Host protease activity classifies pneumonia etiology.

Community-acquired pneumonia (CAP) has been brought to the forefront of global health priorities due to the COVID-19 pandemic. However, classification of viral versus bacterial pneumonia etiology remains a significant clinical challenge. To this end, we have engineered a panel of activity-based nanosensors that detect the dysregulated activity of pulmonary host proteases implicated in the response to pneumonia-causing pathogens and produce a urinary readout of disease. The nanosensor targets were selected based on a human protease transcriptomic signature for pneumonia etiology generated from 33 unique publicly available study cohorts. Five mouse models of bacterial or viral CAP were developed to assess the ability of the nanosensors to produce etiology-specific urinary signatures. Machine learning algorithms were used to train diagnostic classifiers that could distinguish infected mice from healthy controls and differentiate those with bacterial versus viral pneumonia with high accuracy. This proof-of-concept diagnostic approach demonstrates a way to distinguish pneumonia etiology based solely on the host proteolytic response to infection.

Classification of community-acquired outbreaks for the global transmission of COVID-19: Machine learning and statistical model analysis.

BACKGROUND: As Coronavirus disease 2019 (COVID-19) pandemic led to the unprecedent large-scale repeated surges of epidemics worldwide since the end of 2019, data-driven analysis to look into the duration and case load of each episode of outbreak worldwide has been motivated. METHODS: Using open data repository with daily infected, recovered and death cases in the period between March 2020 and April 2021, a descriptive analysis was performed. The susceptible-exposed-infected-recovery model was used to estimate the effective productive number (Rt). The duration taken from Rt > 1 to Rt < 1 and case load were first modelled by using the compound Poisson method. Machine learning analysis using the K-means clustering method was further adopted to classify patterns of community-acquired outbreaks worldwide. RESULTS: The global estimated Rt declined after the first surge of COVID-19 pandemic but there were still two major surges of epidemics occurring in September 2020 and March 2021, respectively, and numerous episodes due to various extents of Nonpharmaceutical Interventions (NPIs). Unsupervised machine learning identified five patterns as "controlled epidemic", "mutant propagated epidemic", "propagated epidemic", "persistent epidemic" and "long persistent epidemic" with the corresponding duration and the logarithm of case load from the lowest (18.6 ± 11.7; 3.4 ± 1.8)) to the highest (258.2 ± 31.9; 11.9 ± 2.4). Countries like Taiwan outside five clusters were classified as no community-acquired outbreak. CONCLUSION: Data-driven models for the new classification of community-acquired outbreaks are useful for global surveillance of uninterrupted COVID-19 pandemic and provide a timely decision support for the distribution of vaccine and the optimal NPIs from global to local community.

Meta-analysis of Calibration, Discrimination, and Stratum-Specific Likelihood Ratios for the CRB-65 Score.

BACKGROUND: The CRB-65 score is recommended as a decision support tool to help identify patients with community-acquired pneumonia (CAP) who can safely be treated as outpatients. OBJECTIVE: To perform an updated meta-analysis of the accuracy, discrimination, and calibration of the CRB-65 score using a novel approach to calculation of stratum-specific likelihood ratios. DESIGN: Meta-analysis of accuracy, discrimination, and calibration. METHODS: We searched PubMed, Google, previous systematic reviews, and reference lists of included studies. Data was abstracted and quality assessed in parallel by two investigators. The quality assessment used an adaptation of the TRIPOD and PROBAST criteria. Measures of discrimination, calibration, and stratum-specific likelihood ratios are reported. KEY RESULTS: Twenty-nine studies met our inclusion criteria and provided usable data. Most studies were set in Europe, none in North America, and 12 were judged to be at low risk of bias. The pooled estimate of area under the receiver operating characteristic curve was 0.74 (95% CI 0.71-0.77) for all studies. Calibration was good although there was significant heterogeneity; the pooled estimate of the ratio of observed to expected mortality for all studies was 1.04 (95% CI 0.91-1.19). The corresponding values for studies at low risk of bias where patients could be treated as outpatients or inpatients were 0.76 (0.70-0.81) and 0.88 (0.69-1.13). Summary estimates of stratum-specific likelihood ratios for all studies were 0.19 for the low-risk group, 1.1 for the moderate-risk group, and 4.5 for the high-risk group, and 0.13, 1.3, and 5.6 for studies at low risk of bias where patients could be treated as outpatients or inpatients. CONCLUSIONS: The CRB-65 is useful for identifying low-risk patients for outpatient therapy. Given a 4% overall mortality risk, patients classified as low risk by the CRB-65 had an outpatient mortality risk of no more than 0.5%.

