Pediatric Primary care

Infectious Diseases

Corinne Levy, Robert Cohen

ECPCP Autumn meeting – Lyon, France

Friday 8 November 2019 - Sunday 10 November

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The questions are:

Why we have to create ambulatory

networks?

And how ?

Activ birth 👼 Before the 1990s, in France, as in many countries, ambulatory pediatricians were

“excluded” from “research”

Nobody had clearly excluded them, but they were not included in any research project

Clinical studies were performed in hospital by "UNIVERSITIES" with "ACADEMICS ».

Compare to patients in ambulatory settings, patients « profile » seen at hospital are

different:

Severity, epidemiology, resistance, etc…

In this context, we created an non-profit research group, “ACTIV” (Pediatric Clinical

and Therapeutical Association of Val de Marne) and performed the first French clinical

study in an ambulatory setting

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Few words of our research group, ACTIV

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ACTIV is a National Non-Profit

Organization founded in 1988

2 main goals:

- Research in the field of

community acquired infections

- Post-graduate teaching

Funding (pharmaceutical industry >

university > government)

ACTIV board: 12 members

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ACTIV team: 12 members

The research platform

Built over several years

The ACTIV Network is widely represented all over France

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Investigators (pediatricians) and their

training are the cornerstone of the

research system

Investigators quickly and directly

found a real benefit from participation

Adaptation of clinical practices

Feedback to the investigators through

congress organized by and for our

network

Infectious diseases are the most frequent reasons for visits in pediatrics (> 50 à 70% of visits)

• Prevention : Immunization programs and other aspects of well baby visits – Pediatricians are good vaccinators

• Management of community acquired viral or bacterial infections – And frequently the question is: does this patient need antibiotics ?

– Why: It is estimated that antibiotics discovery had prolonged human life do 10 years (As vaccination programs and Hygiene)

– However overuse of antibiotics increase antibiotic resistance

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OR = 2,33 CI 95% 2,19-2,49

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The prescriptions of antibiotics should be guided

by several factors

Usually, medical history, interrogation and examination are sufficient

Sometimes point of care tests could be useful

However, pre-test probability determined by the first point is

always the cornerstone of the test’s accuracy

Does this patient should received antibiotics?

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No

Should I re-evaluate the patient?

Point-of-care test to improve the diagnosis

accuracy ?

Urinary dipstick

Influenza RAT

GAS RAT

Rotavirus RAT RSV rapid test

CRP rapid test?

EBV, Chlamydia, proteinomic…

Does this patient should received antibiotics?

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yes

Which ATB according to the level of resistant strains?

What are the consequences of my ATB prescriptions?

Which treatment duration ?

No Point-of-care test to improve diagnostic

accuracy?

Should I re-evaluate the

patient?

Two examples AOM and Pharyngitis

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AOM studies AOM: leading bacterial infection in childhood

McGrath LJ, PLoS One. 2013; 8(12):e81210

AOM: leading cause of ATB prescriptions

Antibiotics are recommended for young children in most countries in the world

The questions are:

• how to improve the diagnosis?

• which treatment

• which duration?

Comparison of 2 types of ATBs, doses, duration of treatment

Rigorous inclusion criteria

The interpretation of tympanic membrane findings varies by the level of pediatrician experience so…

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AOM : the same disease ?

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Congestive Abnormal color or opacity Bulging Otorrhea

< 6 months 6 months to 2 years > 2 years

Tympanic

aspect

< 38°C 38 to 38.4°C > 38.5°C

Patient

age

Fever

Otalgia

0…………3………….6…………..9……………..12… Number of epidodes

OME between AOM

episodes

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AOM studies

Training sessions to better examine ears

Good otoscopic examination: MANDATORY

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For everyone, in french: https://www.activ-france.com/e-learning/

Entérovirus Autres infections à SGA

Whooping cough, influenza, urinary infections…

The e-learning website

The environment changes (30 years)

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Which impact on

AOM?

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2019

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AOM clinical trials with a network of almost 100 primary care

pediatricians

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AOM ATB treatment depends of the involved bacteria resistance

Sp, Hi, Bc

NP samples

Easy to obtain Painless Non-traumatic Epidemiologic value for monitoring change in bacteria distribution and ATB resistance

Central lab +++

Nasopharyngeal samples

!

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Evaluation of the ecological impact of ATBs for AOMs on composition of NP flora

and ATB resistance

2 NP samples were obtained

before ATB treatment

2/6 days after the end of ATB for AOM

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Among Sp carriers, after ATB treatment, rate of

resistant strains increased after beta-lactam ATB

We had to obtain NP samples for all AOM studies

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To perform these studies we had to deal with…

High-quality standards were required For industrial trials

For European and North American drug regulators

Good Clinical Practice

Publications

And feasibility in real life Simplify as much as possible the work of investigators who enrolled patients in

the study

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One visit = one questionnaire (CRF)

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From ATB treatment to prevention with vaccines

The context: in 2000, PCV7 was soon to be implemented in our country…

The advantage of the expertise acquired

>15000 NP samples collected in 10 years

>15 publications in this field

Which allowed us to perform a pivotal study on NP carriage after PCV7 implementation in France

