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Supplemental Digital ContentNewcomer SR, Daley MF, Narwaney KJ, et al. Order of live and inactivated vaccines and risk of non-vaccine-targeted infections in U.S. children ages 11-23 months.eTable 1. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes indicating potential medical contraindication to immunizationeTable 2. Inactivated and live vaccines recommended by the U.S. Advisory Committee on Immunization Practices from birth through age 23 months for U.S. children born 2003-2013 eTable 3. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes for non-vaccine-targeted infections identified in study cohort eTable 4. Procedure codes indicating exclusion from outcome definitioneTable 5. Injury diagnosis codes indicating exclusion from outcome definitioneTable 6. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes for chronic conditions identified in study cohort before age 11 monthseTable 7. Person-years of observation time in study, by type of vaccines receivedeTable 8. Incidence rates and hazard ratios for emergency department and inpatient visits for non-vaccine-targeted infections, by most recent vaccine type, ages 11-23 months, among a sub-cohort of children with records for all recommended immunizations through age 23 monthseTable 9. Incidence rates and hazard ratios for emergency department and inpatient visits for non-vaccine-targeted infections, by most recent vaccine type and separating live rotavirus vaccine exposure from measles-mumps-rubella or varicella vaccine exposure, ages 11-23 monthseTable 10. Mean and median number of days from receipt of last vaccine to non-vaccine-targeted infection diagnosis date in an emergency department or inpatient setting, by vaccine type last received, ages 11-23 monthseTable 1. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes indicating potential medical contraindication to immunizationICD-9-CM codeDescription011.x – 0.18xTuberculosis031.0Pulmonary diseases due to other mycobacteria042.xHuman immunodeficiency virus052.xChickenpox (varicella)a136.3Pneumocystosis140.x-172.x, 174.x- 208.xNeoplasms238.4Polycythemia vera279.xDisorders involving the immune mechanism287.31Immune thrombocytopenic purpura357.0Acute infective polyneuritis446.1Acute febrile mucocutaneous lymph node syndrome560.0Intussusception795.71Nonspecific serologic evidence of human immunodeficiency virus999.4Anaphylactic shock due to serumV08Asymptomatic human immunodeficiency virus infection statusV14.7Personal history of allergy to serum or vaccineV15.03Allergy to eggsV15.07Allergy to latexV42.81Bone marrow replaced by transplantV42.82Peripheral stem cells replaced by transplantV64.03Vaccination not carried out because of immune compromised stateV64.04Vaccination not carried out because of allergy to vaccine or componentAbbreviation: ICD-9-CM: International Classification of Diseases, 9th edition, Clinical Modificationa Children with a diagnosis of chickenpox (varicella) before age 18 months were excluded from the studyeTable 2. Inactivated and live vaccines recommended by the U.S. Advisory Committee on Immunization Practices from birth through age 23 months for U.S. children born 2003-2013 Birth1month2 months4 months6 months12 months15 months18 months19-23 monthsInactivated VaccinesaHepatitis Bb1st dose2nd dose3rd doseDiphtheria-tetanus-acellular pertussis 1st dose2nd dose3rd dose4th doseHaemophilus influenzae type bc1st dose2nd dose3rd dose4th dosePneumococcal conjugate1st dose2nd dose3rd dose4th dosePoliovirus 1st dose2nd dose3rd doseHepatitis Ad2 dose seriesSeasonal influenzaeAnnual vaccination, 1 or 2 doses2009 pandemic H1N1 influenzaVaccination during 2009 pandemic, 1 or 2 dosesLive VaccinesfRotavirusg1st dose2nd dose3rd doseMeasles-mumps-rubella1st doseVaricellah1st doseaThe Hepatitis B (HepB), diphtheria-tetanus-acellular