What is behind phylogenetic analysis of hospital-, community- and livestock-associated methicillin-resistant Staphylococcus aureus?

Methicillin-resistant Staphylococcus aureus (MRSA) has been shown to be the predominant life-threatening pathogen in Egypt. MRSA is a major cause of severe healthcare-associated (HA) infections. During the last decades, the incidence of community-associated (CA) MRSA infections has a complex epidemiology arising from the circulation of different strains in the general population. Moreover, livestock-associated (LA) MRSA emerged recently becomes an emerging threat to public health. Therefore, it is important to illuminate the differences between CA-, HA- and LA-MRSA to shed light on their genetic diversity and evolution. This study presents the first data on analysing the correlation between CA-, LA- and HA-MRSA using antibiogram typing, molecular characteristics and antimicrobial resistance and virulence genes' profiles. Overall, HA-MRSA strains tended to be multidrug resistant and less virulent than both LA- and CA-MRSA strains. Importantly, CA-MRSA strains had a high homology with each of HA- and LA-MRSA. However, no similarity was observed between HA- and LA-MRSA. Our findings suggest that the epidemiological changes in genetic behaviour between HA- and LA-MRSA are due to the presence of CA-MRSA confirming that CA-MRSA has created a public health crisis worldwide.

A Bayesian decision support sequential model for severity of illness predictors and intensive care admissions in pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading causes of morbidity and mortality in the USA. Our objective was to assess the predictive value on critical illness and disposition of a sequential Bayesian Model that integrates Lactate and procalcitonin (PCT) for pneumonia. METHODS: Sensitivity and specificity of lactate and PCT attained from pooled meta-analysis data. Likelihood ratios calculated and inserted in Bayesian/ Fagan nomogram to calculate posttest probabilities. Bayesian Diagnostic Gains (BDG) were analyzed comparing pre and post-test probability. To assess the value of integrating both PCT and Lactate in Severity of Illness Prediction we built a model that combined CURB65 with PCT as the Pre-Test markers and later integrated the Lactate Likelihood Ratio Values to generate a combined CURB 65 + Procalcitonin + Lactate Sequential value. RESULTS: The BDG model integrated a CUBR65 Scores combined with Procalcitonin (LR+ and LR-) for Pre-Test Probability Intermediate and High with Lactate Positive Likelihood Ratios. This generated for the PCT LR+ Post-test Probability (POSITIVE TEST) Posterior probability: 93% (95% CI [91,96%]) and Post Test Probability (NEGATIVE TEST) of: 17% (95% CI [15-20%]) for the Intermediate subgroup and 97% for the high risk sub-group POSITIVE TEST: Post-Test probability:97% (95% CI [95,98%]) NEGATIVE TEST: Post-test probability: 33% (95% CI [31,36%]) . ANOVA analysis for CURB 65 (alone) vs CURB 65 and PCT (LR+) vs CURB 65 and PCT (LR+) and Lactate showed a statistically significant difference (P value = 0.013). CONCLUSIONS: The sequential combination of CURB 65 plus PCT with Lactate yielded statistically significant results, demonstrating a greater predictive value for severity of illness thus ICU level care.

Treatment of community-acquired pneumonia. / Behandling av pneumoni oppstått utenfor sykehus.

