Seasonal flu vaccine: Overview of vaccine regulation and safety monitoring and investigation into adverse events following 2010 seasonal influenza vaccination in young children
Attachment C: Analysis of reports from Western Australia of convulsion following administration of seasonal trivalent influenza vaccine 2010
This document provides a quantification of all Western Australian reports of convulsion/febrile convulsion following seasonal influenza vaccination in 2010 known to the TGA as at close of business 7 May 2010, with an analysis of clinical presentation and causal relationship with the vaccine.
This particular analysis was undertaken because a potential safety signal was first identified in WA and that State has been the largest source of reports of convulsion as a suspected adverse event following immunisation (AEFI) with seasonal influenza vaccine. In addition, WA health authorities have submitted medical records for many of their reports, providing much more comprehensive clinical information than is available from across the other jurisdictions.
In addition, an analysis of reports Australia-wide is also being undertaken. The findings from that analysis will be provided in a second report. It should be noted that the extent of clinical information for cases from jurisdictions other than WA is somewhat less comprehensive than that made available for reports from WA.
WA has historically provided a state-funded childhood seasonal influenza vaccine program for all WA children aged 6 months to < 5 years. WA Health suspended this year's program on 22 April 2010 with the reason that more than 40 children had experienced febrile convulsions following vaccination for seasonal influenza in March and April this year. It had been determined by WA Health that the number of presentations to emergency departments for febrile illnesses and, in particular, febrile convulsion in WA over March-April was higher than would be expected from historical records for 2008 and 2009, despite similar uptake of vaccine in 2009 and 2010.
At the time the WA program was suspended, the TGA had received 25 spontaneous reports (including 2 duplicate reports) of convulsion in children under the age of 10 yrs Australia-wide. Of these, 16 reports (including 2 duplicate reports) had been submitted from WA - 14 had been received by the TGA as recently as 20 April 2010. In comparison, in the first 6 months of 2008 the TGA had received a total of 5 reports of convulsion in association with administration of seasonal influenza vaccines in children aged 0 to 10yrs (none from WA) and in the first 6 months of 2009 only 1 report (none from WA) was received for the same cohort.
The seasonal influenza vaccine used for WA's 2010 program was a trivalent formulation comprising the H1N1 2009 strain (A/California/7/2009), the H3N2 strain (A/Perth/16/2009) and a B strain (B/Brisbane/60/2008). Such vaccine is available via 3 vaccine manufacturers - CSL (Fluvax® and Fluvax Junior®), Sanofi Pasteur (Vaxigrip®, Vaxigrip Junior®), and Solvay (Influvac®).
These same vaccine types have also been supplied under the National Immunisation Program (NIP) for all children and adults aged 6 months to 64 years who have underlying medical conditions that put them at increased risk of complications from influenza. It became apparent, subsequently via email exchanges and at a National Immunisation Committee (NIC) meeting held on 22 April 2010, that health authorities in several other jurisdictions (South Australia and Victoria) had been observing higher than expected rates of reporting of AEFIs in children under the age of 5yrs, particularly cases of fever and vomiting.
Subsequently, on 23 April 2010 the Commonwealth's Chief Medical Officer suspended the use of seasonal influenza vaccine under the NIP for children 5 years and under. It was agreed by the Australian Health Protection Committee (AHPC) that DoHA's Office of Health Protection (OHP) and the TGA would work collaboratively with States and Territories to collect information as follows:
- each jurisdiction was to complete a standardised template to provide data on:
- seasonal influenza vaccine distribution;
- AEFIs reported in children from 6 months to 10 years of age since 1 March 2010; and
- presentations at emergency departments of large metropolitan paediatric centres by children aged 6 months to 10 years with fever and/or febrile convulsions for the period 1 March to 30 April in the three years 2008, 2009, and 2010.
- each reporter of an AEFI case of seizure/convulsion was asked to obtain follow-up clinical information in a standardised format (similar to that used for surveillance during the 2009 Panvax rollout) for submission to the TGA.
In addition, on 29 April 2010 the TGA requested that WA send photocopies of the medical case notes of children with febrile convulsions to the TGA for analysis.
For this review the TGA ADRS database was searched using the 'Reporter' software to identify all reports of convulsion occurring in children aged 10 years or less for 2010. The search captured all reaction terms that mapped to 'convulsion' plus 'status epilepticus'. This broad approach was used to capture reports of febrile convulsion that may have been miscoded or misreported as other types of convulsion. A cut-off date of COB 7 May 2010 was chosen to allow sufficient time for the assessment and investigation of the individual reports by the TGA, which included collation, reconciliation and review of clinical information submitted to the TGA.
The TGA's ADRS cases were then reconciled with:
- the 2010 cases identified in the spreadsheets submitted by each State and Territory;
- information contained within the follow-up clinical information documents sent in by each AEFI reporter (where available); and
- in the case of reports from WA, clinical case/medical records (where submitted).
As at COB 7 May 2010 there were 73 reports of convulsion in children aged 10 years or younger associated with seasonal influenza vaccination on the TGA's ADRS database. These reports have been received and assessed by the TGA and included on the ADRS database as cases of convulsion based on the TGA's assessment of the information provided.
