cb Baxter 2012.

Methods	Retrospective cohort study in which the incidence of medical attended events (MAEs) that occurred in people immunised with LAIV through several seasons was compared with that observed in 2 matched control groups (unvaccinated and immunised with inactivated vaccine). Data for the LAIV‐exposed population were also analysed with a self controlled case series method.
Participants	Participants were members of the Kaiser Permanente (KP) Health Plans in Northern California, Hawaii, and Colorado. Through KP immunisation registries, approximately 20,000 individuals 18 to 49 years of age who were immunised from the 2003 to 2004 to 2007 to 2008 influenza seasons with LAIV as part of routine clinical practice were identified.
Interventions	Intervention hemi‐cohort: Live attenuated influenza vaccine vaccine provided by MedImmune. Each annual formulation of the vaccines contained the strains recommended for inclusion by the US Public Health Service. Study participants with high‐risk underlying medical conditions such as cancer, organ transplantation, diabetes, endocrine and metabolic disorders, blood disorders, liver disorders, kidney disorders, and cardiopulmonary disorders were identified via automated extraction of healthcare databases and excluded from all analysis cohorts. A total of 21,340 participants 18 to 49 years of age were vaccinated with the Ann Arbor strain LAIV during the 5 study seasons. Control hemi‐cohort 1: unvaccinated (n = 21,340). Participants were KP members who participated in the health plan during the same month as the reference LAIV recipients; for the unvaccinated population, the effective vaccination date was the date on which the matched LAIV recipient was vaccinated. Control hemi‐cohort 2: trivalent inactivated vaccine purchased by KP for immunisation practices (n = 18,316). Participants were KP members vaccinated during the same month as the reference LAIV recipient. Both controls were matched for region (Northern California, Hawaii, Colorado), birth date (within 1 year), sex, and prior healthcare utilisation (≤ 1 or > 1 clinic visits during the 180 days before vaccination) 1:1 to the participants of the intervention hemi‐cohort. For Northern California only, participants were also matched on their specific medical clinic. In the case that a match could not be found within a specific control group, the LAIV recipient was excluded from the cohort comparison. For self controlled case series analysis, intervals of 3 and 21 days' postvaccination were compared with control intervals from 4 to 42 days' postvaccination (for the 3‐day risk interval) and 22 to 42 days' postvaccination (for a 0 to 21‐day risk interval).
Outcomes	Medical attended adverse events Based on medical diagnoses found in KP database records and collected from outpatient clinics, emergency departments, and hospital admissions, MAEs occurred in 5 main categories and included events considered to be vaccine associated: Acute respiratory tract events: acute laryngitis, acute laryngotracheitis, acute respiratory failure, acute tracheitis, acute respiratory distress syndrome, asthma, bronchitis, cough, epiglottitis, influenza, influenza with pneumonia, mastoiditis, otitis media, pharyngitis, pneumococcal pneumonia, pneumonia, pulmonary congestion and hypostasis, shortness of breath, sinusitis, tachypnoea, tonsillitis, urinary tract infection, viral pneumonia. Follow‐up 42 days Acute gastrointestinal tract events: abdominal pain, acute gastritis, acute gastroenteritis, appendicitis, intestinal obstruction, intussusception, irritable bowel syndrome, mesenteric adenitis, nausea and vomiting, pancreatitis, paralytic ileus, perforation of intestine, peritonitis, persistent vomiting, small bowel obstruction, ulceration of intestine, and volvulus. Follow‐up 42 days Asthma and wheezing events: asthma/reactive airway disease, wheezing/shortness of breath. Follow‐up 180 days Systemic bacterial infections events: bacteraemia, bacterial meningitis, intracranial and intraspinal abscess, septicaemia, shock: unspecified, shock: endotoxic, and gram‐negative shock. Follow‐up 42 days Rare diagnoses: potentially related to wild‐type influenza infection: encephalitis/encephalopathy, Guillain‐Barré syndrome, meningitis, myocarditis, other paralytic syndromes, pericarditis, polymyositis, Reye syndrome, and viral meningitis. Follow‐up 42 days Severe adverse events Death, inpatient hospitalisation, persistent or significant disability or incapacity, congenital anomaly/birth defect (in the offspring of a participant), or any life‐threatening event. Follow‐up from 0 to 42 days' postvaccination
Notes	Sources of support: "This study was sponsored by MedImmune, LLC. Authors employed by MedImmune were involved in the study design, analysis, and interpretation of data, and in the preparation of the manuscript. Authors employed by Kaiser Permanente were involved in the study design, collection, analysis, and interpretation of data, and in the preparation of the manuscript. The Kaiser Permanente Vaccine Study Center was paid for their services in data collection and analysis but authors were not compensated for their work on this manuscript"
Risk of bias
Bias	Authors' judgement	Support for judgement
PCS/RCS ‐ selection exposed cohort All outcomes	Unclear risk	Selected group of users Participants were screened for underlying medical conditions and provided the appropriate vaccine based on the eligibility criteria in each vaccine’s package insert, physician discretion, and patient choice.
PCS/RCS ‐ selection non‐exposed cohort All outcomes	Unclear risk	No description of the derivation of the non‐exposed cohort
PCS/RCS ‐ comparability All outcomes	Unclear risk	Matched but not very relevant: "TIV‐vaccinated and unvaccinated participants were matched to LAIV recipients on region (Northern California, Hawaii, Colorado), birth date (within one year), sex, and prior healthcare utilization. Prior utilization was calculated based on the number of clinic visits during the 180 days before vaccination and classified as low (≤ 1 visit) and high (> 1 visit) for matching. In Northern California, participants also were matched on their specific medical clinic, of which there were 48"
PCS/RCS ‐ assessment of outcome All outcomes	Low risk	Record linkage
Summary assessment	Unclear risk	Unclear