Venous-plexus-associated lymphoid hubs support meningeal humoral immunity.

There is increasing interest in how immune cells in the meninges-the membranes that surround the brain and spinal cord-contribute to homeostasis and disease in the central nervous system1,2. The outer layer of the meninges, the dura mater, has recently been described to contain both innate and adaptive immune cells, and functions as a site for B cell development3-6. Here we identify organized lymphoid structures that protect fenestrated vasculature in the dura mater. The most elaborate of these dural-associated lymphoid tissues (DALT) surrounded the rostral-rhinal confluence of the sinuses and included lymphatic vessels. We termed this structure, which interfaces with the skull bone marrow and a comparable venous plexus at the skull base, the rostral-rhinal venolymphatic hub. Immune aggregates were present in DALT during homeostasis and expanded with age or after challenge with systemic or nasal antigens. DALT contain germinal centre B cells and support the generation of somatically mutated, antibody-producing cells in response to a nasal pathogen challenge. Inhibition of lymphocyte entry into the rostral-rhinal hub at the time of nasal viral challenge abrogated the generation of germinal centre B cells and class-switched plasma cells, as did perturbation of B-T cell interactions. These data demonstrate a lymphoid structure around vasculature in the dura mater that can sample antigens and rapidly support humoral immune responses after local pathogen challenge.

Coordination of Locomotion by Serotonergic Neurons in the Predatory Gastropod Pleurobranchaea californica.

Similar design characterizes neuronal networks for goal-directed motor control across the complex, segmented vertebrates, insects, and polychaete annelids with jointed appendages. Evidence is lacking for whether this design evolved independently in those lineages, evolved in parallel with segmentation and appendages, or could have been present in a soft-bodied common ancestor. We examined coordination of locomotion in an unsegmented, ciliolocomoting gastropod, the sea slug Pleurobranchaea californica, which may better resemble the urbilaterian ancestor. Previously, bilateral A-cluster neurons in cerebral ganglion lobes were found to compose a multifunctional premotor network controlling the escape swim and feeding suppression, and mediating action selection for approach or avoidance turns. Serotonergic As interneurons of this cluster were critical elements for swimming, turning, and behavioral arousal. Here, known functions were extended to show that the As2/3 cells of the As group drove crawling locomotion via descending signals to pedal ganglia effector networks for ciliolocomotion and were inhibited during fictive feeding and withdrawal. Crawling was suppressed in aversive turns, defensive withdrawal, and active feeding, but not during stimulus-approach turns or prebite proboscis extension. Ciliary beating was not inhibited during escape swimming. These results show how locomotion is adaptively coordinated in tracking, handling, and consuming resources, and in defense. Taken with previous results, they also show that the A-cluster network acts similarly to the vertebrate reticular formation with its serotonergic raphe nuclei in facilitating locomotion, postural movements, and motor arousal. Thus, the general scheme controlling locomotion and posture might well have preceded the evolution of segmented bodies and articulated appendages.SIGNIFICANCE STATEMENT Similar design in the neuronal networks for goal-directed motor control is seen across the complex, segmented vertebrates, insects, and polychaete annelids with jointed appendages. Whether that design evolved independently or in parallel with complexity in body and behavior has been unanswered. Here it is shown that a simple sea slug, with primitive ciliary locomotion and lacking segmentation and appendages, has similar modular design in network coordination as vertebrates for posture in directional turns and withdrawal, locomotion, and general arousal. This suggests that a general neuroanatomical framework for the control of locomotion and posture could have arisen early during the evolution of bilaterians.

Decoding changes in tumor-infiltrating leukocytes through dynamic experimental models and single-cell technologies.

The ability to characterize immune cells and explore the molecular interactions that govern their functions has never been greater, fueled in recent years by the revolutionary advance of single-cell analysis platforms. However, precisely how immune cells respond to different stimuli and where differentiation processes and effector functions operate remain incompletely understood. Inferring cellular fate within single-cell transcriptomic analyses is now omnipresent, despite the assumptions typically required in such analyses. Recently developed experimental models support dynamic analyses of the immune response, providing insights into the temporal changes that occur within cells and the tissues in which such transitions occur. Here we will review these approaches and discuss how these can be combined with single-cell technologies to develop a deeper understanding of the immune responses that should support the development of better therapeutic options for patients.

