Using a targeted metabolomics approach to explore differences in ARDS associated with COVID-19 compared to ARDS caused by H1N1 influenza and bacterial pneumonia.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a life-threatening critical care syndrome commonly associated with infections such as COVID-19, influenza, and bacterial pneumonia. Ongoing research aims to improve our understanding of ARDS, including its molecular mechanisms, individualized treatment options, and potential interventions to reduce inflammation and promote lung repair. OBJECTIVE: To map and compare metabolic phenotypes of different infectious causes of ARDS to better understand the metabolic pathways involved in the underlying pathogenesis. METHODS: We analyzed metabolic phenotypes of 3 ARDS cohorts caused by COVID-19, H1N1 influenza, and bacterial pneumonia compared to non-ARDS COVID-19-infected patients and ICU-ventilated controls. Targeted metabolomics was performed on plasma samples from a total of 150 patients using quantitative LC-MS/MS and DI-MS/MS analytical platforms. RESULTS: Distinct metabolic phenotypes were detected between different infectious causes of ARDS. There were metabolomics differences between ARDSs associated with COVID-19 and H1N1, which include metabolic pathways involving taurine and hypotaurine, pyruvate, TCA cycle metabolites, lysine, and glycerophospholipids. ARDSs associated with bacterial pneumonia and COVID-19 differed in the metabolism of D-glutamine and D-glutamate, arginine, proline, histidine, and pyruvate. The metabolic profile of COVID-19 ARDS (C19/A) patients admitted to the ICU differed from COVID-19 pneumonia (C19/P) patients who were not admitted to the ICU in metabolisms of phenylalanine, tryptophan, lysine, and tyrosine. Metabolomics analysis revealed significant differences between C19/A, H1N1/A, and PNA/A vs ICU-ventilated controls, reflecting potentially different disease mechanisms. CONCLUSION: Different metabolic phenotypes characterize ARDS associated with different viral and bacterial infections.

Predictors of Breakthrough SARS-CoV-2 Infection after Vaccination.

The initial two-dose vaccine series and subsequent booster vaccine doses have been effective in modulating SARS-CoV-2 disease severity and death but do not completely prevent infection. The correlates of infection despite vaccination continue to be under investigation. In this prospective decentralized study (n = 1286) comparing antibody responses in an older- (≥70 years) to a younger-aged cohort (aged 30-50 years), we explored the correlates of breakthrough infection in 983 eligible subjects. Participants self-reported data on initial vaccine series, subsequent booster doses and COVID-19 infections in an online portal and provided self-collected dried blood spots for antibody testing by ELISA. Multivariable survival analysis explored the correlates of breakthrough infection. An association between higher antibody levels and protection from breakthrough infection observed during the Delta and Omicron BA.1/2 waves of infection no longer existed during the Omicron BA.4/5 wave. The older-aged cohort was less likely to have a breakthrough infection at all time-points. Receipt of an original/Omicron vaccine and the presence of hybrid immunity were associated with protection of infection during the later Omicron BA.4/5 and XBB waves. We were unable to determine a threshold antibody to define protection from infection or to guide vaccine booster schedules.

Renin-Angiotensin System Pathway Therapeutics Associated With Improved Outcomes in Males Hospitalized With COVID-19.

