Antibiotic resistance in the patient with cancer: Escalating challenges and paths forward.

Infection is the second leading cause of death in patients with cancer. Loss of efficacy in antibiotics due to antibiotic resistance in bacteria is an urgent threat against the continuing success of cancer therapy. In this review, the authors focus on recent updates on the impact of antibiotic resistance in the cancer setting, particularly on the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.). This review highlights the health and financial impact of antibiotic resistance in patients with cancer. Furthermore, the authors recommend measures to control the emergence of antibiotic resistance, highlighting the risk factors associated with cancer care. A lack of data in the etiology of infections, specifically in oncology patients in United States, is identified as a concern, and the authors advocate for a centralized and specialized surveillance system for patients with cancer to predict and prevent the emergence of antibiotic resistance. Finding better ways to predict, prevent, and treat antibiotic-resistant infections will have a major positive impact on the care of those with cancer.

Anti-Interleukin-23 Autoantibodies in Adult-Onset Immunodeficiency.

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Reappraisal of Idiopathic CD4 Lymphocytopenia at 30 Years.

BACKGROUND: Idiopathic CD4 lymphocytopenia (ICL) is a clinical syndrome that is defined by CD4 lymphopenia of less than 300 cells per cubic millimeter in the absence of any primary or acquired cause of immunodeficiency. Some 30 years after its original identification, ICL has remained a disease of obscure cause, with limited evidence with respect to its prognosis or management, despite diagnostic and therapeutic innovations. METHODS: We evaluated the clinical, genetic, immunologic, and prognostic characteristics of 108 patients who were enrolled during an 11-year period. We performed whole-exome and targeted gene sequencing to identify genetic causes of lymphopenia. We also performed longitudinal linear mixed-model analyses of T-cell count trajectories and evaluated predictors of clinical events, the response to immunization against coronavirus disease 2019 (Covid-19), and mortality. RESULTS: After the exclusion of patients with genetic and acquired causes of CD4 lymphopenia, the study population included 91 patients with ICL during 374 person-years of follow-up. The median CD4+ T-cell count among the patients was 80 cells per cubic millimeter. The most prevalent opportunistic infections were diseases related to human papillomavirus (in 29%), cryptococcosis (in 24%), molluscum contagiosum (in 9%), and nontuberculous mycobacterial diseases (in 5%). A reduced CD4 count (<100 cells per cubic millimeter), as compared with a CD4 count of 101 to 300 cells, was associated with a higher risk of opportunistic infection (odds ratio, 5.3; 95% confidence interval [CI], 2.8 to 10.7) and invasive cancer (odds ratio, 2.1; 95% CI, 1.1 to 4.3) and a lower risk of autoimmunity (odds ratio, 0.5; 95% CI, 0.2 to 0.9). The risk of death was similar to that in the age- and sex-adjusted general population, but the prevalence of cancer was higher. CONCLUSIONS: Among the study patients, ICL continued to be associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer. (Funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute; ClinicalTrials.gov number, NCT00867269.).

Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth.

Immediately after birth, newborn babies experience rapid colonization by microorganisms from their mothers and the surrounding environment1. Diseases in childhood and later in life are potentially mediated by the perturbation of the colonization of the infant gut microbiota2. However, the effects of delivery via caesarean section on the earliest stages of the acquisition and development of the gut microbiota, during the neonatal period (≤1 month), remain controversial3,4. Here we report the disrupted transmission of maternal Bacteroides strains, and high-level colonization by opportunistic pathogens associated with the hospital environment (including Enterococcus, Enterobacter and Klebsiella species), in babies delivered by caesarean section. These effects were also seen, to a lesser extent, in vaginally delivered babies whose mothers underwent antibiotic prophylaxis and in babies who were not breastfed during the neonatal period. We applied longitudinal sampling and whole-genome shotgun metagenomic analysis to 1,679 gut microbiota samples (taken at several time points during the neonatal period, and in infancy) from 596 full-term babies born in UK hospitals; for a subset of these babies, we collected additional matched samples from mothers (175 mothers paired with 178 babies). This analysis demonstrates that the mode of delivery is a significant factor that affects the composition of the gut microbiota throughout the neonatal period, and into infancy. Matched large-scale culturing and whole-genome sequencing of over 800 bacterial strains from these babies identified virulence factors and clinically relevant antimicrobial resistance in opportunistic pathogens that may predispose individuals to opportunistic infections. Our findings highlight the critical role of the local environment in establishing the gut microbiota in very early life, and identify colonization with antimicrobial-resistance-containing opportunistic pathogens as a previously underappreciated risk factor in hospital births.