The vast majority of reports were generated through the public health system, with contributions from the Infection Control Unit at the Princess Margaret Hospital (PMH) (28 reports), with a further report from a specialist at PMH; WA Health (27 reports); and Fremantle, St John of God and Mt Tom Price Hospitals (1 report each). The remaining reports were from GPs or medical centres (10 reports); the AME Line (2 reports - both parental); and directly from parents (2 reports).
One of the reports (ADRS No. 264165) had already been identified as a duplicate and denoted as such in the database. A further 6 reports (ADRS Nos 265168, 265516, 265744, 265762, 265835, 265859) were found to be duplicates during the course of this investigation. When the duplicates are accounted for, there are 66 unique cases of convulsion. These cases are discussed in detail in section 5.
In comparison, at the same date there were 116 reports Australia-wide on the TGA ADRS database. Of these 7 were the duplicate reports from WA and there were a further 2 duplicates reports - one from Victoria (ADRS No. 265272) and one from SA (ADRS No. 265284), giving 107 unique reports distributed across the jurisdictions as follows:
|Jurisdiction||Number of unique reports|
Figure 1 shows the cumulative number of reports of convulsion over time for both WA and Australia. It includes the duplicates, to give a sense of how many reports the TGA had received and when. It shows a relatively low reporting rate up to 20 April 2010, when WA submitted a batch of 14 reports, and then a further marked increase from 27 April through 30 April (once again largely due to reporting activity in WA). Thereafter, the reports from WA plateau whereas reporting continued from other states and territories as cases were identified by them.
Medical records/case notes have been made available for 38/66 (57.6%) of the unique cases1 and clinical follow-up information for an additional 18/66 (27.2%) cases. Only 10/66 (15.2%) cases had no follow-up information available for review - 7 of these were from GPs or medical centres (ADRS Nos 264879, 265750, 265757, 266136, 266140, 266196 and 266575); 2 were from parents (ADRS Nos 265921 - via AME Line - and 266318); and 1 was reported by WA Health (ADRS No. 265337). ADRS No. 265337 was lodged via the web and contained scant information and did not identify the source of the case. Interestingly, this case does not appear on any of the spreadsheets submitted subsequently by WA Health, even though the lodgement date preceded the compilation of the spreadsheet.
Of the 66 unique cases in WA, 42 (64%) occurred in males, 23 (35%) in females and gender was unknown in 1 (1%). This is in keeping with the known predominance of febrile convulsions in males. Age ranged from 6 months to 9 years, with a median age of 1 year. The age distribution (Figure 2) shows that more than 80% of cases were aged 2 years or younger and 90% of cases were aged 3 years or younger. Note this was a fairly crude analysis using ages in years as calculated by the TGA ADRS database. Time constraints precluded the calculation of ages in months, calculation of average age and presentation of data by 6-month age intervals.
Time to onset of event ranged from 3 to 72hrs (mean 9hr; median 7hr) and more than 80% of cases had onset of the seizure event in ≤12hrs of vaccination. It is known that fever typically occurs within 6 to 12 hours in a significant proportion of children under the age of 3 years following their first influenza vaccination. However, in this particular series of cases (where more than 90% of children were aged 3 or less), 20/66 (30.3%) actually had onset within ≤ 6 hours of vaccination. In addition, 32/66 (48.5%) had onset in >6-12 hours; and 5/66 (7.6%) >12 hours after vaccination. Time to onset was unknown in 9/66 (13.6%) cases.
The brand of the vaccine used was known in 60/66 cases and all of these received Fluvax® or Fluvax Junior®. Batch numbers were available for 51 cases. A total of 23 different batches were implicated, but two batches - 27102 and 27801 - accounted for more than half of those cases (38 in total). A more complete summary of the brand and batch data can be found in Tables 1-3 where Australia-wide data are also documented.
Previous seasonal influenza vaccination history was unknown in 18/66 (27.2%) cases, 34/66 (51.5%) cases had no previous vaccination with seasonal influenza vaccine and only 14/66 (21.2%) cases had received a previous vaccination.
During the reconciliation process it became apparent that WA Health had identified 18 more cases of convulsion than appeared on printouts from the TGA's ADRS database. Of these 18 cases, 11 were listed in the spreadsheet with data lock date of 28 April 2010 submitted by WA Health (5 of these also had case notes submitted to the TGA by WA Health); 6 were only identified amongst case notes submitted to the TGA by WA Health and the remaining case was identified on the PMH's detailed spreadsheet.
Key points to note in the 18 additional cases are:
- a report had been received and coded by the TGA for 8 of the 18 cases but there had been no mention of convulsion in the initial report. Consequently these cases did not appear in printouts of database reports of convulsion.
