Rising incidence of Pneumocystis pneumonia: A population-level descriptive ecological study in England.

OBJECTIVES: Pneumocystis pneumonia (PCP) is an opportunistic infection that causes significant morbidity and mortality in the immunocompromised population. This population is growing and diversifying, yet contemporary epidemiology is lacking. We investigated the population-level incidence of PCP over the past decade. METHODS: We conducted a descriptive study of all hospital admissions in England from April 2012 to March 2022. PCP episodes, age, median length of stay, gender and episodes of other respiratory fungal infections were collected. Consumption of Trimethoprim-Sulfamethoxazole was obtained between January 2019 and May 2022. RESULTS: The incidence of PCP increased from 2·2-4·5/100,000 population between 2012/2013 and 2019/2020 (p < 0·0001). There was a drop in 2020/2021 to 2·7/100,000 before returning to 3.9/100,000 in 2021/2022. PCP episodes rose as a proportion of all-cause admissions as well as a proportion of episodes due to other fungal infections. The proportion of PCP patients aged 75+ increased from 14% to 26%. The median length of stay was 13.5 days. Consumption of intravenous Trimethoprim-Sulfamethoxazole increased from 0.24 × 100,000 to 0.30 × 100,000 defined daily doses. CONCLUSIONS: The incidence of PCP is rising rapidly and represents a significant burden to the healthcare system. Further study into who is at risk of PCP is needed to better determine who should be given prophylaxis.

Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial.

BACKGROUND: The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19. METHODS: This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing. FINDINGS: Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8-9]) than participants in the placebo group (11 days [10-11]; HR 1·30, 95% credible interval 0·92-1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial. INTERPRETATION: We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive. FUNDING: Ridgeback Biotherapeutics, the UK National Institute for Health and Care Research, the Medical Research Council, and the Wellcome Trust.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.

Pneumolysin suppresses the initial macrophage pro-inflammatory response to Streptococcus pneumoniae.

Published data for the Streptococcus pneumoniae virulence factor Pneumolysin (Ply) show contradictory effects on the host inflammatory response to infection. Ply has been shown to activate the inflammasome, but also can bind to MRC-1 resulting in suppression of dendritic cell inflammatory responses. We have used an in vitro infection model of human monocyte-derived macrophages (MDM), and a mouse model of pneumonia to clarify whether pro- or anti-inflammatory effects dominate the effects of Ply on the initial macrophage inflammatory response to S. pneumoniae, and the consequences during early lung infection. We found that infection with S. pneumoniae expressing Ply suppressed tumour necrosis factor (TNF) and interleukin-6 production by MDMs compared to cells infected with ply-deficient S. pneumoniae. This effect was independent of bacterial effects on cell death. Transcriptional analysis demonstrated S. pneumoniae expressing Ply caused a qualitatively similar but quantitatively lower MDM transcriptional response to S. pneumoniae compared to ply-deficient S. pneumoniae, with reduced expression of TNF and type I IFN inducible genes. Reduction of the MDM inflammatory response was prevented by inhibition of SOCS1. In the early lung infection mouse model, the TNF response to ply-deficient S. pneumoniae was enhanced and bacterial clearance increased compared to infection with wild-type S. pneumoniae. Overall, these data show Ply inhibits the initial macrophage inflammatory response to S. pneumoniae, probably mediated through SOCS1, and this was associated with improved immune evasion during early lung infection.

Inpatient COVID-19 mortality has reduced over time: Results from an observational cohort.