Unintended Consequences: Risk of Opportunistic Infections Associated With Long-term Glucocorticoid Therapies in Adults.

Glucocorticoids are widespread anti-inflammatory medications used in medical practice. The immunosuppressive effects of systemic glucocorticoids and increased susceptibility to infections are widely appreciated. However, the dose-dependent model frequently used may not accurately predict the risk of infection in all patients treated with long-term glucocorticoids. In this review, we examine the risks of opportunistic infections (OIs) in patients requiring glucocorticoid therapy by evaluating the influence of the glucocorticoid dose, duration, and potency, combined with biological and host clinical factors and concomitant immunosuppressive therapy. We propose strategies to prevent OIs, which involve screening, antimicrobial prophylaxis, and immunizations. While this review focuses on patients with autoimmune, inflammatory, or neoplastic diseases, the potential risks and preventative strategies are likely applicable to other populations. Clinicians should actively assess the benefit-harm ratios of systemic glucocorticoids and implement preventive efforts to decrease their associated infections complications.

Opportunistic Elizabethkingia miricola Infections in Intensive Care Unit, Spain.

In 2021, we identified a cluster of Elizabethkingia miricola cases in an intensive care unit in Spain. Because E. miricola is not considered a special surveillance agent in Spain, whole-genome sequencing was not performed. The bacterial source was not identified. All Elizabethkingia species should be listed as special surveillance bacteria.

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.

Good girl goes bad: Understanding how gut commensals cause disease.

This review examines the complex connection between commensal microbiota and the development of opportunistic infections. Several underlying conditions, such as metabolic diseases and weakened immune systems, increase the vulnerability of patients to opportunistic infections. The increasing antibiotic resistance adds significant complexity to the management of infectious diseases. Although commensals have long been considered beneficial, recent research contradicts this notion by uncovering chronic illnesses linked to atypical pathogens or commensal bacteria. This review examines conditions in which commensal bacteria, which are usually beneficial, contribute to developing diseases. Commensals' support for opportunistic infections can be categorized based on factors such as colonization fitness, pathoadaptive mutation, and evasion of host immune response. Individuals with weakened immune systems are especially susceptible, highlighting the importance of mucosal host-microbiota interaction in promoting infection when conditions are inappropriate. Dysregulation of gut microbial homeostasis, immunological modulation, and microbial interactions are caused by several factors that contribute to the development of chronic illnesses. Knowledge about these mechanisms is essential for developing preventive measures, particularly for susceptible populations, and emphasizes the importance of maintaining a balanced gut microbiota in reducing the impact of opportunistic infections.

Adhesion of Klebsiella oxytoca to bladder or lung epithelial cells is promoted by the presence of other opportunistic pathogens.