This study was performed as a post-licensing commitment requested by the

European Medicines Agency to determine the impact of PCV7

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Aim of the study: Determine the changes in pneumococcal serotypes and

change in ATB resistance after PCV7 implementation

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0

10

20

30

40

50

60

70

80

1 (n=663)

2 (n=573)

3(n=658)

4(n=622)

5(n=750)

6 (n=645)

7(n=530)

8(n=600)

9 (n=601)

10(n=598)

11(n=582)

12(n=591)

13(n=578)

14(n=582)

15(n=547)

16(n=539)

17(n=545)

18(n=536)

Sp PCV7 ST ST 6add+6C Non PCV13 ST

% children

Non

PCV13

6

add+6C

Sp

PCV

7

PCV13 PCV7

Sp Nasopharyngeal Carriage, AOM fever± otalgia, 10 740 children, 18 y

-7%

Study Years (Year 1: Oct 2001/June 2002, Year 18: Oct 2018/ April 2019)

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Carriage and penicillin susceptibility by vaccination status and

ATB use within the last 3 months

%

Vaccinated +

Antibiotics+

N=491

PSP

IC95%

33 [29%; 36%]

21 [18%; 24%]

31 [27%; 35%]

24 [20%; 27%]

PIP

IC95% 27

[24%; 30%]

34 [30%; 38%]

24 [20%; 27%]

23 [20%; 27%]

PRP

IC95% 10

[8%; 12%]

15 [13%; 18%]

4 [3%; 6%]

8 [6%; 11%]

Non-carriers

IC95% 30

[27%; 33%]

30 [26%; 33%]

41 [37%; 45%]

45 [41%; 50%]

Vaccinated -

Antibiotics -

N=782

Vaccinated -

Antibiotics +

N=650

Vaccinated +

Antibiotics –

N=603

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Tonsillopharyngitis diagnosis

GAS Virus

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Antibiotics are recommended in most countries

Antibiotics are not recommended

The accuracy of clinical scores are not sufficient for children

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We are able to confirm that

RADT are >>> clinical scores

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Link with the hospital network

Following the successes of our studies and network in

ambulatory settings,

The French Society of Pediatric Infectious Diseases entrusted us

with the surveillance of community acquired infections visiting

emergency room or hospitalized

It was particularly important for pneumococcal diseases : we

need multifaceted impact of PCV implementation

The ambulatory surveillance was not enough to totally evaluate

IPD

National hospital network for bacterial meningitis

A team of pediatricians (n=230) and microbiologists (n=168) in

each participating center had to report standardized clinical and

laboratory data for meningitis

Close collaboration with experts of national reference centers for

different bacterial species

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Our research line for infectious diseases: ambulatory and hospital

Example of studies Cohorts Number of International Publications

Starting

year

Number of

enrolled patients

Where?

NP carriage (AOM+ healthy

controls)

2001 18 000 Ambulatory N=20 (Clin Infect Dis, Vaccine, PIDJ, BMC inf Dis, J Antim

Chem, Emerg Inf Dis, Plos one)

Bacterial meningitis 2001 7200 Hospital N=35 (Lancet Inf Dis, Clin Infect Dis, Vaccine, PIDJ, BMC

inf Dis, Clin Micr, Infect, An Emerg Med, Acta Ped, EJCMID,

J Ped)

Pneumonia 2009 16 000 Hospital N=6 (Jama Ped, Clin Infect Dis, Vaccine, J Ped Inf Dis,

BMC Ped, Arch Dis Child)

IPD 2010 1000 Hospital N=2 (Clin Infect Dis)

IPD ECDC study (SPIDNET) 2013 250 Hospital N=1 (Lancet Resp Med)

E coli ESBL carriage 2010 3600 Ambulatory N=8 (BMC infect Dis, JAC, Emerg Infect Dis, Plos One, Vaccine)

GAS studies 2012 1600 Ambulatory N=14 (Clin Infect Dis, Plos one, CMAJ, J Clin Epidemio, Eur

J Microb, Int J Med Microbiol )

Pertussis 2002 800 Ambulatory N=3 (Vaccine, Emerg Infect Dis, Arch Ped)

Otorrhea 2015 600 Ambulatory N=1 (Plos One)

https://www.activ-france.com/Publis_en.php

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Epidemiology in primary care?

Yes ! if we address areas of concern for primary care physicians

Most of our research projects try to answer a “daily” clinical question related to professional practice in order to promote a pediatric best practices for the benefit of children

• Improving the diagnosis

• Improving the management of pediatric infectious diseases

• Quick practical application for pediatricians+++

Studies initially dealt with respiratory-tract infections, which are particularly

suitable for clinical or epidemiological studies

– their frequency

– the ease in obtaining samples (NP+++)

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A recipe? By co-opting

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joinmynetwork#pediatricians#research

Conclusion

Always placed investigators and their training at the cornerstone of the research

system

Never forget to provide results of the studies and feedback to the investigators+++ (congress, publications)

Try to have fundings according to the objective of the study scheduled

(government, university and pharmaceutical industry)

Challenges : maintain several well-established

surveillance systems and increase the involvement of

young researcher-pediatricians

“Successes have a thousand fathers, failures are orphans”

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ACKNOWLEDGMENTS