1. očakávaná reakcia po očkovaní
Horúčka –
očakávaná reakcia po očkovaní
Hudáčková D., Urbančíková I.
Centrum na očkovanie detí s komplikáciami po očkovaní a kontraindikáciami očkovania
Detská fakultná nemocnica Košice
VII. Slovenský vakcinologický kongres, , Štrbské Pleso

2. Horúčka - zvýšená telesná teplota nad 38°C
Hypertermia - je výsledkom nedostatočného odvádzania tepla pri nadmernej tvorbe tepla (napr. pri namáhavom cvičení), tepelnom šoku, poruche hypotalamickej termoregulácie
In 1868, Carl Wunderlich determined that “normal body temperature” is actually a range of values rather than a specific temperature, and 38C (100.4F) was established as the upper limit of normal [5, 6]. Although this definition of “normal temperature” has sincebeen questioned [1], it is clear that elevated body temperature due solely to endogenous causes (e.g., fever and pyrexia) rarely exceeds 41C
Mackowiak PA. Concepts of fever. Arch Intern Med 1998; 158:1870–81.
Bouchama A, Knochel JP. Heat stroke. NEngl J Med 2002; 346:1978–88.
Wunderlich CRA. Das Verhalten der Eigenwa¨rme in Krankheiten. Leipzig: Otto Wiegard, 1868.

3. Horúčka
- výskyt horúčky priemerne 2-6/rok - najčastejšia príčina návštev u lekára
Mackowiak PA. Concepts of fever. Arch Intern Med 1998; 158:1870–81.
McCarthy PL. Fever. Pediatr Rev 1998;19:401-7.

4. Horúčka ako AEFI (Adverse Events Following Immunisation)
VAERS (Vaccine Adverse Event Reporting System) – pasívny systém surveillance AEFI v USA: horúčka – najčastejšie hlásená reakcia – vo všetkých vekových skupinách okrem 18–64 ročných (lokálne reakcie)
Kanada – výskyt nežiaducich účinkov (nemocničné záznamy, záznamy o imunizácii) – incidencia hospitalizácií pre horúčku a kŕče bola signifikantne vyššia deň po očkovaní (DTwP)
Podľa klinických štúdií:
- horúčka u 1-10% vakcinovaných, ale môže byť aj oveľa vyššia
- typicky: do 39 °C, self-limitujúci priebeh
Chýbanie ďalších dát a kontrolnej skupiny neočkovaných detí neumožňuje určiť relatívne riziko horúčky po očkovaní v porovnaní s neočkovanou populáciou.
VAERS, has found fever to be the most frequently reported “serious” and “nonserious” AEFI for all age groups, with the exception of persons aged 18–64 years, in whom a wide range of local reactions are more frequently reported as nonserious events
Kohl, Katrin S., et al. "Fever after immunization: current concepts and improved future scientific understanding." Clinical infectious diseases 39.3 (2004):

5. Horúčka ako AEFI (Adverse Events Following Immunisation)
MMR/placebo, vyšší výskyt horúčky u mesačných
očkovaných detí (25% vs. 6%; OR, 3.28; 95% CI, 1.23–4.82; P ! .001)
6 –ročné deti 3% v obidvoch skupinách
88% prípadov horúčky nad 38.5 °C – výskyt nebol spojení s očkovaním1
dvojito zaslepené, placebom kontrolované štúdie
živá vakcíny proti varicele2 a atenuovaná proti hepatitíde A3
nepotvrdili signifikantný rozdiel v incidencii horúčky medzi skupinou, ktorá dostávala
vakcínu alebo placebo
simultánne podanie trivalentnej inaktivovanej vakcíne proti chrípke a
PCV13 bolo spojené s vyšším výskytom horúčky4
1. Peltola, Heikki, Heinonen. The Lancet (1986):
2. Weibel, Robert E., et al. New England Journal of Medicine (1984):
3. Werzberger, Alan, et al. New England journal of medicine (1992):
4. Stockwell, Melissa S., et al. JAMA pediatrics (2014):