BAKGRUNN: Helsedirektoratet gir ut nasjonale retningslinjer for antibiotikabruk i sykehus. For pneumoni oppstått utenfor sykehus anbefales penicillin ved mild til moderat pneumoni og penicillin i kombinasjon med gentamicin ved alvorlig pneumoni. Alvorlighetsgrad vurderes med CRB-65-kriteriene. Vi vet lite om etterlevelse av retningslinjene. METODE: Vi gjennomgikk journalene til pasienter innlagt med pneumoni med Streptococcus pneumoniae eller Haemophilus influenzae ved Infeksjonsmedisinsk avdeling ved Oslo universitetssykehus, Ullevål sykehus, i 2015 (N = 70) og undersøkte om behandlingen som ble gitt, var i samsvar med de nasjonale retningslinjene. RESULTATER: 24 (34 %) av pasientene fikk penicillin i monoterapi, 25 (36 %) fikk kombinasjonen penicillin og gentamicin, 14 (20 %) fikk kefalosporiner, mens 7 (10 %) fikk andre antibiotika. Totalt fikk 38 (54 %) pasienter empirisk antibiotika i henhold til retningslinjene. CRB-65-kriteriene ble ikke dokumentert hos noen av pasientene. 38 av 50 pasienter som fikk penicillin, fikk høyere doser enn anbefalt. 62 (89 %) pasienter fikk justert behandling etter at bakteriesvar forelå. Median lengde av antibiotikabehandling var 10 døgn (interkvartilintervall 8-11 døgn). FORTOLKNING: Bredspektrede antibiotika ble benyttet oftere enn retningslinjene skulle tilsi. Etter at bakteriesvar forelå, ble behandlingen justert i henhold til de nasjonale retningslinjene. Penicillindosene var ofte for høye og behandlingslengden for lang sammenholdt med de nasjonale retningslinjene.

Metabolic profiles in community-acquired pneumonia: developing assessment tools for disease severity.

BACKGROUND: This study aimed to determine whether community-acquired pneumonia (CAP) had a metabolic profile and whether this profile can be used for disease severity assessment. METHODS: A total of 175 individuals including 119 CAP patients and 56 controls were enrolled and divided into two cohorts. Serum samples from a discovery cohort (n = 102, including 38 non-severe CAP, 30 severe CAP, and 34 age and sex-matched controls) were determined by untargeted ultra-high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based metabolomics. Selected differential metabolites between CAP patients versus controls, and between the severe CAP group versus non-severe CAP group, were confirmed by targeted mass spectrometry assays in a validation cohort (n = 73, including 32 non-severe CAP, 19 severe CAP and 22 controls). Pearson's correlation analysis was performed to assess relationships between the identified metabolites and clinical severity of CAP. The area under the curve (AUC), sensitivity and specificity of the metabolites for predicting the severity of CAP were also investigated. RESULTS: The metabolic signature was markedly different between CAP patients and controls. Fifteen metabolites were found to be significantly dysregulated in CAP patients, which were mainly mapped to the metabolic pathways of sphingolipid, arginine, pyruvate and inositol phosphate. The alternation trends of five metabolites among the three groups including sphinganine, p-Cresol sulfate, dehydroepiandrosterone sulfate (DHEA-S), lactate and L-arginine in the validation cohort were consistent with those in the discovery cohort. Significantly lower concentrations of sphinganine, p-Cresol sulfate and DHEA-S were observed in CAP patients than in controls (p < 0.05). Serum lactate and sphinganine levels were positively correlated with confusion, urea level, respiratory rate, blood pressure, and age > 65 years (CURB-65), pneumonia severity index (PSI) and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, while DHEA-S inversely correlated with the three scoring systems. Combining lactate, sphinganine and DHEA-S as a metabolite panel for discriminating severe CAP from non-severe CAP exhibited a better AUC of 0.911 (95% confidence interval 0.825-0.998) than CURB-65, PSI and APACHE II scores. CONCLUSIONS: This study demonstrates that serum metabolomics approaches based on the LC-MS/MS platform can be applied as a tool to reveal metabolic changes during CAP and establish a metabolite signature related to disease severity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03093220 . Registered retrospectively on 28 March 2017.

New Sepsis Definition (Sepsis-3) and Community-acquired Pneumonia Mortality. A Validation and Clinical Decision-Making Study.

