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Seasonal flu vaccine: Overview of vaccine regulation and safety monitoring and investigation into adverse events following 2010 seasonal influenza vaccination in young children
Attachment D: Analysis of Australia-wide reports of convulsion following administration of seasonal trivalent influenza vaccine 2010
This is the second of two reports about convulsion as an adverse event following immunisation (AEFI) with seasonal trivalent influenza vaccine in children under the age of 10 years. It provides a quantification of all reports known to the TGA as at close of business (COB) 7 May 2010, with an analysis of clinical presentation and causal relationship with the vaccine. The analysis is based on all information available to the TGA as at COB 19 May 2010.
An earlier report on cases from WA ("the Report from WA" or RWA) provided a detailed analysis of cases from that State, undertaken because a potential safety signal was first identified in WA and that State had been the largest source of AEFI reports for the trivalent seasonal influenza vaccine. In addition, WA health authorities had submitted medical records for many of their reports, providing much more comprehensive clinical information than is available from across the other jurisdictions.
This second report has been structured in a manner similar to the RWA and should be read in conjunction with the RWA, which contains the relevant background information, including the methodology employed for identification and causality assessment of cases.
As at COB 7 May 2010 there were 116 AEFI reports of convulsion in children under the age of 10 years Australia-wide on the TGA ADRS database. The WA reports are summarised in the RWA. Reports from other States and Territories are presented in this report.
Two of the reports (ADRS Nos 264165 and 265824) had already been identified as duplicates and denoted as such in the database. There were an additional 7 reports (ADRS Nos 265168, 265516, 265744, 265762, 265835, 265859 and 266295) identified as duplicates during the course of the investigation, giving a total of 9 duplicates - 7 from WA and 1 each from Victoria and SA. When the duplicates were accounted for, there were 107 unique cases distributed across the jurisdictions as follows:
|Jurisdiction||Number of unique reports|
Of the 107 unique cases Australia-wide, 63 (59%) occurred in males, 43 (40%) 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 distributions across the States and Territories and for Australia as a whole are shown in (Figure 1). Results for the ACT, Tasmania and the NT are not shown as they had only 2, 1 and 0 cases, respectively. The distributions for WA, Victoria and Qld are similar to that for Australia, which is not surprising given that these 3 States were the major contributors of cases. The numbers of cases in the remaining States were too low to provide any meaningful trends. Overall, 85/107 (79.4%) cases were aged 2 years or younger and 94/107 (88%) 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.
Times to onset of event across the States and Territories and for Australia as a whole are shown in (Figure 2). Once again, the results for the ACT, Tasmania and the NT are not shown. The distributions for WA, Victoria and Qld are again similar to that for Australia and the numbers of cases in the remaining States were too low to provide any meaningful trends.
Across the jurisdictions the time to onset ranged from 5-10 minutes to 2 weeks. There were 3 cases that have been considered as 'outliers' by this reviewer - 2 from Victoria (ADRS Nos 266280 and 266283) and 1 from Qld (ADRS No. 266569). Two of these outliers (ADRS Nos 266283 and 266569) had onset of symptoms within 10 minutes of vaccination. In the first case (ADRS No. 266283) the child was reported to have started shaking, become stiff and pale 5 to 10 minutes post vaccine. The child was reported to be awake but non responsive and to have a fever although the actual temperature was not reported. The "episode" lasted 10 minutes and the child presented to an emergency department (ED) within 20 minutes, by which time the episode (i.e. all symptoms and signs) had resolved without any treatment. The time course for this case - for a fever to develop to such a magnitude as to cause a convulsion and then spontaneously resolve - is quite unusual and therefore questionable. No clinical follow-up form or ED case notes have been received for this case. In the second report (ADRS No. 266569), a parent reported that he saw his daughter faint and hit her head 10 minutes post vaccination and then she had a convulsion. Apparently a nurse told the father the convulsion was caused by the head injury. However, in the opinion of this reviewer, this is more likely to be a case of syncopal convulsion. The third outlier case (ADRS No. 266280) was that of a 1-year-old child who developed an URTI complicated by severe asthma 2 days post vaccination and then had a febrile convulsion (with temperature at that time of 39.9oC) some 2 weeks post vaccination. This reviewer considers there is no temporal relationship between the vaccination and the febrile convulsion and there is also a confounding factor of the infection that occurred in the intervening period, so that the febrile convulsion is unrelated to the seasonal influenza vaccine.
