Maintenance of Certification clinical management series Series editor: James T Li, MD, PhD

Influenza vaccination in asthmatic patients Matthew J. Greenhawt, MD, MBA, MSc

Ann Arbor, Mich

INSTRUCTIONS Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the instructions listed below: 1. Review the target audience, learning objectives and author disclosures. 2. Complete the pre-test online at www.jacionline.org (click on the Online CME heading). 3. Follow the online instructions to read the full version of the article, including the clinical vignette and review components. 4. Complete the post-test. At this time, you will have earned 1.00 AMA PRA Category 1 CME CreditTM. 5. Approximately 4 weeks later you will receive an online assessment regarding your application of this article to your practice. Once you have completed this assessment, you will be eligible to receive 2 MOC Part II Self-Assessment credits from the American Board of Allergy and Immunology. Date of Original Release: April 2014. Credit may be obtained for these courses until March 31, 2015. Copyright Statement: Copyright Ó 2014-2015. All rights reserved. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Creditä. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CLINICAL VIGNETTE A 38-year-old mother of 2 children (aged 5 and 3 years, respectively) is seen for routine follow-up of allergic rhinoconjunctivitis with sensitization to tree, grass, dust mite, cat, Alternaria species, and perennial mold in addition to wellcontrolled asthma. She is managed with 2 puffs of 40 mg of beclomethasone inhaled twice daily, 2 nasal squirts of 50 mg of fluticasone propionate daily, and intermittent use of over-thecounter ketotifen ocular drops as needed. She uses her albuterol inhaler before exercise and intermittently (no more than once per week). In the previous few years, she averaged approximately 4 exacerbations per year, all requiring oral corticosteroid courses, From the University of Michigan Food Allergy Center, Division of Allergy and Clinical Immunology, University of Michigan Health System. Received for publication December 4, 2013; revised February 3, 2014; accepted for publication February 11, 2014. Corresponding author: Matthew J. Greenhawt, MD, MBA, MSc, 24 Frank Lloyd Wright Dr, PO Box 442, Suite H-2100, Ann Arbor, MI 48106. E-mail: [email protected] umich.edu. 0091-6749/$36.00 Ó 2014 American Academy of Allergy, Asthma & Immunology http://dx.doi.org/10.1016/j.jaci.2014.02.009

List of Design Committee Members: Matthew J. Greenhawt, MD, MBA, MSc (author), and James T. Li, MD, PhD (series editor) Activity Objectives 1. To identify conditions that are a high priority for annual influenza vaccination. 2. To identify risk factors that might predispose asthmatic patients to viral respiratory tract infection. 3. To identify specific outcomes related to influenza infection in asthmatic patients. 4. To recognize evidence supporting the effectiveness of annual influenza vaccination in preventing asthma-related influenza outcomes in the setting of evidence supporting the recommendation for universal influenza vaccination. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: M. J. Greenhawt has received research support from the National Center for Research Resources, the National Institutes of Health, and the University of Michigan Food Allergy Center; is a board member for Nutricia; has consultant arrangements with Nutricia, Deerfield Industries, and the National Peanut Board; has provided expert testimony on behalf of stock epinephrine law for the Michigan Allergy and Asthma Society; has received payment for lectures and payment for development of educational presentations from Nutricia; and is an unpaid medical advisory board member for the Kids with Food Allergies Foundation and the International Association for Food Protein Enterocolitis. J. T. Li has consulted for Abbott.

in the setting of presumed viral illness. You are also seeing her 3-year-old son today as well, whom you follow for chronic rhinitis without detectible sensitizations to inhalant allergens and mild asthma under good control on monotherapy with 4 mg of montelukast nightly. Additionally, he has a history of diffuse hives after egg ingestion but is tolerant of extensively heated egg. Both mother and son are in good health at this time, with no current asthma exacerbations or rhinitis flares. As part of routine health screening during the visit, the electronic medical record prompts you to ask the patients about yearly seasonal influenza vaccination. This is based both on age recommendations by the Centers for Disease Control and Prevention (CDC) and best-practice guidelines for asthma. The child’s prompt comes with a disclaimer to ask about the severity of the egg allergy before considering administration of the influenza vaccine. The child has received injectable influenza vaccination in 2 of the 3 previous years, including last year. The mother received influenza vaccine the past 2 years, but review of her records indicates that she has missed several past seasons. On reviewing both the mother’s and child’s risk factors for influenza and offering them both the opportunity to receive vaccination in the office, the mother expresses concern. Last year, she believes 1233