Endoscopic surveillance with systematic random biopsy for the early diagnosis of hereditary diffuse gastric cancer: a prospective 16-year longitudinal cohort study.

BACKGROUND: Hereditary diffuse gastric cancer, generally caused by germline pathogenic variants in CDH1, presents with early-onset signet ring cell carcinoma. Prophylactic total gastrectomy is the definitive treatment. Endoscopic surveillance can inform the timing of prophylactic total gastrectomy through detection of microscopic signet ring cell carcinoma foci. However, evidence is scarce about the optimal endoscopic sampling technique and characterisation of signet ring cell carcinoma foci in hereditary diffuse gastric cancer. We aimed to formally assess the diagnostic yield of different sampling strategies and to identify criteria for the characterisation of endoscopic lesions. METHODS: For this prospective longitudinal cohort study, we included individuals aged 18 years or older at the Cambridge University Hospitals National Health Service (NHS) Foundation Trust who fulfilled testing criteria for hereditary diffuse gastric cancer between June 1, 2005, and July 31, 2021. The primary outcome was detection of intramucosal signet ring cell carcinoma foci. We assessed the detection rate and anatomical location of signet ring cell carcinoma in random biopsy samples taken according to a systematic protocol compared with biopsies targeted to endoscopic findings. Endoscopic lesions were examined with white-light and narrow band imaging with magnification to assess the likelihood of cancerous foci. FINDINGS: 145 individuals were included, of whom 68 (47%) were male and 92 (63%) carried the CDH1 pathogenic variant. 58 (40%) patients were diagnosed with invasive signet ring cell carcinoma over a median follow-up time of 51 months (IQR 18-80). The first diagnosis of signet ring cell carcinoma was most commonly made from random biopsies (29 [50%] of 58 patients), rather than targeted biopsies (15 [26%] patients). The anatomical distribution of signet ring cell carcinoma foci detected by random biopsies more accurately reflected those identified in prophylactic total gastrectomy specimens than did targeted biopsies. Omitting random biopsies in our cohort would have led to an under-diagnosis rate of 42%. Using a novel panel of endoscopic criteria, gastric lesions containing signet ring cell carcinoma were predicted with a sensitivity of 67·3% and a specificity of 90·2%. INTERPRETATION: Random biopsies enhance the early detection of signet ring cell carcinoma and are complementary to targeted biopsies in surveillance of hereditary diffuse gastric cancer. This sampling method should be the standard of care when performing all surveillance endoscopies for individuals with hereditary diffuse gastric cancer. FUNDING: UK Medical Research Council.

Monthly Global Estimates of Fine Particulate Matter and Their Uncertainty.

Annual global satellite-based estimates of fine particulate matter (PM2.5) are widely relied upon for air-quality assessment. Here, we develop and apply a methodology for monthly estimates and uncertainties during the period 1998-2019, which combines satellite retrievals of aerosol optical depth, chemical transport modeling, and ground-based measurements to allow for the characterization of seasonal and episodic exposure, as well as aid air-quality management. Many densely populated regions have their highest PM2.5 concentrations in winter, exceeding summertime concentrations by factors of 1.5-3.0 over Eastern Europe, Western Europe, South Asia, and East Asia. In South Asia, in January, regional population-weighted monthly mean PM2.5 concentrations exceed 90 µg/m3, with local concentrations of approximately 200 µg/m3 for parts of the Indo-Gangetic Plain. In East Asia, monthly mean PM2.5 concentrations have decreased over the period 2010-2019 by 1.6-2.6 µg/m3/year, with decreases beginning 2-3 years earlier in summer than in winter. We find evidence that global-monitored locations tend to be in cleaner regions than global mean PM2.5 exposure, with large measurement gaps in the Global South. Uncertainty estimates exhibit regional consistency with observed differences between ground-based and satellite-derived PM2.5. The evaluation of uncertainty for agglomerated values indicates that hybrid PM2.5 estimates provide precise regional-scale representation, with residual uncertainty inversely proportional to the sample size.

