Infanrix hexa and sudden death: a review of the periodic safety update reports submitted to the European Medicines Agency

There have been a number of spontaneous reports of sudden unexpected death soon after the administration of Infanrix hexa (combined diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenza type B vaccine). The manufacturer, GlaxoSmithKline (GSK), submits confidential periodic safety update reports (PSURs) on Infanrix hexa to the European Medicines Agency (EMA). The latest is the PSUR 19. Each PSUR contains an analysis of observed/expected sudden deaths, which shows that the number of observed deaths soon after immunisation is lower than that expected by chance. This commentary focuses on that aspect of the PSUR which has a bearing on policy decisions. We analysed the data provided in the PSURs. It is apparent that the deaths acknowledged in the PSUR 16 were deleted from the PSUR 19. The number of observed deaths soon after vaccination among children older than one year was significantly higher than that expected by chance once the deleted deaths were restored and included in the analysis. The manufacturer must explain the figures that have been submitted to the regulatory authorities. The procedures undertaken by the EMA to evaluate the manufacturer’s claims in the PSUR need to be reviewed. The Drugs Controller General of India nearly automatically accepts drugs and vaccines approved by the EMA. There is a need to reappraise the reliance on due diligence by the EMA

Commentary – Controversies surrounding mercury in vaccines: autism denial as impediment to universal immunisation.

In 2004, the US Center for Disease Control (CDC) published a paper showing that there is no link between the age at which a child is vaccinated with MMR and the vaccinated children’s risk of a subsequent diagnosis of autism. One of the authors, William Thompson, has now revealed that statistically significant information was deliberately omitted from the paper. Thompson first told Dr S Hooker, a researcher on autism, about the manipulation of the data. Hooker analysed the raw data from the CDC study afresh. He confirmed that the risk of autism among African American children vaccinated before the age of 2 years was 340% that of those vaccinated later.

AEFI and the pentavalent vaccine: looking for a composite picture.

Georg Christoph Lichtenberg’s reference to “a knife without a blade, for which the handle is missing” has been illustrated recently by Broomberg and Oliver Chanarin. In his work, Jokes and their Relation to the Cognitive Unconscious, Freud suggested that the “knife without a blade which has no handle” is as absurd or funny as a “frame without a picture”.

Pseudohypoparathyroidism with Diabetes Mellitus and Hypothyroidism.

We report a12-year-old child with pseudohypoparathyroidism (PHP) whose mother had pseudopseudohypoparathyroidism. The child had low serum calcium, high phosphorous and high parathormone (PTH) levels. PHP occurs due to a defect in the guanine nucleotide binding protein (G protein). She also had hypothyroidism which is known to utilize the G protein pathway. She developed T 1 diabetes mellitus (T1DM) while under follow-up. This is arguably the first time T1DM has been reported associated with PHP.

Nebulized Hypertonic-Saline vs Epinephrine for Bronchiolitis: Proof of Concept Study of Cumulative Sum (CUSUM) Analysis.

Objective: To apply cumulative sum (CUSUM) to monitor a drug trial of nebulized hypertonic-saline in bronchiolitis. To test if monitoring with CUSUM control lines is practical and useful as a prompt to stop the drug trial early, if the study drug performs significantly worse than the comparator drug. Design: Prospective, open label, controlled trial using standard therapy (epinephrine) and study drug (hypertonic-saline) sequentially in two groups of patients. Setting: Hospital offering tertiary-level pediatric care. Patients: Children, 2 months to 2 years, with first episode of bronchiolitis, excluding those with cardiac disease, immunodeficiency and critical illness at presentation. Interventions: Nebulized epinephrine in first half of the bronchiolitis season (n = 35) and hypertonic saline subsequently (n = 29). Continuous monitoring of response to hypertonic-saline using CUSUM control-charts developed with epinephrineresponse data. Main outcome measures: Clinical score, tachycardia and total duration of hospital stay. Results: In the epinephrine group, the maximum CUSUM was +2.25 (SD 1.34) and minimum CUSUM was -2.26 (SD 1.34). CUSUM score with hypertonic-saline group stayed above the zero line throughout the study. There was no statistical difference in the post-treatment clinical score at 24 hours between the treatment groups {Mean (SD) 3.516 (2.816): 3.552 (2.686); 95% CI: -1.416 to + 1.356}, heart rate {Mean (SD) 136 (44): 137(12); 95% CI: -17.849 to +15.849) or duration of hospital stay (Mean (SD) 96.029 (111.41): 82.914 (65.940); 95% CI: -33.888 to +60.128}. Conclusions: The software we developed allows for drawing of control lines to monitor study drug performance. Hypertonicsaline performed as well or better than nebulized epinephrine in bronchiolitis.

