The gut microbiome in alcohol use disorder and alcohol-associated liver disease: A systematic review of clinical studies.

Evidence suggests that a relationship exists between the gut microbiome and the pathogenesis of alcohol use disorder (AUD) and alcohol-associated liver disease (AALD). This systematic review identified studies that investigated the gut microbiome in individuals with an AUD or an AALD. A search was conducted on October 27, 2022, in PubMed, Web of Science, and Embase databases. Fifty studies satisfied eligibility criteria. Most studies found evidence for gut dysbiosis in individuals with AUD and AALD. Microbiome intervention studies have mostly been conducted in AALD patients; fecal microbial transplant interventions show the most promise. Because most studies were conducted cross-sectionally, the causal relationship between the gut microbiome and alcohol use is unknown. Furthermore, almost all studies have been conducted in predominantly male populations, leaving critical questions regarding sex differences and generalizability of the findings. The study summaries and recommendations provided in this review seek to identify areas for further research and to highlight potential gut microbial interventions for treating AUD and AALD.

NK Cell-Monocyte Cross-talk Underlies NK Cell Activation in Severe COVID-19.

NK cells in the peripheral blood of severe COVID-19 patients exhibit a unique profile characterized by activation and dysfunction. Previous studies have identified soluble factors, including type I IFN and TGF-ß, that underlie this dysregulation. However, the role of cell-cell interactions in modulating NK cell function during COVID-19 remains unclear. To address this question, we combined cell-cell communication analysis on existing single-cell RNA sequencing data with in vitro primary cell coculture experiments to dissect the mechanisms underlying NK cell dysfunction in COVID-19. We found that NK cells are predicted to interact most strongly with monocytes and that this occurs via both soluble factors and direct interactions. To validate these findings, we performed in vitro cocultures in which NK cells from healthy human donors were incubated with monocytes from COVID-19+ or healthy donors. Coculture of healthy NK cells with monocytes from COVID-19 patients recapitulated aspects of the NK cell phenotype observed in severe COVID-19, including decreased expression of NKG2D, increased expression of activation markers, and increased proliferation. When these experiments were performed in a Transwell setting, we found that only CD56bright CD16- NK cells were activated in the presence of severe COVID-19 patient monocytes. O-link analysis of supernatants from Transwell cocultures revealed that cultures containing severe COVID-19 patient monocytes had significantly elevated levels of proinflammatory cytokines and chemokines, as well as TGF-ß. Collectively, these results demonstrate that interactions between NK cells and monocytes in the peripheral blood of COVID-19 patients contribute to NK cell activation and dysfunction in severe COVID-19.

Changes in Inflammatory Cytokine Levels in Rectal Mucosa Associated With Neisseria gonorrheae and/or Chlamydia trachomatis Infection and Treatment Among Men Who Have Sex With Men in Lima, Peru.

BACKGROUND: Neisseria gonorrheae and Chlamydia trachomatis are associated with mucosal inflammation and human immunodeficiency virus 1 (HIV-1) transmission. We assessed levels of inflammatory cytokines in men who have sex with men (MSM) with and without rectal gonorrhea and/or chlamydia in Lima, Peru. METHODS: We screened 605 MSM reporting condomless receptive anal intercourse for rectal N. gonorrheae/C. trachomatis using nucleic acid testing. We identified 101 cases of gonorrhea and/or chlamydia and randomly selected 50 N. gonorrheae/C. trachomatis positive cases and matched 52 negative controls. We measured levels of IL-1ß, IL-6, IL-8, and TNF-α in rectal secretions. Tests for HIV-1, rectal N. gonorrheae/C. trachomatis, and mucosal cytokines were repeated after 3 and 6 months. Cytokine levels in cases and uninfected controls were compared using Wilcoxon rank-sum tests and linear regression. RESULTS: MSM with gonorrhea/chlamydia had elevated levels of all cytokines in rectal mucosa compared with matched controls (all P values <.001). Following antibiotic treatment there were no significant differences in cytokine levels at 3- or 6-month follow-up evaluations (all P values >.05). DISCUSSION: Rectal gonorrhea/chlamydia infection is associated with transient mucosal inflammation and cytokine recruitment. Our data provide proof of concept for rectal sexually transmitted infection screening as an HIV prevention strategy for MSM. Clinical Trials Registration. NCT03010020.

