Disseminated Disease After Candidemia in Children and Young Adults: Epidemiology, Diagnostic Evaluation and Risk Factors.

BACKGROUND: Treatment of candidemia may be complicated by hematogenous dissemination. Limited data exist to guide decision-making regarding the evaluation for disseminated disease. We sought to describe the epidemiology of invasive disease after candidemia, report the diagnostic evaluations performed and identify risk factors for disseminated disease. METHODS: We performed a retrospective single-center study of candidemia from January 1, 2012 to December 31, 2022. Disseminated candidiasis was defined as radiologic findings consistent with end-organ disease, abnormal ophthalmologic exam or growth of Candida spp. from a sterile site after an episode of candidemia. A multilevel regression model was used to identify risk factors for dissemination. RESULTS: The cohort included 124 patients with 144 episodes of candidemia. Twelve patients died before an evaluation for dissemination occurred. Only 107/132 patients underwent evaluation for dissemination. Tests obtained included abdominal imaging (93/132), echocardiography (91/132), neuroimaging (45/132) and chest imaging (38/132). A retinal examination was performed in 90/132 patients. Overall, 27/107 patients (25%) had disseminated disease. Frequently identified sites of dissemination were lungs and abdominal organs. Regression modeling identified prematurity [adjusted odds ratio (aOR): 11.88; 95% confidence interval (CI): 1.72-81.90] and mitochondrial and genetic disease (aOR: 5.66; 95% CI: 1.06-30.17) as risk factors for disseminated candidiasis. Each additional day of candidemia increased the odds of dissemination (aOR: 1.36; 95% CI: 1.12-1.66). DISCUSSION: In a heterogeneous cohort of patients, disseminated candidiasis was common. Evaluation for disseminated disease was variable. Those with persistent candidemia had significantly increased risk of dissemination and should undergo a standardized evaluation for disseminated disease.

Reproductive outcomes after pregnancy-induced displacement of preexisting microchimeric cells.

Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (Treg cells). Maternal microchimeric cells and accumulation of Treg cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche. Whereas NIMA-specific tolerance is functionally erased by pregnancy, partner-specific resiliency against pregnancy complications persists in mothers despite paternity changes in intervening pregnancy. Persistent fetal tolerance reflects FOXP3 expression plasticity, which allows mothers to more durably remember their babies, whereas daughters forget their mothers with new pregnancy-imprinted immunological memories.

Pregnancy enables antibody protection against intracellular infection.

Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase5 to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal-fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.

Epidemiology of Pregnancy Complications Through the Lens of Immunological Memory.

In the fifteen minutes it takes to read this short commentary, more than 400 babies will have been born too early, another 300 expecting mothers will develop preeclampsia, and 75 unborn third trimester fetuses will have died in utero (stillbirth). Given the lack of meaningful progress in understanding the physiological changes that occur to allow a healthy, full term pregnancy, it is perhaps not surprising that effective therapies against these great obstetrical syndromes that include prematurity, preeclampsia, and stillbirth remain elusive. Meanwhile, pregnancy complications remain the leading cause of infant and childhood mortality under age five. Does it have to be this way? What more can we collectively, as a biomedical community, or individually, as clinicians who care for women and newborn babies at high risk for pregnancy complications, do to protect individuals in these extremely vulnerable developmental windows? The problem of pregnancy complications and neonatal mortality is extraordinarily complex, with multiple unique, but complementary perspectives from scientific, epidemiological and public health viewpoints. Herein, we discuss the epidemiology of pregnancy complications, focusing on how the outcome of prior pregnancy impacts the risk of complication in the next pregnancy - and how the fundamental immunological principle of memory may promote this adaptive response.

Tacrolimus exposure windows responsible for Listeria monocytogenes infection susceptibility.

Tacrolimus is widely used to prevent graft rejection after allogeneic transplantation by suppressing T cells in a non-antigen-specific fashion. Global T-cell suppression makes transplant recipients more susceptible to infection, especially infection by opportunistic intracellular pathogens. Infection followed by secondary challenge with the opportunistic intracellular bacterial pathogen, Listeria monocytogenes, was used to probe when tacrolimus most significantly impacts antimicrobial host defense. Tacrolimus-treated mice showed no difference in innate susceptibility following primary infection, whereas susceptibility to secondary challenge was significantly increased. Modifying the timing of tacrolimus initiation with respect to primary infection compared with secondary challenge showed significantly reduced susceptibility in tacrolimus-treated mice where tacrolimus was discontinued prior to secondary challenge. Thus, tacrolimus overrides protection against secondary infection primed by primary infection (and presumably live attenuated vaccines), with the most critical window for tacrolimus-induced infection susceptibility being exposure immediately prior to secondary challenge. These results have important implications for strategies designed to boost antimicrobial T-cell-mediated immunity in transplant recipients.

Preconceptual Priming Overrides Susceptibility to Escherichia coli Systemic Infection during Pregnancy.