The intestinal and respiratory tracts of healthy individuals serve as habitats for a diverse array of microorganisms, among which Klebsiella oxytoca holds significance as a causative agent in numerous community- and hospital-acquired infections, often manifesting in polymicrobial contexts. In specific circumstances, K. oxytoca, alongside other constituents of the gut microbiota, undergoes translocation to distinct physiological niches. In these new environments, it engages in close interactions with other microbial community members. As this interaction may progress to co-infection where the virulence of involved pathogens may be promoted and enhance disease severity, we investigated how K. oxytoca affects the adhesion of commonly co-isolated bacteria and vice versa during co-incubation of different biotic and abiotic surfaces. Co-incubation was beneficial for the adhesion of at least one of the two co-cultured strains. K. oxytoca enhanced the adhesion of other enterobacteria strains to polystyrene and adhered more efficiently to bladder or lung epithelial cell lines in the presence of most enterobacteria strains and S. aureus. This effect was accompanied by bacterial coaggregation mediated by carbohydrate-protein interactions occurring between bacteria. These interactions occur only in sessile, but not planktonic populations, and depend on the features of the surface. The data are of particular importance for the risk assessment of the urinary and respiratory tract infections caused by K. oxytoca, including those device-associated. In this paper, we present the first report on K. oxytoca ability to acquire increased adhesive capacities on epithelial cells through interactions with common causal agents of urinary and respiratory tract infections.

Trends in epidemiology and risk factors of opportunistic infections in kidney transplant recipients between 2004 and 2017.

BACKGROUND: While opportunistic infections are a frequent and challenging problem in kidney transplant recipients, their long-term epidemiology remains hardly known. METHODS: Opportunistic infections were recorded in 1144 recipients transplanted in our center between 2004 and 2015. Incidence rates and baseline risk factors were determined using joint frailty models. RESULTS: After a median follow-up of 5.6 years, 544 opportunistic infections occurred in 373/1144 (33%) patients, dominated by viral infections (396/544, 72%), especially cytomegalovirus (CMV) syndromes and diseases (213/544, 39%). One-third of the infected patients experienced at least two opportunistic infections. The incidence of opportunistic infections was 10 times higher during the first year post-transplantation than after that (34.7 infections for 100 patient-years vs 3.64). Opportunistic infections associated with the age of the donor (P = .032), the age of the recipient (P = .049), the CMV serostatus (P < 10-6), a higher class II HLA mismatch (P = .032) and an induction treatment including rabbit anti-thymocyte globulins (P = .026). Repeated opportunistic infections associated with each other (P < 10-6) and with renal death (P < 10-6). CONCLUSION: Opportunistic infections occur with a two-period incidence pattern and many susceptible patients suffer from repeated episodes. This knowledge may help tailor new prevention and follow-up strategies to reduce the burden of opportunistic infections and their impact on transplantation outcome.

Nontuberculous mycobacteria testing and culture positivity in the United States.

BACKGROUND: Nontuberculous mycobacteria (NTM) are environmental bacteria which may cause chronic lung disease. The prevalence of NTM pulmonary infection and disease has been increasing in the United States and globally. The predominant clinically relevant species of NTM in the United States are Mycobacterium avium complex (MAC) species and Mycobacterium abscessus. With the development of rapid species identification methods for NTM (e.g. PCR probes), more testing for NTM is being conducted through commercial labs, such as Laboratory Corporation of America (Labcorp), which provides deidentified real-time testing data to the Centers for Disease Control (CDC) pursuant to a data sharing agreement. Because NTM lung infections are not reportable in most states, other data sources are key to understanding NTM testing patterns, positivity rates, and species distributions to track infection trends and identify clinical care needs. METHODS: We obtained national Labcorp data for the period January 2019 through mid-April 2022. We subset the data to only respiratory samples sent for Acid Fast Bacilli (AFB) cultures. NTM positive results were defined as those which identified an NTM species and are not Mycobacterium tuberculosis, Mycobacterium bovis, or Mycobacterium gordonae. RESULTS: Overall, 112,528 respiratory samples were sent for AFB testing during the study period; 26.3% were from the Southeast U.S., identified as HSS Region IV in the Labcorp dataset, and 23.0% were from the Pacific and South Pacific region (Region IX). The culture positive prevalence ranged from 20.2% in the Southeast to 9.2% in the East North Central region (Region V). In the Southeast US, M. abscessus prevalence was 4.0%. For MAC, the highest prevalence was observed in the Mountain region (Region VII) (13.5%) and the lowest proportion was in the East South Central region (7.3%, Region III). Among positive tests, the proportion which was MAC varied from 61.8% to 88.9% and was highest in the Northeast U.S. The proportion of positive samples which were M. abscessus ranged from 3.8% to 19.7% and was highest in the Southeast. CONCLUSIONS: The Southeastern region of the U.S. has the highest rate of culture positivity in Labcorp tests for total NTM and, of all positive tests, the highest proportion of M. abscessus. These estimates may underrepresent the true number of M. abscessus infections because M. absesscus-specific probes are not commercially available and not all NTM testing in the United States is done by Labcorp. Analysis of real-time testing data from commercial laboratories may provide insights into risk factors for NTM culture positivity in 'hotspot' areas.