RATIONALE: The Sepsis-3 Task Force updated the clinical criteria for sepsis, excluding the need for systemic inflammatory response syndrome (SIRS) criteria. The clinical implications of the proposed flowchart including the quick Sequential (Sepsis-related) Organ Failure Assessment (qSOFA) and SOFA scores are unknown. OBJECTIVES: To perform a clinical decision-making analysis of Sepsis-3 in patients with community-acquired pneumonia. METHODS: This was a cohort study including adult patients with community-acquired pneumonia from two Spanish university hospitals. SIRS, qSOFA, the Confusion, Respiratory Rate and Blood Pressure (CRB) score, modified SOFA (mSOFA), the Confusion, Urea, Respiratory Rate, Blood Pressure and Age (CURB-65) score, and Pneumonia Severity Index (PSI) were calculated with data from the emergency department. We used decision-curve analysis to evaluate the clinical usefulness of each score and the primary outcome was in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Of 6,874 patients, 442 (6.4%) died in-hospital. SIRS presented the worst discrimination, followed by qSOFA, CRB, mSOFA, CURB-65, and PSI. Overall, overestimation of in-hospital mortality and miscalibration was more evident for qSOFA and mSOFA. SIRS had lower net benefit than qSOFA and CRB, significantly increasing the risk of over-treatment and being comparable with the "treat-all" strategy. PSI had higher net benefit than mSOFA and CURB-65 for mortality, whereas mSOFA seemed more applicable when considering mortality/intensive care unit admission. Sepsis-3 flowchart resulted in better identification of patients at high risk of mortality. CONCLUSIONS: qSOFA and CRB outperformed SIRS and presented better clinical usefulness as prompt tools for patients with community-acquired pneumonia in the emergency department. Among the tools for a comprehensive patient assessment, PSI had the best decision-aid tool profile.

[Influenza and community acquired pneumonia in German primary care]. / Influenza und ambulant erworbene Pneumonie in hausärztlich tätigen Arztpraxen in Deutschland.

Influenza and community-acquired pneumonia (CAP) impose a considerable annual burden on the German primary care system. Yet there is a lack of epidemiological data from the country's outpatient sector on groups at risk as well as on the complications of these diseases.The Robert Koch Institute (RKI) initiated the study to identify population groups at increased risk for influenza or CAP as well as related comorbidities and sequelae. We present the methodology of the study and the descriptive analysis of the patients.ICD-10-based data was collected in 89 primary health care practices between January 2012 and April 2015 using a data extraction tool developed on behalf of the RKI. Case-based anonymized information was recorded for all patients in whom influenza, CAP or other acute respiratory infections (ARI) were diagnosed. For each patient information on all diagnoses including the date were retrospectively and prospectively collected (each for six months) as well as age, sex and influenza vaccination.Data on 156,803 patients with ARI was collected, of them 7909 patients with influenza (within influenza waves) and 8528 patients with CAP diagnoses. Influenza diagnoses showed a strong seasonal pattern and captured annual influenza waves in Germany. Of the influenza cases 1.6 % had a following diagnosis of CAP within 30 days. Age-specific prevalence of chronic diseases such as asthma and diabetes was significantly higher in the study population as compared to the German population.The developed tool delivers in a standardized fashion ICD-10-coded epidemiological data on population-based burden of influenza and CAP in Germany. As the descriptive analysis showed, the collected dataset is a reliable and solid basis for the further investigations of the study questions.

[Risk scores for community acquired pneumonia in elderly and geriatric patients]. / Risiko-Scores zur ambulant erworbenen Pneumonie bei älteren und geriatrischen Patienten.

BACKGROUND: Community-acquired pneumonia (CAP) is still an important and serious disease for elderly and geriatric patients. AIMS: For epidemiological and clinical reasons it is important to collate the frequencies of the various degrees of severity of CAP and to obtain information on the spread and degree of the threat to the various risk groups by CAP. In outpatient treatment a simple to execute prognosis score can be used to objectify the assessment of the clinical status of a patient and to support therapeutic decision-making. For this purpose knowledge of the appropriate instruments should be available to potential users. MATERIAL AND METHODS: Since the 1990s a variety of risk scores for stratification of CAP have been developed and evaluated. This article presents the content and value of the available risk scores whereby the advantages and disadvantages of the individual scores are critically compared. Special emphasis is placed on the importance of the risk scores for geriatric patients. RESULTS: At present the decision about outpatient or inpatient treatment is primarily based on the risk score CRB-65. Criteria for intensive care unit admissions are provided by the modified American Thoracic Society (ATS) set of criteria. Overall, risk scores are less reliable for elderly patients than for younger adults. CONCLUSION: For treatment decisions for the elderly, functional aspects should also be considered in addition to the aspects of risk scores discussed here. In particular, the decision about inpatient admission for elderly, geriatric CAP patients should be made on an individual basis taking the benefit-risk relationship into consideration.

