Abstract

Background

The first trivalent live-attenuated influenza vaccine (LAIV3) was licensed in 2003 for use in healthy persons 5–49 years of age. In 2007, the US Food and Drug Administration expanded its indication to healthy children 2–4 years of age.

Methods

We searched the Vaccine Adverse Event Reporting System (VAERS) for US reports after LAIV3 from July 1, 2005 to June 30, 2012 in children aged 2–18 years. Medical records were requested for nonmanufacturer reports coded as serious (ie, death, hospitalization, prolonged hospitalization, life-threatening illness, disability). We characterized electronic data and clinically reviewed all serious reports and reports of special interest. Empirical Bayesian data mining was used to identify new or unexpected adverse events (AEs).

Results

During the study period, VAERS received 2619 US LAIV3 reports for children aged 2–18 years; 197 (7.5%) reports were serious, including 5 deaths. The 2 most frequent nonfatal serious reports involved neurological and respiratory systems, with 56 (29.2%) and 43 (22.4%) reports, respectively. The most frequent neurological diagnoses were seizures and Guillain-Barré Syndrome, and the most frequent respiratory conditions were pneumonia and asthma or reactive airway disease. Data mining showed increased proportions for reports of medication errors, most commonly vaccine administration errors not associated with an AE.

Conclusions

In this VAERS analysis of reports following LAIV3, we found no new or unexpected AEs patterns. Reports of LAIV3 administration to persons, for whom it is not recommended, including children with a history of asthma or reactive airway disease or wheezing, indicate that ongoing monitoring and education in vaccine indications are needed.

In 2003, the US Food and Drug Administration (FDA) licensed trivalent live-attenuated influenza vaccine (LAIV3) (FluMist) for healthy nonpregnant persons aged 5–49 years to prevent influenza caused by 2 influenza A and 1 influenza B virus strains [ 1–3 ]. In 2007, the FDA expanded the age indication to include healthy children aged 2–4 years [ 4–6 ]; the Advisory Committee on Immunization Practices (ACIP) subsequently also included this new age group in its recommendations [ 7 ]. In 2008, ACIP recommended universal influenza vaccination for all children aged ≥6 months [ 8 ] and reiterated that healthy children aged ≥2 years and adolescents who are not pregnant could be vaccinated with either LAIV3 or trivalent-inactivated influenza vaccine (IIV3) [ 5 , 6 , 8 ]. In 2012, the FDA licensed Quadrivalent LAIV4 (FluMist Quadriva-lent), which includes the same strains in the trivalent formulation plus 1 additional type B virus strain [ 9 , 10 ]; the ACIP incorporated LAIV4 into its recommendations for the 2013–2014 influenza season [ 11 , 12 ].

Prelicensure studies [ 13 ] and postlicensure assessment of reports after LAIV3 to the Vaccine Adverse Event Reporting System (VAERS) in the first 2 years after licensure in 2003 [ 14 ] did not identify unexpected serious adverse events (AEs) in persons aged 5–49 years. However, rare AEs may not be detected until a vaccine is widely used in the population [ 15 ]. We analyzed reports to VAERS following LAIV3 in children aged 2–18 years from July 1, 2005 through June 30, 2012 to further assess the pediatric safety profile of LAIV3.

In conjunction with the findings of Izurieta et al. [ 14 ], our results provided baseline information while we monitored the safety of LAIV4 [ 9 , 12 ].

METHODS

Data Source

The Vaccine Adverse Event Reporting System, coadministered by the Centers for Disease Control and Prevention and FDA, is a national spontaneous reporting system for monitoring AEs after vaccines [ 16 , 17 ]. The Vaccine Adverse Event Reporting System accepts reports from vaccine manufacturers, healthcare providers, vaccine recipients, and others. The VAERS form collects information that includes demographics of the vaccinee, type of vaccine(s) received, and AEs experienced. Signs and symptoms of AEs are coded by trained personnel using the Medical Dictionary for Regulatory Activities (MedDRA) [ 18 ] and entered into a database; the codes are not medically confirmed diagnoses. A report may be assigned 1 or more MedDRA-preferred terms (PTs); however, not all reports will include a term describing an AE (eg, report of inappropriate age of administration). A report is classified as serious if 1 of the following is reported: death, life-threatening illness, hospitalization, prolongation of hospitalization, or permanent disability [ 19 ]. Except for reports submitted by manufacturers, which usually include a detailed clinical description, medical records are routinely requested and reviewed for reports categorized as serious. For serious reports, we ascertained the primary event (the event that appeared to trigger the reporter to report to VAERS) and categorized the case into 1 of the diagnostic categories such as neurologic and respiratory events used in a previous analysis [ 20 ]. Cause of death was based on information in the autopsy report, death certificate, or medical record.

