Sepsis Impairs IFN-γ Production in CD8 T Cells through Changes in Local Chromatin Landscape.

Sepsis is a complex condition of inflammatory and immune dysregulation, triggered by severe infection. In survivors, chronic inflammation and immune dysregulation linger, facilitating the emergence of infections. CD8 dysfunction contributes to immunosuppression in sepsis survivors. We devised an animal model that enabled us to identify and analyze CD8-intrinsic defects induced by sepsis. We adoptively transferred CD45.1 CD8 OT-I T cells into CD45.2 congenic mice and subjected them to cecal ligature and puncture, to induce abdominal sepsis. One month later, we isolated the transferred CD8 cells. Surface marker expression confirmed they had not been activated through the TCR. CD8 OT-I T cells isolated from septic (or sham-operated) mice were transferred to second recipients, which were challenged with OVA-expressing Listeria monocytogenes. We compared effector capacities between OT-I cells exposed to sepsis and control cells. Naive mice that received OT-I cells exposed to sepsis had higher bacterial burden and a shorter survival when challenged with OVA-expressing L. monocytogenes. OT-I cells isolated from septic mice produced less IFN-γ but had conserved activation, expansion potential, and cytotoxic function. We observed lower transcript levels of IFN-γ and of the long noncoding RNA Ifng-as1, a local regulator of the epigenetic landscape, in cells exposed to sepsis. Accordingly, local abundance of a histone modification characteristic of active promoter regions was reduced in sepsis-exposed CD8 T cells. Our results identify a mechanism through which inflammation in the context of sepsis affects CD8 T cell function intrinsically.

Clinical features and outcomes of mpox in people with and without HIV: a national comparative study.

BACKGROUND: People who live with HIV (PWLH) have been one of the most affected groups during the current mpox outbreak. They are hypothesized to have a more severe clinical course than people without HIV but comparative data is scarce. We aimed to compare clinical features and outcomes of mpox in people with and without HIV in Mexico. SETTING: Country-wide study in Mexico. METHODS: We performed an observational study using nation-wide epidemiological data. We included all people with confirmed mpox diagnosed between May and November 2022 in Mexico. Clinical and sociodemographic characteristics were compared between people with and without HIV. Multivariable logistic regression models were preformed to determine the association between HIV, clinical features, and outcomes and reported with odds ratios (ORs) and 95% confidence intervals (95% CI). ORs for rare outcomes were interpreted as risk ratios. RESULTS: Among 3291 people with mpox, 59% were PWLH. PWLH had an increased risk of severe mpox (OR 2.6, 2.4-2.9) and death (OR 10.8, 9.7-11.9). They also had a higher risk of otalgia, proctitis, and urethritis. Eleven individuals died, of whom ten were PWLH. All deaths were directly attributed to mpox. CONCLUSION: People with HIV have a higher risk of severe mpox and death due to mpox.

Retiring the term AIDS for more descriptive language.

The term acquired immunodeficiency syndrome (AIDS) was coined to describe a condition marked by weakened cell-mediated immunity in the absence of a clear cause. Due to unfortunate messaging during the early days of the HIV epidemic, this term became loaded with stigma. After the discovery of HIV, the term AIDS became redundant, but its use has persisted and has come to embody negative connotations in the current landscape of the HIV epidemic. People commonly associate AIDS with a terminal illness. This misconception promotes stigma by others, including health-care workers, but also self-stigma, which can prevent individuals from accessing health care. Also, the link between AIDS and gay men generated during the early epidemic with use of the term gay-related immune disorder is misleading regarding which populations are at risk, which can delay diagnosis. The use of the term AIDS is now discouraged by several professional associations, some of which ironically have the word as part of their name. Ending use of the term AIDS would not eradicate stigma. However, this term has outlasted its usefulness, and we should transition towards more descriptive language that aligns with contemporary challenges in HIV.

Predictors of laboratory-confirmed mpox in people with mpox-like illness.

