Trying to make a difference, was it really planned?: the

journey of a clinical researcher

Trainees meeting 2015

Paul Little Professor of Primary Care Research

University of Southampton

Really - me?

The story of research: the story of a researcher

Outline: Antibiotics for common infections– How come infections?….

– Asking a series of questions • From Nepal (descriptive epidemiology) • …through Ivan Illich (sociology) • ….trialling pragmatic strategies (trials methodology)• ….and 'Killer bugs’ (microbiology) • …to complex intervention development to change

behaviours (health psychology)

– Recurring theme: good consultation skills

The story of a researcher:

How come infections?

Not initially!

Lifestyle change in hypertension (Brighton; Lord Trafford )

Lord Trafford

Why infections?: serendipity

‘Behind every successful man is a surprised woman!’

What is the connection?

.…..Neil Weir (ENT) and the charity BRINOS

(British Nepal Otology Service;medical team of the year 2013)

BRINOS’s question?:

What is the prevalence, and main causes of ear disease and hearing impairment in Nepal?

Why Ear Disease in Nepal?• Deafness the biggest disability (WHO survey)

Early research: how difficult could research be?...

The inexperience of youth?

• BRINOS is/was a small charity – Offered £20,000 to do the study…..

• Research in developing countries is difficult • and I still knew nothing...(at least I knew I knew nothing!?)

– Liverpool School Tropical Medicine (LSTM)– Professor Newell

The inexperience of youth?

Professor Newell

Methods

• Screened all reporting ear or hearing problems: field audiometer, otoscopy– and sample of those with ‘no problem’

• Stratified random sample n=15,845– Eastern (wet) and MidWest (dry) regions– 3 areas in each: terai, hills, mountain

Map of Nepal

Nepal - findings

• 16.6% had hearing impairment• Mostly due to otitis media• 55% school age otitis media

• Traditional remedies prevalent• animal urine, leaves!!

• 61% with ear pathology had never been to health post – and when they did, often no antibiotics!

Back to the registrar year

Why infections in a developed

country?…

–The commonest symptoms:• impact NHS/society

sickness disability

–25-30% consult each year RTIs

–Very high expectations for antibiotics, most got antibiotics

‘I’ve got tonsillitis again doctor’

Did the evidence support antibiotics?

BUT..its Friday pm, you are running late…… would you say no antibiotics to these ladies?

Medicalising illness?

Sociology: Ivan Illich – Medical Nemesis and ‘medicalisation’

‘Modern medicine is a negation of health. It isn't organized to serve human health, but only itself, as an institution. It makes more people sick than it heals’

How important is medicalisation in

acute illness?

The potential problem with medicalisation: the iceberg

Self care

Pharmacy/NHS direct

General practice: 1:9

Secondary care: 1:3300

How to assess the importance of

medicalisation?

Sore throat trial

Open trial of prescribing strategies:–No offer of antibiotics– Immediate antibiotic prescription –Delayed prescription

The boss?...not again!?

A great mentor, a good environment!

Compete with training (LSHTM)

Develop (‘bad’) open trial methodology– ?Drug vs no drug: NO: prescribing strategies

– ?Placebo blinded: NO: Patients had to know;

• Structured support for placebo effect

– ?Outcome ‘objective’? (inspect;swabs;pills count etc):

NO: all medicalising, needed light follow-up

• validated diary informed by qualitative work

Main results sore throat trial (n=715)

010

2030

4050

6070

8090

100

% better satis belief Ab future

AntibioticNo antib.delayed

%

p<0.001p<0.001

Even one antibiotic prescription is strongly

medicalising

..fuelling reconsultations,antibiotic use…

Antibiotic prescriptions vs antibiotics usedFigure 1: Time trend in antibiotic prescribing to children in UK general practice 1993-2004 estimated from national prescribing data and the IMS GP prescribing database (1993=100)

0.0

20.0

40.0

60.0

80.0

100.0

120.0

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

IMS data

PPA data

Serendipity: patients’ perception of communication

• Satisfaction:– doctor dealing well

with concerns (chi square 362 kappa 0.79)

00.5

11.5

22.5

33.5

44.5

5

very not

z=3.3, p=0.001

satisfied

Durationdays

Back to antibiotics……

Do antibiotics work any better in

the other infections we see? (series of studies:OM/chest/conjunctivitis/sinus)

More studies…..:…….similar messages!