Four of these 8 cases were reported by the Infection Control Unit at PMH, of which 3 (ADRS Nos 265104, 265109, 265114) did not have any additional information. Of note, none of these cases appeared on the PMH spreadsheet and, in the absence of any other corroborating information, it would appear they had been misidentified in the original spreadsheet sent by WA Health. The fourth report from PMH (ADRS No. 265120) also had no mention of convulsion but this case appeared in the PMH spreadsheet. Furthermore, a clinical follow-up document and emergency department (ED) notes were available to the TGA for review. Of interest, the clinical follow-up document noted the parents had stated there was shaking with tonic-clonic activity. However the ED Dr's notes state "developed fever and shaking....°LOC/ tonic-clonic activity" and the diagnosis by the doctor was "high fevers" with no mention of febrile convulsion. This reviewer has interpreted the ED Dr's annotation as meaning there was no loss of consciousness and no tonic-clonic activity. It is not clear whether the information contained within the clinical follow-up document was obtained from a separate 'look-back' interview of the parents or was based on a transcription of the ED medical notes, in which case there has probably been a misinterpretation of the ED Dr's notes. Thus, this case cannot, based on the currently available information, be considered to have been medically corroborated and the diagnosis of febrile convulsion is quite insecure.
A fifth case (ADRS No. 265934) appeared on the WA Health spreadsheet as a case of febrile convulsion. However, the clinical follow-up documentation received made no mention of convulsion and corroborated the original report of fever and vomiting. WA Health subsequently advised by email on 8 May 2010 that the final diagnosis for this case was rigors and not febrile convulsion.
Two of the 8 cases (ADRS Nos 266443 and 266461) had presented to St John of God Hospital. They did not appear on the spreadsheet sent initially by WA Health but case notes were sent to the TGA. Neither of the original reports mentioned convulsion and the description from the case notes clearly indicates that no convulsion had occurred. WA Health subsequently advised via email on 19 May 2010 that paediatricians had reviewed these cases and concluded they were not cases of febrile convulsion.
The final case (ADRS No. 265269) was originally reported by a medical practice as a case of fever, lethargy and anorexia. However, the clinical follow-up information document referred to a convulsion as well. Whilst the patient identifier and geographical location were able to be reconciled with the original report, the dates of vaccination and the event stated in the follow-up document were different from those in the original report, suggesting a transcription error had occurred at some point (either in the original report or in the follow-up document). This reviewer decided to err on the side of being conservative and include this as having been a case of convulsion, albeit of low diagnostic security.
- suspected AEFI reports for 4 of the 18 cases had been received and coded by the TGA but the neurological features described in those reports were not considered by the coder to represent a convulsion.
ED medical records were available for all 4 cases. In one case (ADRS No. 265373) the child, who had a history of chronic lung disease, presented to the ED because of high fever and respiratory distress and was observed to have a seizure whilst in the ED. Thus a diagnosis of febrile convulsion can be considered to be diagnostically secure in this case and the TGA's ADRS database will be amended accordingly. A further two cases (ADRS Nos 265118 and 265134) were discharged from the ED with a diagnosis of febrile convulsion, based on the ED Dr's interpretation of events related to them by a parent. Interestingly, in ADRS No. 265134 it was noted that, although the main symptom was "shaking legs", it was acknowledged within the history taken by the Dr that the child was in a sleeping bag and it was difficult to see what was actually happening, suggesting there could be some doubt about the diagnosis in that case. In the final case (ADRS No. 265152), both the original report and ED case notes point to localised myoclonic jerks and, therefore, this is not considered to be a case of convulsion, despite it appearing on the WA Health spreadsheet. Also, the child was aged 10 yrs and therefore outside of the typical age range for a diagnosis of febrile convulsion.
- 6 of the 18 cases (Joondalup Health Campus (JHC) cases 1, 2, 3 and 4; pt NW and pt HA) had not been reported to the TGA at all.
Case notes were submitted for each of the JHC cases. Three of these, JHC cases 1, 2 and 4, all had a discharge diagnosis of febrile convulsion based on the history obtained by the ED registrar from a parent. However, for JHC case 2 there was no temporal relationship to the seasonal influenza vaccine, with the vaccination having occurred some 2 weeks earlier and the child had developed an URTI in the intervening period anyway. WA Health subsequently advised via email on 19 May 2010 that paediatricians had reviewed this case and concluded it was not a case of febrile convulsion. Also, for JHC case 3 the diagnosis was less secure, with the registrar recording a diagnosis of "?fever related to flu vac, ?seizure". This reviewer has accepted it may be a case of convulsion, as it would be reasonable to expect that the paediatricians reviewing JHC case 2 would have also reviewed the other cases from JHC and, in the absence of advice to the contrary, confirmed them as cases of febrile convulsion.
Of the 2 remaining cases, one (pt NW) had been identified on the WA Health spreadsheet of 28 April 2010. A clinical information follow-up document had also been submitted and indicated the child had been reviewed at an ED. However the clinical information follow-up document contained minimal information, did not document the child's temperature or who had actually observed the seizure and did not document what the ED discharge diagnosis had been. Thus the diagnosis of febrile convulsion is less secure in this case. The final case (pt HA) was identified from the PMH spreadsheet. No other information is available for assessment and therefore the diagnosis of febrile convulsion is also considered to be less secure in this case. However, it must be acknowledged that cases on the PMH spreadsheet were or will be reviewed by staff specialist paediatricians at PMH. In the absence of advice to the contrary from WA Health, this case has been counted as a case of febrile convulsion at this point in time.