pertussis (DTaP), Haemophilus influenzae type b, and poliovirus vaccines are available for use in U.S. children as individual vaccines and in combination vaccines (e.g., HepB-DTaP-Poliovirus combination vaccine).b Children may receive four hepatitis B vaccine doses if hepatitis B-containing combination vaccines are used at 2, 4 and 6 months.c Haemophilus influenzae type b vaccine at age 6 months is not indicated if PedvaxHib? or Comvax? brand vaccines are administered for the first two doses.d In 2006, the Advisory Committee on Immunization Practices expanded recommendation for Hepatitis A vaccination to include routine recommendation of all children greater than 1 year of age. eTwo doses of seasonal influenza vaccine are recommended for previously unvaccinated children, and one vaccine is indicated per season thereafter. A live, attenuated seasonal influenza vaccine was also approved during the study observation period; however, this vaccine was only approved for use in children ages 24 months and older.f The measles-mumps-rubella and varicella vaccines are available for use in U.S. children as individual vaccines and as a combination vaccine.g Rotavirus vaccine was re-introduced in the U.S. immunization schedule in 2006. The third dose of rotavirus vaccine is not indicated if the Rotarix? brand vaccine is administered for the first two doses.h In 2007, the recommended age for varicella vaccine changed from 12-18 months to 12-15 months. eTable 3. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes for non-vaccine-targeted infections identified in study cohortICD-9-CM CodeDescriptionCategory001.x – 009.xIntestinal infectious diseasesGastrointestinal infections020.x – 027.xZoonotic bacterial diseasesOther infections031.8Other specified mycobacterial diseasesOther infections034.0Streptococcal sore throat Upper respiratory034.1Scarlet feverOther infections036.xMeningococcal infectionOther infections038.xSepticemiaOther infections040.xOther bacterial diseasesOther infections041.x, excluding 041.5Bacterial infection in conditions classified elsewhere and of unspecified siteOther infections047.xMeningitis due to enterovirusOther infections048Other enterovirus diseases of central nervous systemOther infections049.xOther non-arthropod-borne viral diseases of central nervous systemOther infections053.20Herpes zoster dermatitis of eyelidOther infections054.xHerpes simplexOther infections057.xOther viral exanthemataOther infections058.xOther human herpesvirusOther infections060.x-066.xArthropod-borne viral diseasesOther infections074.xSpecific diseases due to Coxsackie virusOther infections075Infectious mononucleosisOther infections077.xOther diseases of conjunctiva due to viruses and ChlamydiaeOther infections078.xOther diseases due to viruses and ChlamydiaeOther infections079.0Adenovirus infection in conditions classified elsewhere and of unspecified siteOther infections079.1Echo virus infection in conditions classified elsewhere and of unspecified siteLower respiratory079.2Coxsackie virus infection in conditions classified elsewhere and of unspecified siteUpper respiratory079.3Rhinovirus infection in conditions classified elsewhere and of unspecified siteUpper respiratory079.59Other specified retrovirusOther infections079.6Respiratory syncytial virus Lower respiratory079.8Other specified viral and chlamydial infectionsOther infections079.83Parvovirus B19Other infections079.89Other specified viral infectionOther infections079.9Unspecified viral and chlamydial infectionsOther infections080.x-088.xRickettsioses and other arthropod-borne diseasesOther infections090.x-099.xSyphilis and other venereal diseasesOther infections100.x-104.xOther spirochetal diseasesOther infections110.x-118.xMycosesOther infections120.x-129.xHelminthiasesOther infections130.x-136.xOther infectious and parasitic diseasesOther