Cytokine Response Patterns in Severe Pandemic 2009 H1N1 and Seasonal Influenza among Hospitalized Adults

BACKGROUND: Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis. METHODS: Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed. RESULTS: 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10)unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their 'responsiveness' to stimuli was shown to change dynamically during the illness course. CONCLUSIONS: A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Regular Testing of HIV and Sexually Transmitted Infections With Self-Collected Samples From Multiple Anatomic Sites to Monitor Sexual Health in Men Who Have Sex With Men: Longitudinal Study

BackgroundRegular HIV and sexually transmitted infection (STI) testing for men who have sex with men (MSM) is an important means of infection prevention, the adoption of which remains suboptimal in the community. ObjectiveOn the hypothesis that engagement plays an important role in sexual health monitoring, this study aimed to pilot-test internet-based HIV and STI testing with self-sampling to enhance engagement of MSM with regular testing. MethodsThis 1-year cohort study was conducted on HIV-negative MSM aged 18 years or older. A designated website was set up to enable participants to make appointments for baseline and follow-up visits at 3-monthly intervals. On-site blood sampling was performed for HIV and syphilis tests, along with self-collection of pharyngeal swabs, rectal swabs, and urine samples for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) testing. Full engagement, as defined by having made at least 3 visits over a 6-12 months’ follow-up period, was compared with partial engagement in the bivariable logistic regression model. ResultsBetween August 2019 and October 2020, 204 MSM were recruited, after the exclusion of 2 baseline HIV-positive MSM. The majority (189/204, 92.7%) were Chinese, the median age was 31 (IQR 26-39) years, and 58.0% (116/200) had experience with pre-exposure prophylaxis (PrEP) at baseline. Full engagement (146/204, 71.6%) was associated with incident STI during the follow-ups (odds ratio [OR] 4.23, 95% CI 1.63-10.94), seeking a medical referral after STI detection (OR 10.25, 95% CI 3.25-29.79), and a synchronized schedule of HIV and STI testing with PrEP visits (OR 51.85, 95% CI 19.30-139.34). No incident HIV was detected in the follow-up period. At baseline, the overall STI (CT, NG, or syphilis) prevalence was 30%, with CT at 18%, NG at 13%, and syphilis at 5%. During follow-up, the incidences were 59.08/100 person-years (py) for any STI, 33.05/100 py for CT, 29.86/100 py for NG, and 10.4/100 py for syphilis. The detection rates of CT and NG in urine samples were lower than with pharyngeal swabs and rectal swabs. The scores for convenience, confidence of correct sampling, and accuracy of self-sampling were high (7 to 8 out of 10). ConclusionsBoth baseline prevalence and incidence of STI were high among MSM engaged in regular testing. A high degree of engagement in regular STI and HIV testing was positively associated with incident STI, history of health-seeking behaviors, and perceived convenience of self-sampling. Self-sampling could be introduced as a means of enhancing engagement in regular HIV and STI testing

Differential MicroRNA Expression in Human Macrophages with Mycobacterium tuberculosis Infection of Beijing/W and Non-Beijing/W Strain Types.

The role of microRNAs in association with Mycobacterium tuberculosis (MTB) infection and the immunology regulated by microRNAs upon MTB infection have not been fully unravelled. We examined the microRNA profiles of THP-1 macrophages upon the MTB infection of Beijing/W and non-Beijing/W clinical strains. We also studied the microRNA profiles of the host macrophages by microarray in a small cohort with active MTB disease, latent infection (LTBI), and from healthy controls.The results revealed that 14 microRNAs differentiated infections of Beijing/W from non-Beijing/W strains (P<0.05). A unique signature of 11 microRNAs in human macrophages was identified to differentiate active MTB disease from LTBI and healthy controls. Pathway analyses of these differentially expressed miRNAs suggest that the immune-regulatory interactions involving TGF-β signalling pathway take part in the dysregulation of critical TB processes in the macrophages, resulting in active expression of both cell communication and signalling transduction systems.We showed for the first time that the Beijing/W TB strains repressed a number of miRNAs expressions which may reflect their virulence characteristics in altering the host response. The unique signatures of 11 microRNAs may deserve further evaluation as candidates for biomarkers in the diagnosis of MTB and Beijing/W infections

Trends in incidence and clinical outcomes of Clostridioides difficile infection, Hong Kong