Caution needed in using oral polio vaccine beyond the cold chain: Vaccine vial monitors may be unreliable at high temperatures.

Background & objectives: Stabilized live attenuated oral polio vaccine (OPV) is used to immunize children up to the age of five years to prevent poliomyelitis. It is strongly advised that the cold-chain should be maintained until the vaccine is administered. It is assumed, that vaccine vial monitors (VVMs) are reliable at all temperatures. VVMs are tested at 37°C and it is assumed that the labels reach discard point before vaccine potency drops to >0.6 log10. This study was undertaken to see if VVMs were reliable when exposed to high temperatures as can occur in field conditions in India. Methods: Vaccine vials with VVMs were incubated (10 vials for each temperature) in an incubator at different temperatures at 37, 41, 45 and 49.5°C. Time-lapse photographs of the VVMs on vials were taken hourly to look for their discard-point. Results: At 37 and 41°C the VVMs worked well. At 45°C, vaccine potency is known to drop to the discard level within 14 h whereas the VVM discard point was reached at 16 h. At 49.5°C the VVMs reached discard point at 9 h when these should have reached it at 3 h. Conclusion: Absolute reliance cannot be placed on VVM in situation where environmental temperatures are high. Caution is needed when using ‘outside the cold chain’ (OCC) protocols.

Evidence-based National Vaccine Policy.

India has over a century old tradition of development and production of vaccines. The Government rightly adopted self-sufficiency in vaccine production and self-reliance in vaccine technology as its policy objectives in 1986. However, in the absence of a full-fledged vaccine policy, there have been concerns related to demand and supply, manufacture vs. import, role of public and private sectors, choice of vaccines, new and combination vaccines, universal vs. selective vaccination, routine immunization vs. special drives, cost-benefit aspects, regulatory issues, logistics etc. The need for a comprehensive and evidence based vaccine policy that enables informed decisions on all these aspects from the public health point of view brought together doctors, scientists, policy analysts, lawyers and civil society representatives to formulate this policy paper for the consideration of the Government. This paper evolved out of the first ever ICMR-NISTADS national brainstorming workshop on vaccine policy held during 4-5 June, 2009 in New Delhi, and subsequent discussions over email for several weeks, before being adopted unanimously in the present form.

Respiratory Viruses in Acute Bronchiolitis in Delhi.

We studied the etiology of bronchiolitis in Delhi. Respiratory syncytial virus (RSV) was the most commonly isolated virus in 72/245 infants (30%). RSV positive cases did not have more severe disease; this argues against routine use of ribavirin.

Calculating prevalence of hepatitis B in India: Using population weights to look for publication bias in conventional meta-analysis.

Publication bias can result from the propensity of researchers to document what is unusual. This can distort the inferences drawn in systematic reviews. To measure the distortion, it has been suggested that a second analysis be done; using weights proportional to the size of the population from which the samples are drawn. We re-evaluate data from a published meta-analysis on prevalence of hepatitis B in India, to see how this approach alters the results. Prevalence of hepatitis B among tribal and non-tribal populations in different States was analyzed. Weights were then assigned according to population of the State. The overall country prevalence was then calculated. Using population-weights it is estimated that the point-prevalence of hepatitis B among non-tribal populations is 3.07% [95% CI: 2.5 - 3.64]. Among tribal populations it is 11.85% (CI 10.76 -12.93). Overall prevalence was 3.70 (CI: 3.17 -4.24) (corresponding to a chronic carrier rate of 2.96%). The present analysis using population-weights has resulted in the estimated prevalence among non tribal populations increasing by 24% and that among tribal populations decreasing by 25.5% when compared to figures of the metaanalysis published earlier. The advantages and drawbacks of this procedure are discussed.

Nasopharyngeal Teratoma as a Cause of Neonatal Stridor.

We report nasopharyngeal teratoma in a term female neonate, that presented within first week of life with episodic stridor, apnea and cyanosis. Laryngoscopy revealed a mass which was confirmed by MRI. The mass was surgically excised and diagnosed as nasopharyngeal teratoma on histopathology. The child is doing well on follow-up