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she contracted influenza and had an asthma exacerbation causing her to miss a day of work despite receiving the vaccine. She reports past asthma flares within a month of vaccination, which in part has motivated her decision to defer influenza vaccination some years. She expresses that she ‘‘doesn’t want to get sick from the vaccine’’ and that some years she feels the vaccine ‘‘doesn’t work.’’ She has no objection to her child being

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vaccinated but inquires whether anything has changed in the recommendations for children with egg allergy to receive influenza vaccine. The full version of this article, including a review of relevant issues to be considered, can be found online at www.jacionline. org. If you wish to receive CME or MOC credit for the article, please see the instructions above.

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REVIEW Influenza A and B viruses are attributable to 300 to 49,000 deaths between the 1976-1977 and 2005-2006 influenza seasons. Young children, adults older than age 65 years, and those with high-risk medical conditions (children aged 6 months to 4 years, pregnant women, immunocompromised subjects, residents of long-term nursing facilities, and subjects with asthma, cardiopulmonary disease, or metabolic disorders) are at the highest risk for complications of influenza infection. The CDC’s Advisory Committee on Immunization Practices recommends universal annual vaccination for these groups to reduce influenza-related mortality and curb viral transmission.E1 Despite the CDC’s recommendations, compliance with yearly vaccination has been low. The CDC set a 60% vaccination rate target for US adults aged 18 to 64 years (Healthy People 2010), but rates among asthmatic adults in 2006-2007 were 33.9% for those aged 18 to 49 years and 54.7% for those aged 50 to 64 years, and 2009 rates were just 26.1% (pandemic H1N1) and 44.8% (seasonal influenza) for those aged 25 to 64 years.E2 In children aged 6 months to 17 years, vaccination rates for the 2011-2012 season were 50.1% and stable compared with those in the 2010-2011 season.E3 Influenza virus Influenza A and B are orthomyxoviruses. Influenza A contains 2 surface antigens, hemagglutinin and neuraminidase, and the major circulating strains include H1N1, H1N2, and H3N2. Influenza B is classified either as the Yamagata or Victoria lineage. Transmission occurs through respiratory droplets between persons or from contact with droplet-contaminated surfaces, with 1- to 4-day incubation and 4- to 7-day viral shedding periods. Both viruses continuously undergo minor within-strain antigenic variation called antigenic drift, which is associated with seasonal outbreaks. Substantial changes to hemagglutinin or neuraminidase, called antigenic shift, can create new strains and global pandemics.E4 Vaccination stimulates production of antibodies against hemagglutinin and neuraminidase, but the vaccines are reformulated yearly because circulating strains vary. Trivalent vaccine contains 2 influenza A strains and 1 influenza B lineage. Quadrivalent vaccines were developed to accommodate both influenza B lineages, which might cocirculate seasonally. The vaccines come as inactivated injectable vaccine (IIV) and live attenuated influenza (nasal) vaccine (LAIV). LAIV generates lower antibody titers than IIV but provides a more robust immune repertoire, including IgG and IgA antibodies and superior cellular immunity.E1,E4 Complications of influenza in asthmatic patients Influenza infection in asthmatic patients carries increased risk for more severe and more frequent viral lower respiratory tract infection, and atopy can predispose to more symptomatic viral illness. Epithelial barrier dysfunction, increased mucus production, goblet cell hyperplasia, poor IFN-g response, delayed TH2 to TH1 transition, and environmental exposures (tobacco smoke and diesel particles) might moderate this susceptibility. Viral clearance in asthmatic patients might be delayed as well.E5 Subjects with underlying cardiopulmonary complications (eg, asthma) are at risk of pneumonia, bronchiolitis, sepsis, and secondary bacterial infection from influenza.E1 Between 1976 and 2007, the death rate from influenza-associated pneumonia was 2.4/100,000, representing 8.5% of all pneumonia-related mortalities, although specific data regarding the number of

