Obesity and infectious diseases: pathophysiology and epidemiology of a double pandemic condition.

The current pandemic due to widespread SARS-CoV-19 infection has again highlighted the role of obesity, whose global prevalence increased up to 13%, as a risk factor for both susceptibility to infections and the occurrence of a more severe disease course. To date, this association has not been sufficiently explored. Obesity-related susceptibility to infectious diseases is mostly thought to be due to an impairment of both innate and adaptive immune responses and vitamin D deficiency. Several cofactors can indirectly favour the onset and/or worsening of infectious diseases, such as impairment of respiratory mechanics, skin and subcutaneous tissue homoeostasis, obesity-related comorbidities and inappropriate antimicrobial therapy. Subjects with obesity have a higher incidence of cutaneous infections, probably due to changes in skin barrier functions and wound healing. Excess weight is also associated with an increased risk of urinary tract infection and its recurrence, as well as with a higher prevalence of both lower and higher respiratory tract infections. Moreover, patients with obesity appear to have an increased risk of surgical site infections when undergoing general, orthopaedic, gynaecological, and bariatric surgery. Data concerning the different infectious diseases related to obesity are rather limited since anthropometric parameters are usually poorly recorded. Furthermore, specific therapeutic protocols in subjects with obesity are lacking, especially regarding antibiotic therapy and further supplements. This review summarizes etiopathogenetic and epidemiological evidence and highlights areas of uncertainty in the field of infectious diseases and obesity, which require further research. It is important to raise public awareness of this additional risk related to obesity and to raise awareness among the scientific community to develop specific clinical protocols for subjects with obesity.

When and why direct transmission models can be used for environmentally persistent pathogens.

Variants of the susceptible-infected-removed (SIR) model of Kermack & McKendrick (1927) enjoy wide application in epidemiology, offering simple yet powerful inferential and predictive tools in the study of diverse infectious diseases across human, animal and plant populations. Direct transmission models (DTM) are a subset of these that treat the processes of disease transmission as comprising a series of discrete instantaneous events. Infections transmitted indirectly by persistent environmental pathogens, however, are examples where a DTM description might fail and are perhaps better described by models that comprise explicit environmental transmission routes, so-called environmental transmission models (ETM). In this paper we discuss the stochastic susceptible-exposed-infected-removed (SEIR) DTM and susceptible-exposed-infected-removed-pathogen (SEIR-P) ETM and we show that the former is the timescale separation limit of the latter, with ETM host-disease dynamics increasingly resembling those of a DTM when the pathogen's characteristic timescale is shortened, relative to that of the host population. Using graphical posterior predictive checks (GPPC), we investigate the validity of the SEIR model when fitted to simulated SEIR-P host infection and removal times. Such analyses demonstrate how, in many cases, the SEIR model is robust to departure from direct transmission. Finally, we present a case study of white spot disease (WSD) in penaeid shrimp with rates of environmental transmission and pathogen decay (SEIR-P model parameters) estimated using published results of experiments. Using SEIR and SEIR-P simulations of a hypothetical WSD outbreak management scenario, we demonstrate how relative shortening of the pathogen timescale comes about in practice. With atttempts to remove diseased shrimp from the population every 24h, we see SEIR and SEIR-P model outputs closely conincide. However, when removals are 6-hourly, the two models' mean outputs diverge, with distinct predictions of outbreak size and duration.

The Role of Extracellular Vesicles from Human Macrophages on Host-Pathogen Interaction.

The nano-sized membrane enclosed extracellular vesicles (EVs) released by virtually all cell types play an essential role in intercellular communication via delivering bio-molecules, such as nucleic acids, proteins, lipids, and other molecules to recipient cells. By mediating an active and steady-state cell-to-cell communication, EVs contribute to regulating and preserving cellular homeostasis. On the other hand, EVs can also spread pathogen-derived molecules during infections, subverting the host immune responses during infections and thus worsening pathophysiological processes. In recent years, the biological functioning of EVs has become a widespread research field in basic and clinical branches of medical sciences due to their potential role in therapeutic applications for several diseases. This review aims to summarize the main recent findings regarding the implication of EVs shed by human macrophages (MΦ-EVs) and how they can modulate the host immune response to control or increase the damage caused by infectious agents. We will also present the methods used to describe MΦ-EVs, as well as the potential of these EVs as disease diagnostic tools for some human pathogens. We believe that an in-depth understanding of the host-pathogen interactions mediated by MΦ-EVs may trigger the development of innovative therapeutic strategies against infectious diseases.