Developing a Tool for Prospective Assessment of Treatment Appropriateness in Urinary Tract Infections.

Background: Antimicrobial resistance is an increasingly serious threat to global public health. Antimicrobial stewardship programs need to identify inappropriate antibiotic use patterns and offer practical recommendations to prescribers and institutions. Urinary tract infection (UTI) is a common syndrome for which a standardized tool would be useful when treatment appropriateness is assessed. To date, few UTI treatment assessment tools have been published, and the available tools do not support appropriateness assessment against published guidelines, or consistent adjudication from one auditor to another. Objective: To develop a tool for auditing UTI antibiotic therapy that assesses treatment appropriateness based on guideline concordance, and with high inter-rater reliability. Methods: An audit tool was developed iteratively by the local antimicrobial stewardship team. Two auditors used the tool to adjudicate treatment appropriateness in a sample of UTI cases against local treatment guidelines. Inter-rater agreement was estimated with Cohen's kappa statistic. Results: The final design of the tool had individual sections for evaluating five aspects of treatment appropriateness, depending on the stage at which a patient was in his or her course of antibiotic therapy: diagnosis, empiric therapy, culture-directed therapy, route of antimicrobial administration, and duration of therapy. A total of 50 cases were assessed; among these, the two auditors agreed on 45 cases (90% agreement). The estimated kappa was 0.8. Conclusion: A unique tool with substantial inter-rater agreement was developed for assessing appropriateness of antimicrobial therapy in UTI. The process and design features that were outlined can be adapted by other antimicrobial stewardship programs to monitor antimicrobial use and improve quality of care.

Oral beta-lactam step down in bacteremic E. coli urinary tract infections.

BACKGROUND: Literature is scarce regarding oral step down to beta-lactams in bacteremic urinary tract infections. Oral fluoroquinolones are an accepted and common step down for bacteremic urinary tract infections; however, their use is associated with mounting safety concerns. We compared clinical cure in patients with E. coli bacteremic urinary tract infections who were stepped down to oral beta-lactams compared to oral fluoroquinolones. METHODS: This multicentre retrospective cohort study included patients with first positive concurrent urine and blood cultures from January 2016 to December 2016. Patients were included if they received empiric intravenous beta-lactam therapy with step down to either oral beta-lactam or fluoroquinolone for treatment completion. The primary outcome was clinical cure. Secondary outcomes were length of hospitalization, all-cause mortality and C. difficile infection. Multivariate analysis and propensity score were used to control for confounding. RESULTS: A total of 207 patients were identified with bacteremic E.coli urinary tract infections. Clinical cure was achieved in 72/77 (94%) in the oral beta-lactam group versus 127/130 (98%) in the oral fluoroquinolone group (absolute difference - 4.2, 95% confidence interval [CI] -10.3 to 1.9%, p = 0.13). The adjusted odds ratio (OR) for clinical cure with oral beta-lactams was 0.31 (95% CI 0.05-1.90, p = 0.21); propensity score adjusted analysis showed a similar result. There was no statistically significant difference in secondary outcomes. CONCLUSIONS: Oral beta-lactams appear to be a safe and effective step down option in bacteremic E. coli urinary tract infections compared to oral fluoroquinolones.

Transient climate and ambient health impacts due to national solid fuel cookstove emissions.

Residential solid fuel use contributes to degraded indoor and ambient air quality and may affect global surface temperature. However, the potential for national-scale cookstove intervention programs to mitigate the latter issues is not yet well known, owing to the spatial heterogeneity of aerosol emissions and impacts, along with coemitted species. Here we use a combination of atmospheric modeling, remote sensing, and adjoint sensitivity analysis to individually evaluate consequences of a 20-y linear phase-out of cookstove emissions in each country with greater than 5% of the population using solid fuel for cooking. Emissions reductions in China, India, and Ethiopia contribute to the largest global surface temperature change in 2050 [combined impact of -37 mK (11 mK to -85 mK)], whereas interventions in countries less commonly targeted for cookstove mitigation such as Azerbaijan, Ukraine, and Kazakhstan have the largest per cookstove climate benefits. Abatement in China, India, and Bangladesh contributes to the largest reduction of premature deaths from ambient air pollution, preventing 198,000 (102,000-204,000) of the 260,000 (137,000-268,000) global annual avoided deaths in 2050, whereas again emissions in Ukraine and Azerbaijan have the largest per cookstove impacts, along with Romania. Global cookstove emissions abatement results in an average surface temperature cooling of -77 mK (20 mK to -278 mK) in 2050, which increases to -118 mK (-11 mK to -335 mK) by 2100 due to delayed CO2 response. Health impacts owing to changes in ambient particulate matter with an aerodynamic diameter of 2.5 µm or less (PM2.5) amount to ∼22.5 million premature deaths prevented between 2000 and 2100.