BACKGROUND: The Covid-19 pandemic in the United Kingdom has seen two waves; the first starting in March 2020 and the second in late October 2020. It is not known whether outcomes for those admitted with severe Covid were different in the first and second waves. METHODS: The study population comprised all patients admitted to a 1,500-bed London Hospital Trust between March 2020 and March 2021, who tested positive for Covid-19 by PCR within 3-days of admissions. Primary outcome was death within 28-days of admission. Socio-demographics (age, sex, ethnicity), hypertension, diabetes, obesity, baseline physiological observations, CRP, neutrophil, chest x-ray abnormality, remdesivir and dexamethasone were incorporated as co-variates. Proportional subhazards models compared mortality risk between wave 1 and wave 2. Cox-proportional hazard model with propensity score adjustment were used to compare mortality in patients prescribed remdesivir and dexamethasone. RESULTS: There were 3,949 COVID-19 admissions, 3,195 hospital discharges and 733 deaths. There were notable differences in age, ethnicity, comorbidities, and admission disease severity between wave 1 and wave 2. Twenty-eight-day mortality was higher during wave 1 (26.1% versus 13.1%). Mortality risk adjusted for co-variates was significantly lower in wave 2 compared to wave 1 [adjSHR 0.49 (0.37, 0.65) p<0.001]. Analysis of treatment impact did not show statistically different effects of remdesivir [HR 0.84 (95%CI 0.65, 1.08), p = 0.17] or dexamethasone [HR 0.97 (95%CI 0.70, 1.35) p = 0.87]. CONCLUSION: There has been substantial improvements in COVID-19 mortality in the second wave, even accounting for demographics, comorbidity, and disease severity. Neither dexamethasone nor remdesivir appeared to be key explanatory factors, although there may be unmeasured confounding present.

Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency.

Bronchiectasis is a well-recognised complication of primary antibody deficiency (PAD) syndromes. Previous data suggest that mortality in common variable immune deficiency (CVID) is not associated with isolated bronchiectasis. A retrospective analysis of patients with CVID and specific antibody deficiency in two tertiary referral centres with lung disease was conducted. Severity of bronchiectasis at presentation was associated with mortality. Lower FEV1, colonisation with Pseudomonas aeruginosa and a diagnosis of COPD were also associated with mortality. Bronchiectasis is an important driver of mortality in patients with PAD syndromes.

Hospital Mortality and Resource Implications of Hospitalisation with COVID-19 in London, UK: A Prospective Cohort Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) had a significant impact on the National Health Service in the United Kingdom (UK), with over 35 000 cases reported in London by July 30, 2020. Detailed hospital-level information on patient characteristics, outcomes, and capacity strain is currently scarce but would guide clinical decision-making and inform prioritisation and planning. METHODS: We aimed to determine factors associated with hospital mortality and describe hospital and ICU strain by conducting a prospective cohort study at a tertiary academic centre in London, UK. We included adult patients admitted to the hospital with laboratory-confirmed COVID-19 and followed them up until hospital discharge or 30 days. Baseline factors that are associated with hospital mortality were identified via semiparametric and parametric survival analyses. RESULTS: Our study included 429 patients: 18% of them were admitted to the ICU, 52% met criteria for ICU outreach team activation, and 61% had treatment limitations placed during their admission. Hospital mortality was 26% and ICU mortality was 34%. Hospital mortality was independently associated with increasing age, male sex, history of chronic kidney disease, increasing baseline C-reactive protein level, and dyspnoea at presentation. COVID-19 resulted in substantial ICU and hospital strain, with up to 9 daily ICU admissions and 41 daily hospital admissions, to a peak census of 80 infected patients admitted in the ICU and 250 in the hospital. Management of such a surge required extensive reorganisation of critical care services with expansion of ICU capacity from 69 to 129 beds, redeployment of staff from other hospital areas, and coordinated hospital-level effort. CONCLUSIONS: COVID-19 is associated with a high burden of mortality for patients treated on the ward and the ICU and required substantial reconfiguration of critical care services. This has significant implications for planning and resource utilisation.

Chest radiography is a poor predictor of respiratory symptoms and functional impairment in survivors of severe COVID-19 pneumonia.