Lymphopenia in hospitalized patients and its relationship with severity of illness and mortality.

BACKGROUND: Lymphopenia is associated with various pathologies such as sepsis, burns, trauma, general anesthesia and major surgeries. All these pathologies are clinically expressed by the so-called Systemic Inflammatory Response Syndrome which does not include lymphopenia into defining criteria. The main objective of this work was to analyze the diagnosis of patients admitted to a hospital related to lymphopenia during hospital stay. In addition, we investigated the relationship of lymphopenia with the four levels of the Severity of Illness (SOI) and the Risk of Mortality (ROM). METHOD AND FINDINGS: Lymphopenia was defined as Absolute Lymphocyte Count (ALC) <1.0 x109/L. ALC were analyzed every day since admission. The four levels (minor, moderate, major and extreme risk) of both SOI and ROM were assessed. A total of 58,260 hospital admissions were analyzed. More than 41% of the patients had lymphopenia during hospital stay. The mean time to death was shorter among patients with lymphopenia on admission 65.6 days (CI95%, 57.3-73.8) vs 89.9 (CI95%, 82.4-97.4), P<0.001. Also, patients with lymphopenia during hospital stay had a shorter time to the mortality, 67.5 (CI95%, 61.1-73.9) vs 96.9 (CI95%, 92.6-101.2), P<0.001. CONCLUSIONS: Lymphopenia had a high prevalence in hospitalized patients with greater relevance in infectious pathologies. Lymphopenia was related and clearly predicts SOI and ROM at the time of admission, and should be considered as clinical diagnostic criteria to define SIRS.

Erythematous ear with drainage.

This case reminded us that not every moist, erythematous, crusting eruption is purely infectious.

Fluid Dynamics of Respiratory Infectious Diseases.

The host-to-host transmission of respiratory infectious diseases is fundamentally enabled by the interaction of pathogens with a variety of fluids (gas or liquid) that shape pathogen encapsulation and emission, transport and persistence in the environment, and new host invasion and infection. Deciphering the mechanisms and fluid properties that govern and promote these steps of pathogen transmission will enable better risk assessment and infection control strategies, and may reveal previously underappreciated ways in which the pathogens might actually adapt to or manipulate the physical and chemical characteristics of these carrier fluids to benefit their own transmission. In this article, I review our current understanding of the mechanisms shaping the fluid dynamics of respiratory infectious diseases.

Blood Levels of Galectin-9, an Immuno-Regulating Molecule, Reflect the Severity for the Acute and Chronic Infectious Diseases.

Galectin-9 (Gal-9) is a ß-galactoside-binding lectin capable of promoting or suppressing the progression of infectious diseases. This protein is susceptible to cleavage of its linker-peptides by several proteases, and the resulting cleaved forms, N-terminal carbohydrate recognition domain (CRD) and C-terminal CRD, bind to various glycans. It has been suggested that full-length (FL)-Gal-9 and the truncated (Tr)-Gal-9s could exert different functions from one another via their different glycan-binding activities. We propose that FL-Gal-9 regulates the pathogenesis of infectious diseases, including human immunodeficiency virus (HIV) infection, HIV co-infected with opportunistic infection (HIV/OI), dengue, malaria, leptospirosis, and tuberculosis (TB). We also suggest that the blood levels of FL-Gal-9 reflect the severity of dengue, malaria, and HIV/OI, and those of Tr-Gal-9 markedly reflect the severity of HIV/OI. Recently, matrix metallopeptidase-9 (MMP-9) was suggested to be an indicator of respiratory failure from coronavirus disease 2019 (COVID-19) as well as useful for differentiating pulmonary from extrapulmonary TB. The protease cleavage of FL-Gal-9 may lead to uncontrolled hyper-immune activation, including a cytokine storm. In summary, Gal-9 has potential to reflect the disease severity for the acute and chronic infectious diseases.

Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease.

Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.

Cardiac Arrest Risk During Acute Infections: Systemic Inflammation Directly Prolongs QTc Interval via Cytokine-Mediated Effects on Potassium Channel Expression.

BACKGROUND: During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. METHODS: We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. RESULTS: In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. CONCLUSIONS: During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

Immune Dysfunction in Uremia 2020.

Cardiovascular disease and infections are major causes for the high incidence of morbidity and mortality of patients with chronic kidney disease. Both complications are directly or indirectly associated with disturbed functions or altered apoptotic rates of polymorphonuclear leukocytes, monocytes, lymphocytes, and dendritic cells. Normal responses of immune cells can be reduced, leading to infectious diseases or pre-activated/primed, giving rise to inflammation and subsequently to cardiovascular disease. This review summarizes the impact of kidney dysfunction on the immune system. Renal failure results in disturbed renal metabolic activities with reduced renin, erythropoietin, and vitamin D production, which adversely affects the immune system. Decreased kidney function also leads to reduced glomerular filtration and the retention of uremic toxins. A large number of uremic toxins with detrimental effects on immune cells have been identified. Besides small water-soluble and protein-bound compounds originating from the intestinal microbiome, several molecules in the middle molecular range, e.g., immunoglobulin light chains, retinol-binding protein, the neuropeptides Met-enkephalin and neuropeptide Y, endothelin-1, and the adipokines leptin and resistin, adversely affect immune cells. Posttranslational modifications such as carbamoylation, advanced glycation products, and oxidative modifications contribute to uremic toxicity. Furthermore, high-density lipoprotein from uremic patients has an altered protein profile and thereby loses its anti-inflammatory properties.

Polymeric nanostructure vaccines: applications and challenges.

INTRODUCTION: The use of biocompatible polymers, from natural or synthetic sources, opened the door for a new era in vaccine research. These polymers offer the possibility to develop nanostructured antigen carriers that can be easily internalized by antigen-presenting cells, due to their nanometric size. Besides, the incorporation of an adjuvant allows increasing and modulating the immune response for both, polymers with or without self-adjuvant properties. AREAS COVERED: The historical background and the state-of-the-art in the use of polymers as antigen carriers are addressed in the first part of this review. Then, an overview of the immunology of vaccination is provided. Finally, the main advances in the field, based on the prototypes that are licensed or undergoing clinical trials, but also the challenges that limit the translation of many polymer-based nanostructure vaccines with promising preclinical results, are discussed. EXPERT OPINION: Polymeric nanostructured vaccines have a great potential in modern vaccinology. However, the translation into the market is hampered due to several limitations. Studies on correlates of protection to provide suitable biomarkers, new and better methods of synthesis to produce more reproducible nanovaccines, a deeper knowledge in the immune system and in the physiopathology of the infectious diseases will surely improve and boost the field in the next years.

Predictors of infection-related rehospitalization in heart failure patients and its impact on long-term survival.