6. porovnávanie výskytu špecifikovaných ochorení u detí 7 dní pred
očkovaním a 7 dní po očkovaní
ochorenia okrem horúčky – častejší výskyt pred očkovaním
horúčka – častejšia po očkovaní

8. Febrilné kŕče 6 mesiacov – 5 rokov (14-18 mesiacov)
2- 5 % detí (5-10% India, 8,8% Japonsko, 0,5 – 1,5% Čína)
rodinný výskyt (10% riziko ak súrodenec, 50% ak rodič)
genetická predispozícia – áno, spôsob dedičnosti ?
(polygénna dedičnosť, AD viacero génov, mutácie v génoch kódujúcich sodíkový kanál a receptor GABA)
patogenéza: aktivácia cytokínov ?
Febrile seizures tend to occur in families. In a child with febrile seizure, the risk of febrile seizure is 10% for the sibling and almost 50% for the sibling if a parent has febrile seizures as well. Although clear evidence exists for a genetic basis of febrile seizures, the mode of inheritance is unclear.[9]
American Academy of Pediatrics. "Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile
seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures." Pediatrics (2008):
Hauser WA. Epilepsia Suppl 2:S1-6.
Chung B, Wat LC, Wong V. Pediatr Neurol Feb. 34(2):121-6. 8

9. Febrilné kŕče
jednoduché: do 15 minút, generalizované, do 24 hodín sa neopakujú, nezvyšujú moralitu
komplexné: prolongované, opakujú sa viac ako 1x, fokálne
rizikové faktory – komplexné kŕče, RA epilepsie, neurologických porúch, oneskorený vývin
zvýšená incidencia epilepsie (2% vs 1%)
1/3 detí – opakované kŕče (rizikové faktory)
nie sú dáta, že rýchly vzostup teploty je príčinou kŕčov
Children with simple febrile seizures do not have increased mortality risk. However, seizures that were complex, occurred before age 1 year, or were triggered by a temperature of less than 39°C were associated with a 2-fold increased mortality rate during the first 2 years after seizure occurrence.[16]
Children with febrile seizures have a slightly higher incidence of epilepsy compared with the general population (2% vs 1%). Risk factors for epilepsy later in life include complex febrile seizure, family history of epilepsy or neurologic abnormality, and developmental delay. Patients with 2 risk factors have up to a 10% chance of developing afebrile seizures.[
American Academy of Pediatrics. "Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures." Pediatrics (2008):

10. Febrilné kŕče a očkovanie
často hlásené ako AEFI (ale zriedkavé)
riziko pri očkovaní: DtwP / MMR
6-9 / prípadov na očkovaných detí
- v porovnaní: osýpky - 1/1000 encefalitída
pertussis - 1/50 kŕče
- 1/250 encefalopatia
Barlow WE et al. N Engl J Med 2001; 345:656–61.
Annegers JF et al. N Engl J Med 1987; 316: 493–8.
Nelson KB, Ellenberg JH. N Engl J Med 1976; 295:1029–33.
Verity CM et al. Br Med J 1985; 290:1311–5.

