Outcome Of Infectious Diseases Research Articles

Effect of Cigarette Smoking on Bacterial Infections: A Review Study

Background: In spite of great advances in the prevention of bacterial infections, they are still considered the most common reason for mortality worldwide. In accordance with the data from the World Health Organization (WHO), around 15% of pediatric mortality was caused by bacterial infections in 2017. Since cigarette smoke can cause serious damage to organs such as the respiratory system and weakening of the immune system, the aim of the present review study was to investigate the effects of cigarette smoking on various bacterial pneumonia. Methods: The present review study was performed on 90 articles obtained through searching in ScienceDirect, Scopus, PubMed, and Google Scholar using keywords such as bacterial pneumonia, Staphylococcus, Streptococcus, Haemophilus, Pseudomonas, Legionella, Mycoplasma, Chlamydia, tuberculosis, and cigarette. Results: Different results of previous studies indicated that given the detrimental effect of cigarettes on the respiratory and immune system of individuals, cigarette smoking affects the prognosis and outcome of infectious diseases. Disease severity, requiring hospitalization at both general and intensive care units, and mortality rate vary across these patients, thereby challenging the treatment. Thus, the cessation of cigarette smoking may help improve the respiratory system function. Conclusion: Given contradictions in the results of previous studies, exposure to cigarette smoke affects the respiratory system and increases the severity of bacterial pneumonia.

Mupirocin enhances the biofilm formation of Staphylococcus epidermidis in an atlE-dependent manner

The pathogenicity of Staphylococcus epidermidis is largely attributed to its exceptional ability to form biofilms. Here, we report that mupirocin, an antimicrobial agent widely used for staphylococcal decolonization and anti-infection, strongly stimulates the biofilm formation of S. epidermidis. Although the polysaccharide intercellular adhesin (PIA) production was unaffected, mupirocin significantly facilitated extracellular DNA (eDNA) release by accelerating autolysis, thereby positively triggering cell surface attachment and intercellular agglomeration during biofilm development. Mechanistically, mupirocin regulated the expression of genes encoding for the autolysin AtlE as well as the programmed cell death system CidA-LrgAB. Critically, through gene knockout, we found out that deletion of atlE, but not cidA or lrgA, abolished the enhancement of biofilm formation and eDNA release in response to mupirocin treatment, indicating that atlE is required for this effect. In Triton X-100 induced autolysis assay, mupirocin treated atlE mutant displayed a slower autolysis rate compared with the wild-type strain and complementary strain. Therefore, we concluded that subinhibitory concentrations of mupirocin enhance the biofilm formation of S. epidermidis in an atlE dependent manner. This induction effect could conceivably be responsible for some of the more unfavorable outcomes of infectious diseases.

Distinct roles of CD4 +and CD8 +Tregs in regulating human autoreactive T cells, B cells, and antibodies in genetically engineered tonsil organoid system

Abstract CD4 +and CD8 +regulatory T cells (Treg) are critical for maintaining immune tolerance, and alternations in number and function are associated with detrimental outcomes in infectious and autoimmune diseases. Despite their importance, their distinct roles and mechanisms in regulating self-tolerance need to be better characterized in humans. Here we analyzed the relative contribution of CD4 +and CD8 +Tregs to control autoreactive T cells, B cells, and antibodies in an entirely human tonsil organoid system in vitro. We disrupted their suppressive functions by knocking out FOXP3 and GZMB genes using CRISPR/Cas9 technology. Normally tonsil organoids make robust antibody and cellular responses to live attenuated flu vaccine, but not to autoantigens. In contrast, FOXP3 KO tonsil organoids produced autoantibodies when stimulated with a panel of classical autoantigens, including double-stranded DNA and others. We also detected increased CD8 +T cells specific for autoantigens, including SMCY antigen. With the GZMB KO, we found a marked increase in follicular helper T cells and autoreactive CD4 +and CD8 +T cells. Interestingly the GZMB KO tonsils showed an expansion of plasmablasts, but only a low level of autoantibodies and autoreactive B cells was detected. This indicates that CD8 +Tregs control the early T and B cell activation but not autoantibody production. Moreover, knocking out FOXP3 generated high-affinity HA-specific antibodies in tonsil organoids compared to control, indicating that CD4 +Tregs are a key checkpoint for high-affinity antibodies and the production of autoantibodies. We conclude that CD8 +and CD4 +Tregs have distinct and complementary roles in regulating cellular and humoral responses and preventing autoimmunity.