BACKGROUND: Infection is the most common non-cardiovascular cause of re-hospitalizations for heart failure patients. We therefore investigated the predictors of infection-related re-hospitalization (IRRH) in heart failure patients and its impact on long-term survival. METHODS AND RESULTS: We prospectively recruited 622 patients after the index hospitalization for decompensated heart fail with primary endpoints of IRRH and all-cause mortality. During follow-up of 3.9 ±â€Š2.7 years, IRRHs occurred in 104 (16.7%) patients. Of the 104 patients who experienced IRRHs, the time from the index hospitalization to IRRH was 1.0 (interquartile range: 0.4-2.6) years. Independent predictors of IRRH were age (hazard ratio: 1.02, 95% confidence interval: 1.01-1.04), diabetes mellitus (2.12, 1.42-3.17), not taking angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (1.67, 1.01-2.78), needing maintenance therapy with a loop diuretic (2.10, 1.36-3.26), hemoglobin levels (0.87, 0.79-0.96), and estimated glomerular filtration rates (eGFRs) (0.99, 0.98-0.99). IRRH independently predicted all-cause mortality (1.99, 1.32-2.98) after adjusting for age, body mass index, New York Heart Association functional class, chronic obstructive pulmonary disease, brain natriuretic peptide, hemoglobin, and eGFR. The increased risk of death associated with IRRHs was predominantly for lower respiratory tract infections (3.71, 2.28-6.04), urogenital tract infections (2.83, 1.32-6.10), and sepsis (3.26, 1.20-8.85). CONCLUSION: IRRHs in patients discharged for acute decompensated heart fail independently predicted worse long-term survival. We further identified independent predictors of IRRHs. These findings warrant future studies for tackling IRRH.

Infection-Related Hospitalization in Heart Failure With Reduced Ejection Fraction: A Prospective Observational Cohort Study.

BACKGROUND: Hospitalization is a common adverse event in people with heart failure and reduced ejection fraction, yet is often not primarily due to decompensated heart failure (HF). We investigated the long-term prognosis following infection-related hospitalization. METHODS: We conducted a prospective observational cohort study of 711 people with heart failure and reduced ejection fraction recruited from 4 specialist HF clinics in the United Kingdom. All hospitalization episodes (n=1568) were recorded and categorized as primarily due to decompensated HF, other cardiovascular disease, infection-related, or other noncardiovascular disease. Survival was determined after the first hospitalization. RESULTS: During 2900 patient-years of follow-up, there were a total of 14 686 hospital days. At least one hospitalization occurred in 467 people (66%); 25% of first hospitalizations were primarily due to infection and these were not associated with typical signs including tachycardia and pyrexia. Compared with other categories of hospitalization, infection-related was associated with older age, lower serum albumin, higher blood neutrophil counts, and greater prevalence of chronic obstructive pulmonary disease at recruitment. Median survival after first infection-related hospitalization was 18.6 months, comparable to that after first decompensated HF hospitalization, even after age-sex adjustment. The burden of all-cause rehospitalization was comparable irrespective of the category of first hospitalization, but infection more commonly caused re-hospitalization after index infection hospitalization. CONCLUSIONS: Infection is a common driver of hospitalization in heart failure and reduced ejection fraction and often presents without classical signs. It is associated with high mortality rates, comparable to decompensated HF, and a major burden of rehospitalization caused by recurrent episodes of infection.

N-Myristoyltransferase as a Glycine and Lysine Myristoyltransferase in Cancer, Immunity, and Infections.

Protein myristoylation, the addition of a 14-carbon saturated acyl group, is an abundant modification implicated in biological events as diverse as development, immunity, oncogenesis, and infections. N-Myristoyltransferase (NMT) is the enzyme that catalyzes this modification. Many elegant studies have established the rules guiding the catalysis including substrate amino acid sequence requirements with the indispensable N-terminal glycine, and a co-translational mode of action. Recent advances in technology such as the development of fatty acid analogs, small molecule inhibitors, and new proteomic strategies, allowed a deeper insight into the NMT activity and function. Here we focus on discussing recent work demonstrating that NMT is also a lysine myristoyltransferase, the enzyme's regulation by a previously unnoticed solvent channel, and the mechanism of NMT regulation by protein-protein interactions. We also summarize recent findings on NMT's role in cancer, immunity, and infections and the advances in pharmacological targeting of myristoylation. Our analyses highlight opportunities for further understanding and discoveries.

Fatal pediatric Stevens-Johnson syndrome/toxic epidermal necrolysis: Three case reports.