Eosinophil recovery in hospitalized COVID-19 patients is associated with lower rates of ICU admission and in-hospital mortality: An observational cohort analysis.

BACKGROUND: Admission eosinopenia (<100 cells/µL) is associated with poor clinical outcomes in hospitalized COVID-19 patients. However, the effects of eosinophil recovery (defined as reaching ≥50 eosinophils/µL) during hospitalization on COVID-19 outcomes have been inconsistent. METHODS: The study included 1,831 patients admitted to UCLA hospitals between February 2020 and February 2021 with PCR-confirmed COVID-19. Using competing risk regression and modeling eosinophil recovery as a time-dependent covariate, we evaluated the longitudinal relationship between eosinophil recovery and in-hospital outcomes including ICU admission, need for mechanical ventilation, and in-hospital mortality. All analyses were adjusted for covariates including age, BMI, tobacco smoke exposure, comorbidities known to be risk factors for COVID-19 mortality, and treatments including dexamethasone and remdesivir. RESULTS: Eosinophil recovery was evaluated in patients with <50 eosinophils/µL on admission (n = 1282). These patients cumulatively amassed 11,633 hospital patient-days; 3,985 of those days qualified as eosinophil recovery events, which were represented by 781 patients achieving at least one instance of eosinophil recovery during hospitalization. Despite no significant difference in the rate of mechanical ventilation, eosinophil recoverers had significantly lower rates of in-hospital mortality (aHR: 0.44 [0.29, 0.65], P = 0.001) and ICU admission (aHR: 0.25 [0.11, 0.61], P = 0.002). CONCLUSION: Trending eosinophil counts during hospitalization is simple and can be performed in resource-limited healthcare settings to track the inflammatory status of a patient. Lack of eosinophil recovery events can identify those at risk for future progression to severe COVID.

Vascular and Non-HLA autoantibody profiles in hospitalized patients with COVID-19.

Introduction: Severe COVID-19 illness is characterized by an overwhelming immune hyperactivation. Autoantibodies against vascular, tissue, and cytokine antigens have been detected across the spectrum of COVID-19. How these autoantibodies correlate with COVID-19 severity is not fully defined. Methods: We performed an exploratory study to investigate the expression of vascular and non-HLA autoantibodies in 110 hospitalized patients with COVID-19 ranging from moderate to critically ill. Relationships between autoantibodies and COVID- 19 severity and clinical risk factors were examined using logistic regression analysis. Results: There were no absolute differences in levels of expression of autoantibodies against angiotensin II receptor type 1 (AT1R) or endothelial cell proteins between COVID-19 severity groups. AT1R autoantibody expression also did not differ by age, sex, or diabetes status. Using a multiplex panel of 60 non- HLA autoantigens we did identify seven autoantibodies that differed by COVID-19 severity including myosin (myosin; p=0.02), SHC-transforming protein 3 (shc3; p=0.07), peroxisome proliferator-activated receptor gamma coactivator 1-beta (perc; p=0.05), glial-cell derived neurotrophic factor (gdnf; p=0.07), enolase 1 (eno1; p=0.08), latrophilin-1 (lphn1; p=0.08), and collagen VI (coll6; p=0.05) with greater breadth and higher expression levels seen in less severe COVID-19. Discussion: Overall, we found that patients hospitalized with COVID-19 demonstrate evidence of auto-reactive antibodies targeting endothelial cells, angiotensin II receptors, and numerous structural proteins including collagens. Phenotypic severity did not correlate with specific autoantibodies. This exploratory study underscores the importance of better understanding of the role of autoimmunity in COVID-19 disease and sequelae.

Changes in Immune-Related Biomarkers and Endocannabinoids as a Function of Frequency of Cannabis Use in People Living With and Without HIV.