When the outliers are excluded, the mean and median time to onset for Australia-wide cases was 9hr and 7.25hr, respectively, noting that almost 18% cases did not have a time to onset recorded (see Table 1). Very similar mean and median results were seen for the 3 largest contributing states of WA, Vic and Qld. Also, despite low numbers of cases in SA and the ACT, the mean and median times were also similar. The results for NSW were somewhat higher, largely due to the fact that 2 of the 6 cases with a reported time to onset had times to onset of 20.5hr and 48hr, respectively. 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 approximately 90% children were aged 3 or less), 31/107 (28.0%) actually had onset within ≤ 6 hours of vaccination. In addition, 50/107 (46.7%) had onset in >6 - 12 hours; and 5/107 (4.7%) > 12 hours after vaccination. Time to onset was unknown in 18/107 (17.8%) cases.
The brand of the vaccine used was known in 96 cases, 94 of which received Fluvax® or Fluvax Junior® and 2 of which received Influvac®. Batch numbers were available for 74 cases. A total of 23 different batches were implicated, but two batches - 27102 and 27801 - accounted for more than half of those cases (41 in total).
Previous seasonal influenza vaccination history was unknown in 49/107 (45.8%) cases, 41/107 (38.3%) cases had no previous vaccination with seasonal influenza vaccine and only 17/107 (15.9%) cases had received a previous seasonal influenza vaccination.
In the aftermath of the suspension of the use of seasonal influenza vaccine under the National Immunisation Program (NIP) for children less than 5 years of age, to assist the TGA in its investigation each jurisdiction was asked and agreed 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 also 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.
As a result of the abovementioned processes, 31 additional cases were identified across the jurisdictions as follows:
|Jurisdiction||Number of additional cases|
The 18 additional cases for WA were summarised in the RWA, with the conclusion that there were 10 additional cases that could be considered to represent reports of convulsion of varying degrees of diagnostic certainty that required assessment from a causality view point.
Key points of note in the 13 additional cases from other jurisdictions in this report are:
- Two cases (ADRS Nos 265453 and 265498), both from SA, had been reported by the Immunisation Section of the Communicable Diseases Branch of SA Health via the web without any mention of convulsion in the initial report. There was no indication of any motor manifestations or loss or alteration of consciousness that would indicate some sort of seizure activity. However, the spreadsheet submitted by SA Health had indicated that both patients had experienced febrile convulsions. In the absence of any follow-up information to the contrary, these reports are considered by this reviewer to be reports of febrile reactions and the spreadsheet entries to be erroneous.
- None of the remaining 11 additional cases had been reported to the TGA. These have been identified by the State or Territory in which they occurred and by a case number.
One case (SA case 1) was witnessed by an ambulance officer and required treatment with i.m. midazolam. The temperature was recorded at 39.5oC. This case can be considered diagnostically secure.
Another case (NSW case 2) was witnessed by nursing staff. However, although the child received midazolam for a presumed seizure whilst being an inpatient for a febrile reaction post vaccination, when the case was reviewed clinically it was concluded that a convulsion was unlikely to have occurred. Therefore, this reviewer considers this case was not medically corroborated.
Two remaining cases from NSW (NSW cases 1 and 3) both had ED discharge diagnoses of febrile convulsion, with recorded temperatures in excess of 39oC. The seizure witnesses were not reported for either case and have been presumed by this reviewer to be parents rather than medical or allied health professionals.