11. Febrilné kŕče a očkovanie
MMR, MMRV
2008: ACIP – 2x zvýšené riziko febrilných kŕčov po MMRV oproti MMR+V
2010: mesačné deti - podanie MMRV +1 febrilné kŕče na každých 2300 dávok1
vakcíny obsahujúce zložku proti osýpkam – znížené riziko kŕčov, ak sú podané vo veku mesiacov2
MMRV a MMR+V - bez zvýšeného rizika febrilných kŕčov u detí vo veku 4-6 rokov3
Kŕče po očkovaní
Verbeek: 2.5% hlásených kŕčov po vakcinácii v prvom roku života, 0,3% v 2. roku – Dravetovej syndróm (SCN1A-mutácia)4
Verbeek: u väčšiny detí s výskytom epilepsie diagnostikovanej po očkovaní bola identifikovaná genetická alebo štrukturálna príčina (35% Dravetovej syndróm, benígna epilepsia, encefalopatia)5
Methods
Data were reviewed of 1,269 children with seizures following immunization in the first two years of life, reported to the safety surveillance system of the Dutch national immunization program between 1 January 1997 and 31 December Selective, prospective follow-up was performed of children with clinical characteristics compatible with a diagnosis of Dravet syndrome.
Results
In 21.9% (n = 279) of children, a diagnosis of Dravet syndrome could not be excluded based on available clinical data (median age at follow-up 16 months). Additional follow-up data were obtained in 83.9% (n = 234) of these children (median age 8.5 years).
15 (1.2% of 1,269; 95%CI:0.6 to 1.8%) children were diagnosed with SCN1A-related Dravet syndrome. Of all reported seizures following vaccinations in the first year of life, 2.5% (95%CI:1.3 to 3.6%) were due to SCN1A-related Dravet syndrome, as were 5.9% of reported seizures (95%CI:3.1 to 8.7%) after 2nd or 3rd DTP-IPV-Hib vaccination.
Seizures in children with SCN1A-related Dravet syndrome occurred more often with a body temperature below 38.5°C (57.9% vs. 32.6%, p = 0.020) and reoccurred more often after following vaccinations (26.7% vs. 4.0%, p = 0.003), than in children without a diagnosis of SCN1A-related Dravet Syndrome.
Conclusions
Although Dravet syndrome is a rare genetic epilepsy syndrome, 2.5% of reported seizures following vaccinations in the first year of life in our cohort occurred in children with this disorder. Knowledge on the specific characteristics of vaccination-related seizures in this syndrome might promote early diagnosis and indirectly, public faith in vaccination safety.
Discussion
In our nation-wide ten-year cohort study, we identified SCN1A-related Dravet syndrome as the underlying cause in 1.2% of children reported with seizures following vaccinations in the first two years of life, including 2.5% of seizures reported after vaccination in the first year of life, and 0.3% in the second year of life. Among seizures reported after the second or third DTP-IPV(-)Hib vaccination, the proportion of SCN1A-related Dravet syndrome was the highest.
The seizure had occurred within 24 h (median 7.5 h) after administration of DT(P)-IPV(-)Hib vaccines in the majority of children diagnosed with SCN1A-related Dravet syndrome.
Children diagnosed with SCN1A-related Dravet syndrome had a younger age at first seizure following vaccination, and more often had second and third seizures reported after subsequent vaccinations than other children.
Both short or prolonged, generalized or unilateral, and febrile or afebrile vaccination-related seizures occurred in children with SCN1A-related Dravet syndrome. Seizures occurred more often with a body temperature below 38.5°C, illustrating the high sensitivity28 also to minor temperature increase in children with SCN1A-related Dravet syndrome.
nterestingly, all detected cases of SCN1A-related Dravet syndrome were reported after vaccination with wP-component
Our study shows that although SCN1A-related Dravet syndrome is a rare disorder, 2.5% of reported seizures following vaccinations in the first year of life occurred in children with this disorder. In children with Dravet syndrome, vaccinations might induce the first and following seizures. Physicians and co-workers of immunization safety surveillance programs should have knowledge of the prevalence of Dravet syndrome among children reported with seizures following vaccinations, and of the discriminating seizure characteristics in this subgroup. This will promote earlier diagnoses of Dravet syndrome which is important for appropriate treatment and genetic counseling. Moreover, an early diagnosis will prevent parents and professionals from assuming that vaccination is the cause of the epilepsy, and will thereby promote faith and participation in immunization programs.
This study was an assessment of the incidence, course, and etiology of epilepsy with vaccination-related seizure onset in a population-based cohort of children.
METHODS: The medical data of 990 children with seizures after vaccination in the first 2 years of life, reported to the National Institute for Public Health and Environment in the Netherlands in 1997 through 2006, were reviewed. Follow-up data were obtained of children who were subsequently diagnosed with epilepsy and had had seizure onset within 24 hours after administration of an inactivated vaccine or 5 to 12 days after a live attenuated vaccine.
RESULTS: Follow-up was available for 23 of 26 children (median age: 10.6 years) with epilepsy onset after vaccination. Twelve children developed epileptic encephalopathy, 8 had benign epilepsy, and 3 had encephalopathy before seizure onset. Underlying causes were identified in 15 children (65%) and included SCN1A–related Dravet syndrome (formerly severe myoclonic epilepsy of infancy) or genetic epilepsy with febrile seizures plus syndrome (n = 8 and n = 1, respectively), a protocadherin 19 mutation, a 1qter microdeletion, neuronal migration disorders (n = 2), and other monogenic familial epilepsy (n = 2).
CONCLUSIONS: Our results suggest that in most cases, genetic or structural defects are the underlying cause of epilepsy with onset after vaccination, including both cases with preexistent encephalopathy or benign epilepsy with good outcome. These results have significant added value in counseling of parents of children with vaccination-related first seizures, and they might help to support public faith in vaccination programs.
Klein, Nicola P., et al. Pediatrics (2010): e1-e8.
2. Rowhani-Rahbar, Ali, et al. JAMA pediatrics
Klein, Nicola P., et al. Pediatrics (2012):
Verbeek, Nienke E., et al. (2013): e65758.
Verbeek, Nienke E., et al. Pediatrics (2014):