Background: Cannabis use is common among people living with HIV (PLWH). Some observational studies of PLWH have linked cannabis use to lower immune markers; however, this is yet to be confirmed. In addition, whether HIV affects the endogenous cannabinoid system has not been studied. Our objective was to examine changes in immune-related biomarkers and endocannabinoids as a function of cannabis use frequency in people living with and without HIV. Materials and Methods: Data were obtained from a longitudinal study of men who have sex with men living in Los Angeles with, or at risk for, HIV. By design, half were PLWH. Those eligible for the parent study were willing and able to return for follow-up every 6 months. Those eligible for inclusion in this study reported varying levels of current cannabis use at follow-up. Specifically, one visit corresponded to a period of daily use and another to a period of infrequent use (weekly, monthly, or less than monthly). Banked serum from all eligible participants was analyzed for immune-related biomarkers, endocannabinoids, and paracannabinoids. Results: The analysis included 36 men, 19 of whom were PLWH. PLWH reported greater lifetime methamphetamine or amphetamine use (68% vs. 0%) and current cigarette use (55% vs. 20%) than people without HIV. Serum levels of HIV-related immune biomarkers including tumor necrosis factor receptor 2 (TNFR2; p=0.013) and CD27 (p=0.004) were greater in PLWH, alongside lower anandamide (AEA) (F1,34=5.337, p=0.027) and oleoylethanolamide (OEA) (F1,34=8.222, p=0.007) levels relative to people without HIV. Frequency of cannabis use did not impact the serum analytes in our study. Conclusions: Higher levels of TNFR2 and CD27 and lower levels of AEA and OEA in PLWH underscore the role of the TNF/TNFR superfamily in HIV, while highlighting a new role for the enzymatic activity of fatty acid amide hydrolase (the enzyme that hydrolyzes AEA and OEA) in HIV. Findings that cannabis frequency did not impact the immune phenotype may not generalize to other populations of PLWH. Additional work is required to further clarify the relationship between immune markers and endocannabinoids as a function of cannabis use frequency in PLWH. ClinicalTrials.gov ID: NCT01201083.

Persistent memory despite rapid contraction of circulating T Cell responses to SARS-CoV-2 mRNA vaccination.

Introduction: While antibodies raised by SARS-CoV-2 mRNA vaccines have had compromised efficacy to prevent breakthrough infections due to both limited durability and spike sequence variation, the vaccines have remained highly protective against severe illness. This protection is mediated through cellular immunity, particularly CD8+ T cells, and lasts at least a few months. Although several studies have documented rapidly waning levels of vaccine-elicited antibodies, the kinetics of T cell responses have not been well defined. Methods: Interferon (IFN)-γ enzyme-linked immunosorbent spot (ELISpot) assay and intracellular cytokine staining (ICS) were utilized to assess cellular immune responses (in isolated CD8+ T cells or whole peripheral blood mononuclear cells, PBMCs) to pooled peptides spanning spike. ELISA was performed to quantitate serum antibodies against the spike receptor binding domain (RBD). Results: In two persons receiving primary vaccination, tightly serially evaluated frequencies of anti-spike CD8+ T cells using ELISpot assays revealed strikingly short-lived responses, peaking after about 10 days and becoming undetectable by about 20 days after each dose. This pattern was also observed in cross-sectional analyses of persons after the first and second doses during primary vaccination with mRNA vaccines. In contrast, cross-sectional analysis of COVID-19-recovered persons using the same assay showed persisting responses in most persons through 45 days after symptom onset. Cross-sectional analysis using IFN-γ ICS of PBMCs from persons 13 to 235 days after mRNA vaccination also demonstrated undetectable CD8+ T cells against spike soon after vaccination, and extended the observation to include CD4+ T cells. However, ICS analyses of the same PBMCs after culturing with the mRNA-1273 vaccine in vitro showed CD4+ and CD8+ T cell responses that were readily detectable in most persons out to 235 days after vaccination. Discussion: Overall, we find that detection of spike-targeted responses from mRNA vaccines using typical IFN-γ assays is remarkably transient, which may be a function of the mRNA vaccine platform and an intrinsic property of the spike protein as an immune target. However, robust memory, as demonstrated by capacity for rapid expansion of T cells responding to spike, is maintained at least several months after vaccination. This is consistent with the clinical observation of vaccine protection from severe illness lasting months. The level of such memory responsiveness required for clinical protection remains to be defined.

Brief Report: Impact of Methamphetamine Use and Rectal STIs on Systemic and Rectal Mucosal Inflammation.