We analyzed VAERS reports received by September 30, 2012 for children aged 2–18 years vaccinated with LAIV3 from July 1, 2005 through June 30, 2012. Reports of vaccinations received outside the United States, duplicate reports, and reports with an unknown age were excluded. We evaluated the characteristics of reports in 2 age groups: 2–4 years and 5–18 years separately.

Clinical Review of Reports

Our clinical review included all serious reports and reports classified as nonserious reports such as the following: (1) anaphylaxis and Guillain-Barré Syndrome (GBS) since the results of previous studies [ 21 ] have suggested that a causal association with LAIV3 is biologically plausible; (2) selected PTs of clinical importance detected through data mining; and (3) reports suggesting that LAIV3 was administered to certain individuals for whom the vaccine is not recommended (ie, pregnant women, individuals with a history of asthma, and persons with egg allergy). To search for prespecified events and reports pertaining to special populations, we used specific MedDRA codes, which are shown in the Appendix. Reports of GBS and anaphylaxis were verified by using the Brighton Collaboration case definitions or a physician's diagnosis [ 22 , 23 ].

Disproportionality Analysis

We used Empirical Bayesian (EB) data mining to identify PTs that were reported more frequently than expected following LAIV3 compared with other vaccines. For consistency with the rest of the analysis, we limited the data to US reports for children 2–18 years of age who had received immunizations 2005–2012 [ 24 ]. We used published criteria by Szarfman et al. [ 25 ] to identify LAIV3 AE pairs with reporting proportions greater than twice that of all other vaccines combined. We ranked event-vaccine pairs based on the lower bound of 90% confidence interval. Clinical reviews were conducted if the EB05 was >2.

The Vaccine Adverse Event Reporting System is a routine surveillance program conducted as a public health function and does not meet the definition of research; thus, it is not subject to Institutional Review Board review and informed consent requirements.

RESULTS

Descriptive Analysis

From July 1, 2005 to June 30, 2012, VAERS received 2619 US LAIV3 reports in children aged 2–18 years (Table 1 ); 197 (7.5%) were serious reports. The number of reports in both age groups (2–4 years and 5–18 years) increased steadily from 2005 to 2011, with a peak during both the 2009–2010 and 2010–2011 influenza seasons, mostly due to increase of nonserious reports (Figure 1 ).

Table 1.

Summary of Reports After LAIV3 in Children Aged 2–18 Years, VAERS, July 1, 2005–June 30, 2012

  2–4 Years
Total = 807
N (%)  
5–18 Years
Total = 1812
N (%)  
LAIV3 only 604 (75) 1332 (74) 
Onset-interval (days)* median (range) 0 (0–938) 0 (0–934) 
Male 373 (46) 851 (47) 
Age (years) median (range) 3 (2–4) 9 (5–18) 
Serious 89 (11) 108 (6) 
LAIV3 with monovalent-inactivated H1N1 vaccine 22 (3) 37 (2) 
Most frequent MedDRA terms ** Fever 189 (23) Expired drug administered 395 (22) 
 Expired drug administration 162 (20) No adverse event 340 (19) 
 No adverse event 113 (14) Fever 312 (17) 
 Cough 81 (10) Headache 199 (11) 
 Vomiting 80 (10) Cough 150 (8) 
 Rhinorrhoea 62 (87) Vomiting 144 (8) 
 Urticaria 62 (8) Urticaria 115 (6) 
 Injection site erythema 53 (7) Erythema 101 (6) 
 Rash 39 (5) Injection site erythema 95 (5) 
 Injection site swelling 37 (5) Dizziness 94 (5) 
  2–4 Years
Total = 807
N (%)  
5–18 Years
Total = 1812
N (%)  
LAIV3 only 604 (75) 1332 (74) 
Onset-interval (days)* median (range) 0 (0–938) 0 (0–934) 
Male 373 (46) 851 (47) 
Age (years) median (range) 3 (2–4) 9 (5–18) 
Serious 89 (11) 108 (6) 
LAIV3 with monovalent-inactivated H1N1 vaccine 22 (3) 37 (2) 
Most frequent MedDRA terms ** Fever 189 (23) Expired drug administered 395 (22) 
 Expired drug administration 162 (20) No adverse event 340 (19) 
 No adverse event 113 (14) Fever 312 (17) 
 Cough 81 (10) Headache 199 (11) 
 Vomiting 80 (10) Cough 150 (8) 
 Rhinorrhoea 62 (87) Vomiting 144 (8) 
 Urticaria 62 (8) Urticaria 115 (6) 
 Injection site erythema 53 (7) Erythema 101 (6) 
 Rash 39 (5) Injection site erythema 95 (5) 
 Injection site swelling 37 (5) Dizziness 94 (5) 