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fatalities occurring in asthmatic patients, vaccinated subjects, or both are not available.E6 Among 830 influenza-related pediatric deaths between 2004 and 2012, 16% of the subjects had asthma, and few deaths occurred in vaccinated subjects.E7 Influenza in asthmatic patients is associated with increased health care services use (hospital admissions, clinic visits, ancillary services, and emergency department visits) versus that seen in nonasthmatic subjects among both children and adults.E1 Between 2003 and 2009, 32% of 2165 children hospitalized for seasonal influenza and 44% of 1160 children hospitalized for pandemic H1N1 infection had asthma, and only 36% to 52% of these children were vaccinated.E8 Children with asthma had 4 times higher odds of pandemic H1N1 infection than nonasthmatic subjects and were hospitalized at significantly higher rates than in prior influenza seasons.E9

Influenza vaccination to prevent influenza-related asthma complications in asthmatic patients A 2012 Cochrane review evaluated 26 studies to determine whether influenza vaccination prevented influenza-related asthma exacerbations, hospital admissions, pneumonias, asthma symptom scores, lung function changes, emergency department visits, use of corticosteroids, and mortality. The 1 identified controlled trial noted no benefit in preventing influenza-related asthma exacerbations, although vaccination might improve specific aspects of asthma-related quality of life among influenza culture–positive children.E10 No trial investigated prevention of influenza-related asthma hospitalization, and 3 trials reaffirmed that IIV is not associated with asthma exacerbations 2 weeks after vaccination. No studies were identified showing LAIV prevented influenza-related asthma exacerbation, although 2 studies noted no association between LAIV and postvaccination asthma exacerbations, reductions in FEV1 at 4 days after vaccination, or increased use of rescue inhalers. Three studies noted no increased risk of asthma exacerbation after IIV versus LAIV in both asthmatic adults and children, although LAIVadministration in very young children was associated with some risk of hospitalization for asthma exacerbation in a single study.E10 A few studies support the hypothesis that IIV vaccination might provide protection against influenza-related asthma exacerbations, but these were not prospective, randomized, or controlled and thus were also excluded from analysis in the Cochrane review. These data note that vaccination was associated with reduced oral steroid use for asthma exacerbationsE11 and a protective effect in reducing severity-adjusted asthma exacerbations by 22% to 45%.E12 In contrast to these studies supporting the efficacy of vaccination, a case-control study (excluded from the Cochrane review) noted that trivalent IIV vaccination in asthmatic children over a 6-year period was associated with significantly higher odds of laboratory-confirmed influenza-related hospitalization versus that seen in unvaccinated children and a significant adjusted association between receiving TIV and hospitalization in asthmatic patients.E13 In addition, an older retrospective pediatric study found that 1- to 19-year-old asthmatic patients vaccinated with trivalent IIV had significantly higher odds of asthma- and pneumonia-related clinic visits versus unvaccinated children.E14 However, both study conclusions might speak more to an overall increased likelihood of such use of service in high-risk populations and not to the effectiveness of IIV.