It is possible to get bored with the same message….

More studies OM/sinusitis/chest infections:

Do Abs help symptoms? : not much!

Evidence from RCTs, systematic reviews

prior duration

duration after seeing doctor

total duration untreated

Benefit from antibiotics

NNT

otitis media

1-2 days 3-5 days 4 days 8-12 hours 18

sore throat

3 days 5 days 8 days 12-18 hours 10-20

sinusitis 5 days 7-10 days 12-15 days 24 hours 13

bronchitis 10 days 10-12 days 20-22 days 24 hours 10-20

Increasing concern?:Headline News March 2012

• Resistance to antibiotics could bring "the end of modern medicine as we know it", WHO claim

………but is it our problem?

Is it our problem?: yes!• Medicine > Agriculture• 80% of (medical) antibiotics are prescribed in

primary care– most patients still get antibiotics!

• But does our prescribing really impact resistance?

Trends in Prescribing of Antibacterials in General Practice in England

© Copyright NHSBSA 2012

0

100

200

300

400

500

600

700

800

Apr.97-Mar.98

Apr.98-Mar.99

Apr.99-Mar.00

Apr.00-Mar.01

Apr.01-Mar.02

Apr.02-Mar.03

Apr.03-Mar.04

Apr.04-Mar.05

Apr.05-Mar.06

Apr.06-Mar07

Apr.07-Mar08

Apr.08-Mar09

Apr.09-Mar.10

Apr.10-Mar.11

Apr.11-Mar.12

Item

s pe

r 100

0 Pa

tient

s

Penicillins Tetracyclines MacrolidesCephalosporins Sulphonamides & trimethoprim QuinolonesMetronidazole & tinidazole All other antibacterial drugs

What is happening to primary care prescribing in England?: progress reversed 2004 onwards

7% increase

Trends in prescribing of antibacterials in General Practice in England

What is going on?...time for qualitative work

What do GPs think about resistance?

What are their key concerns?

GPs views of resistance? (Wood et al)

• recognise the importance of resistance

• BUT: ..not a problem in their practice!

• Blame hospitals/other prescribers!

GPs’ key concerns? (Kumar et al )

• Main concerns: severe symptoms, complications– Matches patient concern

• ad hoc targeting • pus, temperature,demographic, diet etc

Can we improve the evidence for better targeting of antibiotics

for bacterial infections?

…..and will it make any difference!

Flesh eating killer bugs! (=streptococci)

June 2014:

‘A long-serving and well-loved pastor has been killed by a flesh-eating bacteria’

(i.e. necrotising fasciitis)

Can we target strep. in sore throat?

• Options for targeting– Clinical score? e.g. Centor (pus, nodes, fever, no cough):

– Developed for Lancefield Group A

– RADTs? (rapid streptococcal antigen tests)– Group A Strep only

• What about non Group A? (C,G)• Major virulence factors/rates of septicaemia similar

Are C+G strep relevant?: probably!– Strep. in 34-40% (n=517;n=606)

• 25% C or G– similar clinical presentation to group A

Predicting A/C/G streptococci?

FeverPAIN (AUC 0.70):•*Fever last 24h• Pus•*Attend rapidly (<=3 days)•*severely Inflamed tonsils• No cough or coryza (i.e. pharyngeal

illness)

*=univariate and multivariate in both cohorts

Does better diagnosis/targetting (using a clinical score or RADTs)

lead to better outcome?

