What were the limitations of this work?

Active recruitment was suspended between May and September 2011 as there were inadequate numbers of staff to conduct the study effectively. During this period, only potential subjects identified by NHS colleagues were screened and, since there were very few pneumonia cases presenting to the hospital, this effectively meant recruitment stopped (see figure 3.1 central panel). Following the addition of a nurse to the study team, active

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78 case finding resumed in October 2011. Due to the small number

of cases recruited prior to this pause no formal statistical comparison was been made with the main body of subjects; however, no clear differences could be seen and the recruitment criteria were identical before and after.

3.3.3.2 In-eligible patients with CAP

Three quarters of patients being managed as CAP by the hospitals could not join the study as they failed to meet the PASS inclusion criteria. The most common reason for this was the identification of the patient after 24 hours had elapsed since their first dose of in-hospital antibiotics. ‘Late’ identification of patients was a manifestation of the complexity of hospital pathways, and in many instances a late clinical diagnosis. Late clinical diagnoses occur where a patient is not immediately recognised as having CAP – but occult infection is included in the differential diagnosis and antibiotics are administered. As test results arrive and more senior clinicians review the case, or opinions on the CXR change, the diagnosis becomes crystallised as CAP but by that point a study’s opportunity to recruit may have passed. Another frequent reason for a patient being unavailable for recruitment within 24 hours is admission at the weekend. Most of the time PASS was unable to recruit after 1600 on Friday evening and this meant all patients admitted from then to midway through Sunday would be ineligible. Another common reason for ineligibility was dementia of a level that meant the CAP-sym questionnaire could not be completed. A less frequent but important reason for ineligibility were patients who were expected to die shortly after admission or who were rapidly intubated and ventilated.

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79 Ineligibility for the reasons listed above may have influenced our

results. Although the time and day of presentation is unlikely to have affected the findings of the CAP-sym analysis, efferocytosis or microbiota studies – dementia and severe disease requiring ITU care may have done. Patients with dementia may have been more likely to aspirate and or have Gram negative pneumonias. Patients with severe disease may have had a higher incidence of pneumococcal disease.

3.3.3.3 Duration of illness and prior treatment

This was, as far as possible, a pragmatic cohort designed to be representative of CAP in an acute UK hospital. As such a proportion of subjects were several days into their disease episode at the time or recruitment. Some patient’s route to hospital was to see the GP, be diagnosed with lower respiratory tract infection, attend for an outpatient CXR then at GP follow-up they were referred to hospital due to ongoing symptoms. The initial CAP- sym score may therefore not always have captured the initial trajectory of symptoms. Since some patients had been pre-treated with antibiotics in the community prior to enrolment this will undoubtedly have affected the microbiological identification of the casual organism by culture and will also have had an impact on the microbiota identified. However, all patients met the case definition of CAP at recruitment and were prescribed in-hospital antibiotic suggesting they had ongoing symptoms of acute infection. This is reinforced by the high levels of CRP and pro- calcitonin measured in this group suggesting that a large proportion of the cohort were still in an acute inflammatory state at enrolment.

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80 3.3.3.4 Ethnicity

A striking feature of the PASS cohort was its ethnic uniformity with 98% of subjects being white British. The ethnic distribution is PASS is however a very close reflection of the local population. In Liverpool local health authority 84.8% of people report being white British, 2.6% as white other and 1.8% as Black African. In Knowsley local health authority, which is directly in the catchment of University Hospital Aintree, 96.1% of people are white British, 0.2% are Black African and 0.7% white Other.[129] This distribution of ethnicity is very different to many areas of the UK including central Manchester which is only 30 miles away. Ethnicity may impact on the incidence, severity, recovery and, mortality from pneumonia via cultural associations and mechanistic effects. For example dietary differences can significantly affect the gut microbiota which in turns affects immunity at distant sites such as the lung.[130] Differences in Vitamin D levels have had been linked to incidence and outcomes in pneumonia and patients from different ethnic backgrounds can have profound differences in vitamin D metabolism due to dietary, skin pigmentation and microbiome effects.[131]

3.3.3.5 Socioeconomic status

The socioeconomic profile of the PASS cohort was heavily biased towards the lowest end of the socioeconomic spectrum of England. Since the incidence of CAP is 70% higher among the most deprived quintile of England’s population than among the least deprived, patterns of admission for CAP may be different in other areas.[118] Since low socioeconomic status is associated with higher comorbidity and worse outcomes in many diseases this may reduce the generalisability of these findings to more affluent

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81 populations. Future multi-site studies could investigate this by

clustering sites based on socioeconomic data.

3.3.4 Comparison with other published work