Health inequalities in infectious diseases: a systematic overview of reviews

ObjectivesThe aim of this systematic overview of reviews was to synthesise available evidence on inequalities in infectious disease based on three dimensions of inequalities; inclusion health groups, protected characteristics and...

Invited Commentary: To Make Long-Term Gains Against Infection Inequity, Infectious Disease Epidemiology Needs to Develop a More Sociological Imagination.

In a recent article in the Journal, Noppert et al. (Am J Epidemiol. 2023;192(3):475-482) articulated in detail the mechanisms connecting high-level "fundamental social causes" of health inequity to inequitable infectious disease outcomes, including infection, severe disease, and death. In this commentary, we argue that while intensive focus on intervening mechanisms is welcome and necessary, it cannot occur in isolation from examination of the way that fundamental social causes-including racism, socioeconomic inequity, and social stigma-sustain infection inequities even when intervening mechanisms are addressed. We build on the taxonomy of intervening mechanisms laid out by Noppert et al. to create a road map for strengthening the connection between fundamental cause theory and infectious disease epidemiology and discuss its implications for future research and intervention.

Burden of COVID-19 disease and vaccine coverages in Apulian splenectomized patients: A retrospective observational study.

Splenectomy/asplenia is a condition associated with immune-compromission and specific vaccines are recommended for these patients, including the anti-COVID-19 vaccine. Among the high-risk group for which vaccination was prioritized in Italy, the immunocompromised patients after therapies or treatments were included. The Apulian regional archive of hospital discharge forms was used to define the list of splenectomized Apulian inhabitants, considering data from 2015 through 2020. The overall vaccination status of asplenic patients was assessed via data collected from the Regional Immunization Database. The history of SARS-CoV-2 infection and the infectious disease outcomes were extracted from the Italian Institute of Health platform "Integrated surveillance of COVID-19 cases in Italy". 1219 Apulian splenectomized inhabitants were included; the incidence rate of SARS-CoV-2 infection was 15.0 per 100 persons-year with a proportion of re-infection equal to 6.4%; the proportion of hospitalization was 2.9%, with a case-fatality rate of 2.6%. The vaccine coverage (VC) for the anti-COVID-19 vaccine basal routine was 64.2%, for the first booster dose was 15.4%, and for the second booster dose was 0.6%. A multifactorial approach is needed to increase the vaccination uptake in this sub-group population and to increase the awareness of the asplenia-related risks to patients and health personnel.

Accounting for historical injustices in mathematical models of infectious disease transmission: An analytic overview

Differences in infectious disease risk, acquisition, and severity arise from intersectional systems of oppression and resulting historical injustices that shape individual behavior and circumstance. We define historical injustices as distinct events and policies that arise out of intersectional systems of oppression. We view historical injustices as a medium through which structural forces affect health both directly and indirectly, and are thus important to study in the context of infectious disease disparities. In this critical analysis we aim to highlight the importance of incorporating historical injustices into mathematical models of infectious disease transmission and provide context on the methodologies to do so. We offer two illustrations of elements of model building (i.e., parameterization, validation and calibration) that can allow for a better understanding of health disparities in infectious disease outcomes. Mathematical models that do not recognize the historical forces that underlie infectious disease dynamics inevitably lead to the individualization of our focus and the recommendation of untenable individual-behavioral prescriptions to address the burden of infectious disease.