Maternal sepsis is a leading cause of morbidity and mortality during pregnancy. Escherichia coli is a primary cause of bacteremia in women and occurs more frequently during pregnancy. Several key outstanding questions remain regarding how to identify women at highest infection risk and how to boost immunity against E. coli infection during pregnancy. Here, we show that pregnancy-induced susceptibility to E. coli systemic infection extends to rodents as a model of human infection. Mice infected during pregnancy contain >100-fold-more recoverable bacteria in target tissues than nonpregnant controls. Infection leads to near complete fetal wastage that parallels placental plus congenital fetal invasion. Susceptibility in maternal tissues positively correlates with the number of concepti, suggesting important contributions by expanded placental-fetal target tissue. Remarkably, these pregnancy-induced susceptibility phenotypes are also efficiently overturned in mice with resolved sublethal infection prior to pregnancy. Preconceptual infection primes the accumulation of E. coli-specific IgG and IgM antibodies, and adoptive transfer of serum containing these antibodies to naive recipient mice protects against fetal wastage. Together, these results suggest that the lack of E. coli immunity may help discriminate individuals at risk during pregnancy, and that overriding susceptibility to E. coli prenatal infection by preconceptual priming is a potential strategy for boosting immunity in this physiological window of vulnerability.IMPORTANCE Pregnancy makes women especially vulnerable to infection. The most common cause of bloodstream infection during pregnancy is by a bacterium called Escherichia coli This bacterium is a very common cause of bloodstream infection, not just during pregnancy but in all individuals, from newborn babies to the elderly, probably because it is always present in our intestine and can intermittently invade through this mucosal barrier. We first show that pregnancy in animals also makes them more susceptible to E. coli bloodstream infection. This is important because many of the dominant factors likely to control differences in human infection susceptibility can be property controlled for only in animals. Despite this vulnerability induced by pregnancy, we also show that animals with resolved E. coli infection are protected against reinfection during pregnancy, including having resistance to most infection-induced pregnancy complications. Protection against reinfection is mediated by antibodies that can be measured in the blood. This information may help to explain why most women do not develop E. coli infection during pregnancy, enabling new approaches for identifying those at especially high risk of infection and strategies for preventing infection during pregnancy.

Treatment Options for Coronavirus Disease 2019 in Patients With Reduced or Absent Kidney Function.

Coronavirus disease 2019, the disease caused by the severe acute respiratory syndrome coronavirus 2 virus, was first identified in the Hubei Province of China in late 2019. Currently, the only role for therapy is treatment of the disease, as opposed to postexposure prophylaxis, however multiple clinical trials are currently ongoing for both treatment and prophylaxis. Treating coronavirus disease 2019 relies on two components; the first is inhibition of the viral entrance and replication within the body and the second is inhibition of an exacerbated immune response which can be seen in patients with severe disease. Many drugs have shown in vitro antiviral activity; however, clinical trials have not been as promising. This review summarizes the current data for the most commonly used drugs for coronavirus disease 2019 and will cover the unique factors that may affect the dosing of these medications in patients with CKD. While clinical trials are ongoing, most are in patients with normal kidney function. During a pandemic, when patients with CKD are at higher risk of both infection and death, it is imperative to include patients these patients in the clinical trials.

CD8+ T Cell Functional Exhaustion Overrides Pregnancy-Induced Fetal Antigen Alloimmunization.

Pregnancy necessitates physiological exposure, and often re-exposure, to foreign fetal alloantigens. The consequences after pregnancy are highly varied, with evidence of both alloimmunization and expanded tolerance phenotypes. We show that pregnancy primes the accumulation of fetal-specific maternal CD8+ T cells and their persistence as an activated memory pool after parturition. Cytolysis and the potential for robust secondary expansion occurs with antigen re-encounter in non-reproductive contexts. Comparatively, CD8+ T cell functional exhaustion associated with increased PD-1 and LAG-3 expression occurs with fetal antigen re-stimulation during subsequent pregnancy. PD-L1/LAG-3 neutralization unleashes the activation of fetal-specific CD8+ T cells, causing fetal wastage selectively during secondary but not primary pregnancy. Thus, CD8+ T cells with fetal alloantigen specificity persist in mothers after pregnancy, and protection against fetal wastage in subsequent pregnancies is maintained by their unique susceptibility to functional exhaustion. Together, distinct mechanisms whereby fetal tolerance is maintained during primary compared with subsequent pregnancies are demonstrated.

Durability of the hepatitis B vaccination in pediatric renal transplant recipients.

Since hepatitis B virus (HBV) vaccine implementation, HBV infection has significantly decreased. However, adult renal transplant recipients show a higher rate of seroreversion compared to the general population, leading to HBV infection risk. Data are limited in pediatric renal transplant recipients. Retrospective data were collected to determine the seroprotection and durability of HBV vaccination in pediatric renal transplant patients from 2004 to 2014. One hundred subjects were categorized based on pre- and post-transplant hepatitis B surface antibody (HBsAb). Pretransplant, 85 recipients (85%) had a positive HBsAb compared to 15 (15%) with negative HBsAb. In univariable analyses, other than age (P < .05) no significant differences existed pretransplant by demographics, pretransplantation dialysis, or number of vaccinations. Of the 85 pretransplantation responders, 53 (62%) remained HBsAb positive post-transplantation, 28 (32%) seroreverted, and 4 developed indeterminate titers. All seroreversions occurred within 5 years post-transplant. Receipt of a living donor organ had higher risk of reversion (P = .005). No significant differences were found in demographics, pretransplantation dialysis, vaccination number, or acute rejection. Despite vaccination, 15% of pediatric renal transplant candidates were seronegative, and an additional 32% lost seroprotection within 5 years post-transplantation leaving nearly half of transplant recipients at risk for HBV infection.