CORB is the best pneumonia severity score for elderly hospitalised patients with suspected pneumonia.

Pneumonia severity scoring systems have been developed to identify patients at highest mortality risk, and are used in guidelines to limit use of broad-spectrum antibiotics to patients with severe community-acquired pneumonia. A retrospective audit of hospitalised general internal medicine patients with pneumonia was performed to assess the diagnostic performance of various pneumonia severity scores in an elderly general internal medicine population.

Using data-driven rules to predict mortality in severe community acquired pneumonia.

Prediction of patient-centered outcomes in hospitals is useful for performance benchmarking, resource allocation, and guidance regarding active treatment and withdrawal of care. Yet, their use by clinicians is limited by the complexity of available tools and amount of data required. We propose to use Disjunctive Normal Forms as a novel approach to predict hospital and 90-day mortality from instance-based patient data, comprising demographic, genetic, and physiologic information in a large cohort of patients admitted with severe community acquired pneumonia. We develop two algorithms to efficiently learn Disjunctive Normal Forms, which yield easy-to-interpret rules that explicitly map data to the outcome of interest. Disjunctive Normal Forms achieve higher prediction performance quality compared to a set of state-of-the-art machine learning models, and unveils insights unavailable with standard methods. Disjunctive Normal Forms constitute an intuitive set of prediction rules that could be easily implemented to predict outcomes and guide criteria-based clinical decision making and clinical trial execution, and thus of greater practical usefulness than currently available prediction tools. The Java implementation of the tool JavaDNF will be publicly available.

Community-acquired skin infections caused by Staphylococcus aureus: What is the role of the Panton-Valentine leukocidin toxin?

BACKGROUND: The data concerning frequency and relevance of the toxin Panton-Valentine leukocidin (PVL) in skin infections caused by Staphylococcus aureus is controversial. The objective of the study was the identification of the role of the toxin in community-acquired skin infections caused by S. aureus. PATIENTS AND METHODS: We performed a retrospective analysis of 112 patients with the diagnosis of skin infections caused by S. aureus. Frequency of PVL was investigated by PCR for the lukSF gene. Risk factors and severity of the disease were analyzed. Furthermore, spa typing was done in 55 of the isolated S. aureus. RESULTS: PVL occurred in 45 % of patients with skin infections caused by methicillin-susceptible S. aureus; methicillin-resistant strains were positive in 63 %. Mean age was 30.9 years in PVL-positive infections and thus statistically highly significantly lower than in PVL-negative infections. There was no correlation between presence of PVL and severity and course of skin infections or presence of special risk factors. The spa types showed a high variability in PVL-positive as well as in PVL-negative strains. CONCLUSIONS: In our study the PVL status of S. aureus isolated from skin infections was neither correlated with methicillin-resistance nor with the severity of disease. Remarkably, PVL-positive S. aureus strains appeared to be more frequent in younger than in older patients. Our results demonstrate that routine determination of PVL status is not required since the outcome has no diagnostic or therapeutic consequences in daily dermatological practice.

Escalas de gravedad y neumonía adquirida en la comunidad. ¿Por qué no las uso si son tan excelentes? / No disponible

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Healthcare-associated pneumonia: a US disease or relevant to the Asia Pacific, too?

