The 3C cohort study of LRTI in primary care Predicting adverse outcome from lower respiratory tract infection in primary care: The 3C cohort study of LRTI in primary care Moore, M. Little, P., Stuart B, Smith S, Thompson MJ, Knox K, van den Bruel A, Lown,M., Mant,D 01 June 2015

Family Practice in Salisbury University of Southampton No financial or other conflicts of interest

Where?

Overview LRTI- why prescribe? Methods Results Clinical Implications

Background Lower Respiratory Tract Infection LRTI: Is common Antibiotics often prescribed NAPCRG 2016

Respiratory infection account for the majority of outpatient prescribing UK database data 568 practices 2010-11 Median prescribing rates -48% for ‘cough and bronchitis’ -60% for ‘sore throat’ -60% for ‘otitis-media’ Median for RTI 54% (39-69%) lowest/highest

Background Drivers of prescribing in LRTI: Relief of symptoms? Worries about pneumonia? Worries about adverse outcome?

Background- symptom relief? Cochrane review acute bronchitis -17 trials 2936 participants No difference in clinical improvement Some reduction in cough and night cough Modest reduction in cough duration (-0.46 days) Cochrane library 2014

Background- symptom relief? GRACE study whole population n=2061

Background- symptom relief? GRACE study age over 60 NAPCRG 2016

Background- symptom relief? GRACE study: Green sputum NAPCRG 2016

Background- symptom relief? GRACE study: Smokers NAPCRG 2016

Background- symptom relief? GRACE study: Missed radiological pneumonia

Background- symptom relief? In Summary: For symptoms: Overall cochrane review modest treatment effect GRACE study subgroups: Only those with missed radiological pneumonia derived significant benefit Worth thinking about the diagnosis of pneumonia

Background- worry about adverse outcome? Re-consultation with new or worsening illness Admission Death Late onset pneumonia

Methods Adults presenting in UK general practice with LRTI had symptoms, signs, and antibiotic prescribing strategies recorded. Re-consultation with new or non–resolving symptoms, or hospitalisation or death, were documented within 30 days. NAPCRG 2016

Methods Inclusion Patients aged 16 or over presenting in UK general practice with acute LRTI. We used a pragmatic: cough as the main symptom, judged to be infective in origin by the GP. Exclusion: other cause of acute cough (e.g. heart failure, acid reflux, fibrosing alveolitis etc); patients unable to fill out the diary; immune compromised; previously presented with the same episode of illness

Results 28867 adult patients with acute cough were recruited with informed consent by 522 general practices in the UK General Practice Research Network between October 2009 and April 2013

Baseline characteristics Age >60 38% Female 59% Co-morbidity 30% Hx of fever 38% Chills 32% Fever >37.8 6% Sats <95% 6% Low BP 8%

Results -28867 37 same day admission to hospital 6484 patients re-consulted within 30 days 258 hospitalisations in total 720 were referred for a chest x-ray in the first week 30 patients died 7349 (25%) no antibiotic 17573 (61%) immediate antibiotic 3819 (13%) delayed antibiotic prescription

Results- re-consultation Based on notes review including all settings 6,484 re-consultations 268 of these were adverse reactions More severe symptoms at baseline- earlier re-consultation NAPCRG 2016

Results- re-consultation

Results- re-consultation Factors predicting re-consultation (No adjusted RR >1.5) Age >60, Female, Pneumovax Lung co-morbidity, on steroid/inhaler SOB, Fever, Chest pain, coryza (-) Muscle aches, rusty sputum (-) Severity assessment, RR, Fever, pulse>100, low sats, crackles, wheeze, bronchial breathing SAPC 2016

Results- re-consultation Multi-varate model factors predicting re-consultation/death: There are 10 variables that predict hospitalisation or death with a RR of 1.5 or higher Age 60+, comorbidity, shortness of breath, chest pain, crackles, higher severity score, high pulse, high temperature, low oxygen saturation and low blood pressure SAPC 2016

- hospitalisation death Results - hospitalisation death 258 hospitalisations -37 same day 30 deaths, of which 15 deaths in patients not hospitalised None of those admitted on same day died Total of 273 hospitalisations or death. Case review 233 relevant hospitalisations 13 relevant deaths Total of 245 relevant admissions or deaths NAPCRG 2016

Results timing of admission

Results- pneumonia In the cohort of 28,883 participants, there are 1782 chest xrays of whom 720 x-rayed within the first 7 days. The results of these are: Outcome 114/720 (16%) pneumonia in first 7 days 111/1062 (10%) late diagnosis pneumonia 11 clinical diagnosis without xray NAPCRG 2016

Results timing of x-ray diagnosis pneumonia

Results- to summarise Risk of serious adverse outcome after presentation with LRTI is low in this cohort of 28883 6484 (22%) re-consultation 230 (0.8%) x-ray pneumonia Admissions 258, 234 (0.8%) related Deaths 30, 13 related (0.04%) SAPC 2016

