Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8+ and CD4+ T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

Immunologic resilience and COVID-19 survival advantage.

BACKGROUND: The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE: We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS: IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS: IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS: Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Clinical impact of implementation of rapid diagnostic testing of blood cultures with Staphylococcus aureus on patient outcomes.

Rapid diagnostic testing in microbiology labs shortens the time to identification of bacteria in blood cultures. Cepheid® GeneXpert® MRSA/SA PCR can be used to distinguish MRSA and MSSA from non-Staphylococcus aureus organisms in blood cultures. This study aims to determine if implementation of MRSA/SA PCR for blood culture pathogen identification, plus daily antimicrobial stewardship intervention, can reduce time to appropriate therapy, vancomycin duration, 30 day mortality, and 90 day recurrence in veterans. A total of 113 patients in the pre-implementation cohort and 73 patients in the post-implementation cohort were evaluated. Time to appropriate therapy was decreased from 49.8 (pre-implementation) to 20.6 (post-implementation) hours. There was a numerically shorter median duration of vancomycin therapy in the post-implementation group. There was no difference in 30 day mortality or 90 day recurrence between groups. Use of MRSA/SA PCR can improve antimicrobial use when combined with once-daily antimicrobial stewardship review.

Torsades de pointes and QT prolongation Associations with Antibiotics: A Pharmacovigilance Study of the FDA Adverse Event Reporting System.

Introduction: Macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone are known to be associated with Torsades de pointes/QT prolongation (TdP/QTP). Other antibiotics may also lead to TdP/QTP, but no study has systemically compared TdP/QTP associations for many available antibiotics. Objectives: The objective of this study was to evaluate the association between TdP/QTP and many available antibiotics using the FDA Adverse Event Report System (FAERS). Methods: FAERS reports from January 1, 2015 to December 31, 2017 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify TdP/QTP cases. We calculated the Reporting Odds Ratios (RORs) and corresponding 95% confidence intervals (95%CI) for the association between antibiotics and TdP/QTP. An association was considered to be statistically significant when the lower limit of the 95%CI was greater than 1.0. Results: A total of 2,042,801 reports (including 3,960 TdP/QTP reports) were considered, after inclusion criteria were applied. Macrolides had the greatest proportion of TdP/QTP reports. Of the 4,092 reports associated with macrolides, 108 reports (2.6%) were associated with TdP/QTP. Significant TdP/QTP RORs (95%CI) for the antibiotics were (in descending order): macrolides 14.32 (11.80-17.38), linezolid 12.41 (8.52-18.08), amikacin 11.80 (5.57-24.97), imipenem-cilastatin 6.61 (3.13-13.94), fluoroquinolones 5.68 (4.78-6.76), penicillin combinations 3.42 (2.35-4.96), and ceftriaxone 2.55 (1.41-4.62). Conclusion: This study confirms prior evidence for TdP/QTP associations with macrolides, linezolid, imipenem-cilastatin, fluoroquinolones, penicillin combinations, and ceftriaxone. This study also identifies a new association between amikacin and TdP/QTP.

"I don't want to look sick skinny": Perceptions of Body Image and Weight Loss in Hispanics Living with HIV in South Texas.

Objective: Obesity is rising in people with HIV (PLWH) and Hispanics. Both HIV and obesity are associated with cardiovascular disease morbidity and mortality. Our goal is to understand perceptions of body image and lifestyle in Hispanics with HIV to adapt interventions appropriately. Methods: We conducted semi-structured interviews with 22 Hispanic PLWH and 6 providers. Purposive sampling selected patient participants across weights and genders. Interviews were coded and analyzed using grounded theory, comparing perspectives between patients with and without obesity, and patients and providers. Results: Participants felt obesity and diabetes were "normal" in the community. Patients exhibited understanding of healthy diet and lifestyle but felt incapable of maintaining either. Traditionally Hispanic foods were blamed for local obesity prevalence. Five patients equated weight with health and weight loss with illness, and four expressed concerns that weight loss could lead to unintentional disclosure of HIV status. Participants with overweight or obesity expressed awareness of their weight and felt shamed by providers. Providers found weight loss interventions to be ineffective. Conclusion: Interventions in this population must address identified barriers: overweight/obesity as a normative value, lack of self-efficacy, cultural beliefs surrounding food, fear of HIV-associated weight loss and stigma, and provider perspectives on intervention futility.