Age of First Overweight and Obesity, COVID-19 and Long COVID in Two British Birth Cohorts

Longer exposure to obesity, and thus a longer period in an inflamed state, may increase susceptibility to infectious diseases and worsen severity. Previous cross-sectional work finds higher BMI is related to worse COVID-19 outcomes, but less is known about associations with BMI across adulthood. To examine this, we used body mass index (BMI) collected through adulthood in the 1958 National Child Development Study (NCDS) and the 1970 British Cohort Study (BCS70). Participants were grouped by the age they were first overweight (> 25 kg/m2) and obese (> 30 kg/m2). Logistic regression was used to assess associations with COVID-19 (self-reported and serology-confirmed), severity (hospital admission and contact with health services) and long-COVID reported at ages 62 (NCDS) and 50 (BCS70). An earlier age of obesity and overweight, compared to those who never became obese or overweight, was associated with increased odds of adverse COVID-19 outcomes, but results were mixed and often underpowered. Those with early exposure to obesity were over twice as likely in NCDS (odds ratio (OR) 2.15, 95% confidence interval (CI) 1.17–4.00) and three times as likely in BCS70 (OR 3.01, 95% CI 1.74–5.22) to have long COVID. In NCDS they were also over four times as likely to be admitted to hospital (OR 4.69, 95% CI 1.64–13.39). Most associations were somewhat explained by contemporaneous BMI or reported health, diabetes or hypertension; however, the association with hospital admission in NCDS remained. An earlier age of obesity onset is related to COVID-19 outcomes in later life, providing evidence of the long-term impact of raised BMI on infectious disease outcomes in midlife.

Adverse pregnancy outcomes of cancer survivors and infectious disease in their infants: The Japan Environment and Children's Study.

Birth cohort studies examining pregnancy and infant outcomes among adolescent and young adult (AYA) cancer survivors have been limited. The present study examined whether AYA cancer affects pregnancy outcomes of survivors and infectious diseases in their infants up to 1 year of age. Pregnant women were recruited for the Japan Environment and Children's Study, a nationwide, large-scale, prospective cohort study. The present study included 103,060 pregnant women and collected questionnaire-based data during the first and second/third trimester, and at 1 month, 6 months and 1 year after delivery. Adverse pregnancy outcomes and infectious diseases in infants up to 1 year of age were compared between AYA cancer survivors and pregnant women without a history of cancer using binominal logistic regression analyses and a multiple imputation method. Of 99,816 participants (3,244 were missing), 1,102 (1.1%) had a cancer history, including 812 participants (0.8%) with a history of cervical cancer. Among cervical cancer survivors, the adjusted (a)ORs were as follows: 3.25 (95% CI, 2.31-4.57; q=0.00) for a preterm birth <34 weeks' gestation; 2.82 (95% CI, 2.31-3.44; q=0.00) for a preterm birth <37 weeks' gestation; and 1.67 (95% CI, 1.36-2.06; q=0.00) for premature rupture of the membrane. Among the other cancer survivors, the aOR for caesarean section was 1.43 (95% CI, 1.10-1.87; q=0.0). Furthermore, lower respiratory tract inflammation in 1-year-old infants born by vaginal delivery increased significantly in cases with a history of cervical cancer (aOR, 1.77; 95% CI, 1.33-2.36; q=0.00). The present study identified the risk of lower respiratory tract inflammation in 1-year-old infants born by vaginal delivery in cervical cancer survivors for the first time. In addition, the frequency of caesarean section increased in all cancer survivors. No risk of congenital anomalies or other infections were found in the total group of cancer survivors.

Monocyte Distribution Width as a Diagnostic Marker for Infection: A Systematic Review and Meta-analysis