BACKGROUND: Methamphetamine (MA) use is associated with sexual risk behavior as well as systemic and mucosal inflammation, suggesting parallel biological and behavioral mechanisms of HIV transmission among men who have sex with men (MSM) who use MA. Data evaluating the combined biological effects of MA use with concomitant rectal gonococcal and/or chlamydial (GC/CT) infection on inflammation are limited. SETTING: Secondary analysis of stored rectal and plasma specimens from 100 MSM participating in an NIDA-funded longitudinal cohort in Los Angeles, CA. METHODS: This cross-sectional analysis evaluated systemic and rectal inflammatory markers under 2 conditions: (1) recent MA use (by urine drug screen) and (2) rectal GC/CT infection. We evaluated 50 participants with recent MA use (25 with and 25 without rectal GC/CT) and 50 MSM without MA use (25 with and 25 without rectal GC/CT). Log-transformed plasma and rectal immune markers were regressed on MA exposure and rectal GC/CT, controlling for HIV status and age. RESULTS: Median age was 32 (range 19-45) years, and 58% of participants were living with HIV. Plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-1ß, and rectal IL-6 were associated with rectal GC/CT and MA use, independent of HIV status. Higher levels of rectal TNF-α, IL-1ß, and IL-17a were associated with rectal GC/CT. CONCLUSIONS: Systemic and rectal inflammation was positively associated with rectal GC/CT and MA use. Condomless sex in the setting of GC/CT- and MA-induced immune activation may provide a basis for synergistic biobehavioral mechanisms that promote HIV/STI transmission among MSM who use MA.

Direct Detection of 4-Dimensions of SARS-CoV-2: Infection (vRNA), Infectivity (Antigen), Binding Antibody, and Functional Neutralizing Antibody in Saliva.

We developed a 4-parameter clinical assay using Electric Field Induced Release and Measurement (EFIRM) technology to simultaneously assess SARS-CoV-2 RNA (vRNA), nucleocapsid antigen, host binding (BAb) and neutralizing antibody (NAb) levels from a drop of saliva with performance that equals or surpasses current EUA-approved tests. The vRNA and antigen assays achieved lower limit of detection (LOD) of 100 copies/reaction and 3.5 TCID50/mL, respectively. The vRNA assay differentiated between acutely infected (n=10) and infection-naïve patients (n=33) with an AUC of 0.9818, sensitivity of 90%, and specificity of 100%. The antigen assay similarly differentiated these patient populations with an AUC of 1.000. The BAb assay detected BAbs with an LOD of 39 pg/mL and distinguished acutely infected (n=35), vaccinated with prior infection (n=13), and vaccinated infection-naïve patients (n=13) from control (n=81) with AUC of 0.9481, 1.000, and 0.9962, respectively. The NAb assay detected NAbs with an LOD of 31.6 Unit/mL and differentiated between COVID-19 recovered or vaccinated patients (n=31) and pre-pandemic controls (n=60) with an AUC 0.923, sensitivity of 87.10%, and specificity of 86.67%. Our multiparameter assay represents a significant technological advancement to simultaneously address SARS-CoV-2 infection and immunity, and it lays the foundation for tackling potential future pandemics.

Chronic Obstructive Pulmonary Disease is Not Associated with In-Hospital Mortality in COVID-19: An Observational Cohort Analysis.

Background: Chronic obstructive pulmonary disease (COPD) is associated with worsened outcomes in COVID-19 (coronavirus disease 2019). However, data remain fraught with heterogeneity and bias from comorbid conditions. Additionally, data on the impact of COPD-specific factors, such as pre-hospital medications and pulmonologist involvement, remain sparse. Objective: We report a single-center analysis of COPD patients hospitalized with COVID-19 compared to those without COPD. Primary outcomes include ICU admission, mechanical ventilation, and in-hospital mortality. Methods: We evaluated all patients ≥40 years admitted with PCR-confirmed COVID-19 between February 2020 and February 2021. COPD was defined by documented ICD-10 diagnosis of COPD, confirmed smoking history, and active bronchodilator use. We compared outcomes between COPD patients and the remainder of the COVID-19 cohort. Multivariable analyses were adjusted for age, sex, smoking status, and comorbid conditions. Results: Of 1537 hospitalized COVID-19 patients, 122 (7.9%) carried a diagnosis of COPD. The COPD cohort was older (74 ± 13 vs 66 ± 15 years, P < 0.001) and more often former smokers (P < 0.001). Comorbid conditions including diabetes, cardiovascular disease, and kidney disease were more prevalent in the COPD group (P < 0.001). After adjusting for comorbid conditions, the COPD cohort had higher severity scores and trended towards fewer hospital-free days. Among patients with COPD, pre-hospital use of aspirin was associated with decreased ICU admissions (aHR 0.56, P = 0.049) and mechanical ventilation (aHR 0.25, P = 0.008), while LAMAs (long-acting muscarinic antagonists) were associated with decreased in-hospital mortality (aHR 0.34, P = 0.047). Involvement of pulmonology in pre-hospital management of COPD was not found to significantly affect outcomes. Conclusion: When corrected for comorbid illnesses, COPD was associated with more severe disease but not with increased ICU admission, mechanical ventilation, or in-hospital mortality rates. Among COPD patients, prehospital treatment with aspirin and COPD-directed therapies were associated with improved outcomes.