infections320.x-326.x, excluding 320.0Bacterial meningitisOther infections372.x, excluding 372.06Disorders of conjunctivaOther infections373.x, excluding 373.8 and 373.9Inflammation of eyelidsOther infectionseTable 3, continuedICD-9-CM CodeDescriptionCategory380.xDisorders of external earUpper respiratory381.x, excluding 381.04Nonsuppurative otitis media and eustachian tube disordersUpper respiratory382.xSuppurative and unspecified otitis mediaUpper respiratory383.xMastoiditis and related conditionsUpper respiratory422.90Acute myocarditis, unspecifiedOther infections422.91Idiopathic myocarditisOther infections461.xAcute sinusitisUpper respiratory462Acute pharyngitisUpper respiratory463Acute tonsillitisUpper respiratory464.xAcute laryngitis and tracheitisUpper respiratory465.xAcute upper respiratory infections of multiple or unspecified sitesUpper respiratory466.xAcute bronchitis and bronchiolitisLower respiratory473.xChronic sinusitisUpper respiratory480.x – 486.x, excluding 484.3PneumoniaLower respiratory510.xEmpyemaLower respiratory511.xPleurisyLower respiratory513.0Abscess of lungLower respiratory577.0Acute pancreatitisOther infections597.80Urethritis, unspecifiedOther infections680.xCarbuncle and furuncleOther infections681.xCellulitis and abscess of finger and toeOther infections682.xOther cellulitis and abscessOther infections683Acute lymphadenitisOther infections684ImpetigoOther infections686.xOther local infections of skin and subcutaneous tissueOther infections711.0xPyrogenic arthritisOther infections711.4xArthropathy associated with other bacterial diseasesOther infections730.xOsteomyelitis periostitis and other infections involving boneOther infections790.8Viremia, unspecifiedOther infections995.91SepsisOther infections997.09Other nervous system complicationsOther infectionsAbbreviation: ICD-9-CM: International Classification of Diseases, 9th Revision, Clinical ModificationeTable 4. Procedure codes indicating exclusion from outcome definitionaCurrent Procedure Terminology codesCodeDescription00120Anesthesia for procedures on external, middle, and inner ear including biopsy; not otherwise specified00124Anesthesia for procedures on external, middle, and inner ear including biopsy; otoscopy00126Anesthesia for procedures on external, middle, and inner ear including biopsy; tympanotomy69399Unlisted procedure, external ear69420Myringotomy including aspiration and/or eustachian tube inflation69421Myringotomy including aspiration and/or eustachian tube inflation requiring general anesthesia68433Tympanostomy, local or topical anesthesia69436Tympanostomy, general anesthesia69604Revision mastoidectomy, resulting in tympanoplasty69645Tympanostomy with mastoidectomy, radical or complete, without ossicular chain reconstruction92550Tympanostomy and reflex threshold measurements92567TympanometryInternational Classification of Diseases, 9th Revision, Clinical Modification Procedure codesCodeDescription18.09Other incision of external ear18.29Excision or destruction of other lesion of external ear 18.9Other operations on external ear19.4Myringoplasty19.6Revision of tympanoplasty19.9Other repair of middle ear20.01Myringotomy with insertion of ear tube20.09Other myringotomy20.1Removal of tympanostomy tube20.59Other excision of external ear98.11Removal of intraluminal foreign body from ear without incision a Diagnoses for non-vaccine-targeted infections were excluded from the outcome definition if they occurred in an inpatient setting on the same day as one of these procedure codes. This decision was based on findings from a sample medical record review that found inpatient diagnoses of otitis media occurring on the same day as preventive surgeries for chronic otitis media.eTable 5. Injury diagnosis codes indicating exclusion from outcome definitionaInternational Classification of Diseases, 9th edition, Clinical