BACKGROUND: A standardised approach to assessing COVID-19 survivors has not been established, largely due to the paucity of data on medium- and long-term sequelae. Interval chest radiography is recommended following community-acquired pneumonia; however, its utility in monitoring recovery from COVID-19 pneumonia remains unclear. METHODS: This was a prospective single-centre observational cohort study. Patients hospitalised with severe COVID-19 pneumonia (admission duration ≥48 h and oxygen requirement ≥40% or critical care admission) underwent face-to-face assessment at 4-6 weeks post-discharge. The primary outcome was radiological resolution of COVID-19 pneumonitis (Radiographic Assessment of Lung Oedema score <5). Secondary outcomes included clinical outcomes, symptom questionnaires, mental health screening (Trauma Screening Questionnaire, seven-item Generalised Anxiety Disorder assessment and nine-item Patient Health Questionnaire) and physiological testing (4-m gait speed (4MGS) and 1-min Sit-to-Stand (STS) tests). RESULTS: 119 patients were assessed between June 3, 2020 and July 2, 2020 at median (interquartile range (IQR)) 61 (51-67) days post-discharge: mean±sd age 58.7±14.4 years, median (IQR) body mass index 30.0 (25.9-35.2) kg·m-2, 62% male and 70% ethnic minority. Despite radiographic resolution of pulmonary infiltrates in 87%, modified Medical Research Council Dyspnoea (breathlessness) scale grades were above pre-COVID-19 baseline in 44%, and patients reported persistent fatigue (68%), sleep disturbance (57%) and breathlessness (32%). Screening thresholds were breached for post-traumatic stress disorder (25%), anxiety (22%) and depression (18%). 4MGS was slow (<0.8 m·s-1) in 38% and 35% desaturated by ≥4% during the STS test. Of 56 thoracic computed tomography scans performed, 75% demonstrated COVID-19-related interstitial and/or airways disease. CONCLUSIONS: Persistent symptoms, adverse mental health outcomes and physiological impairment are common 2 months after severe COVID-19 pneumonia. Follow-up chest radiography is a poor marker of recovery; therefore, holistic face-to-face assessment is recommended to facilitate early recognition and management of post-COVID-19 sequelae.

The perils of a persistent cough.

Always consider an underlying diagnosis of Aspergillus-related disease when faced with persistent symptoms in an individual with predisposing risk factors (e.g. asthma) http://bit.ly/3aBTQip.

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report.

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.

Opportunistic bacterial, viral and fungal infections of the lung.

Opportunistic infections are a major cause of morbidity and mortality in severely immunocompromised patients, such as those given chemotherapy or biological therapies, and those with haematological malignancy, aplastic anaemia or HIV infection, or recipients of solid organ or stem cell transplants. The type and degree of immune defect dictates the profile of potential opportunistic pathogens; T-cell-mediated defects increase the risk of viral (cytomegalovirus, respiratory viruses) and Pneumocystis jirovecii infections, whereas neutrophil defects are associated with bacterial pneumonia and invasive aspergillosis. However, patients often have combinations of immune defects, and a wide range of other opportunistic infections can cause pneumonia. Importantly, conventional non-opportunistic pathogens are frequently encountered in immunocompromised hosts and should not be overlooked The radiological pattern of disease (best assessed by computed tomography) and speed of onset help identify the likely pathogen(s); this can then be supported by targeted investigation including early use of bronchoscopy in selected patients. Rapid and expert clinical assessment can identify the most likely pathogens, allowing timely appropriate therapy.

Relative Contributions of Extracellular and Internalized Bacteria to Early Macrophage Proinflammatory Responses to Streptococcus pneumoniae.

