Morbidity of community-acquired pneumonia

Background Community-acquired pneumonia (CAP) accounts for 5-12% of lower respiratory tract infections presenting to primary care in the UK. Of patients who present to their GP with suspected CAP, 22- 42% are referred to hospital for further management in the UK. The majority of patients ( ̴90%) admitted for CAP survive to hospital discharge. However, little is known about the morbidity related to recovery from pneumonia. Methods Three studies in this thesis used large-scale hospitalisation data from Hospital Episode Statistics (HES, England), linked to the Clinical Practice Research Datalink (CPRD), and death registration data from Office for National Statistics (ONS). These studies aim to improve our understanding on the morbidity after CAP and the objectives were: (1) to describe the primary care consultations after pneumonia and the reasons for these consultations (2) to determine the incidence of, and risk factors for developing cardiac complications (3) to determine the incidence of recurrent hospitalisation for pneumonia and the association of tobacco smoking. In addition, published literature on cardiac complications, a major morbidity following CAP and tobacco smoking and passive smoke exposure as a risk factor for developing CAP were systematically summarised. Finally, a multicentre retrospective study was conducted during the first wave of COVID-19 pandemic to determine the proportion of laboratory proven co-infection in critically ill adults with COVID-19 infection in England. Results This thesis found a previously unrecognised large burden of morbidity during recovery from pneumonia; 56% of patients consulted primary care within 30 days of discharge. The highest rate of consultation occurred early, within the first 7 days (4.7 per 100 person-days). Nearly 40% of consultations were for a respiratory disorder and 30% of patients consulting received further antibiotics within 30 days of discharge. The systematic review (n=47 studies) found an in-hospital incidence of cardiac complications of between 3-8%. Patients who developed cardiac complications were more likely to die both in-hospital (odds ratio (OR) 3.45, 95% CI 2.38-4.99) and within 30 days (OR 2.65, 95% CI 1.24-5.68) of admission than those who did not. Data from the population-based study showed that those with pneumonia were significantly at higher risk of developing all cardiac complications compared to those without pneumonia. The highest risk was observed for developing arrhythmia at 30 days after discharge (subhazard ratio (sHR) 9.51, 95% CI 8.35-10.83). The systematic review (n=27 studies) found that current and ex-smokers were both significantly at higher risk of developing CAP whilst passive tobacco smoke exposure had a significant effect only in those aged ≥ 65. A dose-response trend with higher risk of CAP amongst current smokers who smoke higher amounts of tobacco was noted. From the population-based study, 9% of patients hospitalised with index pneumonia developed recurrent pneumonia within a year of follow-up. Current tobacco smoking status at index hospitalisation for pneumonia was independently associated with a higher risk of recurrent pneumonia. Finally, bacterial co-infection within 48 hours of hospital admission for COVID-19 infection in adults was uncommon; 1.6% on admission and 5.5% within 48 hours. Patients with co-infections were more likely to die in ICU (crude OR 1.78, 95% CI 1.03-3.08) compared to those without co-infections. Conclusion In conclusion, this thesis highlights that patients experience significant morbidity during recovery from pneumonia. A better understanding of the morbidity after CAP is necessary to develop and implement appropriate interventions to improve the long-term outcomes of patients hospitalised with CAP