Modification diagnosis codes800.x – 829.xFractures830.x – 839.xDislocation 840.x – 848.xSprains and strains of joints and adjacent muscles850.x – 854.xIntracranial injury, excluding those with skull fracture 860.x – 869.xInternal injury of thorax, abdomen and pelvis 870.x – 897.xOpen wounds900.x – 904.xInjury to blood vessels905.x – 909.xLate effects of injuries, poisoning, toxic effects, and other external causes910.x – 919.x Superficial injuries920.x - 929.xContusions 930.x – 939.xForeign bodies940.x - 949.xBurns950.x - 957.xOther injuries958.x – 959.xCertain traumatic complications and unspecified injuries980.x – 989.xToxic effects of substances chiefly nonmedicinal as to sourcea Diagnoses for non-vaccine-targeted infections were not considered as an outcome if they occurred within an emergency department encounter with one of these injury diagnosis codes. This decision was based on a sample medical record review that found examples of emergency department encounters for injuries where mild non-vaccine-targeted infections, usually upper respiratory infections, were noted and diagnosed upon clinical examination.eTable 6. International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes for chronic conditions identified in study cohort before age 11 monthsICD-9-CM codeDescription046.2Subacute sclerosing panencephalitis173.xOther malignant neoplasm of skin237.xNeurofibromatosis240.x – 246.xDisorders of thyroid gland250.xDiabetes mellitus252.xDisorders of parathyroid gland253.xDisorders of the pituitary gland and its hypothalamic control255.xDisorders of adrenal glands260Kwashiorkor261Nutritional marasmus262Other severe protein-calorie malnutrition263.xOther and unspecified protein-calorie malnutrition268.0Rickets, active270.xDisorders of amino-acid transport and metabolism271.xDisorders of carbohydrate transport and metabolism272.xDisorders of lipid metabolism273.xDisorders of plasma protein metabolism275.xDisorders of mineral metabolism277.xOther and unspecified disorders of metabolism281.xOther deficiency anemias282.xHereditary hemolytic anemias283.xAcquired hemolytic anemias284.xAplastic anemia and other bone marrow failure syndromes286.xCoagulation defects288.xDiseases of white blood cells291.81Alcohol withdrawal292.0Drug withdrawal292.89Other specified drug-induced mental disorders293.0Delirium due to conditions classified elsewhere293.9Unspecified transient mental disorder in condition classified elsewhere294.8Other persistent mental disorders due to conditions classified elsewhere294.9Unspecified persistent mental disorders due to conditions classified elsewhere298.9Unspecified psychosis299.10Childhood disintegrative disorder299.80Other specified pervasive developmental disorders300.4Dysthymic disorder300.7Hypochondriasis300.82Undifferentiated somatoform disorder301.51Chronic factitious illness with physical symptoms303.93Other and unspecified alcohol dependence, in remission304.xDrug dependence305.xNondependent abuse of drugs306.xPhysiological malfunction arising from mental factors307.1Anorexia nervosa308.1Predominant disturbance of consciousness310.2Post-concussion syndrome315.xSpecific delays in developmenta318.2Profound intellectual disabilities319.xUnspecified intellectual disabilitiesaeTable 6, continuedICD-9-CM codeDescription330.x – 335.xHereditary and degenerative diseases of the central nervous system340.xMultiple sclerosis343.xInfantile cerebral palsy344.xOther paralytic syndromes345.xEpilepsy and recurrent seizures352.6Multiple cranial nerve palsies356.xHereditary and idiopathic peripheral neuropathy359.xMuscular dystrophies and other myopathies365.14Glaucoma of childhood369.xBlindness and low visiona389.xHearing lossa394.xDiseases of mitral valve395.9Other and unspecific rheumatic aortic diseases393.x – 398.xChronic rheumatic heart disease424.1Aortic valve disorders424.3Pulmonary