OBJECTIVES: We aimed to identify predictors of confirmed monkeypox (mpox) among people with mpox-like illness and to develop a multivariable model for confirmed mpox. METHODS: We performed an observational study using national epidemiologic surveillance data in Mexico from May to November 2022. People with mpox-like illness were reported to the Mexican Ministry of Health and real-time polymerase chain reaction was performed in clinical samples to confirm mpox. Sociodemographic and clinical data were collected with a case report form. We performed univariable logistic regressions to estimate the predictive capability of individual characteristics, reported with ORs and 95% CIs. Variables of interest were included in multivariable logistic regression models and Akaike information criterion was used to retain variables for the final model. Discrimination and calibration of the model were estimated in bootstrap resamples. RESULTS: A total of 5078 people were reported with mpox-like illness. Of 5078 people, 3291 (64.8%) had confirmed mpox. The strongest clinical predictors of confirmed mpox in univariable models were proctitis (OR 6.54, 5.93-7.21), inguinal adenopathy (OR 5.91, 5.36-6.52), and anogenital lesions (OR 5.45, 4.94-6.02). The final model included being a man who has sex with men (8.75, 7.37-10.38), HIV diagnosis (3.04, 2.51-3.69), inguinal adenopathy (2.24, 1.81-2.77), anogenital lesions (2.32, 1.97-2.74), and pustules (1.55, 1.32-1.81). Discrimination capability was excellent (c-statistic 0.88, 95% CI 0.87-0.89) and it was well calibrated (calibration slope 1, 95% CI 0.95-1.05). DISCUSSION: A third of people with mpox-like illness do not have mpox. Factors such as being a man who has sex with men, HIV diagnosis, inguinal adenopathy, pustules, and anogenital lesions are associated with confirmed mpox.

Protection of hybrid immunity against SARS-CoV-2 reinfection and severe COVID-19 during periods of Omicron variant predominance in Mexico.

Background: With the widespread transmission of the Omicron SARS-CoV-2 variant, reinfections have become increasingly common. Here, we explored the role of immunity, primary infection severity, and variant predominance in the risk of reinfection and severe COVID-19 during Omicron predominance in Mexico. Methods: We analyzed reinfections in Mexico in individuals with a primary infection separated by at least 90 days from reinfection using a national surveillance registry of SARS-CoV-2 cases from March 3rd, 2020, to August 13th, 2022. Immunity-generating events included primary infection, partial or complete vaccination, and booster vaccines. Reinfections were matched by age and sex with controls with primary SARS-CoV-2 infection and negative RT-PCR or antigen test at least 90 days after primary infection to explore reinfection and severe disease risk factors. We also compared the protective efficacy of heterologous and homologous vaccine boosters against reinfection. Results: We detected 231,202 SARS-CoV-2 reinfections in Mexico, most occurring in unvaccinated individuals (41.55%). Over 207,623 reinfections occurred during periods of Omicron (89.8%), BA.1 (36.74%), and BA.5 (33.67%) subvariant predominance and a case-fatality rate of 0.22%. Vaccination protected against reinfection, without significant influence of the order of immunity-generating events and provided >90% protection against severe reinfections. Heterologous booster schedules were associated with ~11% and ~ 54% lower risk for reinfection and reinfection-associated severe COVID-19, respectively, modified by time-elapsed since the last immunity-generating event, when compared against complete primary schedules. Conclusion: SARS-CoV-2 reinfections increased during Omicron predominance. Hybrid immunity provides protection against reinfection and associated severe COVID-19, with potential benefit from heterologous booster schedules.

Effectiveness of a nationwide COVID-19 vaccination program in Mexico against symptomatic COVID-19, hospitalizations, and death: a retrospective analysis of national surveillance data.