Gut dysbiosis and inflammatory blood markers precede HIV with limited changes after early seroconversion.

BACKGROUND: Alterations in the gut microbiome have been associated with HIV infection, but the relative impact of HIV versus other factors on the gut microbiome has been difficult to determine in cross-sectional studies. METHODS: To address this, we examined the gut microbiome, serum metabolome, and cytokines longitudinally within 27 individuals before and during acute HIV using samples collected from several ongoing cohort studies. Matched control participants (n=28) from the same cohort studies without HIV but at similar behavioral risk were used for comparison. FINDINGS: We identified few changes in the microbiome during acute HIV infection, but did find alterations in serum metabolites involving secondary bile acid (lithocholate sulfate, glycocholenate sulfate) and amino acid metabolism (3-methyl-2-oxovalerate, serine, cysteine, N-acetylputrescine). Greater microbiome differences, including decreased Bacteroides spp and increased Megasphaera elsdenii, were seen when comparing pre-HIV infection visits to matched at-risk controls. Those who acquired HIV also had elevated inflammatory cytokines (TNF-α, B cell activating factor, IL-8) and bioactive lipids (palmitoyl-sphingosine-phosphoethanolamide and glycerophosphoinositol) prior to HIV acquisition compared to matched controls. INTERPRETATION: Longitudinal sampling identified pre-existing microbiome differences in participants with acute HIV compared to matched control participants observed over the same period. These data highlight the importance of increasing understanding of the role of the microbiome in HIV susceptibility. FUNDING: This work was supported by NIH/NIAID (K08AI124979; P30AI117943), NIH/NIDA (U01DA036267; U01DA036939; U01DA036926; U24DA044554), and NIH/NIMH (P30MH058107; R34MH105272).

Cannabis consumption is associated with lower COVID-19 severity among hospitalized patients: a retrospective cohort analysis.

BACKGROUND: While cannabis is known to have immunomodulatory properties, the clinical consequences of its use on outcomes in COVID-19 have not been extensively evaluated. We aimed to assess whether cannabis users hospitalized for COVID-19 had improved outcomes compared to non-users. METHODS: We conducted a retrospective analysis of 1831 patients admitted to two medical centers in Southern California with a diagnosis of COVID-19. We evaluated outcomes including NIH COVID-19 Severity Score, need for supplemental oxygen, ICU (intensive care unit) admission, mechanical ventilation, length of hospitalization, and in-hospital death for cannabis users and non-users. Cannabis use was reported in the patient's social history. Propensity matching was used to account for differences in age, body-mass index, sex, race, tobacco smoking history, and comorbidities known to be risk factors for COVID-19 mortality between cannabis users and non-users. RESULTS: Of 1831 patients admitted with COVID-19, 69 patients reported active cannabis use (4% of the cohort). Active users were younger (44 years vs. 62 years, p < 0.001), less often diabetic (23.2% vs 37.2%, p < 0.021), and more frequently active tobacco smokers (20.3% vs. 4.1%, p < 0.001) compared to non-users. Notably, active users had lower levels of inflammatory markers upon admission than non-users-CRP (C-reactive protein) (3.7 mg/L vs 7.6 mg/L, p < 0.001), ferritin (282 µg/L vs 622 µg/L, p < 0.001), D-dimer (468 ng/mL vs 1140 ng/mL, p = 0.017), and procalcitonin (0.10 ng/mL vs 0.15 ng/mL, p = 0.001). Based on univariate analysis, cannabis users had significantly better outcomes compared to non-users as reflected in lower NIH scores (5.1 vs 6.0, p < 0.001), shorter hospitalization (4 days vs 6 days, p < 0.001), lower ICU admission rates (12% vs 31%, p < 0.001), and less need for mechanical ventilation (6% vs 17%, p = 0.027). Using propensity matching, differences in overall survival were not statistically significant between cannabis users and non-users, nevertheless ICU admission was 12 percentage points lower (p = 0.018) and intubation rates were 6 percentage points lower (p = 0.017) in cannabis users. CONCLUSIONS: This retrospective cohort study suggests that active cannabis users hospitalized with COVID-19 had better clinical outcomes compared with non-users, including decreased need for ICU admission or mechanical ventilation. However, our results need to be interpreted with caution given the limitations of a retrospective analysis. Prospective and observational studies will better elucidate the effects cannabis use in COVID-19 patients.