12. Profylaxia horúčky
- acetaminofén alebo iné vhodné antipyretiká možno podať dojčatám a deťom s anamnézou kŕčov v čase očkovania DTaP (á 4 hod počas 24 hodín) na zníženie horúčky po očkovaní
(Source: American Academy of Pediatrics.
Active immunization. In: Pickering LK, Baker CJ, Long SS, McMillan J. eds red book: report of the Committee on Infectious Diseases. 27th ed.
Elk Grove Village, IL: American Academy of Pediatrics; 2006)

13. Profylaxia horúčky
2 randomizovavé, kontrolované, open-label štúdie 459 zdravých dojčiat
profylaktické podanie 3 dávok paracetamolu á 6-8 hodín v prvých 24 hodinách po očkovaní 10-valentnou pneumokokovou vakcínou, hexavakcínou, orálnou vakcínou proti rotavírusom
horúčka nad 39,5 °C – nebola častá u oboch skupín
TT > 38 °C – signifikantne nižšia
paracetamolová skupina (94/226 [42%] po základnom očkovaní a 64/178 [36%] po boostri
skupina bez profylaxie (154/233 [66%] po základnom očkovaní: 100/172 [58%] po boostri
koncentrácie protilátok (GMCs - Antibody geometric mean concentrations) – signifikantne nižšie v paracetamolovej skupine po základnom očkovaní (10 sérotypov pneumokokov, proteín B, anti di,te, pertaktín), po boostri – (anti te, protein D, pneumokokové sérotypy okrem 19F)