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Recommendations for influenza vaccination in asthmatic patients The CDC advises universal influenza vaccination (see Table E1) for asthmatic patients, but should the CDC make this recommendation based on the current evidence? The argument to specifically vaccinate asthmatic children older than 6 months to less than 18 years and asthmatic adults older than 65 years is moot. The CDC already has redundant recommendations for annual universal influenza vaccination in these age groups based on other risk factors, irrespective of whether the subject has asthma.E1 Furthermore, data support that both IIV and LAIV vaccination in children and IIV vaccination in adults older than 65 years are cost-effective practices.E1,E15-E17 The argument for vaccination in asthmatic adults aged 18 to 64 years is less clear-cut. There are data supporting that annual influenza vaccination of healthy adults aged 18 to 64 years is cost-effective in this population.E18 Given data supporting vaccination of low-risk adults, it can be deduced that high-risk adults would stand to benefit, and thus despite no clear benefit in preventing influenza-related asthma exacerbations, asthmatic adults aged 18 to 64 years should continue to receive annual influenza vaccination given other benefits that vaccination provides to both the individual and society.E1 Data clearly show that asthmatic patients with influenza are at higher risk for complications and increased health care costs.E1 Therefore the lack of benefit of vaccinating to prevent asthma-related outcomes that can be pooled from the few existing controlled studies is outweighed and might result more from sparse quality research of these outcomes (conducted before the H1N1 pandemic) than poor vaccine efficacy. The authors of the Cochrane review noted this in the limitations of their meta-analysis.E10 Such research is difficult to conduct given short influenza seasons, the large numbers of patients needed to adequately power such studies, and the costs of conducting these studies across multiple seasons to mitigate effects from study of just a single season.E10 Moreover, the effects of quadrivalent vaccine might significantly improve asthma-related outcomes and should be evaluated through future prospective randomized studies. This vaccine might prove to be superior to the trivalent variety. Vaccination is an effective means to reduce influenza infection because it curbs transmission of illness to others and might protect unvaccinated subjects.E1 Despite limited evidence influenza vaccination achieves any desirable asthma-related outcome, recommending vaccination for asthmatic patients should remain favored given a lack of better methods to reduce influenza transmission in this group at a population level.E4 Thus, at present, the CDC recommendation should and ultimately will remain driven by expert level opinion, which is not an uncommon practice where evidence is scant. THE CASE REVISITED You explain to the mother that many studies have disproved that the influenza vaccine itself is linked to causing any asthma flares or contraction of influenza virus but do discuss that vaccination might not prevent influenza-related asthma complications. Furthermore, you do acknowledge that in past years, the main circulating strain of influenza B has not been in the vaccine, validating the mother’s concern that vaccine efficacy might not be optimal in some years. However, you explain that vaccination is still the best recommendation to prevent her from contracting influenza and highlight that new quadrivalent