Abbreviations: LAIV3, trivalent live-attenuated influenza vaccine; MedDRA, Medical Dictionary for Regulatory Activities; VAERS, Vaccine Adverse Event Reporting System.

*Onset from vaccination to the earliest reported symptom.

**Terms are not mutually exclusive.

Figure 1.

Vaccine Adverse Event Reporting System reports after live-attenuated influenza vaccine among children aged 2–4 years and 5–18 years, by influenza season and serious status, 2005–2012.

Figure 1.

Vaccine Adverse Event Reporting System reports after live-attenuated influenza vaccine among children aged 2–4 years and 5–18 years, by influenza season and serious status, 2005–2012.

The proportion of serious reports in children 2–4 years peaked at 25% (15 of 60) during the 2007–2008 influenza season when LAIV3 was approved for use in this age group, and it subsequently declined to 4.8% (7 of 145) during the 2011–2012 season (Figure 1 ). The top 10 MedDRA coding terms (Table 1 ) were similar for both age groups.

Clinical Review

Medical records were available for 136 (69%) of 197 serious reports.

Fatal Reports

We identified 5 death reports in VAERS after LAIV3 vaccinations, all in children aged 5–18 years (Table 2 ). Four of the children had a history of an underlying chronic condition. Except for the case of status asthmaticus, all deaths occurred >30 days after receiving LAIV3.

Table 2.

Reports of Deaths After LAIV3 Among Children Aged 2–18 Years, VAERS 2005–2012

Fatal Serious Reports
 
Age (Years) Gender Medical History Vaccines Coadministered With LAIV3 Onset Interval (Days) Cause of Death/Circumstances Around Death 
5* 2 week history of fever and headache treated with antibiotics, 2 months prior to death None 35 Meningitis (cultures negative for microorganisms) 
6  Premature birth at 29 weeks, developmental delay and weakness None 85 Leigh's disease (mitochondrial disease) 
7  Diagnosed with SSPE 2–3 months before vaccination None 64 Cause of death unknown. Patient hospitalized 16 days after vaccination for changes in mental status and progression of SSPE. 
13 § Asthma None 13 Status asthmaticus due to lymphocytic bronchitis (viral studies negative for influenza A and B) 
13 Frontal lobe seizures (medicated with antiepileptics) HPV4 53 Sudden unexpected death in epilepsy 
Fatal Serious Reports
 
Age (Years) Gender Medical History Vaccines Coadministered With LAIV3 Onset Interval (Days) Cause of Death/Circumstances Around Death 
5* 2 week history of fever and headache treated with antibiotics, 2 months prior to death None 35 Meningitis (cultures negative for microorganisms) 
6  Premature birth at 29 weeks, developmental delay and weakness None 85 Leigh's disease (mitochondrial disease) 
7  Diagnosed with SSPE 2–3 months before vaccination None 64 Cause of death unknown. Patient hospitalized 16 days after vaccination for changes in mental status and progression of SSPE. 
13 § Asthma None 13 Status asthmaticus due to lymphocytic bronchitis (viral studies negative for influenza A and B) 
13 Frontal lobe seizures (medicated with antiepileptics) HPV4 53 Sudden unexpected death in epilepsy 

Abbreviations: CDC, Centers for Disease Control and Prevention; CT, computed tomography scan; F, female; HPV4, quadrivalent, human papillomavirus vaccine; LAIV3, trivalent live-attenuated influenza vaccine; M, male; MRI, magnetic resonance imaging; SSPE, subacute sclerosing panencephalitis; VAERS, Vaccine Adverse Event Reporting System.