Four cases were from Victoria - 2 of these cases (Vic Cases 1 and 2) appeared in the consolidated spreadsheet titled 'Dept of Health Fluvax Report VIC 28 Apr 2010.xls'. In Vic case 1, the child was found "rigoring" and crying in her sleep by her mother and when roused the child complained of being cold. This description does not fit with that of a convulsion in that there does not appear to have been any tonic-clonic motor manifestations and no loss of consciousness. Indeed the child was able to converse with her mother to indicate she felt cold. The child was not reviewed at an ED. In Vic case 2, the child presented to an ED with a temperature of 42.0°C after an episode of "body shaking", with leaning to one side and staring gaze. The seizure witness in this case was not reported but it does not appear to have been witnessed by a medical or allied professional. Furthermore, the description of the motor manifestations is not entirely clear and the alteration of consciousness may be more in keeping with an absence type atypical febrile seizure. This reviewer decided to err on the side of being conservative and include this as having been a case of convulsion, albeit of lesser diagnostic security. The 2 remaining Victorian cases, Vic cases 3 and 4, were listed on a spreadsheet for Monash Medical Centre but did not appear on the Victorian Health Department's main spreadsheet, which casts some doubt as to whether these were truly considered to be cases of febrile convulsion. In Vic case 3, the child was aged 6 years and highest temperature recorded was 37.1°C, which would preclude a diagnosis of febrile convulsion. This child was also noted to have nasal congestion and ear pain, suggestive of an underlying URTI. Vic case 4 had no clinical information beyond a simple description of "vomiting, fever, rigors and convulsion" with a temperature of 38.5°C and no apparent underlying contributory factors. The seizure does not appear to have been witnessed by a medical or allied professional and is, therefore, diagnostically less secure.
Of the remaining 3 cases, one (SA case 2) had reasonably well described tonic-clonic motor manifestations and disturbance of consciousness, associated with a temperature of 40.2°C. The events were witnessed by a parent rather than medical professional. Another case from Tasmania (Tas case 1) was merely documented as a case of febrile convulsion with temperature of 38.3°C with no information about who witnessed the seizure. In the final case (ACT case 1) it is not clear that a seizure even occurred. It was merely recorded that the mother heard strange noises from the child, with the comment "?seizure ?post ictal". This case is not considered by this reviewer to have been medically corroborated.
Based on the assessment above, this reviewer considers there were an additional 7 cases (SA case 1, SA case 2, NSW case 1, NSW case 3, Vic case 2, Vic case 4 and Tas case 1) that can be considered to represent reports of convulsion. Four of the remaining 6 cases (ADRS Nos 265453 and 265498, Vic case 1 and Vic case 3) can be considered not to be cases of febrile convulsion and 2 (NSW case 2 and ACT case 1) have not been medically corroborated.
Australia-wide, there were 17 additional confirmed cases of febrile convulsion (WA 10; SA 2; NSW 2; Vic 2 and Tas 1).
For States and Territories other than WA, the additional cases were identified from the spreadsheets provided from the sentinel paediatric centres. In WA, whilst the additional cases were identified mostly from the spreadsheets, cases were also identified through completed clinical follow-up forms and medical records provided to the TGA1. These activities were coordinated by WA Health, which not only gave a high completion rate for the follow-up clinical information forms, but also higher case ascertainment.
Overall, there were 138 suspected cases of convulsion in children under the age of 10 Australia-wide that were known to the TGA by virtue of either having been coded as such on the TGA ADRS database (107 cases) or having been drawn to the attention of the TGA during the analysis of spreadsheets submitted from sentinel paediatric hospitals and/or case notes (31 cases). The cases were distributed by jurisdiction as follows:
|Jurisdiction||Number of suspected cases of convulsion|
The following summary of the cases should be read in conjunction with Figure 3 which is an adaptation from Figure 3 of the RWA. Note the disposition of the 84 cases from WA will not be re-discussed here. The WA cases in Figure 3 of this current report appear in red font.
As explained in the RWA, Figure 3 depicts the 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.
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.
Six of the 138 reports were in children aged more than 5 years. In addition to being older than 5 years, five of these cases had other factors that would also preclude a diagnosis of febrile convulsion. Two of these cases (ADRS Nos 265152 and 265168) were from WA and discussed in the RWA. The third case (ADRS No. 266156) was identified in a report from a public health unit in NSW that described a 30 second episode of shaking, eyes rolling and crying in a 5 1/2 year old boy. The event was referred to as a "slight seizure". Importantly, there was no loss or alteration of consciousness as the child was said to be crying and the eye rolling and shaking were the only apparent motor manifestations. Without a clearer description of tonic-clonic activity, it is possible this was merely a case of rigors. In the fourth case (ADRS No. 264956), also from NSW, an 8-year-old girl was reported to have developed a fever of 38.4°C and some 20 hours after vaccination experienced multiple seizures, two of which were witnessed by ambulance officers and one in the ED. This case was reported via the AME Line and contained quite detailed descriptions of the event and background medical and immunisation history of the child. No other possible causative agents were identified for this particular case. Neither of the remaining 2 cases from other jurisdictions had evidence of a fever. One of these cases (ADRS No. 266569) was a consumer report in which a parent reported his daughter fainted, hit her head and then convulsed approximately 10 minutes post vaccination, with no suggestion that a fever was present. The features of this case are more consistent with syncopal convulsion. In the other case, Vic case 3, the child was aged 6 years and the highest temperature recorded was only 37.1°C. This child was also noted to have nasal congestion and ear pain, suggestive of an underlying URTI.