Monocyte Distribution Width (MDW) is an emerging biomarker for infection. It is easily and quickly available as part of the complete blood count (CBC), which is routinely performed upon hospital admission. The increasing availability and promising results of MDW as biomarker in sepsis has prompted an expansion of its use to other infectious diseases. What is the diagnostic performance of MDW across multiple infectious disease outcomes and care settings? A systematic review of the diagnostic performance of MDW across multiple infectious disease outcomes was conducted by searching PubMed, EMBASE, Scopus, and Web of Science through February 4th, 2022. Meta-analysis was performed for outcomes with three or more reports identified (sepsis and COVID-19). Diagnostic performance measures were calculated for individual studies with pooled estimates created by linear mixed effects models. We identified 29 studies meeting inclusion criteria. Most examined sepsis (19 studies) and COVID-19 (6 studies). Pooled estimates of diagnostic performance for sepsis differed by reference standard (Sepsis-2 vs Sepsis-3 criteria) and tube anticoagulant used and ranged from an area under the receiver operating characteristic curve (AUC) of 0.74 to 0.94, with mean sensitivity of 0.69 to 0.79 and mean specificity of 0.57 to 0.86. For COVID-19, the pooled AUC of MDW was 0.76, mean sensitivity was 0.79, and mean specificity was 0.59. MDW exhibited good diagnostic performance for sepsis and COVID-19. Diagnostic thresholds for sepsis should be chosen with consideration of reference standard and tube type used. PROSPERO 2022 CRD42020210074.

Identifying Pathogen and Allele Type Simultaneously in a Single Well Using Droplet Digital PCR.

In the transmission control of chronic and untreatable livestock diseases such as bovine leukemia virus (BLV) infection, the removal of viral superspreaders is a fundamental approach. On the other hand, selective breeding of cattle with BLV-resistant capacity is also critical for reducing the viral damage to productivity by keeping infected cattle. To provide a way of measuring BLV proviral load (PVL) and identifying susceptible/resistant cattle simply and rapidly, we developed a fourplex droplet digital PCR method targeting the BLV pol gene, BLV-susceptible bovine major histocompatibility complex (BoLA)-DRB3*016:01 allele, resistant DRB3*009:02 allele, and housekeeping RPP30 gene (IPATS-BLV). IPATS-BLV successfully measured the percentage of BLV-infected cells and determined allele types precisely. Furthermore, it discriminated homozygous from heterozygous carriers. Using this method to determine the impact of carrying these alleles on the BLV PVL, we found DRB3*009:02-carrying cattle could suppress the PVL to a low or undetectable level, even with the presence of a susceptible heterozygous allele. Although the population of DRB3*016:01-carrying cattle showed significantly higher PVLs compared with cattle carrying other alleles, their individual PVLs were highly variable. Because of the simplicity and speed of this single-well assay, our method has the potential of being a suitable platform for the combined diagnosis of pathogen level and host biomarkers in other infectious diseases satisfying the two following characteristics of disease outcomes: (i) pathogen level acts as a critical maker of disease progression; and (ii) impactful disease-related host genetic biomarkers are already identified. IMPORTANCE While pathogen-level quantification is an important diagnostic of disease severity and transmissibility, disease-related host biomarkers are also useful in predicting outcomes in infectious diseases. In this study, we demonstrate that combined proviral load (PVL) and host biomarker diagnostics can be used to detect bovine leukemia virus (BLV) infection, which has a negative economic impact on the cattle industry. We developed a fourplex droplet digital PCR assay for PVL of BLV and susceptible and resistant host genes named IPATS-BLV. IPATS-BLV has inherent merits in measuring PVL and identifying susceptible and resistant cattle with superior simplicity and speed because of a single-well assay. Our new laboratory technique contributes to strengthening risk-based herd management used to control within-herd BLV transmission. Furthermore, this assay design potentially improves the diagnostics of other infectious diseases by combining the pathogen level and disease-related host genetic biomarker to predict disease outcomes.

Associations between livestock keeping, morbidity and nutritional status of children and women in low- and middle-income countries: a systematic review.

