ABSTRACT
INTRODUCTION: From 2011 to 2012, we received an unexpectedly high number of reports of suppurative lymphadenitis following administration of a BCG vaccine used in our childhood vaccination programme in Singapore. We sought to determine the local incidence rates of BCG-associated suppurative lymphadenitis across the 2009 to 2012 vaccinated cohorts, and to analyse the potential factors contributing to this outbreak. METHODS: Reports of lymphadenitis following BCG vaccination from an AEFI active surveillance system at the KK Women's and Children's Hospital (KKH) and passive surveillance data from other healthcare institutions were reviewed. All valid reports received from January 2009 to December 2013 involving neonates vaccinated with the BCG vaccine in 2009 to 2012 that met case definitions were included in our analysis. Details of the demographics and vaccination history of the child, and statistics from the local vaccination programme were also obtained. Potential contributory factors were selected for further investigation based on a literature review of similar outbreaks overseas. RESULTS: We identified 283 cases of lymphadenitis, of which 76% were suppurative. A spike in suppurative lymphadenitis cases was seen in the 2011 vaccinated cohort, with an incidence rate of 3.16 per 1000 vaccinees, as compared to 0.71 to 0.85 per 1000 in the 2009, 2010 and 2012 cohorts. Our investigations identified the likely cause of the outbreak to be batch-related, arising from manufacturing issues encountered by the manufacturer, after ruling out vaccine administration-related and host-related factors. CONCLUSIONS: The three-fold spike in BCG-associated suppurative lymphadenitis cases observed in the 2011 vaccinated cohort, possibly due to batch-to-batch variation of the vaccine, highlights that manufacturing controls can continue to be a challenge. Development of a more sensitive assay to test the reactogenicity of the BCG vaccine may help reduce the occurrence of such outbreaks and improve public confidence in the nation's vaccination programme.
Subject(s)
BCG Vaccine/adverse effects , Disease Outbreaks , Lymphadenitis/chemically induced , Vaccination/adverse effects , Adverse Drug Reaction Reporting Systems , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Infant , Lymphadenitis/epidemiology , Male , Sentinel Surveillance , SingaporeABSTRACT
In this manuscript, we present a simple and reliable method for the quantitation of para-aminohippuric acid (PAH; 2-(4-aminobenzamido)acetic acid) in human plasma and urine using liquid chromatography coupled to electrospray ionisation low-energy collision-induced dissociation tandem mass spectrometry (HPLC-ESI-CID-MS/MS) analysis (negative ion mode) via multiple reaction monitoring (MRM). Sample preparation involved protein precipitation of plasma samples with acetonitrile and subsequent dilution of urine samples with the mobile phase. The internal standard (IS) adopted was para-aminosalicylic acid (PAS; 4-amino-2-hydroxybenzoic acid). Chromatographic separation was achieved on a Cosmosil HILIC column using an isocratic mobile phase consisting of ammonium acetate buffer (20mM) and acetonitrile (45:55, v/v) at a flow rate of 200microl/min. The transactions monitored were m/z 192.9-->149.1 for PAH and m/z 152.1-->108.1 for IS. Linear calibration curves were generated over the PAH concentration range of 0.2-100mg/L in human plasma and urine. The method was validated for selectivity, accuracy, precision, recovery and stability according to USFDA criteria, and has been successfully applied to a pharmacokinetic study in healthy volunteers administered an intravenous dose of 440mg PAH.
Subject(s)
Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , p-Aminohippuric Acid/blood , p-Aminohippuric Acid/urine , Acetonitriles/chemistry , Aminosalicylic Acid/chemistry , Drug Stability , Humans , Least-Squares Analysis , Linear Models , Reproducibility of Results , Sensitivity and Specificity , p-Aminohippuric Acid/pharmacokineticsABSTRACT
This study explored how study design influences the probability of selecting a 'true' covariate from two competing covariate models. The probability of selecting the 'True Model' (lean body weight on clearance) over the 'False Model' (total body weight (WT) on clearance) was compared for designs where WT was either lognormally distributed (i.e. non-stratified), or stratified into 3 equal strata. The probability of selecting the 'True Model' increased as the WT inclusion criterion widened, and was always greater under the stratified design. Incorporating stratification into study designs, in combination with a wide covariate range, can aid identification of true parameter-covariate relationships. This has particular importance if the model is to be extrapolated beyond the studied population (e.g. dosing in obesity).
