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PNAS Nexus Mar 2024Legionnaires' disease (LD) is a severe form of pneumonia (∼10-25% fatality rate) caused by inhalation of aerosols containing , a pathogenic gram-negative bacteria....
Legionnaires' disease (LD) is a severe form of pneumonia (∼10-25% fatality rate) caused by inhalation of aerosols containing , a pathogenic gram-negative bacteria. These bacteria can grow, spread, and aerosolize through building water systems. A recent dramatic increase in LD incidence has been observed globally, with a 9-fold increase in the United States from 2000 to 2018, and with disproportionately higher burden for socioeconomically vulnerable subgroups. Despite the focus of decades of research since the infamous 1976 outbreak, substantial knowledge gaps remain with regard to source of exposure and the reason(s) for the dramatic increase in LD incidence. Here, we rule out factors indicated in literature to contribute to its long-term increases and identify a hitherto unexplored explanatory factor. We also provide an epidemiological demonstration that the occurrence of LD is linked with exposure to cooling towers (CTs). Our results suggest that declining sulfur dioxide air pollution, which has many well-established health benefits, results in reduced acidity of aerosols emitted from CTs, which may prolong the survival duration of in contaminated CT droplets and contribute to the increase in LD incidence. Mechanistically associating decreasing aerosol acidity with this respiratory disease has implications for better understanding its transmission, predicting future risks, and informed design of preventive and interventional strategies that consider the complex impacts of continued sulfur dioxide changes.
PubMed: 38476666
DOI: 10.1093/pnasnexus/pgae085 -
International Journal of Infectious... May 2024The effectiveness of monotherapy and combination therapy with quinolones and macrolides for treating Legionnaires' disease remains uncertain; this study aimed to assess...
OBJECTIVES
The effectiveness of monotherapy and combination therapy with quinolones and macrolides for treating Legionnaires' disease remains uncertain; this study aimed to assess the comparative effectiveness of three treatment approaches.
METHODS
Using a nationwide inpatient database, we analyzed 3560 eligible patients hospitalized for Legionnaires' disease between April 1, 2014, and March 31, 2021; patients were divided into combination therapy, quinolone monotherapy, and macrolide monotherapy groups according to the antibiotics administered within 2 days of admission. We compared in-hospital mortality, total hospitalization costs, and length of stay across these groups using multiple propensity score analysis with inverse probability of treatment weighting.
RESULTS
Of the 3560 patients, there were 564 (15.8%), 2221 (62.4%), and 775 (21.8%) patients in the combination therapy, quinolone monotherapy, and macrolide monotherapy groups, respectively. No significant differences were observed in in-hospital mortality between combination therapy and quinolone monotherapy groups, and between combination therapy and macrolide monotherapy groups. There were no significant differences in total hospitalization costs or length of stay among the three groups.
CONCLUSION
The study suggests that there may not be a significant advantage in using a combination of quinolones and macrolides over monotherapy for the treatment of Legionnaires' disease. Given the potential for increased side effects, careful consideration is advised when choosing this combination therapy.
Topics: Humans; Legionnaires' Disease; Inpatients; Anti-Bacterial Agents; Anti-Infective Agents; Macrolides; Quinolones
PubMed: 38367954
DOI: 10.1016/j.ijid.2024.02.008 -
Cureus Aug 2023Legionnaires' disease is an atypical pneumonia caused by Legionella pneumophila ( pneumonia that features slow onset, nonproductive cough, fatigue, headache, sore...
Legionnaires' disease is an atypical pneumonia caused by Legionella pneumophila ( pneumonia that features slow onset, nonproductive cough, fatigue, headache, sore throat, myalgias, and malaise. It can be difficult to diagnose, as it presents with extrapulmonary symptoms, and delay in treatment can be fatal. Here, we present the case of a previously healthy 32-year-old Caucasian male with Legionnaires disease who only presented to the clinic with abdominal pain and diarrhea. The patient did not have any pulmonary symptoms at the initial presentation. This presentation did not fit the diagnostic tools available for Legionnaires' disease, including a validated clinical prediction rule, which ruled out infection with a sensitivity of 97% and a negative predictive value of 99.4%. Due to the complaint of abdominal pain, a flat/upright abdominal X-ray was ordered, which includes a chest X-ray. Upon analyzing the chest X-ray, a right lower lobe consolidation was identified, prompting an urinary test to be added to the lab orders. This case represents the difficulties in diagnosing Legionnaires' disease due to the diverse clinical complexities of presentations, which may solely involve abdominal complaints.