Morbidity of community-acquired pneumonia

Background Community-acquired pneumonia (CAP) accounts for 5-12% of lower respiratory tract infections presenting to primary care in the UK. Of patients who present to their GP with suspected CAP, 22- 42% are referred to hospital for further management in the UK. The majority of patients ( ̴90%) admitted for CAP survive to hospital discharge. However, little is known about the morbidity related to recovery from pneumonia. Methods Three studies in this thesis used large-scale hospitalisation data from Hospital Episode Statistics (HES, England), linked to the Clinical Practice Research Datalink (CPRD), and death registration data from Office for National Statistics (ONS). These studies aim to improve our understanding on the morbidity after CAP and the objectives were: (1) to describe the primary care consultations after pneumonia and the reasons for these consultations (2) to determine the incidence of, and risk factors for developing cardiac complications (3) to determine the incidence of recurrent hospitalisation for pneumonia and the association of tobacco smoking. In addition, published literature on cardiac complications, a major morbidity following CAP and tobacco smoking and passive smoke exposure as a risk factor for developing CAP were systematically summarised. Finally, a multicentre retrospective study was conducted during the first wave of COVID-19 pandemic to determine the proportion of laboratory proven co-infection in critically ill adults with COVID-19 infection in England. Results This thesis found a previously unrecognised large burden of morbidity during recovery from pneumonia; 56% of patients consulted primary care within 30 days of discharge. The highest rate of consultation occurred early, within the first 7 days (4.7 per 100 person-days). Nearly 40% of consultations were for a respiratory disorder and 30% of patients consulting received further antibiotics within 30 days of discharge. The systematic review (n=47 studies) found an in-hospital incidence of cardiac complications of between 3-8%. Patients who developed cardiac complications were more likely to die both in-hospital (odds ratio (OR) 3.45, 95% CI 2.38-4.99) and within 30 days (OR 2.65, 95% CI 1.24-5.68) of admission than those who did not. Data from the population-based study showed that those with pneumonia were significantly at higher risk of developing all cardiac complications compared to those without pneumonia. The highest risk was observed for developing arrhythmia at 30 days after discharge (subhazard ratio (sHR) 9.51, 95% CI 8.35-10.83). The systematic review (n=27 studies) found that current and ex-smokers were both significantly at higher risk of developing CAP whilst passive tobacco smoke exposure had a significant effect only in those aged ≥ 65. A dose-response trend with higher risk of CAP amongst current smokers who smoke higher amounts of tobacco was noted. From the population-based study, 9% of patients hospitalised with index pneumonia developed recurrent pneumonia within a year of follow-up. Current tobacco smoking status at index hospitalisation for pneumonia was independently associated with a higher risk of recurrent pneumonia. Finally, bacterial co-infection within 48 hours of hospital admission for COVID-19 infection in adults was uncommon; 1.6% on admission and 5.5% within 48 hours. Patients with co-infections were more likely to die in ICU (crude OR 1.78, 95% CI 1.03-3.08) compared to those without co-infections. Conclusion In conclusion, this thesis highlights that patients experience significant morbidity during recovery from pneumonia. A better understanding of the morbidity after CAP is necessary to develop and implement appropriate interventions to improve the long-term outcomes of patients hospitalised with CAP

A case of abdominal sarcoidosis in a patient with acute myeloid leukemia.

The allogeneic bone marrow transplantation usually preceded by induction chemotherapy, in fit patients, represents the gold standard in the acute myeloid leukaemia. In the last years, many trials have been set up with the view of improving the number of remissions during the induction by adding new drugs. Several early or late side effects have been described in the literature. We herein present a patient with acute myeloid leukaemia patient who, after chemotherapy, developed ascites that turned out to be abdominal sarcoidosis

Co-infections in people with COVID-19: a systematic review and meta-analysis

Objectives: In previous influenza pandemics, bacterial co-infections have been a major cause of mortality. We aimed to evaluate the burden of co-infections in patients with COVID-19. Methods: We systematically searched Embase, Medline, Cochrane Library, LILACS and CINAHL for eligible studies published from 1 January 2020 to 17 April 2020. We included patients of all ages, in all settings. The main outcome was the proportion of patients with a bacterial, fungal or viral co-infection. .Results: Thirty studies including 3834 patients were included. Overall, 7% of hospitalised COVID-19 patients had a bacterial co-infection (95% CI 3-12%, n=2183, I2=92∙2%). A higher proportion of ICU patients had bacterial co-infections than patients in mixed ward/ICU settings (14%, 95% CI 5-26, I2=74∙7% versus 4%, 95% CI 1-9, I2= 91∙7%). The commonest bacteria were Mycoplasma pneumonia, Pseudomonas aeruginosa and Haemophilus influenzae. The pooled proportion with a viral co-infection was 3% (95% CI 1-6, n=1014, I2=62∙3%), with Respiratory Syncytial Virus and influenza A the commonest. Three studies reported fungal co-infections.Conclusions: A low proportion of COVID-19 patients have a bacterial co-infection; less than in previous influenza pandemics. These findings do not support the routine use of antibiotics in the management of confirmed COVID-19 infection

Effects of tobacco smoking on recurrent hospitalisation with pneumonia: a population-based cohort study