There were 132 cases in children aged 5 years or younger, 22 of which have been assessed as not having experienced a febrile convulsion. Of these exclusions, 19 were from WA and these have been discussed at length in the RWA. The 3 remaining excluded cases ADRS Nos 265453 and 265498 and Vic case 1 were so called 'additional' cases identified from spreadsheets submitted to the TGA and have been discussed in section 3 of this report.
Of the remaining 110 cases:
- 27 had a seizure that was actually witnessed by a medical practitioner or allied health professional (e.g. ED nurse or ambulance officer). 16 such reports came from WA and all but two of these had medical records available for review - these have been assessed in detail in the RWA. Ordinarily such reports would be considered to have the highest diagnostic security. However, one case, NSW case 2, was witnessed by nursing staff and, although the child received midazolam for a presumed seizure whilst being an inpatient for a febrile reaction post vaccination, when the case was reviewed clinically it was concluded that a convulsion was unlikely to have occurred. Therefore, this reviewer considers this case was not medically corroborated.
- 52 cases had a seizure that was witnessed by a parent and in 31 cases the seizure witness was not identified. Combined, these 83 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 convulsions 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 70 of the 83 cases presented to an ED for review and 8 of the 83 were the subject of a report from a GP/medical practice3.
- Only 5 cases (ADRS Nos 265337, 265344, 265921, 266578 and 266579) were not medically corroborated because they did not present for medical review at either an ED or a GP/medical centre. These appear in the box with the heading "No apparent medical corroboration" on the far left hand side and above the broken line of Figure 3. It should be noted that there were two additional cases that appeared in the corresponding box in Figure 3 of the RWA - ADRS Nos 265120 and 265892. In the RWA report it was acknowledged that these cases had presented to an ED but the occurrence of a convulsion had not been medically corroborated and thus they appeared along-side cases for which no medical review had been sought. For the purposes of this second report, largely because there are a number more cases in a similar vein (viz ADRS Nos 266023, 266025, 266283 and ACT case1), it was considered more appropriate by this reviewer to include them in the analysis of cases that presented to an ED. In other words they have moved boxes but remain above the broken line as non cases of febrile convulsion.
A total of 27 cases have been reported where the seizure was observed by a medical or allied health professional. Of these, two cases are not considered to have been febrile convulsions. ADRS No, 264879 was a case from WA and is discussed in the RWA. The second case (NSW Case 2) had a so called seizure observed by nursing staff whilst the child was febrile (with temperature of 40.0°C) but, on medical review, was considered unlikely to have been a convulsion - suggesting that it may have been rigors that were in fact observed.
A third case (ADRS No. 265607), from WA (discussed in the RWA) was thought more likely to be due to an underlying seizure disorder. Interestingly the highest recorded temperature for this child was well below 38.0°C. Two further cases (ADRS Nos 264975 and 266033) did not have any temperature recorded in the reports received by the TGA. ADRS No. 264975 was a scant GP report of a child who was admitted to hospital with severe febrile convulsions. It is apparent that the child must have experienced repeated or ongoing seizures as he was eventually admitted to ICU. In ADRS No. 266033 a 14-month-old boy had sudden onset of febrile convulsions that required treatment with PR diazepam, indicating that the seizures were observed by medically trained staff. There was no suggestion of any other causative agent in either of these cases and, thus, the causal role of seasonal influenza vaccine is considered to be very likely.
There were 22 cases were a temperature in excess of 38.0°C was documented in association with a convulsion:
- 2 of these cases (ADRS Nos. 265113 and 265272) were also vaccinated with Varilrix® at the time they received Fluvax® and, thus, the causal association of the febrile convulsion with Fluvax® is, at best, possible.