Both intracellular immune sensing and extracellular innate immune sensing have been implicated in initiating macrophage proinflammatory cytokine responses to Streptococcus pneumoniae The S. pneumoniae capsule, a major virulence determinant, prevents phagocytosis, and we hypothesized that this would reduce activation of host innate inflammatory responses by preventing activation of intracellular proinflammatory signaling pathways. We investigated this hypothesis in human monocyte-derived macrophages stimulated with encapsulated or isogenic unencapsulated mutant S. pneumoniae Unexpectedly, despite strongly inhibiting bacterial internalization, the capsule resulted in enhanced inflammatory cytokine production by macrophages infected with S. pneumoniae Experiments using purified capsule material and a Streptococcus mitis mutant expressing an S. pneumoniae serotype 4 capsule indicated these differences required whole bacteria and were not due to proinflammatory effects of the capsule itself. Transcriptional profiling demonstrated relatively few differences in macrophage gene expression profiles between infections with encapsulated S. pneumoniae and those with unencapsulated S. pneumoniae, largely limited to reduced expression of proinflammatory genes in response to unencapsulated bacteria, predicted to be due to reduced activation of the NF-κB family of transcription factors. Blocking S. pneumoniae internalization using cytochalasin D had minimal effects on the inflammatory response to S. pneumoniae Experiments using murine macrophages indicated that the affected genes were dependent on Toll-like receptor 2 (TLR2) activation, although not through direct stimulation of TLR2 by capsule polysaccharide. Our data demonstrate that the early macrophage proinflammatory response to S. pneumoniae is mainly dependent on extracellular bacteria and reveal an unexpected proinflammatory effect of encapsulated S. pneumoniae that could contribute to disease pathogenesis.IMPORTANCE Multiple extra- and intracellular innate immune receptors have been identified that recognize Streptococcus pneumoniae, but the relative contributions of intra- versus extracellular bacteria to the inflammatory response were unknown. We have shown that intracellular S. pneumoniae contributes surprisingly little to the inflammatory responses, with production of important proinflammatory cytokines largely dependent on extracellular bacteria. Furthermore, although we expected the S. pneumoniae polysaccharide capsule to block activation of the host immune system by reducing bacterial internalization and therefore activation of intracellular innate immune receptors, there was an increased inflammatory response to encapsulated compared to unencapsulated bacteria, which is likely to contribute to disease pathogenesis.

A Prospective Real-World Study of the Impact of an Antifungal Stewardship Program in a Tertiary Respiratory-Medicine Setting.

There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to health care systems. An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice-monthly multidisciplinary team meetings, and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team. During the first 18 months of implementation, the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated, followed by asthma and interstitial lung disease. There was a significant sustained reduction in monthly antifungal expenditure (P = 0.005) by £130,000 per month. There was also a significant reduction in antifungal use, measured as the defined daily dose/100 bed days (P = 0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole (P = 0.086) and a significant increase in therapeutic levels of posaconazole (P < 0.0001). This study shows that an effective antifungal stewardship program can significantly reduce expenditure in a specialist respiratory service.

A Quorum-Sensing System That Regulates Streptococcus pneumoniae Biofilm Formation and Surface Polysaccharide Production.

Despite vaccines, Streptococcus pneumoniae kills more than a million people yearly. Thus, understanding how pneumococci transition from commensals to pathogens is particularly relevant. Quorum sensing regulates collective behaviors and thus represents a potential driver of commensal-to-pathogen transitions. Rgg/small hydrophobic peptide (SHP) quorum-sensing systems are widespread in streptococci, yet they remain largely uncharacterized in S. pneumoniae. Using directional transcriptome sequencing, we show that the S. pneumoniae D39 Rgg0939/SHP system induces the transcription of a single gene cluster including shp and capsule gene homologs. Capsule size measurements determined by fluorescein isothiocyanate-dextran exclusion allowed assignment of the system to the regulation of surface polysaccharide expression. We found that the SHP pheromone induced exopolysaccharide expression in R36A, an unencapsulated derivative of D39. In the encapsulated parent strain, overexpression of the Rgg system resulted in a mutant with increased capsule size. In line with previous studies showing that capsule expression is inversely associated with biofilm formation, we found that biofilm formed on lung epithelial cells was decreased in the overexpression strain and increased in an rgg deletion mutant. Although no significant differences were observed between D39 and the rgg deletion mutant in a mouse model of lung infection, in competitive assays, overexpression reduced fitness. This is the first study to reveal a quorum-sensing system in streptococci that regulates exopolysaccharide synthesis from a site distinct from the original capsule locus. IMPORTANCE Quorum sensing regulates bacterial social behaviors by production, secretion, and sensing of pheromones. In this study, we characterized a new quorum-sensing system of the Rgg/SHP class in S. pneumoniae D39. The system was found to directly induce the expression of a single gene cluster comprising the gene for the SHP pheromone and genes with putative functions in capsule synthesis. Capsule size, as measured by dextran exclusion, was increased by SHP exposure in R36A, an unencapsulated derivative of D39. In the encapsulated parent strain, overexpression of the gene cluster increased capsule size, supporting the role of Rgg/SHP in the synthesis of surface polysaccharides. Further, we found that biofilm formation on epithelial cells was reduced by overexpression of the system and increased in a mutant with an rgg deletion. Placing surface polysaccharide expression under quorum-sensing regulation may enable S. pneumoniae to tune interactions with the host and other bacteria in accordance with environmental and cell density conditions.