The incidence of and risk factors for recurrent hospitalisation for pneumonia were investigated using data from Hospital Episode Statistics, linked to a UK primary care database. Within 90 days and 1 year of follow-up, 1733 (3.1%) and 5064 (9.0%), developed recurrent pneumonia respectively. Smoking status at the time of hospitalisation with index pneumonia was associated with the risk of readmission with recurrent pneumonia within a year of discharge: current versus never smokers: adjusted subhazard ratio (sHR) 1.42, 95% CI 1.32 to 1.53, p≤0.001, and ex smokers versus never smokers: adjusted sHR 1.24, 95% CI 1.15 to 1.34, p≤0.001. Other independent risk factors associated with recurrent pneumonia were age, gender, deprivation and underlying comorbidities

Incidence of cognitive impairment and dementia after hospitalisation for pneumonia: a UK population-based matched cohort study

Background Survivors of common infections may develop cognitive impairment or dementia; however, the risk of these conditions in people hospitalised with pneumonia is not well established. Methods A matched cohort study was conducted using Hospital Episode Statistics (HES) data linked to the Clinical Practice Research Database (CPRD). Adults with the first International Classification of Diseases (10th Revision) code for pneumonia recorded in the HES between 1 July 2002 and 30 June 2017 were included, and up to four controls without hospitalisation for pneumonia in the CPRD were matched by sex, age and practice. Cognitive impairment and dementia incidence rates were calculated and survival analysis was performed comparing those hospitalised with pneumonia to the general population. Results The incidence rates of cognitive impairment and dementia were 18 (95% CI 17.3–18.7) and 13.2 (95% CI 13–13.5) per 1000 person-years among persons previously hospitalised with pneumonia and the matched cohort respectively. People previously hospitalised with pneumonia had 53% higher incidence of cognitive impairment and dementia (adjusted hazard ratio (aHR) 1.53, 95% CI 1.46–1.61) than their matched cohort. The highest incidence was observed within 1 year of hospitalisation for pneumonia compared to the general population (aHR 1.89, 95% CI 1.75–2.05). Age modified the effect of hospitalisation for pneumonia on cognitive impairment and dementia such that the size of effect was stronger in people between 45 and 60 years old (p-value for interaction <0.0001). Conclusion Cognitive impairment and dementia are more likely to be diagnosed in people who have been hospitalised for pneumonia, especially in the first year after discharge, than in the general population

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against vaccine serotype pneumococcal pneumonia in adults: A case-control test-negative design study.

BACKGROUND: Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP). METHODS AND FINDINGS: Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 - odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%-40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%-40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI -5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI -37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%-46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups. CONCLUSIONS: In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults

Effect of tobacco smoking on the risk of developing community acquired pneumonia: A systematic review and meta-analysis.

AIM: To summarise and quantify the effect of tobacco smoking on the risk of developing community acquired pneumonia (CAP) in adults. METHODS: We systematically searched MEDLINE, Embase, CINAHL, PsychINFO and Web of Science, from inception to October 2017, to identify case-control and cohort studies and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. The review protocol was registered with the PROSPERO database (CRD42018093943). Study quality was assessed by the Newcastle-Ottawa Scale. Pooled odds ratios (ORs) or hazard ratios (HRs) were estimated using a random-effects model. RESULTS: Of 647 studies identified, 27 studies were included (n = 460,592 participants) in the systematic review. Most of the included studies were of moderate quality with a median score of six (IQR 6-7). Meta-analysis showed that current smokers (pooled OR 2.17, 95% CI 1.70-2.76, n = 13 studies; pooled HR 1.52, 95% CI 1.13-2.04, n = 7 studies) and ex-smokers (pooled OR 1.49, 95% CI 1.26-1.75, n = 8 studies; pooled HR 1.18, 95% CI 0.91-1.52, n = 6 studies) were more likely to develop CAP compared to never smokers. Although the association between passive smoking and risk of CAP in adults of all ages was not statistically significant (pooled OR 1.13, 95% CI 0.94-1.36, n = 5 studies), passive smoking in adults aged ≥65 years was associated with a 64% increased risk of CAP (pooled OR 1.64; 95% CI 1.17-2.30, n = 2 studies). Dose-response analyses of data from five studies revealed a significant trend; current smokers who smoked higher amount of tobacco had a higher risk of CAP. CONCLUSION: Tobacco smoke exposure is significantly associated with the development of CAP in current smokers and ex-smokers. Adults aged > 65 years who are passive smokers are also at higher risk of CAP. For current smokers, a significant dose-response relationship is evident