Improving present day and future estimates of anthropogenic sectoral emissions and the resulting air quality impacts in Africa.

The African continent is undergoing immense social and economic change, particularly regarding population growth and urbanization, where the urban population in Africa is anticipated to increase by a factor of 3 over the next 40 years. To understand the potential health impacts from this demographical shift and design efficient emission mitigation strategies, we used improved Africa-specific emissions that account for inefficient combustion sources for a number of sectors such as transportation, household energy generation, waste burning, and home heating and cooking. When these underrepresented emissions sources are combined with the current estimates of emissions in Africa, ambient particulate matter concentrations from present-day anthropogenic activity contribute to 13 210 annual premature deaths, with the largest contributions (38%) coming from residential emissions. By scaling both the population and the emissions for projected national-scale levels of growth, the predicted health impact grows to approximately 78 986 annual premature deaths by 2030 with 45% now resulting from emissions related to energy combustion. In order to mitigate this resulting increase in premature deaths, three scenarios have been developed which reduce sector-specific future emissions based on prior targets for technological improvements and emission controls in transportation, energy production and residential activities. These targeted potential mitigation strategies can avoid up to 37% of the estimated annual premature deaths by 2030 with the largest opportunity being a reduction of 10 868 annual deaths from switching half of the energy generation in South Africa to renewable technologies.

Response of global particulate-matter-related mortality to changes in local precursor emissions.

Recent Global Burden of Disease (GBD) assessments estimated that outdoor fine-particulate matter (PM2.5) is a causal factor in over 5% of global premature deaths. PM2.5 is produced by a variety of direct and indirect, natural and anthropogenic processes that complicate PM2.5 management. This study develops a proof-of-concept method to quantify the effects on global premature mortality of changes to PM2.5 precursor emissions. Using the adjoint of the GEOS-Chem chemical transport model, we calculated sensitivities of global PM2.5-related premature mortality to emissions of precursor gases (SO2, NOx, NH3) and carbonaceous aerosols. We used a satellite-derived ground-level PM2.5 data set at approximately 10 × 10 km(2) resolution to better align the exposure with population density. We used exposure-response functions from the GBD project to relate mortality to exposure in the adjoint calculation. The response of global mortality to changes in local anthropogenic emissions varied spatially by several orders of magnitude. The largest reductions in mortality for a 1 kg km(-2) yr(-1) decrease in emissions were for ammonia and carbonaceous aerosols in Eastern Europe. The greatest reductions in mortality for a 10% decrease in emissions were found for secondary inorganic sources in East Asia. In general, a 10% decrease in SO2 emissions was the most effective source to control, but regional exceptions were found.

Characterization of Prescribing Practices for Uncomplicated Streptococcal and Enterococcal Bacteremias: The NARRATE Study.