Based on the assessment above, this reviewer considers there were an additional 10 cases (ADRS Nos 265118, 265120, 265134, 265269 and 265373; JHC cases 1, 3 and 4; and pts HA and NW) that can be considered to represent reports of convulsion of varying degrees of diagnostic certainty that should be assessed from a causality view point. The remaining 8 (ADRS Nos 265104, 265109, 265114, 265152, 265934, 266443, 266461 and JHC case 2) can be considered not to be cases of febrile convulsion.
This section presents a reconciliation of all 84 suspected cases of convulsion in children under the age of 10 that are known to the TGA by virtue of either having been coded as such on the TGA ADRS database (66 cases) or having been drawn to the attention of the TGA during the analysis of WA spreadsheets and case notes (18 cases). The following summary should be read in conjunction with Figure 3.
Figure 3 depicts these cases from the viewpoint of both the security of the diagnosis of febrile convulsion and causal relationship to the seasonal influenza vaccine. The information within the figure is located within two parts separated by a broken horizontal line. Cases appearing in boxes above the broken line have been assessed as either definitely not a febrile convulsion or not having been medically corroborated (little diagnostic security). These cases have not been subject to a causality assessment.
The cases below the broken line are arranged from right to left in order of decreasing diagnostic security: those where the seizure was witnessed by a medical or allied health professional represent the highest diagnostic security; those where the child was reviewed and a diagnosis of febrile convulsion made in an ED department are the next most secure; and those where a GP or medical centre has simply reported that a febrile convulsion has occurred having lower diagnostic security (for reasons outlined in further discussion below).
Within the groupings of diagnostic security, cases have been sub-grouped according to presence or otherwise of other factors, such as intercurrent infection, concomitant administration of other vaccines or an underlying seizure disorder, to which the event could also reasonably be attributed. Where such other factors were present, the causal relationship between the seasonal influenza vaccine and febrile convulsion would be possible2. These cases appear in unshaded boxes. Where no other factors are present and the seasonal influenza vaccine is therefore the sole suspected agent, the cases would be assigned a causality rating of very likely. These cases appear in the shaded boxes at the bottom of the figure. The shading of boxes is graduated to give a sense of the level of diagnostic security, with the darkest shading being the more secure.
Two of the 84 reports are in children aged more than 5 years and in both cases there were other factors present that would also preclude a diagnosis of febrile convulsion. In one case occurring in a child of 9 years of age (ADRS 265168), the child in question has suffered from a known seizure disorder (with abnormal EEG) since an episode of viral encephalitis in 2006. The seizure activity had been poorly controlled in the last 6 months and, as recently as February this year, the parents had resisted increasing the child's dose of antiepileptic medication. In the second case (265152) the child was aged 10yrs and had presented with myoclonic jerks in his right arm (see also section 4).
There were 82 cases in children aged 5 years or younger, 19 of which have been assessed as not having experienced a febrile convulsion. Of these exclusions, 11 were notified to the TGA by WA Health - 6 on 8 May 2010 (ADRS Nos 265862, 265868, 265900, 265903, 265934 and 265984) and 5 on 19 May 2010 (ADRS Nos. 265977, 266325, 266443, 266461 and JHC case 2). In addition, this reviewer considers a further 8 cases should be excluded. Three of these (ADRS Nos 265104, 265109 and 265114) were discussed as cases where convulsion was not mentioned in the original AEFI report to the TGA and having probably been erroneously included in the WA spreadsheet of 28 April 2010. Of the other 5 cases, the clinical follow-up document for ADRS No. 265368 indicated that, after discussion with a parent who reported the convulsion, the paediatrician at PMH had concluded that seizure occurrence was unlikely (Note: this case did not appear on the PMH spreadsheet). In the second of these 5 cases, duplicate reports were received via the AME Line (parental report - ADRS No. 265744) and WA Health (PMH) (ADRS No. 265865). In this case the child had presented with a suspected febrile convulsion 3 weeks earlier and on that occasion been diagnosed with viral infection. On the day of the seasonal influenza vaccination the parents reported that they had later found the child to be "burning up", limp, unresponsive and cyanosed. No seizure was actually observed and they merely suspected that another convulsion had occurred. A plausible alternative diagnosis in this situation would be hypotonic-hyporesponsive episode. The medical records for this case have not been made available for review at this point in time.
In the third of the 5 cases (ADRS No. 265883), which was a report from a parent that was submitted via an immunisation clinic, the convulsion was described as spasm and flicking of the left arm (opposite side of vaccination), followed by a period of flaccidity. There was no mention of loss or alteration of consciousness and, indeed, the child was noted to be screaming/crying. There was no presentation to hospital and consequently no medical corroboration either. In the fourth of the 5 cases (ADRS No. 266318) a parent reported fever, convulsions, vomiting, rash and listlessness in her child who was admitted to PMH the same day as vaccination with the seasonal influenza vaccine. This case does not appear on the either WA Health spreadsheet or PMH spreadsheet, from which this reviewer has concluded that the diagnosis on admission/discharge from PMH was not a convulsion. Not surprisingly, no follow-up clinical information or case notes have been received for this report. In the last of the 5 cases (ADRS No. 265372) there was conflicting information as to whether the seizure was witnessed or not. The initial report stated that the child had a seizure at home witnessed by the mother. However, the ED case notes state that the presenting history was that child had fevers, was grunting and lethargic and that the mother was worried as the child may have had a seizure as he was prone to febrile convulsions. The ED Dr's provisional diagnosis was post Fluvax fever, query febrile convulsion. The discharge summary stated "child found drowsy and confused and mother concerned child was post ictal (although no seizure actually seen)". In this reviewer's opinion the documented symptoms were very non specific and could well have been a manifestation of high temperature alone and, in the absence of a witnessed seizure, a diagnosis of febrile convulsion is not supported.