Exposure to welding fumes and lower airway infection with Streptococcus pneumoniae.

BACKGROUND: Welders are at increased risk of pneumococcal pneumonia. The mechanism for this association is not known. The capacity of pneumococci to adhere to and infect lower airway cells is mediated by host-expressed platelet-activating factor receptor (PAFR). OBJECTIVE: We sought to assess the effect of mild steel welding fumes (MS-WF) on PAFR-dependent pneumococcal adhesion and infection to human airway cells in vitro and on pneumococcal airway infection in a mouse model. METHODS: The oxidative potential of MS-WF was assessed by their capacity to reduce antioxidants in vitro. Pneumococcal adhesion and infection of A549, BEAS-2B, and primary human bronchial airway cells were assessed by means of quantitative bacterial culture and expressed as colony-forming units (CFU). After intranasal instillation of MS-WF, mice were infected with Streptococcus pneumoniae, and bronchoalveolar lavage fluid (BALF) and lung CFU values were determined. PAFR protein levels were assessed by using immunofluorescence and immunohistochemistry, and PAFR mRNA expression was assessed by using quantitative PCR. PAFR was blocked by CV-3988, and oxidative stress was attenuated by N-acetylcysteine. RESULTS: MS-WF exhibited high oxidative potential. In A549 and BEAS-2B cells MS-WF increased pneumococcal adhesion and infection and PAFR protein expression. Both CV-3988 and N-acetylcysteine reduced MS-WF-stimulated pneumococcal adhesion and infection of airway cells. MS-WF increased mouse lung PAFR mRNA expression and increased BALF and lung pneumococcal CFU values. In MS-WF-exposed mice CV-3988 reduced BALF CFU values. CONCLUSIONS: Hypersusceptibility of welders to pneumococcal pneumonia is in part mediated by the capacity of welding fumes to increase PAFR-dependent pneumococcal adhesion and infection of lower airway cells.

Community-acquired pneumonia.

PURPOSE OF REVIEW: Community-acquired pneumonia (CAP) is the most common infectious disease cause of death. We summarize recent findings regarding the epidemiology of CAP in adults, efficacy of vaccines against Streptococcus pneumoniae, diagnostics, and discuss the current controversy between CAP and healthcare-associated pneumonia (HCAP). RECENT FINDINGS: The emergence of the Middle East respiratory syndrome coronavirus and the avian influenza A strain H7N9 are of concern but still these are infrequent causes of CAP. Recent data indicate that vaccinating children also protects adults against CAP by generating significant herd immunity, and that the conjugated pneumococcal vaccine in adults may offer some efficacy in preventing CAP caused by vaccine serotypes. The immunochromotagraphic urinary antigen test has improved the diagnostic yield for the aetiology of CAP, and initial data demonstrate that a novel multiplex urinary antigen test will further increase the sensitivity for detection of S. pneumoniae. There has been significant concern that a relatively recently described pneumonia category, HCAP, requires empirical treatment for potentially multidrug-resistant organisms (MDRO). However, new evidence shows that (at least in Europe) pneumonia caused by MDRO remains uncommon even in HCAP category patients. SUMMARY: CAP remains a major cause of morbidity and mortality. Advances in vaccination and diagnosis should help reduce the amount of disease due to S. pneumoniae, the commonest cause of CAP. Outside of the United States, MDRO are relatively uncommon causes of CAP, and the increased mortality of HCAP category patients seems to be related to their comorbidities and age rather than microbial aetiology.