Background: Bloodstream infections (BSIs) rank among the top causes of death in North America. Despite the prevalence of these infections, there remain significant practice variations in the prescribing of antibiotics. Objective: To investigate current prescribing practices for management of uncomplicated streptococcal and enterococcal BSIs. Methods: A retrospective cohort study was conducted using charts for patients admitted to an acute care centre in British Columbia between November 16, 2019, and October 20, 2020. Adult patients (≥ 18 years of age) with a diagnosis of uncomplicated streptococcal or enterococcal BSI were included. Patients were excluded if they had polymicrobial bacteremia or deep-seated infection or had been admitted for no more than 48 hours. The primary outcomes were duration of antibiotic therapy (IV and oral) and time to appropriate oral therapy for treatment of BSI. The secondary outcomes were observed rates of re-initiation of antibiotics and readmission with recurrent BSI. Descriptive statistics were calculated and regression analysis was performed for the primary and secondary outcomes. Results: A total of 96 patients met the inclusion criteria. The median total duration of therapy for uncomplicated streptococcal and enterococcal BSI was about 2 weeks. Streptococcus pneumoniae BSIs were associated with a significantly shorter duration of IV therapy and were more likely to be associated with transition to oral antibiotics. No recurrent BSIs were observed in patients for whom therapy was transitioned to oral antibiotics. Conclusions: Further study is warranted to explore shorter duration of antibiotic therapy and transition to oral therapy as treatment approaches for uncomplicated streptococcal and enterococcal BSI. Other outcomes of interest for future research include determining the optimal time for transition to oral therapy.

Contexte: Les infections du sang (IS), ou bactériémies, se classent parmi les causes principales de décès en Amérique du Nord. Malgré leur prévalence, la pratique de la prescription d'antibiotiques continue de varier grandement. Objectif: Étudier les pratiques actuelles de la prescription pour la gestion des bactériémies à streptocoque et à entérocoque non compliquées. Méthodes: Une étude de cohorte rétrospective a été menée à l'aide de dossiers de patients admis à un centre de soins aigus en Colombie-Britannique entre le 16 novembre 2019 et le 20 octobre 2020. Des patients adultes (≥ 18 ans) ayant reçu un diagnostic de bactériémie a streptocoque ou à entérocoque non compliquée ont été inclus. Les patients étaient exclus s'ils présentaient une bactériémie polymicrobienne ou une infection profonde ou s'ils avaient été hospitalisés depuis moins de 48 heures. Les résultats principaux étaient la durée de l'antibiothérapie (IV et orale) et le temps écoulé avant la transition à une thérapie orale adaptée pour le traitement de l'IS. Les résultats secondaires étaient les taux observés de reprise des antibiotiques et de réadmission avec une IS récurrente. Des statistiques descriptives ont été calculées et une analyse de régression a été effectuée pour les résultats principaux et secondaires. Résultats: Au total, 96 patients répondaient aux critères d'inclusion. La durée totale médiane du traitement pour les bactériémies à streptocoque et à entérocoque non compliquées était d'environ 2 semaines. Les bactériémies à Streptococcus pneumoniae étaient associées à une durée significativement plus courte du traitement IV et étaient plus susceptibles d'être associées à la transition vers des antibiotiques oraux. Aucune IS récurrente n'a été observée chez les patients pour lesquels le traitement était passé à des antibiotiques oraux. Conclusions: Une étude plus approfondie est justifiée pour explorer une durée plus courte de l'antibiothérapie et la transition vers une thérapie orale en tant qu'approches de traitement pour les IS à streptocoque et à entérocoque non compliquées. D'autres résultats d'intérêt pour les recherches futures comprennent la détermination du moment optimal pour la transition vers la thérapie orale.

Inflammatory Gene Expression in Livers Undergoing Ex Situ Normothermic Perfusion Is Attenuated by Leukocyte Removal From the Perfusate.

BACKGROUND: Ex situ normothermic perfusion (ESNP) is a method to evaluate and potentially recondition organs before transplantation. However, increased expression of inflammatory molecules, including by tissue-resident immune cells, may occur during the perfusion process, potentially negating the beneficial effects of perfusion. METHODS: We used RNA sequencing to assess gene expression in 31 livers undergoing ESNP, including 23 donated after circulatory death (DCD) and 8 donated after brain death. In 7 DCD livers, a leucocyte filter was added to the circuit during perfusion. Biopsies were available for transcriptomic assessment in all cases at the start of perfusion and at varying time points postperfusion. RESULTS: During ESNP in DCD livers, we observed an increase in proinflammatory, profibrinolytic, and prorepair pathway genes. SERPINE1, encoding plasminogen activator inhibitor-1, was among the genes most significantly upregulated during perfusion in DCD livers, potentially promoting fibrin clot persistence in vasculature. We also found increased expression of monocyte and neutrophil recruiting chemokine and proinflammatory cytokine transcripts during ESNP, but several prorepair molecules, including thymic stromal lymphopoietin, were also upregulated. In both DCD and donation after brain death livers, interferon-gamma response genes were enriched, whereas oxidative phosphorylation genes decreased in organs with high perfusate alanine transaminase, a biomarker associated with adverse clinical outcomes. The inclusion of a leukocyte filter in the perfusion circuit mitigated the induction of inflammation/immune pathway genes during perfusion and was associated with enrichment in oxidative phosphorylation genes. CONCLUSIONS: Leukocyte removal during ESNP abrogates transcriptional changes that are associated with unfavorable clinical outcomes, potentially benefiting human livers undergoing ESNP.