*Patient presented with febrile seizures before being hospitalized. There was a second visit to the clinic for fever and headache, also treated with antibiotics approximately 6 days before death. A computed tomography scan did not show presence of a brain abscess.

The report of Leigh's disease involved a 6-year-old female with a history of prematurity (29 weeks), pneumonia, and gastroesophageal reflux disease. She presented with weakness prior to vaccination, but weakness became more pronounced after vaccination (unspecified onset interval of weakness), and she had ataxia, difficulty breathing and swallowing, and was subsequently diagnosed with Leigh encephalopathy syndrome while hospitalized. Her condition deteriorated, and she died 21 days after admission.

The diagnosis of SSPE was made based on MRI and lumbar puncture in a patient with no history of measles, although the patient received measles vaccinations.

§ Viral studies done at CDC were negative for influenza A and B.

Nonfatal Serious Reports

The 2 most frequently reported nonfatal serious AEs were neurological and respiratory with 56 (29.2%) and 43 (22.4%) reports, respectively (Table 3 ). Among neurological conditions, the most frequent diagnoses were seizures and GBS. Among respiratory conditions, the most frequent diagnoses were pneumonia and asthma or reactive airway disease with 14 (7.3%) and 12 (6.2%) reports, respectively.

Table 3.

Nonfatal Serious Adverse Event Reports* of 192 Children Aged 2–18 Years After LAIV3 VAERS, 2005–2012, by Body System Categories

Adverse Events N (%) 
Neurological adverse events 56 (29.2) 
 Seizures  15 (7.8) 
 Guillain-Barré Syndrome 14 (7.3) 
 Ataxia 5 (2.6) 
 Encephalitis 4 (2.1) 
 Optic neuritis 3 (1.6) 
 Acute disseminated encephalomyelitis 2 (1.0) 
 Transverse myelitis 2 (1.0) 
 Other neurological  12 (6.2) 
Respiratory adverse events 43 (22.4) 
 Pneumonia 14 (7.3) 
 Asthma/asthma exacerbation/reactive airway disease 12 (6.2) 
 Influenza A/B 4 (2.1) 
 Influenza-like illness 5 (2.6) 
 Croup 3 (1.6) 
 Respiratory distress 2 (1.0) 
 Other respiratory § 3 (1.6) 
Infectious 18 (9.4) 
Gastrointestinal 16 (8.3) 
Hematological 9 (4.7) 
Ear-nose-throat 5 (2.6) 
Musculoskeletal 4 (2.1) 
Cardiovascular 4 (2.1) 
Allergic reactions 3 (1.6) 
Psychiatric 2 (1.0) 
Other  32 (16.7) 
Adverse Events N (%) 
Neurological adverse events 56 (29.2) 
 Seizures  15 (7.8) 
 Guillain-Barré Syndrome 14 (7.3) 
 Ataxia 5 (2.6) 
 Encephalitis 4 (2.1) 
 Optic neuritis 3 (1.6) 
 Acute disseminated encephalomyelitis 2 (1.0) 
 Transverse myelitis 2 (1.0) 
 Other neurological  12 (6.2) 
Respiratory adverse events 43 (22.4) 
 Pneumonia 14 (7.3) 
 Asthma/asthma exacerbation/reactive airway disease 12 (6.2) 
 Influenza A/B 4 (2.1) 
 Influenza-like illness 5 (2.6) 
 Croup 3 (1.6) 
 Respiratory distress 2 (1.0) 
 Other respiratory § 3 (1.6) 
Infectious 18 (9.4) 
Gastrointestinal 16 (8.3) 
Hematological 9 (4.7) 
Ear-nose-throat 5 (2.6) 
Musculoskeletal 4 (2.1) 
Cardiovascular 4 (2.1) 
Allergic reactions 3 (1.6) 
Psychiatric 2 (1.0) 
Other  32 (16.7) 

Abbreviations: LAIV3, trivalent live-attenuated influenza vaccine; VAERS, Vaccine Adverse Event Reporting System.

*Adverse events based on principal diagnosis, as determined by clinical review.

Includes 2 febrile seizures.