Follow-up for 3 years of a pediatric population diagnosed in 2018 with mother-to-child transmission of HIV in 8 Latin American countries in the PLANTAIDS cohort.

INTRODUCTION: The frequency of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV) in Latin America has decreased considerably. However, new infections continue to be recorded, and the pediatric population remains one of the most vulnerable groups in this region. The main objective of the study was to describe the clinical, epidemiological and psychosocial characteristics of new diagnoses of HIV MTCT in 2018 in the PLANTAIDS network (Paediatric Network for Prevention, Early Detection and Treatment of HIV in Children) during the 3 years following diagnosis. METHODOLOGY: Retrospective, multicenter, descriptive study based on a 3-year follow-up of patients diagnosed with HIV infection due to MTCT in 2018 in 10 hospitals in 8 Latin American countries (Costa Rica, Ecuador, Mexico, Honduras, El Salvador, Panama, Guatemala and Venezuela). The hospitals belonged to the PLANTAIDS network, which is included in CYTED (Ibero-American Programme of Science and Technology for Development). RESULTS: The study population comprised 72 pediatric patients (38.9% male). The median age at diagnosis was 2.4 years (IQR: 0.8-5.4). There were 35 cases of opportunistic infections corresponding to 25 patients (34.7%), with tuberculosis being the most common. Adequate childhood vaccination coverage was achieved in 80.5%. There were 3 cases of acute SARS-CoV-2 infection, and these were asymptomatic or mildly symptomatic. According to the Centers for Disease Control and Prevention (CDC) classification, the most frequent clinical-immunological stage at all check-ups was C1. Three patients died from opportunistic infections and/or advanced HIV infection. CONCLUSIONS: It is important to diagnose HIV infection early in pediatrics, since early initiation of ART is associated with a decrease in mortality. Despite this, HIV infection has a poor prognosis in children, necessitating adequate follow-up to ensure adherence to health care and ART, although it can sometimes prove difficult in children.

Implementation of a rapid diagnostic assay package for cryptococcosis, histoplasmosis and tuberculosis in people living with HIV in Paraguay.

BACKGROUND: Opportunistic infections (OIs) are common causes of mortality among people living with HIV (PLHIV). We determined prevalence and 30-day mortality due to histoplasmosis, cryptococcosis, and TB in PLHIV with advanced HIV disease (AHD). METHODS: PLHIV 18 years and older, with a CD4 + T-cell count of less than 350 cells/mm3 newly diagnosed with HIV infection or re-engaged in care after being without ART for more than 90 days (Group A). The second group included symptomatic PLHIV regardless of ART status or CD4 + T-cell count (Group B); all followed for 30 days. Detection of Histoplasma Ag (HisAg) in urine was done by enzyme immunoassay (EIA), Cryptococcus antigen (CrAg) was detected in serum and cerebrospinal fluid (CSF) specimens by lateral flow assay (LFA), and lipoarabinomannan (LAM) detection in urine was by LFA (TB LAM) and in sputum by GeneXpert for diagnosis of Mycobacterium infections. RESULTS: From August 2021 to June 2022, 491 PLHIV were enrolled; 482 (98%) had a CD4 + T-cell result, and 381 patients (79%) were classified with AHD according to CD4 + T-cell count (< 200 CD4/mm3). Frequency of an OI was 38% (n = 145/381). Antigen test positivity rate was 16% (72/467) for TB-LAM, 9% (43/464) for HisAg, and 11% (51/484) for CrAg. Twenty-one of 34 (62%) patients receiving CSF CrAg tests were positive, confirming meningitis. Significant differences in 30-day mortality were observed in patients with an OI (16%) vs. no OI (7%) (p = 0.002). Mortality was highest in patients with histoplasmosis (25%), co-infection (22%), cryptococcosis (18% overall; 19% for cryptococcal meningitis), and TB (10%). CONCLUSIONS: TB and fungal OIs, including co-infection, were common in PLHIV in Paraguay and had high associated mortality. Laboratories and health facilities need access to CD4 + T-cell testing and rapid diagnostic assays.