OBJECTIVES: To determine whether angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are associated with improved outcomes in hospitalized patients with COVID-19 according to sex and to report sex-related differences in renin-angiotensin system (RAS) components. DESIGN: Prospective observational cohort study comparing the effects of ARB or ACE inhibitors versus no ARBs or ACE inhibitors in males versus females. Severe acute respiratory syndrome coronavirus 2 downregulates ACE-2, potentially increasing angiotensin II (a pro-inflammatory vasoconstrictor). Sex-based differences in RAS dysregulation may explain sex-based differences in responses to ARBs because the ACE2 gene is on the X chromosome. We recorded baseline characteristics, comorbidities, prehospital ARBs or ACE inhibitor treatment, use of organ support and mortality, and measured RAS components at admission and days 2, 4, 7, and 14 in a subgroup ( n = 46), recorded d -dimer ( n = 967), comparing males with females. SETTING: ARBs CORONA I is a multicenter Canadian observational cohort of patients hospitalized with acute COVID-19. This analysis includes patients admitted to 10 large urban hospitals across the four most populated provinces. PATIENTS: One-thousand six-hundred eighty-six patients with polymerase chain reaction-confirmed COVID-19 (February 2020 to March 2021) for acute COVID-19 illness were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Males on ARBs before admission had decreased use of ventilation (adjusted odds ratio [aOR] = 0.52; p = 0.007) and vasopressors (aOR = 0.55; p = 0.011) compared with males not on ARBs or ACE inhibitors. No significant effects were observed in females for these outcomes. The test for interaction was significant for use of ventilation ( p = 0.006) and vasopressors ( p = 0.044) indicating significantly different responses to ARBs according to sex. Males had significantly higher plasma ACE-1 at baseline and angiotensin II at day 7 and 14 than females. CONCLUSIONS: ARBs use was associated with less ventilation and vasopressors in males but not females. Sex-based differences in RAS dysregulation may contribute to sex-based differences in outcomes and responses to ARBs in COVID-19.

Positive no-touch surfaces and undetectable SARS-CoV-2 aerosols in long-term care facilities: An attempt to understand the contributing factors and the importance of timing in air sampling campaigns.

BACKGROUND: Long-term care facilities (LTCF) are environments particularly favorable to coronavirus disease (SARS-CoV-2) pandemic outbreaks, due to the at-risk population they welcome and the close proximity of residents. Yet, the transmission dynamics of the disease in these establishments remain unclear. METHODS: Air and no-touch surfaces of 31 rooms from 7 LTCFs were sampled and SARS-CoV-2 was quantified by real-time reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: Air samples were negative but viral genomes were recovered from 20 of 62 surface samples at concentrations ranging from 13 to 36,612 genomes/surface. Virus isolation (culture) from surface samples (n = 7) was negative. CONCLUSIONS: The presence of viral RNA on no-touch surfaces is evidence of viral dissemination through air, but the lack of airborne viral particles in air samples suggests that they were not aerosolized in a significant manner during air sampling sessions. The air samples were collected 8 to 30 days after the residents' symptom onset, which could indicate that viruses are aerosolized early in the infection process. Additional research is needed to evaluate viral viability conservation and the potential role of direct contact and aerosols in SARS-CoV-2 transmission in these institutions.

High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial.

BACKGROUND: Influenza leads to significant cardiopulmonary morbidity and mortality-particularly in patients with cardiovascular disease-that may be prevented with a standard influenza vaccine. However, patients with cardiovascular conditions have a reduced immune response to influenza vaccine, potentially resulting in reduced effectiveness for preventing clinical events. High-dose vaccine augments immune response in cardiac patients, suggesting that a high-dose influenza vaccination strategy may further reduce morbidity and mortality. Alternatively, broader coverage with an influenza vaccine containing an increased number of viral strains is an alternative strategy without direct evaluation. RESEARCH DESIGN AND METHODS: INfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) is a pragmatic, randomized, double-blind, parallel-group, active-controlled trial comparing the effectiveness of an annual vaccination strategy of high-dose trivalent versus standard-dose quadrivalent influenza vaccine in patients with a history of recent heart failure or myocardial infarction hospitalization. The trial will enroll approximately 9,300 patients over 4 influenza seasons. The primary hypothesis is that high-dose influenza vaccine will reduce the composite outcome of all-cause mortality and hospitalization from a cardiovascular or pulmonary cause compared with standard-dose influenza vaccine within each enrolling season. Approximately 1,300 primary outcome events will provide >90% power to detect an 18% relative risk reduction at a 2-sided α level of .05. CONCLUSION: INVESTED is the largest and longest study to assess whether high-dose influenza vaccine is superior to standard-dose influenza vaccine in reducing cardiopulmonary events in a high-risk cardiovascular population (ClinicalTrials.gov Identifier: NCT02787044).