RATIONALE: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are extremely rare but potentially life-threatening disorders. We presented 3 fatal pediatric SJS/TEN cases. PATIENT CONCERNS: Our patients had some severe complications such as septic shock, respiratory failure and obliterans bronchiolitis (BO) etc. DIAGNOSIS:: Three patients diagnosed SJS/TEN with clinical symptoms that were triggered by antibiotics, nonsteroidal anti-inflammatory drugs, previous infection, or neoplasms. INTERVENTIONS: All of them accepted mechanical ventilation, intravenous immunoglobulin (IVIG), blood transfusion, glucocorticoid, and multi-anti-infectious therapy. OUTCOMES: They all died because of out-of-control severe infections. In Patient 1, he died 6 days after being admitted to the PICU on the 28th day from onset. In Patient 2, he died on the 211th day from the onset of illness during the third time of PICU admission. In Patient 3, she died 12 days after PICU admission on the 87th day from onset. LESSONS: We should be aware that mucosal damage occurs on the skin and within the mucosa of visceral organs, leading to the occurrence of bronchiectasia, BO, enterocolitis, acute renal failure, and severe secondary infections. Establish a clinically predictive score that includes severe infection for pediatric patients to evaluate the risk of mortality in children in order to improve poor outcomes.

A Bayesian classification model for discriminating common infectious diseases in Zhejiang province, China.

To develop a classification model for accurately discriminating common infectious diseases in Zhejiang province, China.Symptoms and signs, abnormal lab test results, epidemiological features, as well as the incidence rates were treated as predictors, and were collected from the published literature and a national surveillance system of infectious disease. A classification model was established using naïve Bayesian classifier. Dataset from historical outbreaks was applied for model validation, while sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC) and M-index were presented.A total of 146 predictors were included in the classification model, for discriminating 25 common infectious diseases. The sensitivity ranged from 44.44% for hepatitis E to 96.67% for measles. The specificity varied from 96.36% for dengue fever to 100% for 5 diseases. The median of total accuracy was 97.41% (range: 93.85%-99.04%). The AUCs exceeded 0.98 in 11 of 12 diseases, except in dengue fever (0.613). The M-index was 0.960 (95%CI 0.941-0.978).A novel classification model was constructed based on Bayesian approach to discriminate common infectious diseases in Zhejiang province, China. After entering symptoms and signs, abnormal lab test results, epidemiological features and city of disease origin, an output list of possible diseases ranked according to the calculated probabilities can be provided. The discrimination performance was reasonably good, making it useful in epidemiological applications.

Syndromic surveillance using ambulance transfer data in Tokyo, Japan.

Bioterrorism attacks become more probable when important high-profile international or political events are held, such as G7 summit meetings or mass gathering events including Olympic and Paralympic games and FIFA World Cup tournaments. Outbreaks of infectious disease and widespread incidents of food poisoning are also public health concerns at such times. In Japan, the Tokyo Metropolitan Government operates Ambulance Transfer Syndromic Surveillance (ATSS), which can help monitor such incidents. The present study presents and assesses the ATSS framework. During the study period of October 2017 through November 2018, we monitored 33 areas for symptoms of 9 categories: vomiting/nausea, dizziness, palpitation, unconsciousness, breathing disorder, fever, spasm/paralysis, collapse/weakness, and bloody emesis/nasal hemorrhage. Among all symptoms, we found 9929 low-level aberrations, 2537 medium-level aberrations, and 577 high-level aberrations, with respective frequencies of 9.2%, 2.3%, and 0.5%. Of those, Tokyo Metropolitan Institute of Public Health reported the information to Tokyo Metropolitan Government 28 times during the period. Of the 28 identified clusters, Tokyo Metropolitan Government judged the necessity for investigating 7. All of those were investigated at hospitals by the jurisdictional public health center. Because ATSS covers almost the entire Tokyo metropolitan area, with about 13.8 million residents, it is definitely the largest syndromic surveillance in the world.

Human body cell membranes and antigen control.

The variables involved in the initiation and operation of the human immune system are considered. It is shown that the number of variations associated with disease and other detrimental conditions exceeds the number of lymphocyte cells available for control of these conditions. It is proposed that the immune system functions by changes in the ionic strength of metabolic fluids which in turn control the formation and stability of cell membranes. The application of these conditions to the control of bacterial, virus particle and other antigens is detailed. Observations supporting the proposals are presented.