Beyond the First Year: Epidemiology and Management of Late-Onset Opportunistic Infections After Kidney Transplantation.

Late opportunistic infections (OI) occurring beyond the first year after kidney transplantation (KT) are poorly described and not targeted by prophylactic strategies. We performed a ten-year retrospective monocentric cohort study describing epidemiology, risk factors and impact of late OI occurring 1 year after KT. We included clinically symptomatic OI requiring treatment besides BK virus nephropathy. Control groups included early OI occurring in the first year after KT, and KT recipients without OI since KT and alive with a functional allograft at 1 year. Among 1066 KT recipients, 185 (19.4%) presented a first episode of OI 21.0 (8.0-45.0) months after KT: 120 late OI (64.9%) and 65 early OI (35.1%). Late OI were mainly viral (N = 83, 69.2%), mostly herpes zoster (HZ) (N = 36, 43.4%). Pneumocystis represented most late fungal infections (N = 12/25, 48%). Compared to early OI, we reported more pneumocystis (p = 0.002) and less invasive aspergillosis (p = 0.01) among late OI. Patients with late OI were significatively younger at KT (54.0 ± 13.3 vs. 60.2 ± 14.3 years, p = 0.05). Patient and allograft survival rates between late OI and control groups were similar. Only age was independently associated with mortality. While late OI were not associated with higher mortality or graft loss, implementing prophylactic strategies might prevent such infections.

Position statement on infection screening, prophylaxis, and vaccination of pediatric patients with rheumatic diseases and immunosuppressive therapies, part 3: precautions in situations of surgery, fever, and opportunistic infections.

The objective of this study is to provide practical recommendations on the management of pediatric patients with immune-mediated rheumatic diseases receiving immunosuppressive therapies. The recommendations specifically address the cases of surgery, fever, and opportunistic infections (varicella, herpes-zoster, tuberculosis, invasive fungal disease). A qualitative approach was applied. A narrative literature review was performed via Medline. Primary searches were conducted using MeSH terms and free text to identify publications on infections and vaccinations in pediatric patients with immune-mediated rheumatic diseases receiving immunosuppressive therapies. The results were presented and discussed in a nominal group meeting, comprising a committee of 12 pediatric rheumatologists from the Infection Prevention and Treatment Working Group of the Spanish Society of Pediatric Rheumatology. Several recommendations were generated. A consensus procedure was implemented via a Delphi process; this was extended to members of the Spanish Society of Pediatric Rheumatology and Spanish Society of Pediatric Infectious Disease of the Spanish Association of Pediatrics. Participants produced a score ranging from 0 (totally disagree) to 10 (totally agree). Agreement was defined as a vote ≥ 7 by at least 70% of participants. The literature review included more than 400 articles. Overall, 63 recommendations (19 on surgery, fever, and opportunistic infections) were generated and voted by 59 pediatric rheumatologists and other pediatric specialists. Agreement was reached for all 63 recommendations. The recommendations on special situations cover management in cases of surgery, fever, and opportunistic infections (varicella, herpes-zoster, tuberculosis, and invasive fungal disease).  Conclusions: Hereby, we provided consensus and updated of recommendations about the management of special situations such as surgery, fever, and opportunistic in children with immune-mediated rheumatic diseases receiving immunosuppressive therapies. Several of the recommendations depend largely on clinical judgement and specific balance between risk and benefit for each individual and situation. To assess this risk, the clinician should have knowledge of the drugs, the patient's previous situation as well as the current infectious disease, in addition to experience. What is Known: • Infectious diseases and related complications are a major cause of morbidity and mortality in patients with immune-mediated rheumatic diseases. • Information on how to manage the treatment in situations of fever, opportunistic infections, and surgery in children is limited, and guidelines for action are often extrapolated from adults. What is New: • In the absence of strong evidence, a literature review and a Delphi survey were conducted to establish a series of expert recommendations that could support the clinical practice, providing a practical and simple day-to-day approach to be used by pediatric rheumatologists.