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vaccines are available that will hopefully provide more robust coverage against circulating influenza strains. You offer her this vaccine, which she gladly accepts. As for her son, you highlight recent changes in the CDC guidance that have removed most remaining barriers to subjects with egg allergy from receiving yearly influenza vaccine. Because your records indicate that the child’s most severe reaction was diffuse hives and that he has tolerated past IIV, you are comfortable in complying with the CDC’s recommendations for vaccinating the child in the office.E1 You do ask that the mother remain with him in the office for 30 minutes of observation after vaccine administration and reassure her that your office is equipped to diagnose and manage an anaphylactic reaction, should one occur, although recent data have emphatically proved that subjects with egg allergy are at no increased risk of reacting to IIV than subjects without egg allergy. Both the mother and child are vaccinated without issue, and neither has any asthma-related complications during the influenza season. REFERENCES E1. Centers for Disease Control and Prevention. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices—United States, 2013-2014. MMWR Morb Mortal Wkly Rep 2013;62:1-43. E2. Lu PJ, Euler GL, Callahan DB. Influenza vaccination among adults with asthma: findings from the 2007 BRFSS survey. Am J Prev Med 2009;37:109-15. E3. McIntyre, AF, Gonzalez-Feliciano AG, Santibanez TA, Bryan LN, Greby SM, Biggers BB, et al. Flu vaccination coverage, United States, 20112012 influenza season. Available at: http://www.cdc.gov/flu/professionals/ vaccination/coverage_1112estimates.htm. Accessed November 15, 2013. E4. Influenza. In: Pickering LK, editor. Red book on infectious diseases. Elk Grove Village (IL): American Academy of Pediatrics; 2012. pp. 439-53. E5. James KM, Peebles RS Jr, Hartert TV. Response to infections in patients with asthma and atopic disease: an epiphenomenon or reflection of host susceptibility? J Allergy Clin Immunol 2012;130:343-51. E6. Centers for Disease Control and Prevention. Estimates of deaths associated with seasonal influenza—United States 1976-2007. MMWR Morb Mortal Wkly Rep 2010;59:1057-62. E7. Wong KK, Jain S, Blanton L, Dhara R, Brammer L, Fry AM, et al. Influenza-associated pediatric deaths in the United States, 2004-2012. Pediatrics 2013;132:796-804. E8. Dawood FS, Kamimoto L, D’Mello TA, Reingold A, Gershman K, Meek J, et al. Children with asthma hospitalized with seasonal or pandemic influenza, 2003-2009. Pediatrics 2011;128:e27-32. E9. Kloepfer KM, Olenec JP, Lee WM, Liu G, Vrtis RF, Roberg KA, et al. Increased H1N1 infection rate in children with asthma. Am J Respir Crit Care Med 2012;185:1275-9. E10. Cates CJ, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev 2013;(2):CD000364. E11. Ong BA, Forester J, Fallot A. Does influenza vaccination improve pediatric asthma outcomes? J Asthma 2009;46:477-80. E12. Kramarz P, Destefano F, Gargiullo PM, Chen RT, Lieu TA, Davis RL, et al. Does influenza vaccination prevent asthma exacerbations in children? J Pediatr 2001;138:306-10. E13. Joshi AY, Iyer VN, Hartz MF, Patel AM, Li JT. Effectiveness of trivalent inactivated influenza vaccine in influenza-related hospitalization in children: a case-control study. Allergy Asthma Proc 2012;33:e23-7. E14. Christy C, Aligne CA, Auinger P, Pulcino T, Weitzman M. Effectiveness of influenza vaccine for the prevention of asthma exacerbations. Arch Dis Child 2004;89:734-5. E15. Savidan E, Chevat C, Marsh G. Economic evidence of influenza vaccination in children. Health Policy 2008;86:142-52. E16. Luce BR, Nichol KL, Belshe RB, Frick KD, Li SX, Boscoe A, et al. Cost-effectiveness of live attenuated influenza vaccine versus inactivated influenza vaccine among children aged 24-59 months in the United States. Vaccine 2008;26:2841-8. E17. Gross PA, Hermogenes AW, Sacks HS, Lau J, Levandowski RA. The efficacy of influenza vaccine in elderly persons. A meta-analysis and review of the literature. Ann Intern Med 1995;123:518-27. E18. Bridges CB, Thompson WW, Meltzer MI, Reeve GR, Talamonti WJ, Cox NJ, et al. Effectiveness and cost-benefit of influenza vaccination of healthy working adults: a randomized controlled trial. JAMA 2000;284:1655-63.

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TABLE E1. Recommendations for annual influenza vaccination High-risk groups who should receive annual influenza vaccination* Persons 6 mo through 4 y (59 mo) of age _50 y Persons aged > Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus) Persons who are immunosuppressed (including immunosuppression caused by medications or by HIV) Persons who are or will be pregnant during the influenza season Persons aged 6 mo through 18 y and receiving long-term aspirin therapy who therefore might be at risk for experiencing Reye syndrome after influenza virus infection Persons who are residents of nursing homes and other chronic care facilities American Indians/Alaska Natives _40 kg/m2) Persons who are morbidly obese (body mass index > Health care personnel Persons who are household contacts and caregivers of children aged younger than 5 y and adults aged 50 y and older, with particular emphasis on vaccinating contacts of children aged younger than 6 mo and household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza Adapted from reference E1. *Per the CDC’s Advisory Committee on Immunization Practices, all persons aged 6 months and older should be vaccinated annually. However, these high-risk groups should be prioritized if there is a vaccine shortage.

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Influenza vaccination in asthmatic patients.

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