14. Profylaxia horúčky
Paracetamol znižoval výskyt TT ≥38°C, signifikantne len u dojčiat, reakcie - mierne, TT>39°C zriedkavá, odporúčanie – paracetamol na liečbu nie na profylaxiu1
profylaktické (nie terapeutické) podanie paracetamolu počas vakcinácie malo negatívny vplyv na koncentráciu protilátoky proti VHB u dospelých2
4CMenB (Bexsero) – pri podávaní so základným očkovaním – zvýšený počet reakcií vrátane horúčky, profylaxia paracetamolom - zníženie nežiaducich reakcií, imunitná odpoveď sa neznížila3
systémový prehľad medicínskych databáz (13 RCT, 5077 detí) – profylaktické podávanie antipyretík versus placebo - signifikantné zníženie febrilných reakcií (>38.0°C) po primárnom očkovaní aj po boostri, signifikantné rozdiely v protilátkovej odpovedi, protektívne hladiny protilátok boli prítomné4
Our study showed, in accord with earlier studies published by Prymula et al. [15], that exposure to paracetamol can suppress immune function to antigens derived from bacterial and viral pathogens, and this might have consequences for resistance to infectious agents. The effects noted were modest, but modest suppression on a population basis may have considerable consequences as has been noted with exposure to environmental pollutants inducing similar levels of immune suppression [16]–[18].
The effects of prophylactic and therapeutic paracetamol treatment were observed in a human model in which specific antibody responses to hepatitis B antigen were assessed. The main finding of this study is that prophylactic use of paracetamol exerts a negative effect on the primary antibody response after hepatitis B vaccination in adults. In addition, we show that such an inhibitory effect is not observed when paracetamol is given therapeutically. Apparently, the timing of paracetamol determines its immunomodulatory effects.
Our finding extends the data recently published by Prymula et al. that showed that prophylactic use of paracetamol inhibited the induction of antibodies to a combination of child-hood vaccines in infants [15]. Infants were vaccinated with the hexavalent diphtheria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenza type b and oral human rotavirus vaccines. Prymula et al. aimed to study the effect of paracetamol use on the occurrence of side-effects to vaccination. While pain and fever were reduced, an inhibitory effect of paracetamol on the induction of antibodies to these vaccines was observed. The decrease in GMC that was observed was approximately thirty-five percent. In the present study a decrease of twenty-six percent was measured in the prophylactic paracetamol group indicating that the effects of paracetamol in adults is equivalent to those in infants. In contrast to the inhibitory effects of prophylactic paracetamol treatment on antibody responses, paracetamol did not exert similar significant effects when given therapeutically. Nevertheless, a slightly non-significant decrease in antibody response was visible in the therapeutic paracetamol group compared to the control group. To our knowledge our study is the first in which the effects of prophylactic and therapeutic paracetamol treatment on response to vaccination were compared.
The antibody levels of the control and both paracetamol groups display large variation, reflecting the variation in the human vaccine responses and thus the unique immune response of every individual after vaccination and the various physical and genetic factors that influence the response to vaccination [19], [20]. Although the antibody concentrations in this study were significantly lower in the prophylactic group, all study participants were considered to be protected against hepatitis B after the full schedule since all titers were above 10.0 IU/L, the threshold for protection against hepatitis B, according to the World Health Organization [21]. Since anti-HBs levels are measured quantitative and anti-HBs levels are standardized against an international reference and expressed in International Units, hepatitis B vaccination is a good model to investigate the effects of paracetamol on immune responses after vaccination in a safe manner. However, there is clear evidence that paracetamol has an effect on the functionality of the immune system, which could be relevant under conditions when the immune response to either vaccination or pathogen is already suboptimal.
However, the suppressive effect of paracetamol was not found in a comparable study with influenza vaccinations in elderly people [22]. Participants in the influenza study were many times exposed during their life to influenza viruses before vaccination, whereas infants had their primary contact with the viruses/bacteria vaccine antigens in the study of Prymula et al. Participants of the present study also encountered hepatitis B antigens for the first time. These results indicate that inhibitory effects of paracetamol are especially evident during the vaccinations that prime the immune response.
The development of vaccine antigen-specific memory after vaccination is a slow multistep process taking several days. The effects of paracetamol on the vaccination response in adults found in this study suggest that paracetamol plays an important role in the first six hours after the primary vaccinations. This is exemplified by our observation that the vaccination response was only significantly decreased in the prophylactic paracetamol treatment group and not in the therapeutic treatment group. The finding that paracetamol influences the vaccine response only when given directly at the time of vaccination, point to an effect during the early stages of the immune response, when APC-T cell interaction take place in lymphatic tissues [23]–[25]. Paracetamol may decrease the amount of glutathione thereby impairing respiratory antioxidant defenses [26]. Decreased glutathione levels could influence lymphocyte activation mechanisms [27], [28]. Another potential mechanism is the capacity of paracetamol to suppress fever by influencing the COX-2 activity and the production of prostaglandin E2 that stimulate the accompanying immune cell recruitment [29]. It is tempting to speculate that decreased recruitment of APC to the site of vaccination, and decreased activation of these cells during the early stages of induction of immunity underlie our observation, a mechanism which was already previously proposed by Prymula et al. although their study only included a prophylactic treatment group.
In the present study, we showed that prophylactic paracetamol treatment during vaccination has a negative influence on the antibody concentration after hepatitis B vaccination in adults. In the Netherlands, paracetamol is mostly used therapeutically after vaccination when side effects start to occur. Since therapeutic paracetamol treatment starting 6 hours after vaccination did not significantly inhibit the response to vaccination, our data indicate that treatment of fever and pain may be without disadvantages. These results are not only important for hepatitis B vaccination procedures, but also for other primary vaccinations in the national immunization program, although we cannot exclude effects of therapeutic paracetamol treatment on vaccines other than hepatitis B.
Most important, these findings prompt to consider therapeutic instead of prophylactic treatment to ensure maximal vaccination efficacy and retain the possibility to treat pain and fever after vaccination.
Rose, Markus A., et al. BMC pediatrics 13.1 (2013): 98.
Doedée, Anne MCM, et al. (2014): e98175.
Prymula, Roman, et al. Human vaccines & immunotherapeutics 10.7 (2014):
Das, Rashmi Ranjan, Inusha Panigrahi, and Sushree Samiksha Naik. (2014): e