Exploring the association between erythema multiforme and HIV infection: some mechanisms and implications.

Erythema multiforme (EM) is an immune-mediated mucocutaneous condition characterized by hypersensitivity reactions to antigenic stimuli from infectious agents and certain drugs. The most commonly implicated infectious agents associated with EM include herpes simplex virus (HSV) and Mycoplasma pneumoniae. Other infectious diseases reported to trigger EM include human immunodeficiency virus (HIV) infection and several opportunistic infections. However, studies focusing on EM and human immunodeficiency virus (HIV) infection are scarce. even though the incidence of EM among HIV-infected individuals have increased, the direct and indirect mechanisms that predispose HIV-infected individuals to EM are not well understood. In turn, this makes diagnosing and managing EM in HIV-infected individuals an overwhelming task. Individuals with HIV infection are prone to acquiring microorganisms known to trigger EM, such as HSV, Mycobacterium tuberculosis, Treponema pallidum, histoplasmosis, and many other infectious organisms. Although HIV is known to infect CD4 + T cells, it can also directly bind to the epithelial cells of the oral and genital mucosa, leading to a dysregulated response by CD8 + T cells against epithelial cells. HIV infection may also trigger EM directly when CD8 + T cells recognize viral particles on epithelial cells due to the hyperactivation of CD8 + T-cells. The hyperactivation of CD8 + T cells was similar to that observed in drug hypersensitivity reactions. Hence, the relationship between antiretroviral drugs and EM has been well established. This includes the administration of other drugs to HIV-infected individuals to manage opportunistic infections. Thus, multiple triggers may be present simultaneously in HIV-infected individuals. This article highlights the potential direct and indirect role that HIV infection may play in the development of EM and the clinical dilemma that arises in the management of HIV-infected patients with this condition. These patients may require additional medications to manage opportunistic infections, many of which can also trigger hypersensitivity reactions leading to EM.

Increasing ratio of opportunistic infections associated with sunshine exposure and economic level burdening Chinese inflammatory bowel disease hospitalized patients: the first nationwide survey from 2014 to 2019.

BACKGROUND: The rising prevalence of opportunistic infections (OIs) in inflammatory bowel disease (IBD) in conjunction with the use of biologics/immunosuppressive agents has garnered attention. However, there is a dearth of research on OIs in Mainland China. This study seeks to evaluate the national ratio trend of OIs in IBD and elucidate the influence of economic and climate factors on IBD patients with OIs and their outcomes. METHODS: The nationwide data was obtained from the Inpatient medical record home page via the Health Statistics and Information Reporting System (HSRS). Patients diagnosed with IBD were enlisted for participation, and their demographic and clinical information, encompassing infection type, surgical procedures, and expenses, were gathered. The National Bureau of Statistics provided data on monthly sunshine exposure hours and yearly Gross Domestic Product (GDP). RESULTS: Findings indicate that between 2014 and 2019, a total of 381,752 patients with IBD were admitted to hospitals, with 364,249 patients lacking OIs and 17,503 patients presenting with OIs. The annual proportion of OIs exhibited an upward trend, rising from 3.54% in 2014 to 4.81% in 2019. There was a significant correlation observed between individuals who identified as male, those who visited hospitals in southern regions, or those originating from areas with lower GDP or shorter sunshine exposure hours, and a higher incidence of OIs. Among patients diagnosed with either Crohn's disease (CD) or ulcerative colitis (UC), Clostridium difficile was found to be the most prevalent infection, followed by Epstein-Barr virus and cytomegalovirus. Furthermore, the occurrence of OIs was found to be associated with an increased rate of surgical interventions in UC patients. CONCLUSIONS: The rising prevalence of OIs among hospitalized patients with IBD necessitates heightened attention towards mitigating associated risk factors, particularly among IBD patients residing in less developed regions or experiencing limited exposure to sunlight. This approach aims to minimize hospital stays and associated costs.