valve disorders425.xCardiomyopathy446.xPolyarteritis nodose and allied conditions493.81Exercise induced bronchospasm496.xChronic airway obstruction, not elsewhere classified516.xOther alveolar and parietoalveolar pneumonopathy531.xGastric ulcer532.xDuodenal ulcer533.xPeptic ulcer, site unspecified555.xRegional enteritis556.xUlcerative enteritis571.xChronic liver disease and cirrhosis579.0Celiac disease571.1Tropical sprue581.xNephrotic syndrome582.xChronic glomerulonephritis583.xNephritis and nephropathy, not specific as acute or chronic580.x-589.xNephritis, nephrotic syndrome, and nephrosis694.xBullous dermatoses710.xDiffuse diseases of connective tissue714.xRheumatoid arthritis and other inflammatory polyarthropathies720.xAnkylosing spondylitis and other inflammatory spondylopathies728.x (except 728.87 and 728.9)Disorders of muscle, ligament, and fascia728.87Muscle weakness (generalized)a728.9Unspecified disorder of muscle, ligament, and fasciaa730.1xChronic osteomyelitis732.xOsteochondropathies740.x – 759.x (except 745.5, 753.29, 756.0)Congenital anomalies745.5Ostium secundum type atrial septal defecta753.29Other obstructive defects of renal pelvis and uretera756.0Anomalies of skull and face bonesa760.71Alcohol affecting fetus or newborn via placenta or breast milk770.7Chronic respiratory disease arising in the perinatal period771.1Congenital cytomegalovirus infectioneTable 6, continuedICD-9-CM codeDescription771.2Other congenital infections specific to the perinatal period854.xIntracranial injury of other and unspecified nature994.1Drowning and nonfatal submersionAbbreviation: ICD-9-CM: International Classification of Diseases, 9th Revision, Clinical Modificationa Two diagnosis codes on separate days were required.eTable 7. Person-years of observation time in study, by vaccine type last receivedVaccine type last receivedType of live vaccinePerson-years of observation timeInactivated and live vaccines concurrentlyMMR and/or varicella173,001Rotavirus18,135Live vaccine(s) onlyMMR and/or varicella6,426Rotavirus30Inactivated vaccine(s) onlyn/a238,401Total person-years of observation time in study:435,993eTable 8. Incidence rates and hazard ratios for emergency department and inpatient visits for non-vaccine-targeted infections, by most recent vaccine type, ages 11-23 months, among a sub-cohort of children with records for all recommended immunizations through age 23 monthsaSexMost recent vaccine type EventsPerson-yearsUnadjusted Incidence Rate per 100,000 person-yearsUnadjusted HR (95% CI)Adjusted HRb(95% CI)Overall n=222,418Inactivated and live vaccines concurrently9,77389,70510,8951.02(95% CI: 0.98 – 1.05)Live vaccine(s) only2112,2589,3431.00(95% CI: 0.87 – 1.15)Inactivated vaccine(s) only13,268134,0289,899ReferenceFemalesn=108,449Inactivated and live vaccines concurrently4,10344,0099,3230.99(95% CI: 0.94 – 1.04)1.00(95% CI: 0.96 – 1.06)Live vaccine(s) only931,0928,5201.05(95% CI: 0.85 – 1.29)1.16(95% CI: 0.92 – 1.45)Inactivated vaccine(s) only5,69565,9748,632ReferenceReferenceMalesn=113,969Inactivated and live vaccines concurrently5,67045,69712,4081.04(95% CI: 0.99 – 1.08)0.94(95% CI: 0.89 – 0.98)Live vaccine(s) only1181,16710,1120.95(95% CI: 0.79 – 1.14)0.83(95% CI: 0.67 – 1.04)Inactivated vaccine(s) only7,57368,05511,128ReferenceReferenceAbbreviations: HR=Hazard ratio; CI=confidence intervala Cox regression models use an age time scale and are stratified by year and month of birth and integrated health system site. Children in this sub-cohort had ≥3 Hepatitis B, 4 diphtheria-tetanus- acellular pertussis, 3 or 4 Haemophilus influenzae type b vaccines (depending on brand), ≥4 pneumococcal vaccines, 3 inactivated polio vaccines, 1 measles-mumps-rubella vaccine, 1 varicella vaccine, ≥2 seasonal influenza vaccines, and ≥1 Hepatitis A vaccine. Children born after re-introduction of the rotavirus