Dominant CD8+ T Cell Nucleocapsid Targeting in SARS-CoV-2 Infection and Broad Spike Targeting From Vaccination.

CD8+ T cells have key protective roles in many viral infections. While an overall Th1-biased cellular immune response against SARS-CoV-2 has been demonstrated, most reports of anti-SARS-CoV-2 cellular immunity have evaluated bulk T cells using pools of predicted epitopes, without clear delineation of the CD8+ subset and its magnitude and targeting. In recently infected persons (mean 29.8 days after COVID-19 symptom onset), we confirm a Th1 bias (and a novel IL-4-producing population of unclear significance) by flow cytometry, which does not correlate to antibody responses against the receptor binding domain. Evaluating isolated CD8+ T cells in more detail by IFN-γ ELISpot assays, responses against spike, nucleocapsid, matrix, and envelope proteins average 396, 901, 296, and 0 spot-forming cells (SFC) per million, targeting 1.4, 1.5, 0.59, and 0.0 epitope regions respectively. Nucleocapsid targeting is dominant in terms of magnitude, breadth, and density of targeting. The magnitude of responses drops rapidly post-infection; nucleocapsid targeting is most sustained, and vaccination selectively boosts spike targeting. In SARS-CoV-2-naïve persons, evaluation of the anti-spike CD8+ T cell response soon after vaccination (mean 11.3 days) yields anti-spike CD8+ T cell responses averaging 2,463 SFC/million against 4.2 epitope regions, and targeting mirrors that seen in infected persons. These findings provide greater clarity on CD8+ T cell anti-SARS-CoV-2 targeting, breadth, and persistence, suggesting that nucleocapsid inclusion in vaccines could broaden coverage and durability.

Humoral responses to SARS-CoV-2 mRNA vaccines: Role of past infection.

Two mRNA vaccines (BNT162b2 and mRNA-1273) against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) are globally authorized as a two-dose regimen. Understanding the magnitude and duration of protective immune responses is vital to curbing the pandemic. We enrolled 461 high-risk health services workers at the University of California, Los Angeles (UCLA) and first responders in the Los Angeles County Fire Department (LACoFD) to assess the humoral responses in previously infected (PI) and infection naïve (NPI) individuals to mRNA-based vaccines (BNT162b2/Pfizer- BioNTech or mRNA-1273/Moderna). A chemiluminescent microparticle immunoassay was used to detect antibodies against SARS-CoV-2 Spike in vaccinees prior to (n = 21) and following each vaccine dose (n = 246 following dose 1 and n = 315 following dose 2), and at days 31-60 (n = 110) and 61-90 (n = 190) following completion of the 2-dose series. Both vaccines induced robust antibody responses in all immunocompetent individuals. Previously infected individuals achieved higher median peak titers (p = 0.002) and had a slower rate of decay (p = 0.047) than infection-naïve individuals. mRNA-1273 vaccinated infection-naïve individuals demonstrated modestly higher titers following each dose (p = 0.005 and p = 0.029, respectively) and slower rates of antibody decay (p = 0.003) than those who received BNT162b2. A subset of previously infected individuals (25%) required both doses in order to reach peak antibody titers. The biologic significance of the differences between previously infected individuals and between the mRNA-1273 and BNT162b2 vaccines remains uncertain, but may have important implications for booster strategies.

Primary, Recall, and Decay Kinetics of SARS-CoV-2 Vaccine Antibody Responses.