OBJECTIVES: Vaccination has been effective in ameliorating the impact of COVID-19. Here, we report vaccine effectiveness (VE) of the nationally available COVID-19 vaccines in Mexico. METHODS: Retrospective analysis of a COVID-19 surveillance system to assess the VE of the BNT162b2, messenger RNA (mRNA)-12732, Gam-COVID-Vac, Ad5-nCoV, Ad26.COV2.S, ChAdOx1, and CoronaVac vaccines against SARS-CoV-2 infection, COVID-19 hospitalization, and death in Mexico. The VE was estimated using time-varying Cox proportional hazard models in vaccinated and unvaccinated adults, adjusted for age, sex, and comorbidities. VE was also estimated for adults with diabetes, aged ≥60 years, and comparing the predominance of SARS-CoV-2 variants B.1.1.519 and B.1.617.2. RESULTS: We assessed 793,487 vaccinated and 4,792,338 unvaccinated adults between December 24, 2020 and September 27, 2021. The VE against SARS-CoV-2 infection was the highest for fully vaccinated individuals with mRNA-12732 (91.5%, 95% confidence interval [CI] 90.3-92.4) and Ad26.COV2.S (82.2%, 95% CI 81.4-82.9); for COVID-19 hospitalization, BNT162b2 (84.3%, 95% CI 83.6-84.9) and Gam-COVID-Vac (81.4% 95% CI 79.5-83.1), and for mortality, BNT162b2 (89.8%, 95% CI 89.2-90.2) and mRNA-12732 (93.5%, 95% CI 86.0-97.0). The VE decreased for all vaccines in adults aged ≥60 years, people with diabetes, and periods of Delta variant predominance. CONCLUSION: All the vaccines implemented in Mexico were effective against SARS-CoV-2 infection, COVID-19 hospitalization, and death. Mass vaccination with multiple vaccines is useful to maximize vaccination coverage.

Posterior reversible encephalopathy syndrome during convalescence from COVID-19.

Background and aim: With an ever-increasing population of patients recovering form severe coronavirus disease 2019 (COVID-19), recognizing long-standing and delayed neurologic manifestations is crucial. Here, we present a patient developing posterior reversible encephalopathy syndrome (PRES) in the convalescence form severe coronavirus disease 2019 (COVID-19).Case presentation: A 61-year-old woman with severe (COVID-19) confirmed by nasopharyngeal real-time reverse transcription-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) required invasive mechanical ventilation 24-hours after admission. During her intensive care unit stay, she developed transient acute kidney injury and septic shock. She was extubated after 22 days. On day 25, she developed generalized tonic-clonic seizures. Magnetic resonance imaging (MRI) of the brain showed bilateral subcortical lesions on the parietal and occipital lobes and multiple micro-and macro-bleeds, consistent with PRES. At this point, RT-PCR for SARS-CoV-2 in a respiratory specimen and cerebrospinal fluid was negative. She was discharged home 35 days after admission on oral levetiracetam. Control MRI five months after discharge showed bilateral focal gliosis. On follow-up, she remains seizure-free on levetiracetam.Conclusions: PRES has been observed before as a neurological manifestation of acute COVID-19; to our knowledge, this is the first PRES case occurring in a hospitalized patient already recovered from COVID-19. A persistent proinflammatory/prothrombotic state triggered by SARS-CoV-2 infection may lead to long-standing endothelial dysfunction, resulting in delayed PRES in patients recovering from COVID-19. With a rapid and exponential increase in survivors of acute COVID-19, clinicians should be aware of delayed (post-acute) neurological damage, including PRES.

Epidemiological and clinical characteristics of patients with human monkeypox infection in Mexico: a nationwide observational study.