- 5 of the cases (ADRS Nos 265160, 265338, 265379, 265840 and 265870) had intercurrent infection, which offer a plausible alternative causal explanation for the febrile convulsion. The causality for these cases is, therefore, only possible. All these cases came from WA and were discussed in the RWA.
- 15 cases 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. Thus, in these cases a causal relationship to the seasonal influenza vaccination is highly likely. More than half of these reports came from WA (ADRS Nos. 265110, 265149, 265373, 265596, 265741, 265946, 265947 and 266382). Medical records were available for 7 of these 8 cases and were considered to provide robust evidence of both the diagnosis of febrile convulsion and the absence of other likely causative agents (see RWA for more detailed discussion). The remaining reports (ADRS Nos 265324, 265381, 266110, 266288, 266560, 266731 and SA case 1) were reasonably well documented, although only 1 case (ADRS No. 265324) had detailed follow-up information in the form of hospital case notes and 1 case (ADRS Nos 266560) had a completed clinical follow-up document which provided an actual description of the seizure observed in the ED.
There were 70 cases where a parent(s) was the only witness of the seizure, following which they presented with the child to an ED.
In one case (ADRS No. 265994), from WA, 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.
A further 6 cases can be considered not to have been medically corroborated as being a febrile convulsion even though the child presented to an ED. Two of these (ADRS Nos 265120 and 265892) were discussed in the RWA. Of the remaining 4 cases in this subgroup, ACT case 1 was discussed on page 4 of this report. In another case from the ACT (ADRS No. 266025), a medical centre reported a 2-year-old child had experienced a high fever and "?seizure". Importantly, there was no loss of consciousness and it was stated the child was distressed and pulling at his ears at the time whilst he was kicking his legs out and stiffening his body - which would not be consistent with a true convulsion. Furthermore, this case did not appear on the ACT spreadsheet despite the child having presented to the sentinel hospital. In ADRS No. 266032 a child presented to ED after one of her parents had observed what was reported to have been 3 convulsions in her sleep. However, the comments from NSW Health contained within the supporting documents for this case on the TGA's ADRS database stated this was considered unlikely to be a true convulsion. The last case (ADRS No. 266283) was an outlier for time to onset of the event -with the fever and convulsion reported to have occurred within 5 to 10 minutes of vaccination, all of which had resolved by the time the child presented to ED at RCH. Of note, this case does not appear on the spreadsheets submitted by the Victorian Department of Health, which included all cases with final diagnosis of febrile convulsion at RCH.
51 of the 70 cases presenting to ED had a temperature in excess of 38.0°C. Of these:
- 9 cases 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. Six of these were from WA (ADRS Nos. 265107, 265134, 265162, 265664, 265974 and 266380) and have been discussed in the RWA. Of the 3 cases from other jurisdictions, 2 received more than one concomitant vaccine - ADRS No. 264495 also received Hib/MMR/Men C and ADRS No. 265490 also received the standard immunisations for a 1-year-old. The remaining case (ADRS No. 266284) also received Varilrix®.
- 4 cases had intercurrent infection, which offers a plausible alternative causal explanation for the febrile convulsion and the causality for these cases is, therefore, only possible. All 4 cases (ADRS Nos 265141, 265611, 265879 and JHC case 4) were from WA and have been discussed in the RWA4.
- 1 case (ADRS No. 266280) had no temporal relationship with the seasonal influenza vaccine, occurring some 2 weeks after vaccination, during which time the child also experienced a viral URTI. This case is therefore considered to have a causality rating as being unrelated.
- ADRS No. 266296 was a report of a febrile convulsion lasting 20 minutes with onset 10hrs post vaccination, at which time the child's temperature was 40.8°C. There was no evidence of the child having any intercurrent infection or having received concomitant vaccines. However, it was noted by this reviewer that the treatment rendered included "midazolam....by mother as per usual regime", suggesting an underlying seizure disorder. A request for additional information, in particular the child's current medical conditions and past medical history, was sent to the reporter but no further information has been received to date. In the absence of this important additional information, a role of the underlying seizure disorder has not been excluded and, therefore, the causality for this case is only possible.