Risk factors for the development of active methicillin-resistant Staphylococcus aureus (MRSA) infection in patients colonized with MRSA at hospital admission.

BACKGROUND: Patients who present to Veterans Affairs hospitals are screened for methicillin-resistant Staphylococcus aureus (MRSA) colonization. Those who test positive are isolated during their hospital stay. However, it is unknown which of these patients are most likely to subsequently develop active MRSA infections. METHODS: This retrospective case-control study characterized risk factors for active MRSA infection among patients colonized with MRSA at hospital admission. Potential demographic and clinical risk factors were identified using electronic queries and manual chart abstraction; data were compared by standard statistical tests, and variables with P ≤ .05 in bivariable analysis were entered into a multivariable logistic regression model. RESULTS: There were 71 cases and 213 controls. Risk factors associated with MRSA infection included diabetes mellitus with or without end organ damage (26% vs 14%, P = .02), hemiplegia (9% vs 2%, P = .01), chronic kidney disease (33% vs 20%, P = .03), postcolonization inpatient admission within 90 days (44% vs 29%, P = .03), surgery (41% vs 9%, P < .01), and dialysis (10% vs 3%, P = .02). On multivariable analysis, surgery during follow-up, dialysis during follow-up, and hemiplegia remained significant. CONCLUSIONS: Among patients with MRSA colonization, surgery or dialysis during follow-up and history of hemiplegia were associated with subsequent MRSA infection. Knowledge of these risk factors may allow for future targeted interventions to prevent MRSA infections among colonized patients.

High risk of obesity and weight gain for HIV-infected uninsured minorities.

BACKGROUND: Obesity and HIV disproportionately affect minorities and have significant health risks, but few studies have examined disparities in weight change in HIV-seropositive (HIV+) cohorts. OBJECTIVE: To determine racial and health insurance disparities in significant weight gain in a predominately Hispanic HIV+ cohort. METHODS: Our observational cohort study of 1214 nonunderweight HIV+ adults from 2007 to 2010 had significant weight gain [≥3% annual body mass index (BMI) increase] as the primary outcome. The secondary outcome was continuous BMI over time. A 4-level race-ethnicity/insurance predictor reflected the interaction between race-ethnicity and insurance: insured white (non-Hispanic), uninsured white, insured minority (Hispanic or black), or uninsured minority. Logistic and mixed-effects models adjusted for baseline BMI, age, gender, household income, HIV transmission category, antiretroviral therapy type, CD4 count, plasma HIV-1 RNA, observation months, and visit frequency. RESULTS: The cohort was 63% Hispanic and 14% black; 13.3% were insured white, 10.0% uninsured white, 40.9% insured minority, and 35.7% uninsured minority. At baseline, 37.5% were overweight, 22.1% obese. Median observation was 3.25 years. Twenty-four percent of the cohort had significant weight gain, which was more likely for uninsured minority patients than insured whites [adjusted odds ratio = 2.85, 95% confidence intervals (CIs): 1.66 to 4.90]. The rate of BMI increase in mixed-effects models was greatest for uninsured minorities. Of 455 overweight at baseline, 29% were projected to become obese in 4 years. CONCLUSIONS AND RELEVANCE: In this majority Hispanic HIV+ cohort, 60% were overweight or obese at baseline, and uninsured minority patients gained weight more rapidly. These data should prompt greater attention by HIV providers for prevention of obesity.

Mendelian randomization: potential use of genetics to enable causal inferences regarding HIV-associated biomarkers and outcomes.