The term 'health care-associated pneumonia' (HCAP) was introduced by the American Thoracic Society and the Infectious Diseases Society of America in 2005 to describe a distinct entity of pneumonia that resembles hospital-acquired pneumonia rather than community-acquired pneumonia (CAP) in terms of occurrence of drug-resistant pathogens and mortality in patients that--while not hospitalized in the traditional sense--have been in recent contact with the health-care system. It was proposed that HCAP should be treated empirically with therapy for drug-resistant pathogens. Over the last few years, there has been increasing controversy over whether HCAP is a helpful definition, or leads to unnecessary and potentially problematic overtreatment. The term HCAP has been extensively criticized in Europe. While most studies have shown that HCAP is associated with more frequent drug-resistant pathogens and higher mortality than CAP, there is no clear evidence that this is due to inappropriate antibiotic therapy. Therapy consistent with HCAP treatment guidelines has also not been found to improve mortality. Based on current evidence, we suggest broad-spectrum antibiotic therapy to treat possible pathogens not usually covered in CAP be based on assessment of individual risk factors rather than applying a HCAP classification system in the Asia-Pacific Region.

Performance of SOAR (systolic blood pressure, oxygenation, age and respiratory rate) scoring criteria in community-acquired pneumonia: a prospective multi-centre study.

BACKGROUND: severity assessment in community-acquired pneumonia (CAP) is important as it is associated with significant mortality. In this study, we compared a previously suggested severity assessment rule for CAP- SOAR (systolic blood pressure, oxygenation, age and respiratory rate)- against the CURB-65 criteria. METHODS: we conducted a prospective study in three hospitals in Norfolk and Suffolk, UK. Consecutive patients with CAP were scored for severity with CURB-65 (n = 190), and SOAR (when there was sufficient information, n = 112). Mortality data was collected at 6 weeks. RESULTS: there were 100 males (53%). The age range was 18-101 years (mean 72 years, median 76 years). Sixty-five (34%) had severe pneumonia by CURB-65, and 56 patients out of 112 (50%) had severe pneumonia by SOAR. Patients with severe CAP were significantly more likely to be older, female, and to have higher urea levels and a lower PaO(2):FiO(2) ratio on admission. There were a total of 54 deaths during follow-up (33 of these in the SOAR-categorised group). There were 32 deaths (50%) in the severe and 22 deaths (18%) in the non-severe groups by CURB-65. There were 23 deaths (70%) in the severe and 22 deaths (30%) in the non-severe groups by SOAR. For CURB-65, sensitivity, specificity, positive and negative predictive values were 60.6, 72.2, 47.6 and 81.4%. For SOAR, the respective values were 69.7%, 58.2, 41.1 and 82.1%. CONCLUSION: SOAR had demonstrably better sensitivity, but lower specificity compared with CURB-65 in this patient cohort. SOAR might be more suitable for assessing disease severity as an alternative or adjunct to CURB-65, particularly in the elderly.

Australasian respiratory and emergency physicians do not use the pneumonia severity index in community-acquired pneumonia.

BACKGROUND AND OBJECTIVE: The value of community-acquired pneumonia (CAP) severity scoring tools is almost exclusively reliant upon regular and accurate application in clinical practice. Until recently, the Australasian Therapeutic Guidelines has recommended the use of the Pneumonia Severity Index (PSI) in spite of poor user-friendliness. METHODS: Electronic and postal survey of respiratory and emergency medicine physician and specialist registrar members of the Royal Australasian College was undertaken to assess the use of the PSI and the accuracy of its application to hypothetical clinical CAP scenarios. The confusion, urea, respiratory rate, blood pressure, age 65 or older (CURB-65) score was also assessed as a simpler alternative. RESULTS: Five hundred thirty-six (228 respiratory, 308 emergency) responses were received. Only 12% of respiratory and 35% of emergency physicians reported using the PSI always or frequently. The majority were unable to accurately approximate PSI scores, with significantly fewer respiratory than emergency physicians recording accurate severity classes (11.8% vs 21%, OR 0.50, 95% CI: 0.37-0.68, P < 0.0001). In contrast, significantly more respiratory physicians were able to accurately calculate the CURB-65 score (20.4% vs 15%, OR 1.45, 95% CI: 1.10-1.91, P = 0.006). CONCLUSIONS: Australasian specialist physicians primarily responsible for the acute management of CAP report infrequent use of the PSI and are unable to accurately apply its use to hypothetical scenarios. Furthermore, respiratory and emergency physicians contrasted distinctly in their use and application of the two commonest severity scoring systems--the recent recommendation of two further alternative scoring tools by Australian guidelines may add to this confusion. A simple, coordinated approach to pneumonia severity assessment across specialties in Australasia is needed.