PRISM Trial

– Empirical delayed prescribing (control )– 5 item clinical score (FeverPAIN)

• 0-1 <20% strep (none), • 2-3 39% strep (delayed), • 4+ 63% strep (immediate)

– RADT • Similar but test for higher scores (3+)

Results: Delayed(control)

FeverPAIN RADT

Duration (moderately bad or worse Sx)

Median 5 days

HR 1.30* (1.03 to 1.63 )

HR 1.11(0.88 to 1.40)

Antibiotic use 75/164 (46%)

RR 0.71*(0.05 to 0.95)

RR 0.73*(0.52 to 0.98)

All models controlled for fever and symptom severity at baselineNo difference in returns within one month or following

So better diagnosis (targeting using FeverPAIN) improves symptom control and lowers

antibiotic use

• RADTs similar but no clear advantages to a clinical score alone.

Targeting:How common are complications

and can we predict them?

Does delayed prescribing prevent complications?

DESCARTE sore throat cohort

• n>13,000!

• Multi-centre collaboration: Friendship groups SW SAPC– trusted colleagues to build major multi-centre

collaborations – The social nature of research

DESCARTE

Results: Complications are uncommon

No antibiotics Antibiotics DelayedAntibiotics

Complications (total) 73/4536 (1.6%) 75/5750(1.3%) 16/1664 (1.0%)

Quinsy 11/4,536 (0.2%) 30/5750 (0.5%) 4/1,664 (0.2%)

Sinusitis 23/4,536(0.5%)

10/5750(0.2%) 2/1,664 (0.1%)

Otitis media  

30/4,536(0.7%)

26/5750 (0.5%)

10/1,664 (0.6%)

Celluliltis/impetigo 10/4,536(0.2%)

9/5750 (0.2%) 0/1,664 (0.00%)

Can we predict complications in sore throat?: Not very well!

• Only two variables:– severe tonsillar inflammation (OR 1.92) – severe earache (OR 3.02)

• modest utility AUROC 0.61 (chance=0.5!)– 70% complications when neither variable present!

Delayed prescribing prevents complications as effectively as

immediate antibiotics.

No antibiotics Antibiotics DelayedAntibiotics

Adjusted RRs

StratifiedPropensity score(Multiple Imputation)

1.00 0.61(0.40;0.94)

0.55(0.31,0.98)

..and lowers reconsultations more effectively than immediate

antibiotics

Adjustment No antibiotics Antibiotics DelayedAntibiotics

Adjusted RRsAll control for clustering

StratifiedPropensity score(Multiple Imputation)

1.00 0.76(0.68;0.86)

0.58(0.49,0.67)

• So complications are uncommon, and we cannot very effectively predict them

• But if considering an antibiotic, consider delayed prescribing?– prevents complications, reduces reconsultations – at least as effective as immediate antibiotics.

DESCARTE sore throat cohort

Targeting in chest infections?:

The patient: ‘I’ve got green sputum doctor’

The doctor: ‘how do I know antibiotics won’t work for my particular patient?’

(green sputum, smoker etc)?

…….the overall data is modest (few RCTs) and not helpful for subgroups?

• 3012 adult patients with LRTI in 12 countries– acute cough (<28 d) main symptom

• or GP suspects acute bronchitis or pneumonia

• 2061 randomised: amoxycillin 1 gr TID or placebo

GRACE trial :

GRACE Network: Again friendships to build major

collaborations!

1. General practice Respiratory Infections Network (GRIN)

2. Flexibility; trust;

.....?requiring less dosh for the University?