Livestock keeping can positively influence the nutritional status of populations and households through increased consumption of animal-source foods (ASF) and other indirect pathways, but can also adversely affect health by increasing the risk of diseases. We conducted a systematic review synthesising the current state of knowledge on the associations among livestock keeping, infectious disease and the nutritional status of children under 5 years and women of reproductive age in low- and lower-middle-income countries (LMICs). A comprehensive search of 12 electronic databases and grey literature sources published from 1991 to the end of December 2020 was conducted. Investigations exploring relationships between livestock keeping and risk of infectious disease transmission and nutritional status were selected using pre-defined inclusion criteria. After screening and filtering of 34,402 unique references, 176 references were included in the final synthesis. Most (160/176, 90.1%) of the references included in the final synthesis were from sub-Saharan Africa (SSA) and Asia. About two out of every five (42%) studies reviewed showed that livestock production is associated with improved height-for-age Z scores (HAZ) and weight-for-length/height Z scores (WHZ), while close to a third (30.7%) with improved weight-for-age Z scores (WAZ). Similarly, livestock production showed a positive or neutral relationship with women's nutritional status in almost all the references that reported on the topic. Conversely, four-fifths (66/81, 79.5%) of the references reporting on infection and morbidity outcomes indicated that livestock keeping is linked to a wide range of infectious disease outcomes, which are spread primarily through water, food and insects. In conclusion, in many LMIC settings, livestock production is associated with better nutritional outcomes but also a higher risk of disease transmission or morbidity among women and children.This review was prospectively registered on PROSPERO 2020 [CRD42020193622].

1024. Transitions of Care Quality Metrics in Patients Discharged on Parenteral Antimicrobial Therapy in a Large Urban Hospital that Lacks a Formal Outpatient Parenteral Antimicrobial Therapy Program

Abstract Background With the evidence demonstrating the need for antimicrobial stewardship in the transition from inpatient to outpatient intravenous (IV) antibiotic therapy, it is imperative to have effective communication and coordination in a multidisciplinary team. Studies have demonstrated the utility of initiating a formal Outpatient Parenteral Antimicrobial Therapy (OPAT) program. The goal of this study is to assess quality metrics in a sample of patients discharged on IV antibiotics prior to initiation of a pilot OPAT program. Methods This is a retrospective, multicenter chart review of patients admitted to Temple University Health System from 10/1/2020 - 10/31/2021 who were discharged on IV antibiotics. There were no exclusion criteria. Patients with multiple admissions were documented as separate occurrences. Qualitative data were collected on the appropriateness of OPAT indication, pathogens targeted, antibiotics used, performance of infectious diseases (ID) consult, line selected, outcomes, and demographics. The primary endpoint is the percentage of global IV antibiotic prescribing errors (antibiotic, dose, route, frequency, duration, parenteral access device). Results There were 748 total discharges on IV antimicrobials in 705 unique patients. We chose a random sample of 109 discharges. Twenty (18%) had an oral antimicrobial available as an option. Antibiotic selection, dosing, duration, and access were correct 92%, 82%, 64% and 65% respectively (Table 2). ID recommended laboratory monitoring for 44 (40%) patients, of which 8 (18%) were sent to ID clinic; all had abnormal findings. Of the 25 patients who required ID follow-up, 11 had a scheduled ID appointment of which 8 attended. There was no mortality within 30 days from the 8 patients, but 2 were readmitted within 30 days. Overall, 39% patients readmitted within 30 days, 6% had mortality within 30 days and 50% were known to have completed therapy. Conclusion Our study captured a 65% rate of prescribing errors in a sample of 109 patients receiving IV antibiotics at discharge. The findings demonstrate an urgent need for an OPAT program to help with antimicrobial, parenteral access selection, monitoring, and follow-up with ID. By implementing this program, we hope to improve our ID follow-up, lab monitoring, and readmission metrics. Disclosures All Authors: No reported disclosures.