No 225-Lignes directrices quant à la prise en charge des patientes en obstétrique chez lesquelles la présence du syndrome respiratoire aigu sévère (SRAS) est soupçonnée ou probable, et des nouveau-nés issus de ces patientes.

OBJECTIF: Le présent document résume notre expérience limitée quant à la présence du SRAS pendant la grossesse et suggère des lignes directrices quant à sa prise en charge. ISSUES: Les exposés de cas issus d'Asie laissent entendre que les issues maternelles et fœtales sont aggravées par la présence du SRAS pendant la grossesse. RéSULTATS: Des recherches ont été menées dans Medline afin d'en tirer les articles pertinents publiés en anglais entre 2000 et 2007. Des exposés de cas ont été analysés et nous avons sollicité l'opinion de spécialistes. VALEURS: Les recommandations ont été formulées conformément aux lignes directrices élaborées par le Groupe d'étude canadien sur les soins de santé préventifs. COMMANDITAIRE: La Société des obstétriciens et gynécologues du Canada. RECOMMANDATIONS.

No. 225-Management Guidelines for Obstetric Patients and Neonates Born to Mothers With Suspected or Probable Severe Acute Respiratory Syndrome (SARS).

OBJECTIVE: This document summarizes the limited experience of SARS in pregnancy and suggests guidelines for management. OUTCOMES: Cases reported from Asia suggest that maternal and fetal outcomes are worsened by SARS during pregnancy. EVIDENCE: Medline was searched for relevant articles published in English from 2000 to 2007. Case reports were reviewed and expert opinion sought. VALUES: Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada.

SOGC Clinical Practice Guideline. Management guidelines for obstetric patients and neonates born to mothers with suspected or probable severe acute respiratory syndrome (SARS). No. 225, April 2009.

OBJECTIVE: This document summarizes the limited experience of SARS in pregnancy and suggests guidelines for management. OUTCOMES: Cases reported from Asia suggest that maternal and fetal outcomes are worsened by SARS during pregnancy. EVIDENCE: Medline was searched for relevant articles published in English from 2000 to 2007. Case reports were reviewed and expert opinion sought. VALUES: Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care.

Management guidelines for obstetric patients and neonates born to mothers with suspected or probable severe acute respiratory syndrome (SARS).

OBJECTIVE: This document summarizes the limited experience of SARS in pregnancy and suggests guidelines for management. OUTCOMES: Cases reported from Asia suggest that maternal and fetal outcomes are worsened by SARS during pregnancy. EVIDENCE: Medline was searched for relevant articles published in English from 2000 to 2007. Case reports were reviewed and expert opinion sought. VALUES: Recommendations were made according to the guidelines developed by the Canadian Task Force on Preventive Health Care. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada. Recommendations 1. All hospitals should have infection control systems in place to ensure that alerts regarding changes in exposure risk factors for SARS or other potentially serious communicable diseases are conveyed promptly to clinical units, including the labour and delivery unit. (III-C) 2. At times of SARS outbreaks, all pregnant patients being assessed or admitted to the hospital should be screened for symptoms of and risk factors for SARS. (III-C) 3. Upon arrival in the labour triage unit, pregnant patients with suspected and probable SARS should be placed in a negative pressure isolation room with at least 6 air exchanges per hour. All labour and delivery units caring for suspected and probable SARS should have available at least one room in which patients can safely labour and deliver while in need of airborne isolation. (III-C) 4. If possible, labour and delivery (including operative delivery or Caesarean section) should be managed in a designated negative pressure isolation room, by designated personnel with specialized infection control preparation and protective gear. (III-C) 5. Either regional or general anaesthesia may be appropriate for delivery of patients with SARS. (III-C) 6. Neonates of mothers with SARS should be isolated in a designated unit until the infant has been well for 10 days, or until the mother's period of isolation is complete. The mother should not breastfeed during this period. (III-C) 7. A multidisciplinary team, consisting of obstetricians, nurses, pediatricians, infection control specialists, respiratory therapists, and anaesthesiologists, should be identified in each unit and be responsible for the unit organization and implementation of SARS management protocols. (III-C) 8. Staff caring for pregnant SARS patients should not care for other pregnant patients. Staff caring for pregnant SARS patients should be actively monitored for fever and other symptoms of SARS. Such individuals should not work in the presence of any SARS symptoms within 10 days of exposure to a SARS patient. (III-C) 9. All health care personnel, trainees, and support staff should be trained in infection control management and containment to prevent spread of the SARS virus. (III-A) 10. Regional health authorities in conjunction with hospital staff should consider designating specific facilities or health care units, including primary, secondary, or tertiary health care centres, to care for patients with SARS or similar illnesses. (III-A).