PubMed: 37779758
DOI: 10.7759/cureus.44368 -
Emerging Infectious Diseases Jan 2024We determined whether the incidence rates of travel-associated Legionnaires' disease (TALD) in hotels in Germany increased after a previous occurrence and whether...
We determined whether the incidence rates of travel-associated Legionnaires' disease (TALD) in hotels in Germany increased after a previous occurrence and whether control measures required by the European Legionnaires' Disease Surveillance Network after a cluster (>2 cases within 2 years) restored the rate to baseline. We analyzed TALD surveillance data from Germany during 2015-2019; a total of 307 TALD cases (163 domestic, 144 nondomestic) in hotels were reported. The incidence rate ratio was 5.5 (95% CI 3.6-7.9) for a second case and 25 (95% CI 11-50) for a third case after a cluster had occurred, suggesting that control measures initiated after the occurrence of TALD clusters might be inadequate to restore the incidence rate to baseline. Our findings indicate that substantial LD preventive measures should be explored by hotels or other accommodations after the first TALD case occurs to reduce the risk for future infections.
Topics: Humans; Incidence; Legionnaires' Disease; Travel; Germany
PubMed: 38146962
DOI: 10.3201/eid3001.231064 -
Cell Reports Apr 2024Small GTPases of the Ras subfamily are best known for their role as proto-oncoproteins, while their function during microbial infection has remained elusive. Here, we...
Small GTPases of the Ras subfamily are best known for their role as proto-oncoproteins, while their function during microbial infection has remained elusive. Here, we show that Legionella pneumophila hijacks the small GTPase NRas to the Legionella-containing vacuole (LCV) surface. A CRISPR interference screen identifies a single L. pneumophila effector, DenR (Lpg1909), required for this process. Recruitment is specific for NRas, while its homologs KRas and HRas are excluded from LCVs. The C-terminal hypervariable tail of NRas is sufficient for recruitment, and interference with either NRas farnesylation or S-acylation sites abrogates recruitment. Intriguingly, we detect markers of active NRas signaling on the LCV, suggesting it acts as a signaling platform. Subsequent phosphoproteomics analyses show that DenR rewires the host NRas signaling landscape, including dampening of the canonical mitogen-activated protein kinase pathway. These results provide evidence for L. pneumophila targeting NRas and suggest a link between NRas GTPase signaling and microbial infection.
Topics: Legionella pneumophila; Humans; Membrane Proteins; MAP Kinase Signaling System; GTP Phosphohydrolases; Bacterial Proteins; Down-Regulation; HEK293 Cells; Legionnaires' Disease; Vacuoles; Proto-Oncogene Proteins p21(ras)
PubMed: 38568811
DOI: 10.1016/j.celrep.2024.114033 -
The Lancet. Digital Health Jul 2024Cooling towers containing Legionella spp are a high-risk source of Legionnaires' disease outbreaks. Manually locating cooling towers from aerial imagery during outbreak...
BACKGROUND
Cooling towers containing Legionella spp are a high-risk source of Legionnaires' disease outbreaks. Manually locating cooling towers from aerial imagery during outbreak investigations requires expertise, is labour intensive, and can be prone to errors. We aimed to train a deep learning computer vision model to automatically detect cooling towers that are aerially visible.
METHODS
Between Jan 1 and 31, 2021, we extracted satellite view images of Philadelphia (PN, USA) and New York state (NY, USA) from Google Maps and annotated cooling towers to create training datasets. We augmented training data with synthetic data and model-assisted labelling of additional cities. Using 2051 images containing 7292 cooling towers, we trained a two-stage model using YOLOv5, a model that detects objects in images, and EfficientNet-b5, a model that classifies images. We assessed the primary outcomes of sensitivity and positive predictive value (PPV) of the model against manual labelling on test datasets of 548 images, including from two cities not seen in training (Boston [MA, USA] and Athens [GA, USA]). We compared the search speed of the model with that of manual searching by four epidemiologists.