Of the remaining 63 cases:
- 16 had a seizure that was actually witnessed by a medical or allied health professional (e.g. ED nurse or ambulance officer). These cases can be considered to have a secure diagnosis of convulsion. Medical records were received by the TGA for all but 2 of these cases (ADRS Nos 264879 and 265947).
- 31 cases had a seizure that was witnessed by a parent and in 16 cases the seizure witness was not identified. Combined, these 47 cases can be considered somewhat less secure diagnostically than those where the seizure was observed by health professionals. However, it must be recognised that the vast majority of febrile convulsion are only ever observed by parents and a final diagnosis is made by medical professionals on the basis of a history obtained from the parent(s) some time after the event. In this regard it has to be noted that 38 of the 47 cases presented to an ED for review and 7 of the 47 were the subject of a report from a GP/medical practice, where presumably the practitioner or a nurse had taken a history from a parent some time after the event and reached a diagnosis of febrile convulsion. Medical records were submitted for analysis for 28 of the 38 cases that presented to ED. However, no clinical information other than a clinical follow-up document for ADRS No. 265269 has been received for any of the cases that were reported by GPs or private medical practices. This is of significance because as a group the GP reports were of low quality, often merely stating that a "febrile convulsion" had occurred without providing any description of the event (in terms of level of consciousness, motor manifestations, recorded temperature etc) to allow an independent assessment of the diagnosis. Another two cases (ADRS Nos. 265120 and 265892) presented to ED but in the mind of this reviewer must be considered not to have been medically corroborated and thus appear within the box for that category in Figure 3, leaving 36 cases discussed under subsection (b), below. ADRS 265120 is discussed in section 4. For the case described in ADRS No. 265892, the follow-up clinical information document describes a child waking from sleep disorientated, shivering, with a temperature to 40.0oC. A convulsion was stated to have occurred half an hour later, following which he was taken to the ED. A second convulsion was said to have occurred in the ED but was again witnessed only by the parents. The ED triage notes refer only to "vomiting and rigoring" and the ED doctor's notes referred to shivering and shaking uncontrollably and a degree of uncertainty was expressed as to whether a convulsion had occurred - "?seizure/ ?rigor". There was no record of any seizure having occurred in the ED. The recorded diagnosis was "Post immunisation fever/?feb convulsion".
- 2 cases (ADRS Nos 265337 and 265921) did not present for medical review and have not been medically corroborated.
A total of 16 cases have been reported where the seizure was observed by a medical or allied health professional. Of these, 14 occurred either in the ED or whilst the child was admitted to hospital, one (ADRS No. 265149) was observed by the child's parents who are both doctors, and one (ADRS No. 264879) was observed whilst the child was at a nursing clinic.
Two of the 16 cases were afebrile in the sense that the highest temperature recorded was well below 38.0°C, which is the threshold used in the standard definition of febrile convulsion3. In one of these (ADRS No. 264879), a 6 minute seizure was witnessed by staff at a nursing clinic who administered midazolam and oxygen. Later the child was evacuated to Derby Hospital where the final diagnosis was that of a non-febrile convulsion (temperature had been recorded as 37.5°C) and URTI. In the second of such cases (ADRS No. 265607), the highest temperature recorded was 37.2°C. This child was reported to have experienced 5 seizures, several of which were witnessed while the child was in hospital. Temperatures recorded at the time of two of the seizures were 36.0 and 37.2°C, respectively. Of note, this patient had a known history of absence epilepsy for which he was receiving Tripletil. He had been admitted to hospital in March 2010 for management of seizures following multiple presentations to ED with up to 7 seizures per episode. An MRI had shown anterior band heterotopia which can be associated with epilepsy. Importantly, the seizures observed in hospital were confirmed by parents as being of the same character as the child's usual absence seizures, which would suggest a more likely causality related to the underlying seizure disorder.
In the remaining 14 of 16 cases, all were found to have temperatures in excess of 38.0°C:
- 1 of these cases (ADRS No. 265113) was also vaccinated with Varilix® at the time he received Fluvax® and, thus, the causal association of the febrile convulsion with Fluvax® is, at best, possible.
