Funded by the European Union Pediatric Considerations Pieter

Funded by the European Union

Pediatric Considerations Pieter Fraaij Erasmus. MC-Sophia Dept. Viroscience Funded by the European Union

Disclosures Pieter Fraaij Companies/funders Sponsoring or research fee EU FP 7 project PREPARE (#602525) • VIRGO (FES 0908). • Honorarium or other endorsement for • Hoffmann-la Roche IRIS STUDY participation in advisory boards or • SHIRE education • GSK None of the above mentioned were paid to me in person, all expenses were paid to the Erasmus-MC Funded by the European Union

Why not perform studies in Children During outbreaks research already difficult and… • Inclusion children in studies even more complex • Study/clinical procedures in children difficult • Obtaining ethical approval pediatric studies troublesome • (Ethical) belief children to be protected from clinical research • Unwillingness to approach parents/sick children for research participation Cohen J Clin Epi. 2007; Gal Submitted Funded by the European Union

The case of Ebola • Overall case fatality rate children EVD > 60% • Younger age higher rate of death • Highest CFR in children < 5 years. • Common clinical features on admission – Fever – fatigue – Gastrointestinal signs and symptoms – Bleeding signs uncommon • Asymptomatic infections uncommon Chérif. Eur J Pediatr. 2017; Glynn Lancet Infect Dis. 2017 Source: John Moore/Getty Images Funded by the European Union

The case of Ebola • (EVD) outbreak in West Africa claimed >11 000 lives • Avoidable all-cause mortality was estimated three times higher than non-outbreak periods • EVD associated with reduced utilization of health services • Suspected EVD patients isolated in “Red Zones” in Ebola holding units (EHUs) • For children only 1 symptom and fever was sufficient, vs 3 symptoms in adults Fitzgerald. Emerg Infect Dis 2016; Elston J Public Health 2015; Sesay Public Health Action 2017, WHO 2014; Fitzgerald CID 2017; Glynn Lancet Infect Dis. 2017 Funded by the European Union

“Risk in the “Redzone”: Outcomes for children admitted to Ebola Holding Units in Sierra Leone without EVD Children lower threshold for admission compared to adults and higher risk of exposure to nosocomial infection • • • Children only 1 symptom and fever: EVD suspected Many children admitted alone Difficult to ensure ambulant children stayed in bed space and not touch (potentially) infectious items Fitzgerald CID 2017 Funded by the European Union

“Risk in the “Redzone”: Outcomes for children admitted to Ebola Holding Units in Sierra Leone without EVD Children lower threshold for admission compared to adults and higher risk of exposure to nosocomial infection • • • Children only 1 symptom and fever: EVD suspected Many children admitted alone Difficult to ensure ambulant children stayed in bed space and not touch (potentially) infectious items • 3/630 (0. 5%) children discharged testing negative were readmitted EVD-positive. Fitzgerald CID 2017 Funded by the European Union

“Risk in the “Redzone”: Outcomes for children admitted to Ebola Holding Units in Sierra Leone without EVD in a m e r d l te u Children lower threshold for admission compared to aand higher o adults b w e risk of exposure to nosocomial infection a d t of a d r l e asuspected t t • Children only 1 symptom and fever: EVD t o a v i • Many children admitted alone m p n s i i • Difficult to ensure ambulant children stayed in bed space and not touch a h t m (potentially) infectious items h e c dr r a n e s na • 3/630 (0. 5%) children discharged testing negative were readmitted e r w EVD-positive. t u no o ith unk W Fitzgerald CID 2017 Funded by the European Union

PATHOGENIS/DISEASE IN CHILDREN DIFFERENT FROM ADULTS Funded by the European Union

Source: WHO; Google Funded by the European Union

Outbreaks and children Lessons learned from flu Children Highest influenza attack rates during pandemic and interpandemic periods 1 Greater risk of transmitting influenza than adults 2 Develop disease earlier in epidemic than other age groups 3 School absenteeism tends to occur in the early stages of epidemic 4 School children are important in the dissemination of influenza 1 1. Glezen WP. Epidemiol Rev 1996; 18: 64– 76; 2. Viboud C, et al. Br J Gen Prac 2004; 54: 684– 9; 3. Glezen WP. Epidemiol Rev 1982; 4: 25– 44; 4. Glezen WP, Couch RB. N Engl J Med 1978; 298: 587– 92. Funded by the European Union

Immune response in Children Lessons learned from flu Bodewes, Fraaij & Rimmelzwaan. 2012 ; Exp Rev Vac Funded by the European Union

Cartography and influenza Herfst et al. Science 366, 2012. Funded by the European Union Smith and Fouchier et al. Science 305, 2004.