15. Profylaxia febrilných kŕčov
American Academy of Pediatrics. "Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures." Pediatrics (2008):

16. Profylaxia febrilných kŕčov
prehľad článkov EBM (viac ako 300 medicínskych článkov) od r. 1998
Kontinuálna antikonvulzívna liečba: fenobarbital – áno, primidone – áno, k. valproová - áno, karbamazepín - nie, fenytoin – nie
- potenciálna toxicita > malým rizikom spojeným s kŕčmi!
neodporúča sa!
Intermitentná antikonvulzívna liečba: diazepam – áno
v prípade „parental anxiety“
Intermitentná antipyretická liečba: acetaminofen, ibuprofen – nie
nezabránia vzniku febrilným kŕčom
American Academy of Pediatrics. "Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures." Pediatrics (2008):

17. Horúčka – fyziologická reakcia nie choroba !
Obava z horúčky ?
Horúčka – fyziologická reakcia nie choroba !
jeden z mnohých klinických príznakov
dôkladné klinické zhodnotenie – anamnéza, fyzikálny nález, vek,...
febrilné kŕče - neznižujú IQ, nezvyšujú riziko epilepsie, nespôsobujú úmrtie
- zvýšené riziko opakovaných febrilných kŕčov
- genetická predispozícia
These misconceptions can give rise to an unwarranted fear of severe side effects, such as permanent brain damage, leading to inappropriate or excessive temperature measurement, as well as unnecessary clinic visits, laboratory testing, and antipyretic and antimicrobial therapy. Concern over a febrile seizure may precipitate hospital admission and performance of lumbar punctures or other costly tests attempting to define the cause of the fever. When seen in this context, it is not surprising that “fever phobia,” with or without accompanying signs or symptoms of illnesses (such as upper respiratory tract infection or ear infection), is one of the most common reasons that parents seek medical attention for their children
Despite these fears, only a small proportion of febrile infants and children with elevated temperature have a serious bacterial infection [24, 25]. Conversely, invasive life-threatening and other infections, such as acute otitis media, can occur in the absence of fever (e.g., up to 45% of children with acute otitis media do not present with fever) or even with hypothermia
American Academy of Pediatrics. "Steering Committee on Quality Improvement and Management, Subcommittee on Febrile Seizures. Febrile seizures: clinical practice guideline for the long-term management of the child with simple febrile seizures." Pediatrics (2008):

18. Horúčka – očakávaná reakcia po očkovaní !
Očkovanie a horúčka
Horúčka – očakávaná reakcia po očkovaní !
Profylaxia
???
Vyhodnotenie horúčky nielen v kontexte časovej súvislosti s očkovaním, ale
v spojení s anamnézou, klinickým vyšetrením - koincidencia a nesúvisiace príčiny.

19. Ďakujem za pozornosť!