Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.

Background: Clinicians cannot reliably predict complications of acute hematogenous osteomyelitis (AHO). Methods: Consecutive cases of AHO from 2 pediatric centers in the United States were analyzed retrospectively to develop clinical tools from data obtained within 96 hours of hospitalization to predict acute and chronic complications of AHO. Two novel composite prediction scores derived from multivariable logistic regression modeling were compared with a previously published severity of illness (SOI) score, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) using area under the receiver operating characteristic curve analyses. Results: The causative organisms were identified in 73% of 261 cases. Bacteremia (45%), abscesses (38%), and associated suppurative arthritis (23%) were relatively common. Acute or chronic complications occurred in 24% and 11% of patients, respectively. Multivariable logistic regression identified bone abscess (odds ratio [OR], 2.3 [95% confidence interval {CI}, 1.0–5.2]), fever > 48 hours (OR, 2.7 [95% CI, 1.2–6.0]), suppurative arthritis (OR, 3.2 [95% CI, 1.3–7.5]), disseminated disease (OR, 4.6 [95% CI, 1.5–14.3]), and delayed source control (OR, 5.1 [95% CI, 1.4–19.0]) as strong predictors of acute complications. In a separate model, CRP ≥ 100 mg/L at 2–4 days after antibiotics (OR, 2.7 [95% CI, 1.0–7.3]), disseminated disease (OR, 3.3 [95% CI, 1.1–10.0]), and requirement for bone debridement (OR, 6.7 [95% CI, 2.1–21.0]) strongly predicted chronic morbidity. These variables were combined to create weighted composite prediction scores for acute (A-SCORE) and chronic (C-SCORE) osteomyelitis, which were superior to SOI, CRP, and ESR and had negative predictive values > 90%. Conclusions: Two novel composite clinical scores were superior to existing tools to predict complications of pediatric AHO.

Cryptococcus albidus, synonymous with Naganishia albida, rarely causes opportunistic infection in immunocompromised individuals. Its clinical features, particularly in children, are not well defined. Here, we report a case of C albidus fungemia in an immunosuppressed child; we also present results of a systematic review, for which we searched PubMed, Embase, and Web of Science using the keywords "cryptococcus" and "albidus." Our goal was to describe the spectrum of disease, diagnostic approaches, therapies, and outcomes. We identified 20 cases of invasive infection, only 2 of which involved children, and 7 cases of noninvasive infection. The reports originated in the Americas, Europe, and Asia. Of those with invasive infection, 16 (80%) patients had an underlying chronic disorder or had received immunosuppressive therapy, 8 (40%) had fungemia, and 6 (30%) had a central nervous system infection. The attributable case fatality rate was 40%. C albidus is an opportunistic yeast that can rarely cause life-threatening fungemia and central nervous system infection in individuals of any age, especially those who are immunocompromised.

Severe Fever with Thrombocytopenia Syndrome (SFTS) is a life-threatening emerging infectious disease caused by the SFTS virus. The aim of this systematic review and meta-analysis was to gain new insights into the routes of transmission to humans and assess whether tick bites are the dominant mechanism, as previously reported in the medical literature. Original articles were searched through Embase, Medline, and Global Health from 2009 to 2022. We performed meta-analyses to pool adjusted odds ratio (aOR) estimates using a fixed-effects model. Of 1683 articles, 41 eligible articles from three countries met the inclusion criteria, and five case-control studies were included in the meta-analysis. The most commonly reported route of transmission in the systematic review of individual participant data was person-to-person contact, particularly through exposure to blood or body fluids. Other routes included tick bites and contact with infected animals, especially cats and dogs. The meta-analysis included studies reporting transmission through human contact (n = 1), tick bites (n = 4), and animal contact (n = 1). Human contact via exposure to bodily fluids significantly increased the odds of infection (aOR: 6.27, 95 % CI: 1.23-42.81). Tick bites had a pooled aOR of 6.36 (95 % CI: 3.34-12.11). Among animal contacts, only dog contact was significant (OR: 3.60, 95 % CI: 1.04-12.51). The typical settings for SFTS transmission were human or animal hospitals, homes, and natural tick habitats. Education and effective interventions to prevent human-to-human spread, in addition to preventing transmission by tick bites, are urgently needed.

Our objective was to quantify the risk of acquiring malaria among progeny of women with malaria during pregnancy. We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library for eligible prospective studies. The primary predictor was malaria during pregnancy defined as placental malaria, parasitemia, clinical malaria, or pregnancy-associated malaria. Primary outcomes were parasitemia or clinically defined malaria of young children. We performed meta-analyses to pool adjusted risk estimates using a random-effects model. Nineteen of 2053 eligible studies met inclusion criteria for the systemic review. Eleven of these studies were quantitative and were included in the meta-analyses. The pooled adjusted odds ratio (aOR) or adjusted hazard ratio (aHR) of malaria during pregnancy for detection of parasitemia in young children were 1.94 (95% confidence interval [CI], 0.93–4.07; P = .08) and 1.46 (95% CI, 1.07–2.00; P < .001), respectively. The pooled aOR or aHR for clinically defined malaria in young children were 2.82 (95% CI, 1.82–4.38; P < .001) and 1.31 (95% CI, 0.96–1.79; P = .09), respectively. Our results confirmed that malaria during pregnancy significantly increased the overall risk of malaria in young children via indeterminate mechanisms and emphasize the urgent need to implement safe and highly effective strategies to prevent malaria during pregnancy.

Multisystem Inflammatory Syndrome in Children (MIS-C) is a potentially life-threatening complication of COVID-19. The pathophysiological mechanisms leading to severe disease are poorly understood. This study leveraged clinical samples from a well-characterized cohort of children hospitalized with COVID-19 or MIS-C to compare immune-mediated biomarkers. Our objective was to identify selected immune molecules that could explain, in part, why certain SARS-CoV-2-infected children developed MIS-C. We hypothesized that type-2 helper T cell-mediated inflammation can elicit autoantibodies, which may account for some of the differences observed between the moderate–severe COVID-19 (COVID⁺) and MIS-C cohort. We enumerated blood leukocytes and measured levels of selected serum cytokines, chemokines, antibodies to COVID-19 antigens, and autoantibodies in children presenting to an academic medical center in Connecticut, United States. The neutrophil/lymphocyte and eosinophil/lymphocyte ratios were significantly higher in those in the MIS-C versus COVID⁺ cohort. IgM and IgA, but not IgG antibodies to SARS-CoV-2 receptor binding domain were significantly higher in the MIS-C cohort than the COVID⁺ cohort. The serum levels of certain type-2 cytokines (interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10, IL-13, and IL-33) were significantly higher in children with MIS-C compared to the COVID⁺ and SARS-CoV-2-negative cohorts. IgG autoantibodies to brain antigens and pentraxin were higher in children with MIS-C compared to SARS-CoV-19-negative controls, and children with MIS-C had higher levels of IgG anti-contactin-associated protein-like 2 (caspr2) compared to the COVID⁺ and SARS-CoV-19-negative controls. We speculate that autoimmune responses in certain COVID-19 patients may induce pathophysiological changes that lead to MIS-C. The triggers of autoimmunity and factors accounting for type-2 inflammation require further investigation.