Pneumococcal serotypes and risk factors in adult community-acquired pneumonia 2018–20: a multicentre UK cohort study

Background: Higher-valency pneumococcal vaccines are anticipated. We aimed to describe serotype distribution and risk factors for vaccine-serotype community-acquired pneumonia (CAP) in the two years pre-SARS-CoV-2 pandemic. Methods: We conducted a prospective cohort study of adults hospitalised with CAP at three UK sites between 2018 and 2020. Pneumococcal serotypes were identified using a 24-valent urinary-antigen assay and blood cultures. Risk factors associated with vaccine-type pneumonia caused by serotypes in the 13-, 15- and 20-valent pneumococcal conjugate vaccines (PCV13, PCV15, PCV20) and 23-valent pneumococcal polysaccharide vaccine (PPV23) were determined from multivariable analysis. Findings: Of 1921 adults hospitalised with CAP, 781 (40.7%, 95% confidence intervals (CI) 38.5–42.9%) had pneumococcal pneumonia. A single PCV13-serotype was detected in 242 (31.0%, 95% CI 27.8–34.3%) pneumococcal CAP patients, mostly serotype 3 (171/242, 70.7%, 95% CI 64.5–76.0%). The additional two PCV15-serotypes were detected in 31 patients (4%, 95% CI 2.8–5.6%), and PCV20-non13-serotypes in 192 (24.6%), with serotype 8 most prevalent (123/192, 64.1%, 95% CI 57.1–70.5%). Compared to PCV13-serotype CAP, people with PCV20-non13 CAP were younger (median age 62 versus 72 years, p < 0.001) and less likely to be male (44% versus 61%, p = 0.01). PPV23-non13-serotypes were found in 252 (32.3%, 95% CI 29.1–35.6%) pneumococcal CAP patients. Interpretation: Despite mature infant pneumococcal programmes, the burden of PCV13-serotype pneumonia remains high in older adults, mainly due to serotype 3. PCV20-non13-serotype pneumonia is more likely in younger people with fewer pneumococcal risk factors. Funding: Unrestricted investigator-initiated research grant from Pfizer, United Kingdom; support from National Institute for Health Research (NIHR) Biomedical Research Centre, Nottingham

Co-infection in critically ill patients with COVID-19: an observational cohort study from England

Introduction. During previous viral pandemics, reported co-infection rates and implicated pathogens have varied. In the 1918 influenza pandemic, a large proportion of severe illness and death was complicated by bacterial co-infection, predominantly Streptococcus pneumoniae and Staphylococcus aureus . Gap statement. A better understanding of the incidence of co-infection in patients with COVID-19 infection and the pathogens involved is necessary for effective antimicrobial stewardship. Aim. To describe the incidence and nature of co-infection in critically ill adults with COVID-19 infection in England. Methodology. A retrospective cohort study of adults with COVID-19 admitted to seven intensive care units (ICUs) in England up to 18 May 2020, was performed. Patients with completed ICU stays were included. The proportion and type of organisms were determined at 48 h following hospital admission, corresponding to community and hospital-acquired co-infections. Results. Of 254 patients studied (median age 59 years (IQR 49–69); 64.6 % male), 139 clinically significant organisms were identified from 83 (32.7 %) patients. Bacterial co-infections/ co-colonisation were identified within 48 h of admission in 14 (5.5 %) patients; the commonest pathogens were Staphylococcus aureus (four patients) and Streptococcus pneumoniae (two patients). The proportion of pathogens detected increased with duration of ICU stay, consisting largely of Gram-negative bacteria, particularly Klebsiella pneumoniae and Escherichia coli . The co-infection/ co-colonisation rate >48 h after admission was 27/1000 person-days (95 % CI 21.3–34.1). Patients with co-infections/ co-colonisation were more likely to die in ICU (crude OR 1.78,95 % CI 1.03–3.08, P=0.04) compared to those without co-infections/ co-colonisation. Conclusion. We found limited evidence for community-acquired bacterial co-infection in hospitalised adults with COVID-19, but a high rate of Gram-negative infection acquired during ICU stay