PURPOSE OF REVIEW: It is unknown whether biomarkers simply correlate with or are causal for HIV-associated outcomes. Mendelian randomization is a genetic epidemiologic approach used to disentangle causation from association. Here, we discuss the potential use of Mendelian randomization for differentiating whether biomarkers are correlating with or causal for HIV-associated outcomes. RECENT FINDINGS: Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. In observational epidemiology, this refers to the use of genetic variants to estimate a causal effect between a modifiable risk factor and an outcome of interest. A formal Mendelian randomization study using a genetic marker as a proxy for the biomarker has not been conducted in the HIV field. However, in the postgenomic era, this approach is being used increasingly. Examples are evidence for the causal role of BMI in blood pressure and noncausal role of C-reactive protein in coronary heart disease. We discuss the conceptual framework, uses, and limitations of Mendelian randomization in the context of HIV infection as well as specific biomarkers (IL-6, C-reactive protein) and genetic determinants (e.g., in CCR5, chemokine, and DARC genes) that associate with HIV-related outcomes. SUMMARY: Making the distinction between correlation and causality has particular relevance when a biomarker (e.g., IL-6) is potentially modifiable, in which case a biomarker-guided targeted treatment strategy may be feasible. Although the tenets of Mendelian randomization rest on strong assumptions, and conducting a Mendelian randomization study in HIV infection presents many challenges, it may offer the potential to identify causal biomarkers for HIV-associated outcomes.

Recognizing and meeting the challenge of Chagas disease in the USA.

It is estimated that over 300,000 people with Chagas disease are living in the USA, with more than 30,000 cases of Chagas cardiomyopathy expected per year. The epidemiology of Chagas disease in Central and South America differs from that of the USA, where particular attention must focus on blood bank screening, organ donation and vertical transmission. It is essential that healthcare practitioners have heightened awareness of Chagas disease in the differential diagnosis of certain patients and are aware of recommendations for the management of these patients in the USA. Ongoing attention must focus on trials that determine whether all patients will benefit from treatment as well as studies of new agents for therapy.

Diagnostic discrimination of live attenuated influenza vaccine strains and community-acquired pathogenic strains in clinical samples.

Live vaccines can generate false-positive results on common influenza assays including reverse transcriptase-PCR (RT-PCR), culture and antigen tests. This threatens the integrity of epidemiological data and may misdirect treatment and control efforts. We report the development of RT-PCR tests that distinguish live FluMist vaccine (FMV) strains from circulating influenza strains in clinical samples. Primers were validated using influenza-positive samples from unvaccinated patients, packaged FMV, and one PCR-positive asymptomatic vaccine. Furthermore, the assay was used to experimentally test our lab's collection of influenza-positive samples from the 2004-05 and 2005-06 influenza seasons and several 2005 preseason isolates to determine the rate of vaccine-derived false-positive results under differing epidemiological conditions. Analytical and clinical validations show that the assay is both sensitive and specific. Experimental results demonstrate that 51 out of 51 influenza-positive samples collected during influenza season from ill, previously-vaccinated military personnel represent real infections with circulating strains. Finally, the assay shows that four preseason influenza-positive samples were false positives resulting from vaccine shedding. The vaccine-discriminatory RT-PCR methods described here provide the first test designed to distinguish FMV strains from circulating strains. The results show that the test is effective, and demonstrate the importance of such tests in the age of live vaccines.

Identifying influenza viruses with resequencing microarrays.

Identification of genetic variations of influenza viruses is essential for epidemic and pandemic outbreak surveillance and determination of vaccine strain selection. In this study, we combined a random amplification strategy with high-density resequencing microarray technology to demonstrate simultaneous detection and sequence-based typing of 25 geographically distributed human influenza virus strains collected in 2004 and 2005. In addition to identification, this method provided primary sequence information, which suggested that distinct lineages of influenza viruses co-circulated during the 2004-2005 season, and simultaneously identified and typed all component strains of the trivalent FluMist intranasal vaccine. The results demonstrate a novel, timely, and unbiased method for the molecular epidemiologic surveillance of influenza viruses.