- 36 cases 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. Half of the 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) came from WA. Comment on these cases appears in the RWA. Of the 18 cases from jurisdictions other than WA:
- 6 were identified as additional cases from the spreadsheets submitted by jurisdictional health authorities - NSW case 1, NSW case 3, Vic case 2, Vic case 4, SA case 2, Tas case 1. Generally the spreadsheets contained minimal descriptive information;
- 6 (ADRS Nos 264965, 265127, 265526, 265976, 266337 and 266564) had completed clinical follow-up documents which confirmed the occurrence of a seizure, however no medical records or discharge summaries were available for these cases; and
- 6 cases (ADRS Nos 265716, 265958, 266151, 266267, 266287 and 266563) had no information available other than the original database report but the event was corroborated by a spreadsheet from the corresponding jurisdictional health authority for all cases except ADRS No. 266151.
12 cases presenting to an ED either did not have a temperature recorded or the temperature was below 38.0°C. 10 cases had no temperature reading recorded and, of these, 5 were from WA (ADRS Nos. 265106, 265856, 265880, 265898 and pt NW) and were reported by the parent to have a fever or be hot to touch. The 5 cases from other jurisdictions (ADRS Nos 264505, 265563, 266128, 266565 and 266594) also had minimal information but again there was usually a comment that a fever had been present. Only two cases, both from WA (ADRS Nos 265108 and JHC case 1) had temperatures recorded and in both cases the recorded temperature at presentation to ED was above 37.5°C. Three of the 12 cases (ADRS Nos 264505, 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. A fourth case (ADRS No. 266594) also received concomitant Infanrix and Pneumococcal vaccine. This child also had a history of cerebral palsy secondary to hypoxia with an underlying seizure disorder requiring treatment with phenobarbitone. ADRS Nos 265106, 265108, 265563, 265898, 266128, 266565, JHC case 1 and pt NW 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.
There were 8 reports where information has been obtained solely from GPs (ADRS Nos 265269, 2265750, 265757, 266123, 266136, 266140, 266196 and 266575). All of these, except ADRS No. 266123, were from WA and have been discussed in the RWA. ADRS No. 266123 was a somewhat scant report of a seizure/febrile convulsion in association with a temperature of 38.5oC and increased respiratory rate in an 8-month-old child. There was no mention of any other potential causative agents.
A total of 5 cases were not medically corroborated because they did not present for medical review at either an ED or a GP/medical centre. ADRS Nos 265337 and 265921 were from WA and have been discussed in the RWA. ADRS Nos 265344, 266578 and 266579 were parental reports direct to the TGA that merely stated the child had "convulsed"5.
On the basis of a review of all information available, there were 96 confirmed cases of febrile convulsion in children under the age of 5 years reported to the TGA as at close of business on 7 May 2010, 57 of which were from WA. Of the 96 cases, 95 were causally related to vaccination with the seasonal influenza and 1 case was considered unrelated by this reviewer because of the absence of a temporal relationship between the convulsion and vaccination. Of the 95 causally related cases, 69 have a causality rating of 'very likely' because no other potential causative factors have been identified. The remaining 26 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 62 cases where the brand of the seasonal influenza vaccine was known. Twenty one different batches were implicated, with two batches accounting for more than half of the cases - 27801 (22 cases) and 27102 (12 cases).
Of the 96 cases of febrile convulsion, 25 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 25 cases, 17 are very likely to be causally related to vaccination with the seasonal influenza vaccine and 8 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 71 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 - 63 presented to an ED and 8 to a GP/medical centre. Of these 71 cases, 52 are highly likely to be causally related to vaccination with the seasonal influenza vaccine, a further 18 are possibly causally related to the vaccine because they can also be explained by the use of concomitant vaccines and/or concurrent infection, and 1 was causally unrelated.
The distributions of patient age and time to onset of convulsion in the 95 confirmed cases that were causally related to the vaccination are shown in figures 4 and 5, respectively. These figures display two sets of results - those for 'All database cases', which are reproduced from the TGA ADRS data analysed in section 2 of this report (see also figures 1 and 2) and those for 'Causally related cases', which represents the 95 causally related, confirmed cases identified by the analysis in section 4. It can be appreciated that the distributions are very similar. Also, of the 95 causally related cases, 54 (57%) were male and 41 (43%) were female) which is, again, very similar to the analysis presented in section 2.