Risk factors for and outcomes associated with clinical isolates of Escherichia coli and Klebsiella species resistant to extended-spectrum cephalosporins among patients admitted to Canadian hospitals.

BACKGROUND: Clinical features associated with Gram-negative bacterial isolates with extended-spectrum beta-lactamase (ESBL)- and AmpC-mediated resistance identified in Canadian hospitals is largely unknown. The objective of the present study was to determine the demographics, risk factors and outcomes of patients with ESBL- or AmpC-mediated resistant organisms in Canadian hospitals. METHODS: Patients with clinical cultures of Escherichia coli or Klebsiella species were matched with patients with a similar organism but susceptible to third-generation cephalosporins. Molecular identification of the AmpC or ESBL was determined using a combination of polymerase chain reaction and sequence analysis. Univariate and multivariate logistic regression analysis was performed to identify variables associated with becoming a case. RESULTS: Eight Canadian hospitals identified 106 cases (ESBL/AmpC) and 106 controls. All risk factors identified in the univariate analysis as a predictor of being an ESBL/AmpC cases at the 0.20 P-value were included in the multivariate analysis. No significant differences in outcomes were observed (unfavourable responses 17% versus 15% and mortality rates 13% versus 7%, P not significant). Multivariate logistic regression found an association of becoming an ESBL/AmpC case with: previous admission to a nursing home (OR 8.28, P=0.01) or acute care facility (OR 1.96, P=0.03), length of stay before infection (OR 3.05, P=0.004), and previous use of first-generation cephalosporins (OR 2.38, P=0.02) or third-generation cephalosporins (OR 4.52, P=0.01). Appropriate antibiotics were more likely to be given to controls (27.0% versus 13.3%, P=0.05) and number of days to appropriate antibiotics was longer for cases (median 2.8 days versus 1.2 days, P=0.05). CONCLUSION: The importance of patient medical history, present admission and antibiotic use should be considered for all E coli or Klebsiella species patients pending susceptibility testing results.

At the threshold: defining clinically meaningful resistance thresholds for antibiotic choice in community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia caused by Streptococcus pneumoniae is a major source of morbidity and mortality. Macrolide antibiotics are recommended as empirical first-line therapy for patients with community-acquired pneumonia. Guidelines suggest a 25% rate of high-level macrolide resistance in the community as the threshold beyond which macrolides should not be used. We evaluated the implications of this threshold for clinical failure rates. METHODS: We developed a theoretical model linking the prevalence of macrolide resistance to patient outcomes, based on the epidemiological concept of risk difference. We estimated the risk of clinical failure as a function of the likelihood and impact of discordant therapy and of the probability of clinical failure even in the presence of optimal therapy. The model was parameterized on the basis of the best available data derived from the published medical literature, and clinical failures were valued monetarily using an expected net benefit approach. RESULTS: Under the proposed 25% resistance threshold, the risk difference for such therapy would be 1.2% (95% credible interval, 0.5%-3.1%) for death, 1.6% (95% credible interval, 0.5%-3.2%) for bacteremia, and 3.3% (95% credible interval, 1.1%-5.7%) for prolonged clinical course; excess risks of death were valued at >$10,000 per empirical treatment of community-acquired pneumonia and were further elevated in high-risk populations. Excluding low-level resistance resulted in a 4-fold underestimation of projected risks. CONCLUSION: A 25% resistance threshold that fails to consider low-level resistance will result in high excess rates of morbidity and mortality because of discordant therapy. Whether projected failure rates are classified as unacceptable is an important health policy question, because risk of clinical failure needs to be weighed against other considerations.