Resolution of bad symptoms: overall data

Day 7-8 ‘survivor’

Log rank Hazard ratio P/NNT

Whole data set(n=1799)

0.465 vs 0.395

P=0.172 1.06

(0.96 to 1.18)

NNT 15

P=0.229

Resolution of moderately bad symptoms ( whole data set)

0.0

00.2

50.5

00.7

51.0

0

0 10 20 30analysis time

groupnumber = 0 groupnumber = 1

Kaplan-Meier survival estimates

time to resolution of moderately bad symptoms

What about my particular patient?Hazard ratio P

Interaction term?(p)

Smokersn=486

1.20(p=0.121)

1.23(1.01 to 1.50)

0.044

NNT 9

Age 60+n=550

0.86(p=0.166)

0.95(0.79 to 1.14)

0.555

NNT 143

Green Sputumn=346

1.28(p=0.059)

1.31(1.05 to 1.65)

0.019

NNT 8

Comorbid n=438

0.99(p=0.914)

1.06(0.86 to 1.31)

0.581

NNT 14

Green sputum subgroup0.0

00.2

50.5

00.7

51.0

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0 10 20 30analysis time

groupnumber = 0 groupnumber = 1

Kaplan-Meier survival estimates

time to symptom resolution - green phlegm subgroup

Smokers0.0

00.2

50.5

00.7

51.0

0

0 10 20 30analysis time

groupnumber = 0 groupnumber = 1

Kaplan-Meier survival estimates

time to symptom resolution - current smoker subgroup

Benefits vs harms: side effects!

• Nausea, rash, or diarrhoea

Antibiotic 29%

Placebo 24%• NNH 21

Targetting?: 6 symptoms and signs predict consolidation

History (day 1)

Severe cough present

931 (33)

56 (40)

1.4 (1.0-2.0)

. 1.1 (0.7-1.6)

Phlegm present 2239 (79) 120 (86) 1.6 (1.0-2.6) N.A. Breathlessness present Severe breathlessness present

1594 (57) 197 (7)

96 (69) 17 (12)

1.7 (1.2-2.5) 1.9 (1.1-3.4)

1.4 (1.0-2.1) 1.3 (0.7-2.4)

0.025 0.419

Runny nose absent 807 (29) 61 (44) 2.0 (1.4-2.8) 1.9 (1.3-2.7) <0.001 Fever present 989 (35) 82 (59) 2.8 (2.0-3.9) N.A. Chest pain present Severe chest pain present

1304 (46) 141 (5)

80 (57) 13 (9)

1.6 (1.1-2.2) 2.1 (1.2-4.0)

1.2 (0.8-1.7) 1.5 (0.8-3.1)

0.402 0.224

Diarrhoea present 199 (7) 15 (11) 1.6 (0.9-1.8) 1.5 (0.8-1.8) 0.165 Physical examination (day 1) General toxicity 739 (26) 43 (31) 1.3 (0.9-1.8) 1.1 (0.7-1.6) 0.728 Diminished vesicular breathing 362 (13) 31 (22) 2.0 (1.3-3.1) 1.7 (1.1-2.6) 0.013 Crackles 264 (9) 44 (31) 5.3 (3.6-7.7) 3.5 (2.3-5.2) <0.001 Tachycardia (pulse >100 beats/min) 111 (4) 17 (12) 3.7 (2.2-6.5) 2.3 (1.3-4.3) 0.003 Tachypnoea (>24 breaths/min) 55 (2) 6 (4) 2.4 (1.0-5.7) 1.4 (0.9-2.0) 0.421 Blood pressure <90/60 mmHg 71 (3) 9 (6) 2.9 (1.4-5.9) N.A. Temperature >37.8°C 156 (6) 22 (16) 3.5 (2.1-5.7) 2.5 (1.4-4.4) <0.001

Simple risk stratification

• 2 history: Breathless, no coryza• 2 chest signs: bronchial, crackles• 2 vital signs: pulse >100, temp. >37.8

• 0 = 1% have consolidation• 1-2= 5% (most here…)• 3 = 20%

Will antibiotics work for my particular patient with a chest infection?:

• Modest benefits even in key clinical subgroups, modest disbenefits…

• Don’t prescribe for the vast majority! – Consider antibiotics/delayed antibiotics for

3+ key symptoms/signs?

So we need to be able to communicate effectively……

Can we improve communication, and will it help reduce antibiotic use?