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 the various jurisdictions.
At the time of finalising this report a further 19 reports had been lodged on the TGA's ADRS database:
- 7 were from WA. ADRS Nos 266788 and 267314 had been covered in the post script of the RWA and are new cases. The remaining 5 cases had in fact been identified in the WA spreadsheets and therefore considered as part of the RWA and counted amongst the 138 cases considered in section 5 above:
- ADRS No. 268285
- ADRS No. 268286
- ADRS No. 268290
- ADRS No. 268296
- ADRS No. 268294
- 6 were reports from CSL - ADRS Nos. 266733, 266739, 266741, 266744, 266826 and 266828. 4 of the 6 reports (ADRS Nos 266739, 266741, 266744 and 266826) were based solely on media reports of reactions to the influenza vaccine and, collectively, contained insufficient information to permit verification of the diagnosis or assessment and classification of the cause. As a case in point, the information contained with ADRS 265744 referred to a doctor being quoted in the media that a patient with initials BK had been taken to John Hunter Hospital with a fever of 44 degrees and a heart rate of 220bpm. There was, apparently, no mention of a seizure by the doctor. However, the report then also stated that another media report had said the patient suffered from fever and convulsion. Clearly such hearsay is not able to be evaluated further.
In another report (ADRS No. 266828), a pharmacist reported to CSL that a 19-month-old boy had a febrile convulsion and turned purple 5 hours after vaccination with Fluvax® and went to hospital. No patient details (i.e. initials, DOB or MRN) or no medical history were provided to allow further assessment of this case. In the remaining case (ADRS 266733), a consumer report to CSL, a 1-year-old child (MV) developed a fever in excess of 40oC approximately 6.5hrs after vaccination with Fluvax® (batch 27901). The child then developed convulsions and was reported to have been rushed to hospital by ambulance and admitted for observation overnight.
- 3 reports from Qld:
- ADRS No. 267220 is a duplicate of ADRS No. 265563.
- ADRS Nos 268095 and 268096 were virtually identical reports via Qld Health by a mother of two siblings aged 1 and 3 years, respectively. The initial reports stated that both children developed high temperature within 3 hours of vaccination with Fluvax® (batch 27901) and had "convulsions all day", accompanied by vomiting and in, the son, diarrhoea as well. No medical attention was sought. The completed clinical follow-up forms described a single episode of each child being hot, rolling their eyes back and shaking that lasted a few seconds during which the children were "semi-conscious". These cases have not been medically corroborated and the inconsistent histories cast doubt on the diagnosis. It is more than likely that rigors have been misinterpreted as convulsions in these cases.
- 2 cases from Victoria:
- ADRS NO. 267233 was a report from a GP via SAEFVIC of a 1-year-old boy who developed a fever of 41oC following his first dose of Fluvax® (batch 27501) and was subsequently admitted to hospital following a febrile convulsion.
- The second case (ADRS No. 267247) was also a GP report via SAEFVIC. In this case a 3-year-old girl was reported to have had a febrile convulsion during the night and presented to an ED after receiving her first dose of Fluvax® (batch 27901).
- 1 case SA. ADRS No. 267229 was a report from SA Health of a 4-year-old girl who developed a fever of 39.9°C, was vomiting and "very flat and dopey" after receiving Fluvax®. The time to onset was not reported. The child had a past history of febrile convulsion and the mother thought she may have had a convulsion because she recognised symptoms from the previous episode. The child was taken to WCH where she was rehydrated and given paracetamol. Of note, WCH was a sentinel hospital and the case does not appear on their spreadsheet as a case of febrile convulsion. It is apparent that no seizure was witnessed and presumably the mother interpreted the listlessness as being post ictal features. However these could be equally explained by the fever and vomiting and therefore this case is considered by this reviewer not to have been medically corroborated.
In the opinion of this reviewer, only 5 of the 19 cases can be considered to have been confirmed with any degree of security - ADRS Nos. 266733, 266788, 267233, 267314 and 267247.
Additionally, on 21 May 2010 WA Health advised by email (TRIM R10/104697) that a further 2 PMH cases (ADRS Nos 265104 and 265879) had been re-classified as not being febrile convulsions following review by paediatricians at PMH:
- 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 original AEFI report and a completed clinical follow-up information document submitted by WA Health.