Background: Human monkeypox, a zoonosis historically endemic to West and South Africa, has led to a worldwide outbreak driven by human-to-human transmission resulting in an international public health emergency. Endemic and outbreak monkeypox cases may differ in their affected populations, clinical features, and outcomes. Thus, profiling cases of the current monkeypox outbreak worldwide is crucial. Methods: We performed a nationwide observational surveillance-based study from May 24 to September 5, 2022. Patients that met the operational clinical definition of monkeypox or symptomatic close contacts of confirmed cases were tested by real-time polymerase chain reaction. Clinical data were collected with a standardized case-report form. We report epidemiologic, sociodemographic, and clinical characteristics of confirmed cases. Findings: Five-hundred and sixty-five human monkeypox confirmed cases were analysed; 97.2% were men, of whom 59.5% identified as men who have sex with men, and 54.5% had human immunodeficiency virus infection. The median age was 34 years. All patients but one had rash (99.8%), 78.9% had fever, and 47.8% reported myalgia. The anogenital area was the most commonly affected one by rash (49.6%), and proctitis occurred in 6.2% of patients. Six patients required hospitalization, of which one died due to causes unrelated to monkeypox. Interpretation: The 2022 monkeypox outbreak in Mexico is mainly driven by middle-aged men who have sex with men, of which a large proportion are persons who live with human immunodeficiency virus infection. Clinical features such as the high proportion of anogenital lesions suggest sexual contact is a pivotal transmission mechanism in this outbreak. Funding: This research was supported by grant A1-S-18342 from Consejo Nacional de Ciencia y Tecnología (CONACyT), Mexico (to S.I.V.-F.).

Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial.

BACKGROUND: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. METHODS: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. RESULTS: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). CONCLUSION: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

Circulating HMGB1 is increased in myelodysplastic syndrome but not in other bone marrow failure syndromes: proof-of-concept cross-sectional study.

Background: Myelodysplastic syndrome (MDS) is associated with persistent immune activation. High mobility group box-1 (HMGB1) is a ubiquitous, functionally diverse, non-histone intranuclear protein. During acute and chronic inflammatory states, HMGB1 is actively released by inflammatory cells, further amplifying the inflammatory response. A role in MDS and other hypoplastic bone marrow (BM) disorders is incompletely understood. Objectives: The objective of the study is to evaluate whether circulating HMGB1 is elevated in patients with MDS and other BM failure syndromes [namely, aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH)]. Design: This is a observational, cross-sectional, single-center, exploratory study. Methods: We evaluated circulating concentrations of HMGB1, interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α in patients with MDS and age-matched hematologically healthy controls as well as patients with AA and PNH. Results: We included 66 patients with MDS and 65 age-matched controls as well as 44 patients with other BM failures (AA = 27, PNH = 17). Circulating levels of HMGB1 were higher in patients with MDS [median, 4.9 ng/ml; interquartile range (IQR): 2.3-8.1] than in AA (median, 2.6 ng/ml; IQR: 1.7-3.7), PNH (median, 1.7 ng/ml; IQR: 0.9-2.5), and age-matched healthy individuals (median, 1.9 ng/ml; IQR: 0.9-2.5) (p = 0.0001). We observed higher concentrations of HMGB1 in the very low/low-risk MDS patients than in the intermediate/high/very high-risk ones (p = 0.046). Finally, in comparison with patients with AA, those with hypocellular MDS (h-MDS) had significantly higher levels of circulating HMGB1 (n = 14; median concentration, 5.6 ng/ml, IQR: 2.8-7.3; p = 0.006). We determined a circulating HMGB1 value of 4.095 ng/ml as a diagnostic cutoff differentiator between h-MDS and AA. Conclusion: These observations indicate that circulating HMGB1 is increased in patients with MDS. HMGB1 (but not IL-1ß or TNF-α) differentiated between MDS and other BM failures, suggesting that HMGB1 may be mechanistically involved in MDS and a druggable target to decrease inflammation in MDS.

Psychological and Psychiatric Events Following Immunization with Five Different Vaccines against SARS-CoV-2.