Other neurological diagnosis included 1 report of each of the following: idiopathic autoimmune cerebellitis, complex ticks, third nerve palsy, hearing loss, narcolepsy/cataplexy, altered mental status, abducens (6th) nerve injury, viral meningitis, and acute demyelinating encephalomyelitis, Alper's syndrome, paresthesias/weakness and difficulty walking.

§ Other respiratory diagnosis included 1 report each of the following: pneumothorax, acute respiratory failure due to H1N1 influenza/pneumonia, and status asthmaticus.

Other diagnoses included the following: cellulitis (3), Stevens Johnson Syndrome (2), Kawasaki disease (2), trauma (2), and 1 report each of possible rheumatic fever, new onset diabetes mellitus type 1, erythema multiforme, hydronephrosis, obstructive sleep apnea, ovarian cyst rupture, leg laceration, concussion, congenital anomaly, nephritic syndrome, Arthus reaction (DTaP arm), syncope, back pain, diabetic ketoacidosis, lower extremity pain, headache and bilateral foot pain, proctitis, hyperthermia, dizziness, acute mental status changes/fever, failure to thrive.

Among the 15 serious seizure reports, 8 were male and the median age was 4 years (range, 2–13 years). Two reports were febrile seizures (ages 2 and 10 years old). The median onset interval was 1 day (range, 0–24 days). Of the other 13 reports, 4 had a previous history of seizures and 2 had a family history of seizures. Eight (53%) recovered by the time the VAERS form was submitted.

Prespecified Adverse Events

Guillain-Barré Syndrome

A total of 14 (7.3%) of 192 nonfatal serious reports were reported as GBS. Ages ranged from 3 through 18 years, and 11 were (79%) males. We verified all 14 GBS reports; 8 reports met the Brighton case definition criteria level 1, 5 were level 2, and 1 was level 3 [ 22 ]. Five (35.7%) reports of GBS were received during the 2009–2010 season; no one received concomitant inactivated H1N1 vaccine with the LAIV3. The other 9 were evenly distributed during the other influenza seasons. Thirteen had an onset interval within 42 days of vaccination, and 1 had an onset interval of 46 days (Figure 2 ). In 5 of 14 reports, patients presented with upper respiratory infection or fever or diarrheal disease within 6 days before vaccination. Four cases occurred in males who were vaccinated in military hospitals or clinics; all 4 received other vaccines simultaneously with LAIV3.

Figure 2.

Guillain-Barré Syndrome reports after live-attenuated influenza vaccine among children aged 2–18 by onset-interval (days), Vaccine Adverse Event Reporting System 2005–2012.

Figure 2.

Guillain-Barré Syndrome reports after live-attenuated influenza vaccine among children aged 2–18 by onset-interval (days), Vaccine Adverse Event Reporting System 2005–2012.

Anaphylaxis

Five reports described anaphylaxis in children 2–18 years after LAIV3. One report met Brighton level 1 and 2 Brighton level 2 [ 23 ]. Two reports did not have medical records to verify the diagnosis. All were male; 3 were classified as serious. Onset interval ranged from 5 minutes to 5 hours after LAIV3. Two reports included 4 or more additional vaccines administered at the same visit. One anaphylaxis report (Brighton level 2) involved an 8-year-old male with a history of atopic dermatitis and food allergy (including egg allergy) since 5 months of age. The patient ingested eggs before receiving LAIV3 and within 5 hours presented with diffuse urticarial rash, wheezing, and dyspnea; he was treated with epinephrine and diphenhydramine and recovered.

Adverse Events in Special Populations

History of Asthma, Reactive Airway Disease, or Wheezing

One hundred nineteen reports after LAIV involved patients with a history of asthma, reactive airway disease, or wheezing. Twenty-five (21.0%) were serious reports, which included a death report with status asthmaticus as the cause of death. Among the 119 reports, 10 had a diagnosis of asthma exacerbation, 3 of which were coded as serious. Ninety-five (79.8%) reports described at least 1 AE, with respiratory as the most common diagnostic category (47; 39.5%). Twenty-four (20.2%) reports were vaccination errors; most were due to exposure to LAIV3 in a person in whom it is contraindicated. Among the 12 serious reports in which the main diagnosis was asthma, 7 had a prior history of asthma.