Lack of time

Acute infection: a quick consultation?

How to change clinician prescribing behaviour?

GRACEINTRO (INternet TRaining for

antibiOtic use) Trial

Web based training: four groups

• No training

• Communication– enhanced communication training + booklet

• CRP training – cut points; kit demonstration

• Both: Communication and CRP

n=6771 baseline Post-intervention n=4264

Enhanced Communication/Information sharing

• Addressing the patients world– Concerns, – Expectations, – Attitudes

• Information exchange: booklet– Natural history; – Risks/benefits of antibiotics– Self-help – Safety netting

• Wrap up– Summarise– Check understanding, other concerns

We can communicate effectively and it makes an important difference:

RR(adjusted for patient variables)

p

Control 1.0

CRP 0.47 (0.35 to 0.64) <0.001

Communic’n 0.66 (0.50 to 0.85) <0.001

Both 0.39 (0.28 to 0.54) <0.001

Can we help symptoms with simple advice (PIPS study)?

PIPS study • Randomised strategies

– analgesic strategies

• Paracetamol vs ibuprofen vs combination;

– steam inhalation (factorial design)

Patients complied … BUT trivial differences in symptom severity overall

Pmol(control)

Ibuprofen Both

Whole cohort(743/889;84%)

1.67 +0.04(-0.11 to 0.19)

+0.11(-0.04 to 0.26)

• 10 symptoms: 0=no problem……6 as bad as it could be

Ibuprofen better in chest infections and for children

Ibuprofen interfering with the immune response?:

More reconsultations:same/new/worse symptoms

Pmol(control)

Ibuprofen Both

Reconsultation(same Sx, new Sx, or worse Sx)

35/300(12%)

58/295(20%)**

48/295(17%) 1

Adjusted RR

1 1.67 (1.12 to 2.38)

1.49(0.98 to 2.18)

** p=<=0.01 1 p=0.06

Complications higher

Pmol(control)

Ibuprofen Both

Complication 2/300 (0.6%)1 cellulitis1OM

11/295 (3.7%):1 Quinsy3 sinusitis1 meningitis1pneumonia5 OM(2 not new)

4/295 (1.4%):1 Quinsy2 sinusitis(1 not new)1 cerv. adenitis

Steam?– No benefit– Mild thermal injury in 4 patients (2%) who

returned full diaries• No reconsultations with scalding

We are probably doing more harm than good with widely given self help advice!

• ibuprofen little help overall– ? for chest infections and children. – BUT progression of symptoms/complications

• Advice to use steam does not help– and occasional harm

Can we prevent infections?

The PRIMIT trial of a web based behavioural intervention to reduce infection transmission

(in press)

Handwashing?

• Hand-washing widely advocated– e.g. H1N1 pandemic– but role of handwashing debated!

• No good randomised evidence among adults in our (resource rich) setting.

Developing a complex intervention

• Initial qualitative/questionnaire studies: – Confirm useful target behaviour (handwashing)

• determinants; barries/facilitators

• Further qualitative/questionnaire studies: – (‘think aloud’) for draft materials– tested key assumptions

• Randomised pilot of prototype website: – Changed behaviour (increased handwashing) .

Results: infections prevented 20,066 randomised

16,908 (84%) followed-up

Intervention Control p

Any RTI at 4 months 51% 59% <0.001

Any RTI (in household) 44% 49% <0.001

Transmission reduced to and from household members

Intervention Control p

Transmission to household

7.8% 9% <0.001

Transmission from household

6.8% 8.8% <0.001

Infections slightly less severe

Intervention Control p

Days more severe symptoms if RTI

4.1 days 4.3 days 0.008

Reduced consultations, reduced GI infections

Intervention Control p

Consultations for RTIs (notes)

18.9% 20% <0.001

GI infections  

21.5% 25% <0.001

We can prevent infections!

• A free standing web intervention increases hand-washing – reduces infections, their severity, and transmission,

• ?Pandemic: will access internet for advice.