BACKGROUND: Despite the high number of vaccines administered against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, the information on the psychological/psychiatric adverse events following immunization (AEFI) with these newly developed vaccines remains scarce. OBJECTIVE: To describe the frequency of psychological/psychiatric symptoms among recipients of five different anti-SARS-CoV-2 vaccines and to explore the factors associated with their development reported in the nationwide Mexican registry of AEFI against SARS-CoV-2. METHODS: Descriptive study of all the psychological/psychiatric symptoms, including anxiety, panic attacks, insomnia, and agitation reported to the Mexican Epidemiological Surveillance System from 21 December 2020 to 27 April 2021, among adult (≥18 years old) recipients of 7,812,845 doses of BNT162b2, ChAdOx1 nCov-19, rAd26-rAd5, Ad5-nCoV, or CoronaVac. The factors associated with their development are determined by multivariate regression analysis. RESULTS: There were 19,163 AEFI reports during the study period; amongst them, 191 (1%) patients had psychological/psychiatric symptoms (median age of 41 years, interquartile range of 32-54; 149 [78%] women) for an observed incidence of 2.44 cases per 100,000 administered doses (95% confidence interval [CI] 2.12-2.82), 72.8% of psychiatric AEFIs were reported among recipients of BNT162b2. The median time from vaccination to symptom onset was 35 min (interquartile range: 10-720). Overall, the most common psychological/psychiatric symptoms were anxiety in 129 (67.5%) patients, panic attacks in 30 (15.7%), insomnia in 25 (13%), and agitation in 11 (5.7%). After adjusting for the confounding factors, the odds for developing psychological/psychiatric symptoms were higher for those concurrently reporting syncope (odds ratio [OR]: 4.73, 95% CI: 1.68-13.33); palpitations (OR: 2.47, 95% CI: 1.65-3.70), and dizziness (OR: 1.59, 95% CI: 1.10-2.28). CONCLUSION: In our population, psychological/psychiatric symptoms were extremely infrequent AEFIs. No severe psychiatric AEFIs were reported. Immunization stress-related responses might explain most of the detected cases.

Seizures following COVID-19 vaccination in Mexico: A nationwide observational study.

The COVID-19 pandemic led to the development and emergency approval of an array of effective vaccines against SARS-CoV-2. Given the relatively small number of patients included in vaccine trials, postapproval epidemiological surveillance is crucial to detect infrequent vaccine-related adverse events. We conducted a nationwide retrospective descriptive study evaluating the incidence of seizures among recipients of SARS-CoV-2 vaccines in Mexico from December 24, 2020 (date of administration of first doses nationwide) to October 29, 2021. Among 81 916 351 doses of any vaccine that were administered, we documented seizures in 53 patients, of which 31 (60%) were new onset seizures. The incidence rate of seizures per million doses was highest for mRNA-1273 (Moderna) with 2.73 per million, followed by BNT162b2 (Pfizer-BioNTech) with 1.02 per million, and Ad5-nCoV (CanSino) with 1.01 per million. Thus, we found that seizures following SARS-CoV-2 vaccination are exceedingly rare events.

Anaphylaxis to SARS-CoV-2 Vaccines in the Setting of a Nationwide Passive Epidemiological Surveillance Program.

BACKGROUND: Information on anaphylaxis among recipients of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains scarce. OBJECTIVE: To identify the observed incidence of anaphylaxis in recipients of different anti-SARS-CoV-2 vaccines. METHODS: A nationwide observational study among recipients of 61,414,803 doses of seven different anti-SARS-CoV-2 vaccines, describing the incidence and characteristics of adult patients (age ≥ 18 years) who developed anaphylaxis as an adverse event following immunization (AEFI) against SARS-CoV-2 vaccines between December 24, 2020, and October 15, 2021, in Mexico. RESULTS: Sixty-six patients developed anaphylaxis as an AEFI, for an overall observed incidence of 1.07 cases per 1,000,000 (95% CI 0.84-1.37) administered doses. Eighty-six percent of the patients were female, consistent with previous reports of AEFI to COVID-19 vaccines. mRNA-based vaccine recipients had the highest frequency of anaphylaxis, followed by adenovirus-vectored vaccines and inactivated virus recipients, with an observed incidence of 2.5, 0.7, and 0.2 cases per 1,000,000 doses administered, respectively. Only 46% of the patients received correct treatment with epinephrine as the first-line treatment through the appropriate route and dose. We detected one case of anaphylactic reaction-related death occurring 5 min following immunization with ChAdOx1 nCov-19 for a mortality rate of 1.5% among those who developed this AEFI. CONCLUSIONS: In our population, anaphylactic reactions were infrequent. Our study provides further evidence supporting the security of these newly developed vaccines.

Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19.

The biological determinants underlying the range of coronavirus 2019 (COVID-19) clinical manifestations are not fully understood. Here, over 1,400 plasma proteins and 2,600 single-cell immune features comprising cell phenotype, endogenous signaling activity, and signaling responses to inflammatory ligands are cross-sectionally assessed in peripheral blood from 97 patients with mild, moderate, and severe COVID-19 and 40 uninfected patients. Using an integrated computational approach to analyze the combined plasma and single-cell proteomic data, we identify and independently validate a multi-variate model classifying COVID-19 severity (multi-class area under the curve [AUC]training = 0.799, p = 4.2e-6; multi-class AUCvalidation = 0.773, p = 7.7e-6). Examination of informative model features reveals biological signatures of COVID-19 severity, including the dysregulation of JAK/STAT, MAPK/mTOR, and nuclear factor κB (NF-κB) immune signaling networks in addition to recapitulating known hallmarks of COVID-19. These results provide a set of early determinants of COVID-19 severity that may point to therapeutic targets for prevention and/or treatment of COVID-19 progression.

Incidence of Guillain-Barré syndrome following SARS-CoV-2 immunization: Analysis of a nationwide registry of recipients of 81 million doses of seven vaccines.

BACKGROUND AND PURPOSE: Information on Guillain-Barré syndrome (GBS) as an adverse event following immunization (AEFI) against SARS-CoV-2 remains scarce. We aimed to report GBS incidence as an AEFI among adult (≥18 years) recipients of 81,842,426 doses of seven anti-SARS-CoV-2 vaccines between December 24, 2020, and October 29, 2021, in Mexico. METHODS: Cases were retrospectively collected through passive epidemiological surveillance. The overall observed incidence was calculated according to the total number of administered doses. Vaccines were analyzed individually and by vector as mRNA-based (mRNA-1273 and BNT162b2), adenovirus-vectored (ChAdOx1 nCov-19, rAd26-rAd5, Ad5-nCoV, and Ad26.COV2-S), and inactivated whole-virion-vectored (CoronaVac) vaccines. RESULTS: We identified 97 patients (52 males [53.6%]; median [interquartile range] age 44 [33-60] years), for an overall observed incidence of 1.19/1,000,000 doses (95% confidence interval [CI] 0.97-1.45), with incidence higher among Ad26.COV2-S (3.86/1,000,000 doses, 95% CI 1.50-9.93) and BNT162b2 recipients (1.92/1,00,000 doses, 95% CI 1.36-2.71). The interval (interquartile range) from vaccination to GBS symptom onset was 10 (3-17) days. Preceding diarrhea was reported in 21 patients (21.6%) and mild COVID-19 in four more (4.1%). Only 18 patients were tested for Campylobacter jejuni (positive in 16 [88.9%]). Electrophysiological examinations were performed in 76 patients (78.4%; axonal in 46 [60.5%] and demyelinating in 25 [32.8%]); variants were similar across the platforms. On admission, 91.8% had a GBS disability score ≥3. Seventy-five patients (77.3%) received intravenous immunoglobulin, received seven plasma exchange (7.2%), and 15 (15.5%) were treated conservatively. Ten patients (10.3%) died, and 79.1% of survivors were unable to walk independently. CONCLUSIONS: Guillain-Barré syndrome was an extremely infrequent AEFI against SARS-CoV-2. The protection provided by these vaccines outweighs the risk of developing GBS.