Pregnancy

Eighteen pregnant adolescents received LAIV3 (median age, 15 years; range, 14–18 years). Of the 12 reports with information on duration of pregnancy, 8 received LAIV3 in the first trimester, 3 in the second trimester, and 1 in the third trimester. Two experienced spontaneous abortions and 3 had live births at term. In 13 reports, the outcome was unknown.

Egg Allergy

VAERS received 10 reports of children with a history of egg allergy; 3 were serious AEs: (1) ataxia, (2) pneumonia and reactive airway disease, and (3) headache with bilateral foot pain. As noted previously, 1 was a report of anaphylaxis in a child with a history of egg allergy.

Disproportionality Analysis

Data mining analysis identified 14 PTs with an EB05 >2.0. Four PTs referred to signs and symptoms that were observed during prelicensure trials and were included in the manufacturer's package insert (rhinorrhea, nasal congestion, oropharyngeal pain, and cough). (Some reports were identified through chart review of other serious outcomes.) Two PTs referred to laboratory results (influenza B test positive, influenza B virus test) and were not further reviewed. The remaining 8 PTs included epistaxis, influenza, pneumonia, sleep apnea, expired drug administered, medication error, accidental exposure, and contraindication to vaccine.

After clinical review, we found that reports with the PT “epistaxis” were mild and did not require hospitalization, except for 1 serious report in a patient hospitalized for H1N1 influenza. Among reports with the PT “sleep apnea,” 3 of 4 serious reports required hospitalization for medical conditions unrelated to sleep apnea. In 1 nonserious report, sleep apnea was a preexisting condition.

Pneumonia

There were 13 reports, of which 9 met the regulatory definition of serious [ 19 ]. The median interval from vaccination to symptom onset was 1 day (range, 0–39 days). Seven reports described preexisting medical conditions, which included 2 reports with a history of asthma, reactive airway disease, or wheezing; 1 report was of a patient whose brother was diagnosed with streptococcal A pharyngitis 3 days before the patient's vaccination, and 1 report of a patient who was exposed to a contact with an upper respiratory infection. Four reports had additional diagnoses other than pneumonia, including: reactive airway disease; pleural effusion and dehydration; respiratory failure due to H1N1 influenza and status asthmaticus; Kawasaki disease; and aseptic meningitis. Of the 9 serious reports, 8 required hospitalization and 6 recovered by the time the VAERS form was submitted.

Influenza

Among the 86 reports with a PT of influenza, 13 (15.1%) were marked as serious [ 19 ]. Forty-three cases (50%) were male, and the median age was 6.5 years (range, 2–18 years). The median onset was 3 days after vaccination. Thirty-four (39.5%) were vaccinated during the 2009–2010 H1N1 pandemic.

Vaccine Administration Errors

Ninety-nine percent of the 479 reports with PTs pertaining to vaccine administration errors (expired drug administered [n = 425], medication error [n = 24], accidental exposure [n = 18], and contraindication to vaccine [n = 12]) did not describe any AE. Nonserious AEs were reported, such as epistaxis, eye photosensitivity, ocular hyperemia, influenza-like illness, and nausea and vomiting. However, there were 2 serious reports: (1) a fatal report due to Leigh syndrome (Table 2 ) that included a PT of “expired drug administered,” and (2) a serious report of a 2-year-old male with a history of asthma, who experienced an asthma exacerbation after receiving LAIV3.

DISCUSSION

Since 2005, approximately 50 million doses of LAIV3 have been distributed for use in adults and children (personal communication; MedImmune, July 2013). Our review of the 2619 reports submitted to VAERS after LAIV3 vaccination in children aged 2–18 years did not identify any new or unexpected safety concerns. Our results are consistent with the first VAERS LAIV3 review by Izurieta et al. [ 14 ]. Other post-marketing studies in the United States comparing the safety of LAIV3 to control groups (IIV3 and unvaccinated) did not report unexpected AEs [ 26–28 ]. Baxter et al. [ 27 ] evaluated LAIV safety in children 5–17 years and found a similar pattern of medically attended AEs for both LAIV3 and control groups. Our results are consistent with previously reported pre- and postlicensure studies that suggest that LAIV3 has a favorable safety profile when used according to indications [ 28 ].