1388. Seasonality of Microbiology of Combat-related Wound Infections in Afghanistan

Abstract Background We examined the seasonality of wounds and wound infections, including occurrence of multidrug resistance, among combat casualties injured in Afghanistan. Methods The Trauma Infectious Disease Outcomes Study is a retrospective observational study of infectious complications among military personnel wounded during deployment (06/09-12/14). Wound cultures obtained ≤7 days following injury in Afghanistan were assessed. Epidemiologic, clinical, and microbiologic data were analyzed by injury season [winter (1 Dec-28/29 Feb), spring (1 Mar-31 May), summer (1 Jun-31 Aug), and fall (1 Sep-30 Nov)]. Multidrug-resistant (MDR) determinations for Gram-negative and Gram-positive organisms were per standardized definitions. Results The study population included 316 patients with a median of 3.5 (IQR 3-5) days from injury to initial culture. Gram-negatives (N=188, 59.5%) were more commonly isolated from wound cultures in summer (N=81, 43.1%) and fall (N=57, 30.3%) versus winter (N=18, 9.6%) and spring (N=32, 17%) (p&amp;lt; 0.001). The MDR Gram-negatives (N=69, 21.8%) were more common in summer (N=26, 37.7%), and fall (N=26, 37.7%) versus winter (N=3, 4.3%) and spring (N=14, 20.3%) (p=0.028). Wound infections were diagnosed in 198 (63%) patients. The pattern for infecting Gram-negative isolates (N=143, 72.2%, Table 1) was similar to that of overall Gram-negative isolates: summer (79.5%) and fall (83.6%; p&amp;lt; 0.001); MDR Gram-negatives (summer, 25.6%) and (fall, 41.8%; p=0.015). Escherichia coli and Enterobacter spp. were the most common infecting Gram-negative bacilli with no significant difference across the seasons. There was a higher proportion of infecting Acinetobacter baumannii isolates in the summer and fall compared to winter and spring. Infecting Gram-positive isolates (N=128, 65%) were not significantly different by season. Anaerobes associated with infections were also identified (N=30, 15%) with a higher proportion in the winter compared to summer, fall, and spring (p=0.036). Conclusion Gram-negatives, including MDR Gram-negative infecting organisms, were more common in summer/fall months in service members injured in Afghanistan. This may have implications for empiric antibiotic coverage during these months. Disclosures David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

1207. Epidemiology and Timing of Infectious Complications from Battlefield-Related Burn Injuries

Abstract Background Thermal injury alters the host response, making burn patients more susceptible to infections. In fact, infections represent the most frequent complication and cause of mortality in burn patients. We describe the epidemiology, clinical characteristics, timing, and outcomes of infections among wounded military personnel with burns. Methods Data were collected through the Trauma Infectious Disease Outcomes Study, an observational study of US service members injured in Iraq and Afghanistan (6/09-12/14). Patients who sustained ≥1 burn injury and were admitted to the Burn Center at Brooke Army Medical Center were included in the analysis. Infections were defined using standardized criteria. For patients with multiple infections, only the initial infection was assessed. Results Among 144 burn patients, 99% were males and 62% had combat-related burns with a median total body surface area (TBSA) of 6% (IQR 3-14%) thermally injured. Infections were diagnosed in 26 (18%) patients with pneumonia being the predominant initial syndrome (N=16, 62%), followed by skin and soft-tissue infections (N=6, 23%), bloodstream infections (N=3, 12%), and intra-abdominal infections (N=1, 4%). Median number of days to each of these initial infecting syndromes were 4 (IQR 3-5), 7 (IQR 4-12), 7 (IQR 6-7), and 17 (IQR 17-17) days, respectively. Patients with infections were more severely injured with greater TBSA (median 31 vs 5) and Baux scores (median 59 vs 29), and were more likely to have combat trauma, inhalation injury, require mechanical ventilation, and have longer time to definitive grafting (Table 1). Microbiology of initial infections varied with 35% of patients having polymicrobial infections (Table 2). Gram-negative organisms were recovered from 20 (77%) patients, of whom 20% had a multidrug-resistant Gram-negative. Gram-positive organisms and fungi were identified in 42% and 8% of patients, respectively. Conclusion Improved understanding of risk factors and the timing of infections in this unique population is critical for effective management. Patients with infections were more severely injured, had higher rates of inhalational injury, and longer days to definitive grafting. Initial infections were more commonly pneumonia. Disclosures David R. Tribble, DrPH, AstraZeneca: The HJF, in support of the USU IDCRP, was funded to conduct or augment unrelated Phase III Mab and vaccine trials as part of US Govt. COVID19 response.