FINDINGS
The model identified visible cooling towers with 95·1% sensitivity (95% CI 94·0-96·1) and a PPV of 90·1% (95% CI 90·0-90·2) in New York City and Philadelphia. In Boston, sensitivity was 91·6% (89·2-93·7) and PPV was 80·8% (80·5-81·2). In Athens, sensitivity was 86·9% (75·8-94·2) and PPV was 85·5% (84·2-86·7). For an area of New York City encompassing 45 blocks (0·26 square miles), the model searched more than 600 times faster (7·6 s; 351 potential cooling towers identified) than did human investigators (mean 83·75 min [SD 29·5]; mean 310·8 cooling towers [42·2]).
INTERPRETATION
The model could be used to accelerate investigation and source control during outbreaks of Legionnaires' disease through the identification of cooling towers from aerial imagery, potentially preventing additional disease spread. The model has already been used by public health teams for outbreak investigations and to initialise cooling tower registries, which are considered best practice for preventing and responding to outbreaks of Legionnaires' disease.
FUNDING
None.
Topics: Humans; Disease Outbreaks; Legionnaires' Disease; Deep Learning; Air Conditioning; Philadelphia; New York; Legionella; Satellite Imagery
PubMed: 38906615
DOI: 10.1016/S2589-7500(24)00094-3 -
Journal of Clinical Microbiology Apr 2024The unprecedented precision and resolution of whole genome sequencing (WGS) can provide definitive identification of infectious agents for epidemiological outbreak...
The unprecedented precision and resolution of whole genome sequencing (WGS) can provide definitive identification of infectious agents for epidemiological outbreak tracking. WGS approaches, however, are frequently impeded by low pathogen DNA recovery from available primary specimens or unculturable samples. A cost-effective hybrid capture assay for WGS analysis directly on primary specimens was developed. DNA from a diverse range of sputum and autopsy specimens PCR-positive for serogroup 1 (LPSG1) was enriched with this method, and WGS was performed. All tested specimens were determined to be enriched for reads (up to 209,000-fold), significantly improving the discriminatory power to compare relatedness when no clinical isolate was available. We found the WGS data from some enriched specimens to differ by less than five single-nucleotide polymorphisms (SNPs) when compared to the WGS data of a matched culture isolate. This testing and analysis retrospectively provided previously unconfirmed links to environmental sources for clinical specimens of sputum and autopsy lung tissue. The latter provided the additional information needed to identify the source of these culture-negative cases associated with the South Bronx 2015 Legionnaires' disease (LD) investigation in New York City. This new method provides a proof of concept for future direct clinical specimen hybrid capture enrichment combined with WGS and bioinformatic analysis during outbreak investigations.IMPORTANCELegionnaires' disease (LD) is a severe and potentially fatal type of pneumonia primarily caused by inhalation of -contaminated aerosols from man-made water or cooling systems. LD remains extremely underdiagnosed as it is an uncommon form of pneumonia and relies on clinicians including it in the differential and requesting specialized testing. Additionally, it is challenging to obtain clinical lower respiratory specimens from cases with LD, and when available, culture requires specialized media and growth conditions, which are not available in all microbiology laboratories. In the current study, a method for using hybrid capture by RNA baiting was developed, which allowed us to generate sufficient genome resolution from serogroup 1 PCR-positive clinical specimens. This new approach offers an additional tool for surveillance of future LD outbreaks where isolation of is not possible and may help solve previously unanswered questions from past LD investigations.
Topics: Humans; Legionnaires' Disease; Retrospective Studies; Legionella pneumophila; Legionella; Whole Genome Sequencing; Disease Outbreaks; Pneumonia; DNA
PubMed: 38511938
DOI: 10.1128/jcm.01305-23 -
MBio Oct 2023is an intracellular bacterium responsible of Legionnaires' disease, a severe pneumonia that is often fatal when not treated promptly. The pathogen's ability to...
is an intracellular bacterium responsible of Legionnaires' disease, a severe pneumonia that is often fatal when not treated promptly. The pathogen's ability to efficiently colonize the host resides in its ability to replicate intracellularly. Essential for intracellular replication is translocation of many different protein effectors a specialized secretion system. One of them, called RomA, binds and directly modifies the host chromatin at a unique site (tri-methylation of lysine 14 of histone H3 [H3K14me]). However, the molecular mechanisms of binding are not known. Here, we resolve this question through structural characterization of RomA together with the H3 peptide. We specifically reveal an active role of the ankyrin repeats located in its C-terminal in the interaction with the histone H3 tail. Indeed, without the ankyrin domains, RomA loses its ability to act as histone methyltransferase. These results discover the molecular mechanisms by which a bacterial histone methyltransferase that is conserved in strains acts to modify chromatin.