Our clinical review of 5 fatal serious reports after LAIV3 revealed varying causes of death. In 1 of the fatal reports, a patient with a history of asthma died of status asthmaticus. We also found that more than half of the patients with a reported reaction of asthma or reactive airway disease had a preexisting history of asthma. The manufacturer's package insert [ 1 ] contains a statement in the Warning and Precautions section, regarding the risk of wheezing in individuals with a prior history of asthma and wheezing. We also noted inadvertent administration of LAIV3 in pregnant teenagers [ 29 ]. These cases indicate the need for greater efforts to educate vaccine providers on the proper indications for LAIV3 to prevent the administration of the vaccine to those in whom the product's safety and effectiveness have not been established.

Among serious reports, the most common medical conditions reported after LAIV3 were neurological and respiratory AEs, which comprised more than half of all serious reports. Afebrile seizures and GBS were the most common neurological diagnosis. Guillain-Barré Syndrome is an acute, immune-mediated paralytic disorder of the peripheral nervous system. Guillain-Barré Syndrome has been linked to IIV3, but several studies have not shown any increased risk [ 30 , 31 ]. Guillain-Barré Syndrome is rare in children with an incidence of 0.62 and 0.75 cases per 100 000 person-years in those 0–9 years and 10–19 years, respectively [ 32 ]. In 10 (90.9%) of 14 VAERS reports of GBS following LAIV3 in children, the interval between date of vaccination and symptom onset was within the commonly accepted window of biologic plausibility of 5–42 days [ 20 , 21 , 32 ]. We did not calculate GBS reporting rates because doses distributed were unavailable by age group. We also did not find disproportionate reporting for GBS. Six (42.9%) of the 14 verified GBS cases were vaccinated during the 2009–2010 season, which may reflect stimulated reporting during the 2009 H1N1 influenza pandemic season [ 20 ]. We also found that 4 of 14 GBS reports after LAIV3 were reported by vaccine providers from military clinics, which may tend to report certain AEs more frequently than civilian facilities [ 33 ].

Anaphylaxis is causally associated with influenza vaccination [ 8 , 21 ]. Although our review identified 5 cases of anaphylaxis, concomitant administration with other vaccines made it difficult to assess whether LAIV3 contributed to the reaction. We also found reports in children with egg allergy for whom LAIV3 is contraindicated [ 34 , 35 ], further highlighting the importance of educating providers regarding proper indications and contraindications for use of LAIV3.

We found 12 serious reports of asthma or wheezing. Similar to our findings, the earlier VAERS LAIV3 post-marketing study also found asthma episodes among children aged 6–15 years [ 14 ]. However, the present analysis did not demonstrate disproportionately higher reporting for asthma and wheezing. Some prior studies have suggested an increase in wheezing events in young children after LAIV3 [ 5 , 6 ]. A study that included children aged 2–4 years, however, did not find an increase in rates of medically attended wheezing after LAIV3 vs IIV [ 36 ]. In addition, more recent post-marketing studies did not observe an increased rate of asthma and wheezing among children who received LAIV3 compared to those who received IIV3 [ 26–28 ].

Medication errors can have potentially serious consequences [ 37 ]. Administration errors comprised a disproportionately large share of reports submitted to VAERS following LAIV3. Administration of expired drug was the most common medication error; this result may be due to the shorter shelf-life for LAIV3 (18 weeks) compared with inactivated influenza vaccines (12 months) [ 1 ]. Administration of an expired dose of LAIV3, however, is not known to increase the risk of reactogenicity or other adverse outcomes, other than potential lack of influenza protection (personal communication; MedImmune, September 2013).

Passive surveillance systems such as VAERS are subject to limitations, including underreporting and incomplete information [ 16 , 17 ]. Because of these limitations, it is usually not possible to verify causal associations between vaccines and AEs from spontaneous reports to VAERS. However, as a national surveillance system, VAERS has the advantage that it may be used to detect signals of potential vaccine safety concerns, which can be further explored in carefully designed epidemiological studies [ 15 , 20 ].

CONCLUSIONS

Our review of reports to VAERS after LAIV3 vaccination in children aged 2–18 years during 7 influenza seasons did not identify any new or unexpected safety concerns. We did identify reports in persons for whom LAIV is contraindicated (ie, children with egg allergy or asthma, administration to pregnant teenagers), demonstrating the need for greater efforts to educate vaccine providers and administrators on the proper indications for LAIV. Continued assessment of the safety of LAIV and other influenza vaccines is needed as more children are vaccinated annually, including with the recently approved LAIV4 vaccine [ 9 , 10 ].