The Role of Non-Alcoholic Fatty Liver Disease in Infections.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, affecting one third of the Western population. The hallmark of the disease is excessive storage of fat in the liver. Most commonly, it is caused by metabolic syndrome (or one of its components). Even though the development of NAFLD has multiple effects on the human organism resulting in systemic chronic low-grade inflammation, this review is focused on NAFLD as a risk factor for the onset, progression, and outcomes of infectious diseases. The correlation between NAFLD and infections is still unclear. Multiple factors (obesity, chronic inflammation, altered immune system function, insulin resistance, altered intestinal microbiota, etc.) have been proposed to play a role in the development and progression of infections in people with NAFLD, although the exact mechanism and the interplay of mentioned factors is still mostly hypothesized. In this article we review only the selection of well-researched topics on NAFLD and infectious diseases (bacterial pneumonia, COVID, H. pylori, urinary tract infections, C. difficile, bacteremia, hepatitis B, hepatitis C, HIV, and periodontitis).

Impact of active pulmonary tuberculosis on the prognosis of patients with upper aerodigestive cancers: An 8-year observational study in a nationwide cohort

Background and objectiveTuberculosis (TB), a contagious disease with high morbidity and mortality, is prevalent among immunocompromised patients including those with cancers. We describe the risk subgroups and impact of active TB on the prognosis of patients with upper aerodigestive cancers. MethodsWe conducted a retrospective, nationwide cohort study from January 2009 to December 2014, and followed up until the end of 2016, using the database of the Taiwanese National Health Insurance (NHI) program. Patients newly diagnosed with oral, nasopharyngeal, laryngeal, and esophageal cancers were defined as the upper aerodigestive cancer cohort. Active pulmonary TB infection was identified as a time-dependent variable in the analysis of the risk subgroups and prognostic impact in our study cohort. ResultsA total of 57,543 patients were enrolled, and 890 patients (1.55 %) had active pulmonary TB during the follow-up period. The TB incidence was highest in patients with esophageal cancer and lowest in patients with nasopharyngeal cancer (1443 and 236 per 100, 000 person-years, respectively). Moreover, advanced cancer stage and inoperable cancer are considered risk factors for TB. Furthermore, patients with TB infection had a shorter survival (HR: 1.86, 95 % CI: 1.70–2.04), after matching cancer type, stage, and calendar year of diagnosis with patients without TB. ConclusionActive pulmonary TB is prevalent in patients with upper aerodigestive cancers and is independently associated with an increased risk of death. Identifying the risk factors for TB in these cancer patients is important both for infectious disease control and outcome evaluation.

Caspase-Mediated Regulation and Cellular Heterogeneity of the cGAS/STING Pathway in Kaposi's Sarcoma-Associated Herpesvirus Infection.

As a result of the ongoing virus-host arms race, viruses have evolved numerous immune subversion strategies, many of which are aimed at suppressing the production of type I interferons (IFNs). Apoptotic caspases have recently emerged as important regulators of type I IFN signaling both in noninfectious contexts and during viral infection. Despite being widely considered antiviral factors since they can trigger cell death, several apoptotic caspases promote viral replication by suppressing innate immune response. Indeed, we previously discovered that the AIDS-associated oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) exploits caspase activity to suppress the antiviral type I IFN response and promote viral replication. However, the mechanism of this novel viral immune evasion strategy is poorly understood, particularly with regard to how caspases antagonize IFN signaling during KSHV infection. Here, we show that caspase activity inhibits the DNA sensor cGAS during KSHV lytic replication to block type I IFN induction. Furthermore, we used single-cell RNA sequencing to reveal that the potent antiviral state conferred by caspase inhibition is mediated by an exceptionally small percentage of IFN-β-producing cells, thus uncovering further complexity of IFN regulation during viral infection. Collectively, these results provide insight into multiple levels of cellular type I IFN regulation that viruses co-opt for immune evasion. Unraveling these mechanisms can inform targeted therapeutic strategies for viral infections and reveal cellular mechanisms of regulating interferon signaling in the context of cancer and chronic inflammatory diseases. IMPORTANCE Type I interferons are key factors that dictate the outcome of infectious and inflammatory diseases. Thus, intricate cellular regulatory mechanisms are in place to control IFN responses. While viruses encode their own immune-regulatory proteins, they can also usurp existing cellular interferon regulatory functions. We found that caspase activity during lytic infection with the AIDS-associated oncogenic gammaherpesvirus Kaposi's sarcoma-associated herpesvirus inhibits the DNA sensor cGAS to block the antiviral type I IFN response. Moreover, single-cell RNA sequencing analyses unexpectedly revealed that an exceptionally small subset of infected cells (<5%) produce IFN, yet this is sufficient to confer a potent antiviral state. These findings reveal new aspects of type I IFN regulation and highlight caspases as a druggable target to modulate cGAS activity.