The Effect of Salvia tomentosa Miller Extracts, Rich in Rosmarinic, Salvianolic and Lithospermic Acids, on Bacteria Causing Opportunistic Infections.

Methanolic-aqueous extracts of Salvia tomentosa Miller roots, aerial parts, and inflorescences were examined for their content of polyphenolic derivatives and the antimicrobial and cytotoxic effect. In the polyphenolic-rich profile, rosmarinic, salvianolic, and lithospermic acids along with various derivatives were predominant. A total of twenty phenolic compounds were identified using the UPLC/DAD/qTOF-MS technique. These were caffeic acid, rosmarinic acid derivatives, lithospermic acid derivatives, salvianolic acids B, F, and K derivatives, as well as sagerinic acid, although rosmarinic acid (426-525 mg/100 g of dry weight-D.W.) and salvianolic acid B (83-346.5 mg/100 g D.W.) were significantly predominant in the metabolic profile. Strong antibacterial activity of S. tomentosa extracts was observed against Staphylococcus epidermidis (MIC/MBC = 0.625 mg/mL) and Bacillus cereus (MIC = 0.312-1.25 mg/mL). The extracts showed low cytotoxicity towards the reference murine fibroblasts L929 and strong cytotoxicity to human AGS gastric adenocarcinoma epithelial cells in the MTT reduction assay. The observed cytotoxic effect in cancer cells was strongest for the roots of 2-year-old plant extracts.

[Lomentospora prolificans Fungemia in a Patient With T-Cell Large Granular Leukemia: A Rare Pathogen in Türkiye]. / T-hücreli Büyük Granüler Lösemili Bir Hastada Lomentospora prolificans Fungemisi: Türkiye'de Nadir Bir Etken.

Scedosporium/Lomentospora is an opportunistic fungal pathogen found worldwide. While Scedosporium apiospermum and Scedosporium boydii are commonly observed globally, Lomentospora prolificans, which mainly affects immunosuppressed individuals, is rarely encountered and is more prevalent in arid climates, particularly in Australia and Spain. L.prolificans is a fungus commonly found in environmental sources such as contaminated water and soil. This species is known as an opportunistic pathogen that can cause deep-seated fungal infections, especially in immunosuppressed individuals. In this case report, a fatal case of L.prolificans fungemia in a patient with T-cell large granular leukemia during profound neutropenia was presented. The patient admitted to the hospital with prolonged fever, neutropenia, and shortness of breath. Antibiotherapy was administered to the patient for febrile neutropenia, but the fever persisted and his clinical status rapidly deteriorated. L.prolificans was isolated from the blood culture, and considering its antifungal resistance, combination therapy of voriconazole and terbinafine was initiated. However, the patient died of septic shock and multiple organ failure. In conclusion, although L.prolificans infections are rare, they can be life-threatening, especially in immunosuppressed individuals. Diagnosis and treatment of such infections may be difficult, therefore rapid diagnostic methods and appropriate treatment protocols should be developed. Consideration of infections caused by rare fungal pathogens in patients with risk factors may be critical for patient care. The literature review revealed that the first case of L.prolificans fungemia from Türkiye was reported in 2023. This case presentation represents the second reported case. However, in our case, L.prolificans fungemia occurred in 2018, it can be considered that L.prolificans may have been an invasive fungal pathogen of significant concern in Türkiye much earlier than previously documented.