Had enough?

Have we learned anything useful?

• Antibiotic resistance: a public health problem we generate!• Antibiotic prescribing: medicalises, fuels demand/resistance• For symptoms: antibiotics overall/subgroups mostly not helpful

• A ‘bacterial’ score in sore throat helps symptoms, reduces antibiotics • Commonly given advice (steam/ibuprofen) is probably harmful!

• For complications:• Sore throat: Uncommon/difficult to predict:

– Good safety netting skills– if antibiotics are considered, consider delayed prescribing?

• Chest infections: basic clinical history/exam. help identify consolidation

• For prevention: a behavioural web handwashing intervention helps• prevents infections, reduces severity, and reduces transmission

Reflections on infection research• Acute infections are relatively quick/easy consultations

in a world of increasing demands…BUT:– a central public health role– a central role for better communication

• a little more time, BUT saves time in future!• brief training for experienced GPs helps

• Practice changing research:– Good mentorship and training – Large collaborations (friendship!)

• Powered for subgroups/adverse outcome

– Mixed methods, carefully developing complex interventions • really understand and change behaviours!

• …Is such research valued?

Having ideas and getting grants…..rejection?

Rejection

Don’t let it get you down ?Recycle or resubmit:

• If the referees points are answerable

Picking the ones to resubmit (otherwise they might get tired of

you!)

• BUT……..Keep going if it’s a good idea!

Why we don’t write enough grants? Perfectionism?

• The best is the enemy of the good…… Insufficient protected time

• Structural (other responsibilities; competing demands)

• distraction;faffing……. Failure?......expectations?..assume

2:3 or more to go down• Aim to be working on 2-3 ideas at any

one time……• Try and recycle……

Other excuses…..

• SO PUT ASIDE TIME IN THE DIARY• DON’T ANSWER EMAILS………….(AND DON’T HAVE A BEER BEFORE!)

Success? (5 S’s)

Space/time, Story (idea), Sharp (methods),Support (peers/team/social)Stamina

James McKenzie

‘For some years I went blundering on, gradually falling into a routine, i.e. giving some drug that seemed to act favourably on the patient, till I became dissatisfied with my work and resolved to try and improve my knowledge by more careful observation.’

Lack of timeWhat aspects of communication

are important to patients?:

Patient-centredness cohort

• Assessed patients’ perceptions of patient centredness:– develop questionnaire – assess domains empirically (factor analysis)

• Communication and Partnership• A personal Relationship• Health Promotion• A positive and Clear approach to the problem• Interest (of the doctor) in the effect of the illness on life

• Determine relationship of 5 domains to outcome (n=865; all conditions)

Stem (unless specified): The doctor ..... % agree Factorloading

Factor 1 communication and partnership

Was interested in my worries about the problem 80 0.68Was interested when I talked about my symptoms 93 0.80Was interested in what I wanted to know 86 0.67(Full question:) I felt encouraged to ask questions 80 0.54Was careful to explain the plan of treatment 80 0.58Was sympathetic 85 0.59

Was interested in what I thought the problem was 80 0.80Discussed and agreed together what the problem was 75 0.62Was interested in what I wanted done 75 0.67Was interested in what treatment I wanted 62 0.52Discussed and reached agreement with me on the plan of treatment 76 0.56

Results: Factor analysis of patients’ perceptions

Cronbach’s alpha 0.96

Relationship of domains to outcome: Satisfaction (MISS) : communication, positive

beta

Enablement: interest in life, health promotion, positive

beta

Symptom burden (MYMOP): positive, health promotion

beta

Results III• Referrals less if ‘personal’ relationship

– odds ratio 0.70 (0.54 to 0.90)

So are domains of communication important?

• There probably are distinct domains of patients perceptions of communication– Probably reliable– support the patient centred model

• Different domains => different outcomes (satisfaction, enablement,symptoms,referrals)– important for both patients and health service