Clinical and etiological characteristics of pneumonia in children with a poor outcome of infectious diseases

Purpose: to study the clinical and etiological features of pneumonia in children with a poor outcome of infectious diseases.Materials and methods. The retrospective analysis of clinical, anamnestic, laboratory, instrumental data of 46 children who died from infectious diseases during the period from December 2009 to November 2019 was carried out, of which 26 patients had pneumonia at autopsy. The etiology of pneumonia was determined in vivo and postmortem using cultural, molecular genetic, serological methods and immunohistocytochemical examination of lung tissue. Pneumonia was classified into primary and secondary.Results. In patients with pneumonia in the structure of generalized infections (n=26) secondary forms prevailed (septic – 14 cases, ventilator-associated (VAP) – 5, aspiration – 2); primary pneumonia was detected in 5 children. Clinical polymorphism and frequent absence of typical symptoms of pneumonia (cough, shortness of breath, auscultatory and percussion changes) were shown, that led to intravital underdiagnosis of pneumonia in 31% of patients. The probable etiology of pneumonia was detected in vivo and postmortem in 58% and 98% of cases respectively. S. pneumoniae (40%) and H. influenzae type b (40%) were main pathogens in primary pneumonia, N. meningitidis (36%) and S. pneumoniae (29%) – in septic pneumonia, commensals of naso- and oropharynx (S. salivarius) – in aspiration pneumonia, nosocomial bacteria (S. aureus and coagulase-negative staphylococci) – in VAP. In children with HIV infection, pneumonia was associated with opportunistic pathogens (P. jirovecii, C. neoformans). In 87% of cases polymicrobial associations were found in lower airways, that makes it difficult to identify the main causative agent of pneumonia.Conclusions. Most of symptoms of pediatric pneumonia in the structure of generalized infections are nonspecific. Post-mortem study improves the etiological verification of pneumonia and allow to suggest the most pathogenetically and thanatogenetically significant pathogen.

A stakeholder-driven framework for measuring potential change in the health risks of people who inject drugs (PWID) during the COVID-19 pandemic.

BackgroundPeople who inject drugs (PWID) have likely borne disproportionate health consequences of the COVID-19 pandemic. PWID experienced both interruptions and changes to drug supply and delivery modes of harm reduction, treatment, and other medical services, leading to potentially increased risks for HIV, hepatitis C virus (HCV), and overdose. Given surveillance and research disruptions, proximal, indirect indicators of infectious diseases and overdose should be developed for timely measurement of health effects of the pandemic on PWID.MethodsWe used group concept mapping and a systems thinking approach to produce an expert stakeholder-generated, multi-level framework for monitoring changes in PWID health outcomes potentially attributable to COVID-19 in the U.S. This socio-ecological measurement framework elucidates proximal and distal contributors to infectious disease and overdose outcomes, many of which can be measured using existing data sources.ResultsThe framework includes multi-level components including policy considerations, drug supply/distribution systems, the service delivery landscape, network factors, and individual characteristics such as mental and general health status and service utilization. These components are generally mediated by substance use and sexual behavioral factors to cause changes in incidence of HIV, HCV, sexually transmitted infections, wound/skin infections, and overdose.ConclusionThis measurement framework is intended to increase the quality and timeliness of research on the impacts of COVID-19 in the context of the current pandemic and future crises. Next steps include a ranking process to narrow the drivers of change in health risks to a concise set of indicators that adequately represent framework components, can be written as measurable indicators, and are quantifiable using existing data sources, as well as a publicly available web-based platform for summary data contributions.