-type allergy skin testing to help confirm that the reaction was IgE mediated and determine the responsible component of the vaccine. (B) Skin testing with vaccine should be performed to determine whether the vaccine was responsible for a patient’s apparent allergic reaction. The vaccine should first be tested by using the prick method. If the past vaccine reaction was lifethreatening, it is appropriate to use dilute vaccine for the skin prick test; in all other cases, full-strength vaccine should be used for the skin prick test. If the full-strength skin prick test result is negative, with appropriate positive and negative controls, an intradermal test with the vaccine diluted 1:100 should be performed, again with appropriate controls. Aswith any skin test reagent and particularly withmaterials not standardized for skin testing, such as vaccines, false-positive (irritant) results and clinically irrelevant positive results can TABLE III. Latex in vaccine packaging*