Neutrophil extracellular traps protect the kidney from ascending infection and are required for a positive leukocyte dipstick test.

Lower urinary tract infection (UTI) is common but only rarely complicated by pyelonephritis. However, the mechanisms preventing extension to the kidney are unclear. Here, we identified neutrophil extracellular traps (NETs) in healthy human urine that provide an antibacterial defense strategy within the urinary tract. In both in vivo murine models of UTI where uropathogenic E. coli are inoculated into the bladder and ex vivo human urine models, NETs interacted with uromodulin to form large webs that entrapped the bacteria. Peptidyl arginine deiminase 4 (PADI4) inhibition in mice blocked NETosis and resulted in progression of cystitis into pyelonephritis, suggesting that NETosis of urinary neutrophils acts to prevent bacterial ascent into the kidney. Analysis of UK Biobank data revealed that genetic variants in PADI4 that associated with increased risk of rheumatoid arthritis in multiple genome-wide association studies were consistently associated with reduced susceptibility to UTI. Last, we showed that urine dipstick testing for leukocyte esterase was negative in the presence of intact blood neutrophils but became positive when neutrophils were stimulated to NET, and this could be prevented by selective PADI4 inhibition, demonstrating that this test does not detect absolute neutrophil count, as has long been assumed, but specifically detects neutrophils that have undergone NETosis. These findings highlight the role of NETosis in preventing ascending infections in the urinary tract and improve our understanding of one of the most common clinical tests in medicine.

Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity.

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7+ DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7+ DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7+ DCs co-localise with PD-1+CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells.

Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity.

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.

Inhaled corticosteroids and risk of recurrent pneumonia: a population-based, nested case-control study.

BACKGROUND: Studies have suggested an increased risk of pneumonia with inhaled corticosteroid (ICS) use, although this association is inconsistent. We evaluated the risk of recurrent pneumonia associated with ICS use in a high-risk population of individuals who survived an episode of pneumonia. METHODS: Clinical and 5-year follow-up data were collected on all adults aged ≥ 65 years with pneumonia over a period of 2 years. Using a nested case-control design, first cases (patients with recurrent pneumonia ≥ 30 days after initial episode) and then controls (free of pneumonia and matched on age, sex, and chronic obstructive pulmonary disease [COPD]) were identified. ICS use was classified as never, past (remote, only before initial pneumonia), or current. Our primary outcome measure was recurrent pneumonia assessed using conditional multivariate logistic regression after adjustment of demographics and clinical data. RESULTS: During 5 years of follow-up, 653 recurrent pneumonia cases were matched with 6244 controls; mean age was 79 (SD, 8) years, 3577 (52%) were male, 2652 (38%) had COPD, and 2294 (33%) ever used ICS. Overall, 123 of 870 (14%) current ICS users had recurrent pneumonia compared to 395 of 4603 (9%) never-users (adjusted odds ratio, 1.90; 95% confidence interval, 1.45-2.50; P < .001; number need to harm = 20). Conversely, there was no association between past (remote) use of ICS and pneumonia: 9% of past users versus 9% never-users (P = .36). CONCLUSIONS: ICS use was associated with a 90% relative increase in the risk of recurrent pneumonia among high-risk pneumonia survivors. This should be considered when prescribing ICS and when deciding which patients might need more intensive follow-up.