vaccine at each integrated health plan after 2006 were required to have 2 or 3 rotavirus vaccines (depending on brand), and children ages 6-24 months in October 2009- March 2010 were required to have two 2009 H1N1 pandemic influenza vaccines. b As with the primary analysis shown in Table 2, this model is adjusted for preterm birth, presence of a chronic condition before age 11 months, number of outpatient visits in ages 1-10 months, and an interaction term of outpatient visits between ages 1 and 11 months and time. P-value for interaction between most recent vaccine type and sex was p=0.01; therefore, the interaction term was retained in the adjusted model and hazard ratios are presented separately for females and males.eTable 9. Incidence rates and hazard ratios for emergency department and inpatient visits for non-vaccine-targeted infections, by most recent vaccine type and separating live rotavirus vaccine exposure from measles-mumps-rubella or varicella vaccine exposurea, ages 11-23 monthsSexMost recent vaccine type EventsPerson-yearsUnadjusted Incidence Rate per 100,000 person-yearsUnadjusted HR (95% CI)Adjusted HRb(95% CI)Overall n=428,608Rotavirus, with or without inactivated vaccine(s) concurrently2,27618,16412,5300.99(95% CI: 0.94 - 1.04)MMR/Varicella with inactivated vaccine(s) concurrently17,714173,00110,2390.99(95% CI: 0.96 - 1.01)MMR/Varicella only5626,4268,7450.93(95% CI: 0.85 - 1.01)Inactivated vaccine(s) only23,523238,4019,867ReferenceFemalesn=209,449Rotavirus, with or without inactivated vaccine(s) concurrently9138,85710,3080.93(95% CI: 0.85 - 1.01)1.44(95% CI: 1.32 - 1.57)MMR/Varicella with inactivated vaccine(s) concurrently7,61285,2928,9250.98(95% CI: 0.95 - 1.02)0.91(95% CI: 0.88 - 0.94)MMR/Varicella only2483,1297,9260.96(95% CI: 0.85 - 1.09)0.99(95% CI: 0.86 - 1.13)Inactivated vaccine(s) only10,108117,4348,607ReferenceReferenceMalesn=219,159Rotavirus, with or without inactivated vaccine(s) concurrently1,3639,30714,6451.04(95% CI: 0.97 - 1.11)1.14(95% CI: 1.05 - 1.23)MMR/Varicella with inactivated vaccine(s) concurrently10,10287,70911,5180.99(95% CI: 0.96 - 1.02)0.89(95% CI: 0.87 - 0.92)MMR/Varicella only3143,2979,5220.90(95% CI: 0.80 - 1.01)0.82(95% CI: 0.72 - 0.93)Inactivated vaccine(s) only13,415120,96811,090ReferenceReferenceeTable 9, continuedaMMR/Varicella indicates that either vaccine was administered, or both were administered together. Overall, there were only 2 events that occurred when rotavirus was last administered alone (i.e., without any other vaccines on the same day). Cox regression models use an age time scale and are stratified by year and month of birth and integrated health system site. b As with the primary analysis shown in Table 2, this model is adjusted for preterm birth, presence of a chronic condition before age 11 months, number of outpatient visits in ages 1-10 months, and an interaction term of outpatient visits between ages 1 and 11 months and time. Since an interaction between most recent vaccine type and sex was statistically significant (p<0.0001), the interaction term was retained in the adjusted model and hazard ratios are presented separately for females and males.eTable 10. Mean and median number of days from receipt of last vaccine to non-vaccine-targeted infection diagnosis date in an emergency department or inpatient setting, by vaccine type last received, ages 11-23 monthsa Most recent vaccine typeMean (standard deviation)MedianRotavirus, with or without inactivated vaccine(s) concurrently181.4 (53.8)170MMR/Varicella with inactivated vaccine(s) concurrently88.8 (69.8)74MMR/Varicella only74.4 (61.9)60.5Inactivated vaccine(s) only87.8 (66.5)75a Among n=44,075 individuals who had an non-vaccine-targeted infection diagnosis in an emergency department or inpatient setting. ................
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