- 5 of the remaining 14 cases had intercurrent infection, which offer a plausible alternative causal explanation for the febrile convulsion. The causality for these cases is, therefore, only possible:
- in ADRS No. 265160 the child had symptoms of a URTI at the time of vaccination and on review in ED was found to have inflamed tympanic membranes and throat, a crusted nose and cervical lympadenopathy;
- in ADRS No.265338 the child had been found febrile and lethargic by her parents and was observed to have a prolonged seizure in ED where treatment with midazolam and phenytoin was required. The child experienced ongoing metabolic acidosis and hypoglycaemia and was subsequently found to have extensive brain ischaemia on MRI scanning. The child had previously had a 4 week history of cough and 1 week history of rhinorrhoea. She later tested positive for rhinovirus and RSV whilst undergoing treatment in hospital;
- in ADRS No. 265379 a child with a known seizure disorder following an episode of encephalitis in 2007 presented to ED following a generalised tonic-clonic seizure of 1.5min duration and was observed to have a second seizure whilst in the ED. These seizures were quite different from those normally experienced by her, suggesting that this was not a presentation of the underlying seizure disorder. However, it is of note that the child had been unwell for a week with an URTI, which could have contributed to the fever of 39.1;
- in ADRS No. 265840 a child presented to ED 3 days post vaccination because of ongoing abdominal pain, fever and rigors which predated the vaccination and was observed to have a seizure whilst in the ED (at which time her temperature was 38.1°C). She was subsequently found to have an E coli urinary tract infection on MSU culture; and
- in the final case (ADRS No. 265870), the child had a seizure witnessed in ED where he had presented because of fever and malaise for several days with what was diagnosed as a viral URTI. Examination in the ED revealed the child had inflamed tonsils, pharynx and tympanic membranes as well as cervical lymphadenopathy.
- 8 of the remaining 14 febrile cases (ADRS Nos. 265110, 265149, 265373, 265596, 265741, 265946, 265947 and 266382) had no evidence of concurrent disease or exposure to other vaccines, medicines of chemicals that would offer an alternative causal explanation for the febrile convulsion. Medical records were available for 7 of these 8 cases (the exception being ADRS No.2659474) and provide robust evidence of both the diagnosis of febrile convulsion and the absence of other likely causative agents. Thus, in these cases a causal relationship to the seasonal influenza vaccination is highly likely. With regard to ADRS No. 265947, a seizure was said to have been witnessed in the ED of PMH, with a temperature of 38.0oC. This patient is known to be immuno-compromised as a consequence of treatment with anti-rejection medication following a liver transplant for a metabolic disorder in 2008. The metabolic disorder had presumably been corrected as a result of the liver transplant, so the only alternative cause would be infection secondary to immunosuppression. However, there was no indication of this in the information received to date and the vaccination remains the sole suspected agent. Of note, however, this case does not appear on the PMH spreadsheet (although it did appear on the WA Health spreadsheet), so it is possible that on receipt of further information this case would be reclassified to one of only a possible causal relationship with the influenza vaccine.
There were 38 cases where a parent(s) was the only witness of the seizure, following which they presented to an ED, two of which were considered not to have been medically corroborated (ADRS Nos 265120 and 265892).
Of the remaining 36 cases, in one case (ADRS No. 265994) a 1-year-old child with a previous history of febrile convulsions presented to ED following a convulsion that was witnessed by the mother 12 hours after vaccination. No temperature recordings were available from either the initial report or the clinical follow-up information document. Ordinarily, one would expect that a parent might not have access to a thermometer, or think to take the child's temperature at the time of witnessing a febrile seizure but in most cases would relate the fact that the child was hot or "burning up". However, in this particular case, the mother had specifically stated the child did not have a temperature and was not hot to touch, suggesting that this was an afebrile seizure. Of note, there was a family history of convulsions. No medical records were available to allow further assessment of the case.
28 of the 36 cases presenting to ED had a temperature in excess of 38.0°C. Of these:
- 6 cases (ADRS Nos. 265107, 265134, 265162, 265664, 265974 and 266380) received vaccination with concomitant vaccines at the time they received Fluvax® and, thus, the causal association of the febrile convulsion with Fluvax® is, at best, possible. Two cases received more than one concomitant vaccine - ADRS No. 266380 received Hib/MMR/Men C and ADRS No. 265162 received Infanrix® and Prevanar® as well. The most common concomitant vaccines were Infanrix-Hexa® and Varilix® (2 cases each), with hepatitis B vaccine, Prevanar®, and Hib/MMR/Men C with once case each.
- 4 cases had intercurrent infection, which offers a plausible alternative causal explanation for the febrile convulsion. The causality for these cases is, therefore, only possible:
- in ADRS No. 265141 the mother reported the child had a runny nose, cough and puffy eyes and the child was found to have throat inflammation on examination, suggestive of a viral URTI;
- in ADRS No. 265611 the child had recently been receiving antibiotics for the treatment of pneumonia5;
- in ADRS No. 265879 a child receiving high dose steroids for chronic lung disease presented to ED at PMH with fever, shortness of breath, difficulty breathing and convulsions. Two days later RSV infection was diagnosed. Of note, this case does not appear on the PMH spreadsheet; and
- in JHC case 4, the child was noted to have rhinorrhoea and the paediatric registrar at JHC made a diagnosis of "febrile convulsion with viral infection ?post immunisation".