Studies of two SARS-CoV-2 mRNA vaccines suggested that they yield ∼95% protection from symptomatic infection at least short-term, but important clinical questions remain. It is unclear how vaccine-induced antibody levels quantitatively compare to the wide spectrum induced by natural SARS-CoV-2 infection. Vaccine response kinetics and magnitudes in persons with prior COVID-19 compared to virus-naïve persons are not well-defined. The relative stability of vaccine-induced versus infection-induced antibody levels is unclear. We addressed these issues with longitudinal assessments of vaccinees with and without prior SARS-CoV-2 infection using quantitative enzyme-linked immunosorbent assay (ELISA) of anti-RBD antibodies. SARS-CoV-2-naïve individuals achieved levels similar to mild natural infection after the first vaccination; a second dose generated levels approaching severe natural infection. In persons with prior COVID-19, one dose boosted levels to the high end of severe natural infection even in those who never had robust responses from infection, increasing no further after the second dose. Antiviral neutralizing assessments using a spike-pseudovirus assay revealed that virus-naïve vaccinees did not develop physiologic neutralizing potency until the second dose, while previously infected persons exhibited maximal neutralization after one dose. Finally, antibodies from vaccination waned similarly to natural infection, resulting in an average of ∼90% loss within 90 days. In summary, our findings suggest that two doses are important for quantity and quality of humoral immunity in SARS-CoV-2-naïve persons, while a single dose has maximal effects in those with past infection. Antibodies from vaccination wane with kinetics very similar to that seen after mild natural infection; booster vaccinations will likely be required.

Comparative impact of methamphetamine and other drug use on viral suppression among sexual minority men on antiretroviral therapy.

BACKGROUND: Substance use decreases the likelihood of achieving undetectable HIV viremia; however, the comparative effects by drug have not been fully described. In this study, we compare the effects of methamphetamine use versus other drugs on viremia in sexual minority men on antiretroviral therapy (ART). METHODS: HIV-positive participants currently on ART (N = 230) were selected from an ongoing cohort of diverse young sexual minority men (mSTUDY) enrolled from August 2014 to May 2018. Substance use and sociodemographic factors associated with viremia outcomes were assessed using ordinal regression analysis with generalized estimating equations. Viremia outcomes were grouped as undetectable (<20 copies/mL), low level suppressed (21-200 copies/mL), or not suppressed (>200 copies/mL). RESULTS: The prevalence of drug use across 825 study visits was 73 %, with methamphetamine use most prevalent (50 %). After adjusting for unstable housing and ART adherence, methamphetamine use, either alone (adjusted OR = 1.87; 95 % CI 1.03-3.40) or with other drugs (adjusted OR = 1.82; 95 % CI 1.12-2.95), was associated with higher odds of increasing viremia compared to no drug use. Other drug use excluding methamphetamine did not show a similar association (adjusted OR = 1.29; 95 % CI 0.80-2.09). Among our study population, nearly half the instances of viremia could be reduced if methamphetamine was discontinued (attributable fraction = 46 %; 95 % CI 3-71 %). CONCLUSIONS: Methamphetamine use, either alone or in combination with other drugs, is associated with failure of viral suppression among sexual minority men on ART independent of adherence and sociodemographic factors. This accounts for nearly half of the observed instances of unsuppressed viremia in this study.

Discharge Clinical Characteristics and Post-Discharge Events in Patients with Severe COVID-19: A Descriptive Case Series.

BACKGROUND: As the SARS-CoV-2 pandemic continues, little guidance is available on clinical indicators for safely discharging patients with severe COVID-19. OBJECTIVE: To describe the clinical courses of adult patients admitted for COVID-19 and identify associations between inpatient clinical features and post-discharge need for acute care. DESIGN: Retrospective chart reviews were performed to record laboratory values, temperature, and oxygen requirements of 99 adult inpatients with COVID-19. Those variables were used to predict emergency department (ED) visit or readmission within 30 days post-discharge. PATIENTS (OR PARTICIPANTS): Age ≥ 18 years, first hospitalization for COVID-19, admitted between March 1 and May 2, 2020, at University of California, Los Angeles (UCLA) Medical Center, managed by an inpatient medicine service. MAIN MEASURES: Ferritin, C-reactive protein, lactate dehydrogenase, D-dimer, procalcitonin, white blood cell count, absolute lymphocyte count, temperature, and oxygen requirement were noted. KEY RESULTS: Of 99 patients, five required ED admission within 30 days, and another five required readmission. Fever within 24 h of discharge, oxygen requirement, and laboratory abnormalities were not associated with need for ED visit or readmission within 30 days of discharge after admission for COVID-19. CONCLUSION: Our data suggest that neither persistent fever, oxygen requirement, nor laboratory marker derangement was associated with need for acute care in the 30-day period after discharge for severe COVID-19. These findings suggest that physicians need not await the normalization of laboratory markers, resolution of fever, or discontinuation of oxygen prior to discharging a stable or improving patient with COVID-19.