Adding the 5 additional cases (ADRS Nos. 266733, 266788, 267233, 267314 and 267247) to and subtracting ADRS No. 265879 from the 96 confirmed cases as at COB 7 May 2010, gives a final total at the time of completing this report of 100 confirmed cases of febrile convulsion Australia-wide.
|Number of cases||66||15||11||8||4||2||1||107|
|Male||42 (64%)||9 (60%)||5 (45.5%)||5 (62.5%)||0||1 (50%)||1 (100%)||63 (59%)|
|Female||23 (35%)||6 (40%)||6 (54.5%)||3 (37.5%)||4 (100%)||1 (50%)||43 (40%)|
|Unknown||1 (1%)||1 (1%)|
|Time to onset|
|Range||3hr - 72hr||5min - 2wks||10min - 8.5hr||5 - 48hr||5 - 9hr||5 - 12hr||NR||5 min - 2 wks|
|Mean (hr)||9||7.45 1||7.25 2||17.75||7.25||8.5||NR||9.0 3|
|Median (hr)||7||7 1||8 2||11.5||7.5||8.5||NR||7.25 3|
|NR||9 (13.6%)||2 (13.3%)||4 (36.4%)||2 (25%)||0||0||1 (100%)||18 (17.8%) 4|
|≤ 6hr||20 (30.3%)||5 (33.3%)||3 (27.2%)||1 (12.5%)||1 (25%)||1 (50%)||31 (28.0%) 4|
|>6-12hr||32 (48.5%)||7 (46.4%)||4 (36.4%)||3 (37.5%)||3 (75%)||1 (50%)||50 (46.7%)|
|>12-24hr||4 (6.1%)||1 (12.5%)||5 (4.7%)|
|>1d-3d||1 (1.5%)||1 (12.5%)||2 (1.9%)|
|>7d||1 (6.7%)||1 (0.9%)|
|Previous seasonal influenza vaccination|
|Yes||14 (21.2%)||2 (13.3%)||0||0||1 (25.0%)||0||17 (15.9%)|
|No||34 (51.5%)||2 (13.3%)||3 (27.3%)||1 (12.5%)||1 (25.0%)||0||41 (38.3%)|
|Unknown||18 (27.2%)||11 (73.4%)||8 (72.7%)||7 (87.5%)||2 (50.0%)||2 (100%)||1 (100%)||49 (45.8%)|
- minus outliers 266280 and 266283
- minus outlier 266569
- minus all outliers - 26280, 266283 and 266569
- these figures differ from those provided in the report for WA - additional information provided for 266564 (received by TGA at that time but not assessed by this reviewer) indicated time to onset was 5.5hr whereas it was previously unreported.
Figure 3 All reports of convulsion across Australia - database plus additional cases submitted by health authorities
Figure 4 Age distribution of febrile convulsions causally related to seasonal influenza vaccine
Figure 5 Distribution of time to onset of febrile convulsions causally related to seasonal influenza vaccine
- As noted in the RWA, on 29 April 2010 the TGA requested that photocopies of the medical case notes of children with febrile convulsions be sent to the TGA for analysis. Some of the case notes, as well as clinical follow-up forms received from WA Health were for cases that did not appear in the TGA's ADRS database.
- 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.
- There were 8 reports from GPs/medical centres in WA, 1 of which (ADRS No. 266325) had information from both a GP, who was the initial reporter, and medical notes from JHC. The medical notes were far more comprehensive than the GP report and so, for the purposes of the WA analysis, this case has been included among those that presented to ED and so in effect there were 7 "GP reports" from WA. In comparison, in the other jurisdictions combined, there were a total of 7 reports from GPs/medical centres. However, 6 of these appeared on spreadsheets from sentinel paediatric hospitals indicating they had received some sort of review in an ED. They are therefore considered among the 64 cases that presented to an ED. The remaining case (ADRS No. 266123) has been added to the 7 "GP reports" from WA.
- Note ADRS No. 265879 was also discussed in the Post Script section of the RWA in relation to additional information received after the cut-off of 19 May 2010. See also Post Script section of this report.
- ADRS Nos 266578 and 266579 were from the same parent for different children.