We conducted a territorywide survey to investigate the epidemiology, risk factors, and clinical outcomes of Clostridioides difficile infection (CDI) among hospitalized patients in Hong Kong. A total of 17,105 cases of CDI were identified, of which 15,717 (91.9%) were healthcare-associated and 1,025 (6.0%) were community-associated. Although CDI incidence increased substantially from 2006 to 2017, it plateaued in 2018 and 2019. The 30-day mortality rates decreased from 20.1% in 2015 to 16.8% in 2019, whereas the 60-day recurrence rates remained constant at ≈11% during the study period. Cross-correlation statistic showed significant correlations between incidence trend and overall antimicrobial drug use (r = 0.865, p<0.001), which has decreased as a result of an antibiotic stewardship program initiated in 2017. Our data suggest a turning point in C. difficile epidemiology that could be related to the changing pattern of antimicrobial drug use.Published versionThis project is supported by the Hong Kong University Grants Committee Research Grant Council (Early Career Scheme no. 21153816/24103516) and the Hong Kong Food and Health Bureau Commissioned Health and Medical Research Fund (CID-CUHK-C)

Risk factors for drug-resistant bacterial pneumonia in older patients hospitalized with pneumonia in a Chinese population

Background: The relationship between healthcare-associated pneumonia (HCAP) and resistant bacteria is unclear. The aim of this study was to identify the risk factors for pneumonia caused by drug-resistant bacteria (DRB). Methods: A prospective cohort study was conducted at a tertiary teaching hospital in Hong Kong. Consecutive older patients (aged ≥65 years) were hospitalized with pneumonia from January 2004 to June 2005. DRB comprised methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, extended-spectrum β-lactamase (ESBL) producing Enterobacteriaceae and Acinetobacter baumannii. Results: The entire cohort consisted of 1176 older patients. Of 472 (40.1%) patients with etiological diagnosis established, bacterial pneumonia was found in 354 (30.1%) cases. DRB were isolated in 48 patients: P. aeruginosa (41), MRSA (5) and ESBL producing enteric bacilli (3). Co-infection with P. aeruginosa and MRSA was found in one patient. The prevalence of DRB in culture-positive pneumonia was 20.1% (48/239). Patients with DRB were more likely to have limitation in activities of daily living, bronchiectasis, dementia, severe pneumonia, recent hospitalization and recent antibiotic use. Logistic regression revealed that bronchiectasis [relative risk (RR) 14.12, P = 0.002], recent hospitalization (RR 4.89, P < 0.001) and severe pneumonia (RR 2.42, P = 0.010) were independent predictors of drug-resistant bacterial pneumonia. Conclusions: Recent hospitalization is the only risk factor for HCAP which is shown to be associated with DRB. Nursing home residence is not a risk factor. The concept of HCAP may not be totally applicable in Hong Kong where the prevalence of drug-resistant pathogens in pneumonia is low

Prospection deficits in patients with first-episode schizophrenia: a cross-sectional comparative study

Prospection refers to the ability to simulate and pre-experience future events. Schizophrenia patients have difficulty in anticipating pleasure in future events, but previous studies examined prospection deficits in chronic schizophrenia patients. This study aimed to investigate prospection deficits in first-episode schizophrenia patients. Thirty first-episode schizophrenia patients and 31 healthy controls completed the Affective Prospection Task, which utilized pictorial cues to involve positive, neutral and negative prospection. Participants' ratings regarding the phenomenal characteristics of their prospected events were collected, and their prospected narratives were coded using a valid scoring manual. We also assessed intelligence, working memory and logical memory. The results showed, in all participants, valence of the cues significantly influenced participants' sense of pre-experience, temporal distance, emotion experience, vividness and participation of the prospected events, as well as the richness of sensory details. The two groups did not differ in self-report phenomenal characteristics of their prospected events. For coded characteristics, schizophrenia patients' prospected narratives were less rich in thought/emotion than controls, even after controlling for intelligence and memory deficits. We extended empirical evidence for prospection deficits from chronic schizophrenia samples to first-episode schizophrenia patients

Clustering analysis of the 11 miRNAs was performed using DataAssist 3.0v based on ΔCt-values of the TLDA results.

<p>Upregulated miRNAs are designated by various shades of red and down-regulated miRNAs by various shades of green. Clinical phenotypes are labelled in different colours: active MTB infection (red), latent infection (blue), and healthy controls (green).</p

MicroRNAs differentially expressed in THP-1 macrophages infected with Beijing/W and non-Beijing/W clinical TB strains.

<p>^aFold difference in miRNA expression in THP-1 cells infected with Beijing/W clinical strains vs non-Beijing/W strains.</p><p>^bP-value was calculated by Mann-Whitney test.</p><p>MicroRNAs differentially expressed in THP-1 macrophages infected with Beijing/W and non-Beijing/W clinical TB strains.</p

Previously reported microRNAs with differential expression related to current study of MTB infections and their validated transcript targets.

<p>Previously reported microRNAs with differential expression related to current study of MTB infections and their validated transcript targets.</p