Results- modelling Is it possible to predict those at risk of serious adverse outcome (admission death) For the clinician- Well if I don’t decide to admit you today- how can I tell who might do badly? 273 hospitalisations or deaths Exclude those - admitted on the day -unrelated to index consultation 122 late diagnosis pneumonia (clinical +xray)

Results- modelling Risk factors at first consultation for death or hospitalization from LRTI complications within 30 days or late-onset or unresolved pneumonia confirmed by x-ray or re-consultation 8-30 days after first consultation (n=325) Analyses controlled for antibiotics at index consultation Prior probability of serious adverse outcome 325/28830= (1.1%)

Patient characteristics

Presenting Symptoms

Examination findings

Results- clinical score Items carried forward significant at the 1% level Nine items combined into a total score which ranges from 0 (none of these) to 9 (all of these). The AUROC of this score is 0.72 (Bootstrapped 95% CI 0.69, 0.75).

Results- clinical score   Risk Ratio (95% CI) p-value O2 sat < 95% 2.37 (1.80, 3.12) <0.001 Age 60+ years 2.02 (1.59, 2.57) SBP< 90 or DBP < 60 mmHg 1.65 (1.16, 2.33) 0.005 Temp > 37.8°C 1.81 (1.29, 2.55) 0.001 Any co-morbidity 1.61 (1.23, 2.11) Chills 1.37 (1.07, 1.74) 0.011 No coryza 1.49 (1.16, 1.91) 0.002 Sputum: purulent 0.74 (0.58, 0.95) 0.015 Severity assessment > 5/10 1.51 (1.15, 1.97) 0.003 Crackles 1.30 (0.95, 1.78) 0.098 Shortness of breath 1.32 (0.98, 1.79) 0.070 Chest pain Headache 0.81 (0.62, 1.06) 0.119 NAPCRG 2016

Results- clinical score   Risk Ratio (95% CI) p-value O2 sat < 95% 2.37 (1.80, 3.12) <0.001 Age 60+ years 2.02 (1.59, 2.57) SBP< 90 or DBP < 60 mmHg 1.65 (1.16, 2.33) 0.005 Temp > 37.8°C 1.81 (1.29, 2.55) 0.001 Any co-morbidity 1.61 (1.23, 2.11) Chills 1.37 (1.07, 1.74) 0.011 No coryza 1.49 (1.16, 1.91) 0.002 Sputum: purulent 0.74 (0.58, 0.95) 0.015 Severity assessment > 5/10 1.51 (1.15, 1.97) 0.003 Crackles 1.30 (0.95, 1.78) 0.098 Shortness of breath 1.32 (0.98, 1.79) 0.070 Chest pain Headache 0.81 (0.62, 1.06) 0.119

Score Items Age 60+, Co-morbidity No coryza History of chills/shivering Presence of chest pain Severity score 6 or over (out of 10) Low BP (systolic <90 diastolic <60) Temp>37.8 O2 saturation <95% ,

Distribution of clinical score N (%) of total cohort with each score None 1293 (5.5%) 1 4071 (17.3%) 2 6456 (27.4%) 3 6119 (25.9%) 4 3693 (15.7%) 5 1444 (6.1%) 6 435 (1.8%) 7 80 (0.3%) 8 9 (0.04%) 9 1 (0.00%)

Predictive value of clinical score Cut off score to use N (%) of total cohort Sensitivity Specificity NPV PPV 1 or more 22,308 (94.5%) 99.2% 5.3% 99.8% 1.2% 2 or more 18,237 (77.3%) 96.2% 22.9% 1.4% 3 or more 11,781 (49.9%) 82.4% 50.4% 99.6% 1.8% 4 or more 5,662 (24.0%) 53.4% 76.3% 99.3% 2.5% 5 or more 1,969 (8.3%) 27.1% 91.9% 99.1% 3.6% 6 or more 525 (2.2%) 11.8% 97.9% 99.0% 5.9% 7 or more 90 (0.4%) 3.8% 99.7% 98.9% 11.1%

Applying in practice? A score of 3 or less (76% of population) NPV 99.6% No treatment A score of 4 (16% of population) PPV 2.5% NPV 99.3% Delayed? A score of 5 or more 8.3% of population PPV 3.6% Immediate prescription

Other scores Some common factors with other risk scores Fever, Low Sats (CCC cohort pneumonia score) Age, Blood Pressure (CRB 65 mortality risk score) Absence of coryza and temp>37.8 (GRACE pneumonia model) Low sats might be a proxy for SOB in GRACE score NAPCRG 2016

Strengths and Limitations Observational data residual confounding Large numbers of patients in real life practice Over fitting of model No validation sample

Implications for Practice A clinical score can be used to predict the risk of hospitalisation/death/late onset pneumonia Although complex (9 item) it could be used to direct antibiotic strategy

Wrapping up Overall little symptomatic benefit from antibiotics It is worth spotting ‘missed pneumonia’ Adverse outcomes are rare after LRTI Use a score to identify those at low risk of adverse outcome This low risk group have little or nothing to gain from antibiotics

Any Questions?