Acknowledgments

We thank Drs. Lisa Grohskopf and Frank DeStefano for their in-depth review of this manuscript.

Disclaimer. The findings and conclusions in this article are those of the authors and do not necessarily represents the official position of the Department of Health and Human Services, the Centers for Disease Control and Prevention, or the US Food and Drug Administration.

Potential conflicts of interest . All authors: No reported conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

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Appendix

Medical dictionary for regulatory activities (MedDRA) Preferred Terms Used for the Search of Prespecified and Special Population Adverse Events

Prespecified Adverse Events/Medical Conditions  MedDRA Terms 1 
Guillain-Barre Syndrome GUILLAIN-BARRE SYNDROME, MILLER FISHER SYNDROME, DEMYELINATING POLYNEUROPATHY 
Anaphylaxis ANAPHYLACTIC SHOCK, ANAPHYLACTIC REACTION, ANAPHYLACTOID REACTION, ANAPHYLACTOID SHOCK 
Pregnancy DRUG EXPOSURE DURING PREGNANCY, MATERNAL EXPOSURE DURING PREGNANCY 
Asthma/Wheezing  ASTHMA, BRONCHIAL HYPERREACTIVITY, WHEEZING (OTHER SYMPTOMS – BOX18-19)
Include text string: ASTHMA, REACTIVE AIRWAY, REACTIVE AIRWAY DISEASE, WHEEZING from history, or/and prex_illness (pre-existing illness)  
Egg Allergy  Include text strings: EGG
Exclude text strings: NO ALLERGIES TO EGGS, TESTS NEGATIVE FOR EGG, LEGGED, LEGG, NEGATIVE INCLUDING EGGS, LEGG-PERTHES DISEASE, POST H/O EGG ALLERGY WITH NEGATIVE TEST RESULTS, NEGATIVE TO EGGS, VEGGIES, EATS EGGS DAILY, SWELLING SIZE OF AN EGG, ALLERGIES (NOT EGG), TESTING TO EGGS NEGATIVE, CHILD WITH NO EGG ALLERGY TO EGGS, TOLERATED EGG WITHOUT EVIDENCE OF RXN, NO ALLERGY TO EGGS, PAST DISEASE: EGG ALLERGY, NO EGG ALLERGY from symptom text, lab data, history, or/and prex_illness (pre-existing illness)  
Prespecified Adverse Events/Medical Conditions  MedDRA Terms 1 
Guillain-Barre Syndrome GUILLAIN-BARRE SYNDROME, MILLER FISHER SYNDROME, DEMYELINATING POLYNEUROPATHY 
Anaphylaxis ANAPHYLACTIC SHOCK, ANAPHYLACTIC REACTION, ANAPHYLACTOID REACTION, ANAPHYLACTOID SHOCK 
Pregnancy DRUG EXPOSURE DURING PREGNANCY, MATERNAL EXPOSURE DURING PREGNANCY 
Asthma/Wheezing  ASTHMA, BRONCHIAL HYPERREACTIVITY, WHEEZING (OTHER SYMPTOMS – BOX18-19)
Include text string: ASTHMA, REACTIVE AIRWAY, REACTIVE AIRWAY DISEASE, WHEEZING from history, or/and prex_illness (pre-existing illness)  
Egg Allergy  Include text strings: EGG
Exclude text strings: NO ALLERGIES TO EGGS, TESTS NEGATIVE FOR EGG, LEGGED, LEGG, NEGATIVE INCLUDING EGGS, LEGG-PERTHES DISEASE, POST H/O EGG ALLERGY WITH NEGATIVE TEST RESULTS, NEGATIVE TO EGGS, VEGGIES, EATS EGGS DAILY, SWELLING SIZE OF AN EGG, ALLERGIES (NOT EGG), TESTING TO EGGS NEGATIVE, CHILD WITH NO EGG ALLERGY TO EGGS, TOLERATED EGG WITHOUT EVIDENCE OF RXN, NO ALLERGY TO EGGS, PAST DISEASE: EGG ALLERGY, NO EGG ALLERGY from symptom text, lab data, history, or/and prex_illness (pre-existing illness)  

1 Some reports were identified through chart review of other serious outcomes.