Clinical Characteristics and Outcomes of Coronavirus Disease 2019 Patients Who Received Compassionate-Use Leronlimab.

BACKGROUND: Leronlimab, a monoclonal antibody blocker of C-C chemokine receptor type 5 originally developed to treat human immunodeficiency virus infection, was administered as an open-label compassionate-use therapeutic for coronavirus disease 2019 (COVID-19). METHODS: Twenty-three hospitalized severe/critical COVID-19 patients received 700 mg leronlimab subcutaneously, repeated after 7 days in 17 of 23 patients still hospitalized. Eighteen of 23 received other experimental treatments, including convalescent plasma, hydroxychloroquine, steroids, and/or tocilizumab. Five of 23 received leronlimab after blinded, placebo-controlled trials of remdesivir, sarilumab, selinexor, or tocilizumab. Outcomes and results were extracted from medical records. RESULTS: Mean age was 69.5 ±â€…14.9 years; 20 had significant comorbidities. At baseline, 22 were receiving supplemental oxygen (3 high flow, 7 mechanical ventilation). Blood showed markedly elevated inflammatory markers (ferritin, D-dimer, C-reactive protein) and an elevated neutrophil-to-lymphocyte ratio. By day 30 after initial dosing, 17 were recovered, 2 were still hospitalized, and 4 had died. Of the 7 intubated at baseline, 4 were fully recovered off oxygen, 2 were still hospitalized, and 1 had died. CONCLUSIONS: Leronlimab appeared safe and well tolerated. The high recovery rate suggested benefit, and those with lower inflammatory markers had better outcomes. Some, but not all, patients appeared to have dramatic clinical responses, indicating that unknown factors may determine responsiveness to leronlimab. Routine inflammatory and cell prognostic markers did not markedly change immediately after treatment, although interleukin-6 tended to fall. In some persons, C-reactive protein clearly dropped only after the second leronlimab dose, suggesting that a higher loading dose might be more effective. Future controlled trials will be informative.

Using Serologic Testing to Assess the Effectiveness of Outbreak Control Efforts, Serial Polymerase Chain Reaction Testing, and Cohorting of Positive Severe Acute Respiratory Syndrome Coronavirus 2 Patients in a Skilled Nursing Facility.

We characterized serology following a nursing home outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) where residents were serially tested by reverse-transcription polymerase chain reaction (RT-PCR) and positive residents were cohorted. When tested 46-76 days later, 24 of 26 RT-PCR-positive residents were seropositive; none of the 124 RT-PCR-negative residents had confirmed seropositivity, supporting serial SARS-CoV-2 RT-PCR testing and cohorting in nursing homes.

Brief Report: HIV-1 Seroconversion Is Not Associated With Prolonged Rectal Mucosal Inflammation.

OBJECTIVE: Determine the impact of HIV-1 seroconversion on inflammatory cytokines in the rectal mucosa. SETTING: Secondary analysis of data from men who have sex with men and transgender women who participated in a HIV prevention trial Lima, Peru. METHODS: From July to December 2017, 605 men who have sex with men and transgender women were screened for rectal gonorrhea/chlamydia (GC/CT). Fifty GC/CT-positive cases were randomly selected and matched with 52 GC/CT-negative controls by age and number of receptive anal intercourse partners in the last month. All participants were HIV-negative at baseline and those with GC/CT at baseline and/or follow-up received appropriate antibiotic therapy. Participants underwent sponge collection of rectal secretions for the measurement of inflammatory cytokines (IL-1ß, IL-6, IL-8, and TNF-α) and were screened for rectal GC/CT and HIV at baseline, 3 months, and 6 months. Wilcoxon rank-sum tests compared inflammatory cytokine levels between participants diagnosed with HIV during follow-up and persons who remained HIV-negative. RESULTS: Eight participants were diagnosed with HIV at the 3-month (n = 6) or 6-month (n = 2) visit. The median number of receptive anal intercourse partners in the month before HIV diagnosis was the same for those who acquired HIV and those who did not. There were no significant differences in inflammatory cytokine levels in rectal mucosa between participants who did and did not experience HIV seroconversion at any time point. CONCLUSIONS: Despite a surge in viral replication during acute infection, findings from this study suggest that there is no prolonged effect of HIV-1 seroconversion on inflammatory cytokine levels in the rectal mucosa.