Topics: Humans; Legionella pneumophila; Chromatin; Histones; Ankyrins; Histone Methyltransferases; Legionnaires' Disease; Bacterial Proteins
PubMed: 37795993
DOI: 10.1128/mbio.01655-23 -
Annals of Agricultural and... Mar 2024is the primary etiological agent of Legionnaires' disease. These are opportunistic pathogens causing lung infections by inhalation of contaminated aerosols. Controlling...
INTRODUCTION
is the primary etiological agent of Legionnaires' disease. These are opportunistic pathogens causing lung infections by inhalation of contaminated aerosols. Controlling the presence of these bacteria in domestic distribution water systems (mainly hot water systems) is important for reducing the threat they pose to human health. pathogens are detected and quantified during routine testing of water samples according to procedures included in PN-EN ISO 11731:2017. However, these procedures are labour-intensive, and the results are obtained after a relatively long time. Implementing the Legiolert™/Quanti-Tray test as an alternative method may constitute a good solution: it simplifies the testing procedure and significantly reduces the time necessary to obtain the final result.
OBJECTIVE
The aim of the study was to compare the relative recovery of from water samples tested according to PN-EN ISO 11731:2017, and the alternative method of the most probable number (MPN) with the Legiolert™/Quanti-Tray (IDEXX) test, and to assess the suitability of the alternative method for routine testing.
MATERIAL AND METHODS
Parallel testing was conducted of 38 hot water samples to detect and determine acc. to PN-EN ISO 11731:2017 and the Legiolert™/Quanti-Tray test. Statistical analysis of the results was performed according to PN-EN ISO 17994:2014 and the McNemar's test.
RESULTS
The Legiolert™ test was confirmed to be comparable in performance to the reference standardized method in both qualitative and quantitative detection of in hot water samples.
CONCLUSIONS
The study confirmed that the Legiolert™ test is specific and easy to use, and may constitute an alternative to standardized procedures used in the quantification of in water.
Topics: Humans; Legionella pneumophila; Water Microbiology; Respiratory Aerosols and Droplets; Legionnaires' Disease; Drinking Water; Legionella
PubMed: 38549473
DOI: 10.26444/aaem/173402 -
PLoS Pathogens May 2024Legionella pneumophila strains harboring wild-type rpsL such as Lp02rpsLWT cannot replicate in mouse bone marrow-derived macrophages (BMDMs) due to induction of...
Legionella pneumophila strains harboring wild-type rpsL such as Lp02rpsLWT cannot replicate in mouse bone marrow-derived macrophages (BMDMs) due to induction of extensive lysosome damage and apoptosis. The bacterial factor directly responsible for inducing such cell death and the host factor involved in initiating the signaling cascade that leads to lysosome damage remain unknown. Similarly, host factors that may alleviate cell death induced by these bacterial strains have not yet been investigated. Using a genome-wide CRISPR/Cas9 screening, we identified Hmg20a and Nol9 as host factors important for restricting strain Lp02rpsLWT in BMDMs. Depletion of Hmg20a protects macrophages from infection-induced lysosomal damage and apoptosis, allowing productive bacterial replication. The restriction imposed by Hmg20a was mediated by repressing the expression of several endo-lysosomal proteins, including the small GTPase Rab7. We found that SUMOylated Rab7 is recruited to the bacterial phagosome via SulF, a Dot/Icm effector that harbors a SUMO-interacting motif (SIM). Moreover, overexpression of Rab7 rescues intracellular growth of strain Lp02rpsLWT in BMDMs. Our results establish that L. pneumophila exploits the lysosomal network for the biogenesis of its phagosome in BMDMs.
Topics: Legionella pneumophila; Animals; rab GTP-Binding Proteins; Mice; Phagosomes; rab7 GTP-Binding Proteins; Lysosomes; Macrophages; Legionnaires' Disease; Sumoylation; Mice, Inbred C57BL; Endosomes
PubMed: 38739652
DOI: 10.1371/journal.ppat.1011783