Broad-spectrum respiratory tract pathogen identification using resequencing DNA microarrays.

The exponential growth of pathogen nucleic acid sequences available in public domain databases has invited their direct use in pathogen detection, identification, and surveillance strategies. DNA microarray technology has offered the potential for the direct DNA sequence analysis of a broad spectrum of pathogens of interest. However, to achieve the practical attainment of this potential, numerous technical issues, especially nucleic acid amplification, probe specificity, and interpretation strategies of sequence detection, need to be addressed. In this report, we demonstrate an approach that combines the use of a custom-designed Affymetrix resequencing Respiratory Pathogen Microarray (RPM v.1) with methods for microbial nucleic acid enrichment, random nucleic acid amplification, and automated sequence similarity searching for broad-spectrum respiratory pathogen surveillance. Successful proof-of-concept experiments, utilizing clinical samples obtained from patients presenting adenovirus or influenza virus-induced febrile respiratory illness (FRI), demonstrate the ability of this approach for correct species- and strain-level identification with unambiguous statistical interpretation at clinically relevant sensitivity levels. Our results underscore the feasibility of using this approach to expedite the early surveillance of diseases, and provide new information on the incidence of multiple pathogens.

Use of resequencing oligonucleotide microarrays for identification of Streptococcus pyogenes and associated antibiotic resistance determinants.

Group A streptococci (GAS) are responsible for a wide variety of human infections associated with considerable morbidity and mortality. Ever since the first systematic effort by Lancefield to group Streptococcus species by M protein variants, the detection and characterization of Streptococcus by different methods have been an evolving process. The ideal assay for GAS identification not only would provide quick and accurate diagnostic results but also would reveal antibiotic resistance patterns and genotype information, aiding not only in treatment but in epidemiologic assessment as well. The oligonucleotide microarray is a promising new technology which could potentially address this need. In this study, we evaluated the usefulness of oligonucleotide resequencing microarrays for identifying GAS and its associated antibiotic resistance markers. We demonstrated an assay platform that combines the use of resequencing DNA microarrays with either random nucleic acid amplification or multiplex PCR for GAS detection. When detecting Streptococcus pyogenes from coded clinical samples, this approach demonstrated an excellent concordance with a more established culture method. To this end, we showed the potential of resequencing microarrays for efficient and accurate detection of GAS and its associated antibiotic resistance markers with the benefit of sequencing information from microarray analysis.

HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels.

Studies in humans and in experimental models of HIV-1 infection indicate an important role for monocyte chemoattractant protein-1 (MCP-1; also known as CC chemokine ligand 2), a potent chemoattractant and activator of mononuclear phagocytes (MP) in the pathogenesis of HIV-associated dementia (HAD). We determined the influence of genetic variation in MCP-1 on HIV-1 pathogenesis in large cohorts of HIV-1-infected adults and children. In adults, homozygosity for the MCP-1 -2578G allele was associated with a 50% reduction in the risk of acquiring HIV-1. However, once HIV-1 infection was established, this same MCP-1 genotype was associated with accelerated disease progression and a 4.5-fold increased risk of HAD. We examined the molecular and cellular basis for these genotype-phenotype associations and found that the mutant MCP-1 -2578G allele conferred greater transcriptional activity via differential DNA-protein interactions, enhanced protein production in vitro, increased serum MCP-1 levels, as well as MP infiltration into tissues. Thus, MCP-1 expression had a two-edged role in HIV-1 infection: it afforded partial protection from viral infection, but during infection, its proinflammatory properties and ability to up-regulate HIV-1 replication collectively may contribute to accelerated disease progression and increased risk of dementia. Our findings suggest that MCP-1 antagonists may be useful in HIV-1 infection, especially for HAD, and that HIV+ individuals possessing the MCP-1 -2578G allele may benefit from early initiation of antiretroviral drugs that effectively cross the blood-brain barrier. In a broader context, the MCP-1 -2578G allele may serve as a genetic determinant of outcome of other disease states in which MP-mediated tissue injury is central to disease pathogenesis.