- 18 cases (ADRS Nos 265112, 265116, 265118, 265138, 265339, 265364, 265586, 265592, 265849, 265895, 265942, 265948, 265987, 265991, 266319, 266381, JHC case 3 and pt HA) had no evidence of concurrent disease or exposure to other vaccines, medicines or chemicals that would offer an alternative causal explanation for the febrile convulsion, under which circumstances a causality rating of 'very likely' would apply. Medical records were made available for 16 of these cases (the exceptions being 265991 and pt HA) and provided varying degrees of detail in that some provided quite detailed descriptions of the characteristics of the motor manifestations and level of consciousness and investigation undertaken to exclude other causes, whereas in others simply stated "had febrile convulsion". In the case of the latter, it has to be accepted that the diagnosis of febrile convulsion based on the history obtained from the parents by medical professionals experienced in the assessment of such cases. However, some cases require further comment:
- in ADRS No. 265116 it was difficult to reconcile the initial report from the PMH infection Control Unit, which stated a second seizure occurred in ED, with the ED notes that made no reference to a seizure in the ED;1 There was conflicting information from different sources as to the underlying infection. The report from PMH referred to URTI, whereas the clinical follow-up information document referred to pneumonia.
- in ADRS No. 265849 there was no record of an MSU having been collected in the child who had a history of vesico-ureteric reflux and recurrent urinary infections;
- in ADRS No.265942 the mother of the child reported that the child had been pulling at his ears for several days prior to vaccination but had no fever until after the vaccination. The right ear drum was found to be red on examination in ED but it was not bulging and antibiotics were not prescribed and there was no mention of URTI in the discharge diagnosis; and
- one further case (ADRS No. 265364) had an underlying absence seizure disorder as well as a very complex medical history that included a pineal cyst, growth hormone deficiency and Arnold Chiari malformation with gastrostomy and jejunostomy. As recently as 3 days prior to vaccination she had experienced an absence seizure. However, the seizure described on the day of influenza vaccination was generalised and tonic clonic in character, which is quite different to the underlying seizure disorder and, according to the mother, of the same character as during a recent hospital admission (discharge 10 days prior to the vaccination) for febrile convulsion secondary to sepsis of unknown origin. The underlying seizure disorder appears not to be a contributory factor in this case and the possibility of an infective cause also appears to have been ruled out by the presence of a normal blood count and no growth on blood cultures.
Of the remaining 7 cases in this group of 36, 5 cases (ADRS Nos. 265106, 265856, 265880, 265898 and pt NW) did not have a temperature recorded but in all cases were reported by the parent to have a fever or be hot to touch. In the other 2 cases (ADRS No. 265108 and JHC case 1) the recorded temperature at presentation to ED was above 37.5°C. Two of the 7 cases (ADRS Nos 265856 and 265880) received concomitant Varilix®at the time they received Fluvax® and, thus, the causal association of the febrile convulsion with Fluvax® is, at best, possible. ADRS Nos 265106, 265108, 265898, JHC case 1 and pt NW had no evidence of concurrent disease or exposure to other vaccines, medicines of chemicals that would offer an alternative causal explanation for the febrile convulsion, under which circumstances a causality rating of very likely would apply.
All 7 reports where information has been obtained solely from GPs (ADRS Nos 265269, 2265750, 265757, 266136, 266140, 266196 and 266575) offered scant information and in the case of ADRS No. 265269 there was conflicting information in that the original report made no mention of a convulsion (see earlier discussion under section 4). None of the reports had any other apparent contributory factors such as intercurrent illness or other vaccines/medicines. Only 3 of the cases (ADRS Nos 265750, 265757 and 265269) included a recorded/ documented fever of ≥ 38.0°C.
Four cases were not medically corroborated. ADRS Nos. 265120 and 265892 have been discussed previously. Of the other reports in this classification, one (ADRS No. 265337) was reported by WA Health via the web and contained scant information and did not identify the source of the case. Interestingly, this case does not appear on any of the spreadsheets submitted subsequently by WA Health, even though the lodgement date preceded the compilation of the spreadsheet. In the second case (ADRS No. 265921), a parental report via the AME Line, the child was stated to have had a "convulsion" while "blisteringly hot" in which the shoulders were contracted and the knees drawn every 15 to 30 secs. This does not appear to have the frequency of repetitive movement one would associate with a convulsion and there was no apparent loss of consciousness. In the absence of medical corroboration and/or additional information in either of these cases, the diagnosis of febrile convulsion is somewhat doubtful and no assessment of causality has been made.
On the basis of a review of all information available, there were 57 cases of febrile convulsion in children under the age of 5yrs reported to the TGA as at close of business on 7 May 2010, 38 of which are very likely to be causally related to vaccination with the seasonal influenza vaccine. A further 19 cases are only possibly causally related to the vaccine because they can also be explained by the use of concomitant vaccines and/or concurrent infection. Fluvax® or Fluvax Junior® was used in all 54 cases where the brand of the seasonal influenza vaccine was known.