Hemagglutination inhibition assay data 1 antigenic unit = 2 -fold HI difference Virus 2003 Se 1997 Se 2003 2 -fold dilutions Courtesy Bjorn Koel Funded by the European Union

Antigenic map based on the hemagglutination inhibition (HI) titers of the sera of responders and representative virus isolates of different antigenic clusters Judith M. Fonville et al. J Infect Dis. 2016; 213: 31 -38 © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. Funded by the European Union

HI titer differences between viruses with wild-type or mutant HAs against human sera. ADULTS INFANTS Björn F. Koel et al. J. Virol. 2015; 89: 3763 -3775 Funded by the European Union

Transmission dynamics High exposure to RTIs with • • • Crowding Different transmission route High number of contacts Poor hygiene Co-infections Funded by the European Union

Frequent co-detection of pathogens even in absence of disease Spuessens et al. 2013; PLo. S Med Self et al. 2015 JID epub Funded by the European Union

Frequent co-detection of pathogens even in absence of disease Spuessens et al. 2013; PLo. S Med Self et al. 2015 JID epub Funded by the European Union

A pathogen? A retrospective study HBo. V RSV Any virus positive; 5 yrs n = 990 HBo. V q. PCR positive RSV q. PCR positive n = 178 n = 366 Admitted to PICU: HBo. V Admitted to PICU: RSV n = 49 n = 72 Viral/Bacterial coinfections excluded Only HBo. V suspected Only RSV suspected n=7 n = 17 NGS, co-detection NONE one rhino + HBo. V SOLE PATHOGEN RSV SOLE PATHOGEN n=7 n = 14 Moesker. Clin Microbiol Infect. 2015 Funded by the European Union

Specific Death Rate The Flu Orphans. Children in the Alaskan village of Nushagak survived the Spanish flu 2500 2000 1500 Alaska State Library 1000 500 0 1911 -1917 1918 <1 1 to 4 5 to 14 1524 2534 3544 4554 5564 65 - 75 - 22 >85 74 Funded 84 by the European Union

Infections in children The infectious diseases ‘’honeymoon period’’ 1918 Alaskan Flu orphans Herpes viruses autoimmune (ie SLE/sarcoidosis) rare SARS/MERS * Ahmed, Oldstone, Palese Nat Med 2007 23 Funded by the European Union

Host genomic response: aged vs young macaques infected with SARS-Co. V -> Differential activation of pathogenic pathways in aged macaques Smits et al. Plos Path 2010 Funded by the European Union

DISEASE PHENOTYPES DIFFERENT IN CHILDREN COMPARED TO ALDULTS Funded by the European Union

Silvennoinen et al. , Eur J Clin Microbiol Infect Dis 2012 Funded by the European Union

Front Microbiol. 2017 Funded by the European Union

Not all infections are the common cold! Incidental transmission zoonotic influenza virus to Chidlren § School-aged patient mild eczema § Respiratory disease after contact pigs § Within days PICU admission and ECMO § Start antivirals -> until full recovery Fraaij Euro Surveill. 2016 Funded by the European Union

Not all infections are the common cold! Incidental transmission zoonotic influenza virus to Chidlren § School-aged patient mild eczema § Respiratory disease after contact pigs § Within days PICU admission and ECMO § Start antivirals -> until full recovery § Typing: Eurasian avian A(H 1 N 1) SIV § Contact tracing no further transition events Fraaij Euro Surveill. 2016 Funded by the European Union

Need for studies in Children • Children obvious and relevant group to include in clinical research during outbreaks: • Excluding young people from research results in – Absence age specific disease (incl. transmission) data – Absence evidence for many medical interventions • Current common clinical practice: use off-label/unlicensed medicines guided by clinicians experience and extrapolation adult data • Families happy to participate in research when a child is sick even when the situation is stressful. Cohen J Clin Epi. 2007; Shilling V. HTA 201’; Abernethy L. E. Paed Emerg Care 2013; Ruggieri 2015, Knellwolf, 2011, Lindell-Osuagwi 2013 Funded by the European Union

Needs to make paediatric epi/pandemic research more feasible as identified by expert panel Area No Regulatory processes 1 2 3 Pre-approved 4 protocols Communication 5 and trust 6 7 8 Area required to make paediatric epi/pandemic research more feasible at a National and European level Recognition of a common purpose and improved relationship between regulatory bodies, ethics committees and researchers Simplified regulatory processes for observational research involving collection, use and sharing of anonymised clinical data (relevant to infectious disease epi/pandemics). Simplified regulatory processes for research involving the collecting, using and sharing of anonymised surplus clinical samples (relevant to infectious disease epi/pandemics). Acceptance of pre-approved protocols for epi/pandemic research Good two-way communicating between researchers and senior government regarding research requirements for emerging infectious disease outbreaks Establishing trust between researchers and senior government regarding research requirements for emerging infectious disease outbreaks A strategy for engagement and good communications with the media Parent and young person engagement and education about epi/pandemic research Gal. Et al. Submitted Funded by the European Union

For consideration while setting up a study protocol: Procedures Funded by the European Union

Make sure to normalize clinical and lab data for age Source: WHO; Google Funded by the European Union

Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants, Children, and Adolescents. Kearns GL et al. N Engl J Med 2003; 349: 1157 -1167.

Procedures in Children Blood University Michigan Medical School: good health, ht not < 38%, 3 months period Body Weight 0 -5 6 -10 11 -15 16 -20 21 -25 26 -30 31 -35 36 -40 41 -45 46 -50 >50 20 30 50 100 150 200 250 300 350 400 450 (kg) Blood Volume (ml) Funded by the European Union ISBER. Biopreservation and Biobanking 2012; Source pictures: Google

Take Home Messages • NEED FOR STUDIES IN CHILDREN • PATHOGENIS/DISEASE IN CHILDREN MAY BE DIFFERENT FROM THAT IN ALDULTS • DISEASE PHENOTYPES MAY BE DIFFERENT IN CHILDREN COMPARED TO ADULTS • CHANGES IN REGULATORY PROCESSES MY HELP FURTHER FACILITATE FUTURE RESEARCH IN CHILDREN • STUDIES IN CHILDREN NEED TO BE ‘’TAILOR MADE’’ Funded by the European Union

Funded by the European Union