Dietary intake of elderly living in Toronto long-term care facilities: comparison to the dietary reference intake.

OBJECTIVE: To compare the dietary intake of elderly living in 11 long-term care facilities (LTCFs) to the Estimated Average Requirement set as part of the Dietary Reference Intake for older adults. DESIGN: A cross-sectional assessment of dietary intake using a 3 days food record among 407 elderly with mean age of 85.2 +/- 7.7 years and BMI of 23.8 +/- 5.7 kg/m(2). This population sample was similar to the one living in LTCFs in the province of Ontario. RESULTS: The daily energy intake was 1513 +/- 363 kcal (6330.4 +/- 1518.8 kJ). Percentage of energy from fat, saturated fat, polyunsaturated fat, protein, and carbohydrate were 30%, 11%, 5.2%, 15%, and 56%, respectively. Although these values were close to the recommendations, 29.5% had protein intake below the recommended 0.8 g/kg; and 38.3% of subjects had cholesterol intake more than the recommended 300 mg/d. More than 50% of the subjects had suboptimal intake of calcium, magnesium, zinc and vitamins E, B(6), and folate. In addition, greater than 15% had suboptimal intakes of other micronutrients such as vitamins A, C, niacin, and copper. CONCLUSIONS: Elderly subjects living in LTCFs in Toronto despite having a normal body mass index (BMI), do not meet the recommended levels of intake for protein and many of the micronutrients. LTCFs staff should monitor dietary intake. Menu modification and micronutrient supplementation may be required in order to meet the daily requirements of these elderly.

Community-associated methicillin-resistant Staphylococcus aureus in horses and humans who work with horses.

OBJECTIVE: To evaluate the prevalence of nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) in horses and horse personnel. DESIGN: Prospective prevalence study. SAMPLE POPULATION: 972 horses and 107 personnel from equine farms in Ontario, Canada and New York state. PROCEDURE: Nasal swab specimens were collected from horses and humans on farms with (targeted surveillance) and without (nontargeted surveillance) a history of MRSA colonization or infection in horses during the preceding year. Selective culture for MRSA was performed. Isolates were typed via pulsed-field gel electrophoresis, and antibiograms were determined. RESULTS: MRSA was isolated from 46 of 972 (4.7%) horses (0/581 via nontargeted surveillance and 46/391 [12%] via targeted surveillance). Similarly, MRSA was isolated from 14 of 107 (13%) humans (2/41 [5%] from nontargeted surveillance and 12/66 [18%] from targeted surveillance). All isolates were subtypes of Canadian epidemic MRSA-5, an uncommon strain in humans. All isolates were resistant to at least 1 antimicrobial class in addition to beta-lactams. On all farms with colonized horses, at least 1 human was colonized with an indistinguishable subtype. For horses, residing on a farm that housed > 20 horses was the only factor significantly associated with MRSA colonization. For humans, regular contact with > 20 horses was the only identified risk factor. CONCLUSIONS AND CLINICAL RELEVANCE: Results confirm a reservoir of colonized horses on a variety of farms in Ontario and New York and provide evidence that 1 MRSA strain is predominantly involved in MRSA colonization in horses and humans that work with horses.

Economic evaluation of oseltamivir phosphate for postexposure prophylaxis of influenza in long-term care facilities.