Of the 57 cases of febrile convulsion, 15 can be considered to have the highest diagnostic security on the basis that they were observed by a medical or allied health practitioner. Of these 15 cases, 8 are very likely to be causally related to vaccination with the seasonal influenza vaccine and 7 are only possibly causally related to the vaccine because they can also be explained by the use of concomitant vaccines and/or concurrent infection. In the remaining 42 cases the seizures were observed by parents and the diagnosis of febrile convulsion was made by a medical professional on the basis of a history obtained from the parent(s) after the event - 35 presented to an ED and 7 to a GP/medical centre. Of these 42 cases, 30 are highly likely to be causally related to vaccination with the seasonal influenza vaccine and a further 12 are possibly causally related to the vaccine because they can also be explained by the use of concomitant vaccines and/or concurrent infection.
These WA data confirm the presence of a safety signal of febrile convulsion for Fluvax® or Fluvax Junior®, demonstrating the need for risk quantification through epidemiological methods.
A cut-off date of 7 May 2010 was chosen for this review to allow sufficient time for the assessment and investigation of reports by the TGA which included consideration of the large amount of information submitted by WA Health to assist in the review of cases. Only 2 reports of convulsion from WA have been submitted to the TGA since the 7 May:
- ADRS No. 266788 was a 4-year-old male child with a previous history of seasonal influenza vaccination who had a febrile convulsion following immunisation with his first dose of Fluvax® (Batch number 26902). The seizure was witnessed by his mother and he was treated in hospital. Time to onset was 7 hours. The child's temperature was not reported. Fluvax® was the sole suspected causative agent.
- ADRS No. 267314 was a 3 year old male who was found fitting by his mother 5.5 hours after vaccination with Fluvax® (Batch number 27002). No follow-up information has been received from the reporter in response to a request from the TGA. Within the original AEFI report there was no information about the child's medical history or previous seasonal influenza vaccination history - although the reporter stated this was the "4th dose", which may reflect immunisations in previous years. It was stated that a doctor friend staying at the house gave paracetamol and tepid sponging, which is suggestive of the child having a fever although a temperature recording was not given. It is not explicitly stated that the doctor friend observed the seizure which would have increased the security of the diagnosis. On the basis of the information provided so far, Fluvax® appears to be the sole suspected causative agent.
Neither report is a duplicate of any case received to date.
Also, on 21 May 2010 WA Health advised by email (TRIM R10/104697) that a further 2 PMH cases had been re-classified as not being febrile convulsions following review by paediatricians at PMH - ADRS Nos 265104 and 265879:
- ADRS No. 265104 had been already excluded by this reviewer on the basis that the initial AEFI report did not mention a convulsion and the case did not appear on the PMH spreadsheet; and
- ADRS 265879 was considered by this reviewer to be only possibly causally related to seasonal influenza vaccine because the child had developed RSV infection shortly after the presentation to ED. No case notes were submitted for this case by the 19 May 2010 cut-off for this review and so the assessment was based on an original AEFI report and a completed clinical follow-up information document submitted by WA Health.
This gives a total of 58 cases of febrile convulsion in WA.
|WA database||AUST database|
|Range||3hr - 72hr||5min - 2 weeks|
|Mean||8.9hr||12.7hr (minus outlier 9.0)|
|Median||7hr||7.5 (minus outlier 7.25)|
|≤ 6hr||20 (30.3%)||30 (28.0%)|
|>12-24hr||4 (6.1%)||5 (4.7%)|
|NR||9 (13.6%)||19 (17.8%)|
|Batch no||51||5||7||6||4||1||-||74 (68% reports)|
|Batch no||1||1||1||2 (100%)|
- All but 2 of these cases (266319 and 266325) also had clinical information follow-up forms completed.
- The WHO categories for causality of AFEIs apply, of which the most relevant are:
Very likely - a clinical event with a plausible time relationship to vaccine administration and which cannot be explained by concurrent disease or other drugs or chemicals;
Probable - a clinical event with a reasonable time relationship to vaccine administration; is unlikely to be attributed to concurrent disease or other drugs or chemicals;
Possible - a clinical event with a reasonable time relationship to vaccine administration, but which could also be explained by concurrent disease or other drugs or chemicals;
Unlikely - a clinical event whose time relationship to vaccine administration makes a causal connection improbable, but which could be plausibly explained by underlying disease or other drugs or chemicals.
The rating 'certain' is not applicable given the circumstances of this particular investigation. 'Certain' is used in rare instances where there is a demonstration of relationship, e.g. such as mumps vaccine-related aseptic meningitis with isolation of the vaccine strain. The rating 'unrelated' applies to events where there is an incompatible time relationship. This would have been appropriate for JHC case 2, had it not been disqualified on diagnostic grounds (see section 4)
- See the following 2 Brighton Collaboration definition documents:
- Bonhoffer J, Menkes J, Gold M et al. Generalised convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis and presentation. The Brighton Collaboration Fever Working Group. Vaccine 2004; 22: 557-562.
- Marcy S, Kohl K, Dagan R et al. Fever as an adverse event following immunization: case definition and guidelines of data collection, analysis, and presentation. The Brighton Collaboration Fever Working Group. Vaccine 2004; 22: 551-556.
- A clinical information follow-up form was submitted but merely restated the information in the original report.
- There was conflicting information from different sources as to the underlying infection. The report from PMH referred to URTI, whereas the clinical follow-up information document referred to pneumonia.