OBJECTIVES: To compare the cost-effectiveness of oseltamivir postexposure prophylaxis during influenza A outbreaks with that of amantadine postexposure prophylaxis or no postexposure prophylaxis in long-term care facilities (LTCFs). DESIGN: Cost-effectiveness analysis based on decision analytic model from a government-payer perspective. SETTING: A Canadian LTCF, with high staff vaccination, at the beginning of influenza season. PARTICIPANTS: Elderly, influenza-vaccinated patients living in a Canadian LTCF. MEASUREMENTS: Incremental costs (or savings) per influenza-like illness case avoided compared with usual care. RESULTS: From a government-payer perspective, this analysis showed that oseltamivir was a dominant strategy because it was associated with the fewest influenza-like illness cases, with cost savings of $1,249 per 100 patients in 2001 Canadian dollars compared with amantadine and $3,357 per 100 patients compared with no prophylaxis. Costs for amantadine dose calculation and hospitalization for adverse events contributed to amantadine being a more-expensive prophylaxis strategy than oseltamivir. Both prophylaxis strategies were more cost-effective than no prophylaxis. CONCLUSION: Despite high influenza vaccination rates, influenza outbreaks continue to emerge in LTCFs, necessitating cost-effective measures to further limit the spread of influenza and related complications. Although amantadine has a lower acquisition cost than oseltamivir, it is associated with more adverse events, lower efficacy, and individualized dosing requirements, leading to higher overall costs and more influenza-like illness cases than oseltamivir. Therefore the use of oseltamivir postexposure prophylaxis is more cost-effective than the current standard of care with amantadine prophylaxis or no prophylaxis.

Microbiologic findings and risk factors for antimicrobial resistance at myringotomy for tympanostomy tube placement--a prospective study of 601 children in Toronto.

CONTEXT: There is limited information on the identity and antibiotic susceptibility of bacterial pathogens in children with chronic otitis media whose repeated antibiotic use may place them at increased risk of antibiotic-resistant bacteria. OBJECTIVE: To determine, at myringotomy for tympanostomy tube placement, (1) the prevalence of bacteria, (2) the extent and patterns of antibiotic resistance, and (3) the risk factors associated with the presence and resistant status of pathogens. DESIGN: Prospective, multi-site, cohort study. SETTING AND PATIENTS: Children undergoing myringotomy for tympanostomy tube placement between November 1, 1999 and March 31, 2000 in seven hospitals in Toronto, Ontario, were identified. If fluid was present, aspirates were submitted for bacteriologic testing. A follow-up telephone questionnaire was administered to patient caregivers in order to identify risk factors for the presence of (1) culturable pathogens and (2) resistant pathogens. MAIN OUTCOME MEASURES: The identification and prevalence of bacteria cultured from the middle ears of subjects, and the degree of nonsusceptibility to commonly prescribed antibiotics. RESULTS: Among 601 patients (mean age 3.9 years, 60.7% male), both a telephone interview (n=544) and an ear specimen (n=527) were obtained for 478. Pathogens were found in middle ear effusions of 37% of the children in the study; including at least one 'definite' pathogen in 189 children (31.4%), and a further 32 children (5.3%) with at least one 'possible' pathogen. Definite pathogens included Haemophilus influenzae in 17% of the children, followed by Moraxella catarrhalis (9%) and Streptococcus pneumoniae (6%); ampicillin nonsusceptibility was found in 40, 100 and 24%, respectively. Overall, 123 children (20.5%) were found to have definite pathogens with resistance to ampicillin/penicillin, trimethoprim-sulfamethoxazole, or clarithromycin/erythromycin. Patient characteristics included premature birth and/or long length of stay in the nursery (23%), first infection before the age of 6 months (26%), put to bed with a bottle (28%), household smoker (34%), in out-of-home child care (38%), history of eczema, bronchiolitis and/or asthma (39%), and use of pacifiers (40%). Household characteristics were smoking (34%), married/common law parents (85%), and 60% had completed college or university; in 26% both parents were born outside of Canada; 73% of children were Caucasian. Of the 75% who responded to the question regarding income, 42% had household income over $60,000 (CAN). Risk factors for the presence of a pathogen and for a resistant pathogen in multivariate analysis included younger age, lower maternal education, day care centre attendance, no previous adenoidectomy and bilateral, primarily winter infections as well as amoxicillin use in the previous 6 months. CONCLUSION: Modifiable risk factors for otitis media including household smoking and pacifier use are present in many children undergoing tympanostomy tube placement; child care centre attendees are over-represented. Multiple antibiotic courses were commonly prescribed prior to surgery. H. influenzae and M. catarrhalis are important pathogens and therapy in clinical failures should be directed against them. The 7-valent protein conjugate polysaccharide vaccine (Prevnar) would have covered 73% of the serotypes of S. pneumoniae isolated in this study.