Dawn Nolt

Long-Term Control of Mycobacterium tuberculosis Infection Is Mediated by Dynamic Immune Responses

The primary goal of this study was to determine how chronic exposure to Ag influences the functionality of Mycobacterium tuberculosis-specific T cell responses. The frequency of IFN-γ-producing effector CD4+ and CD8+ T cells dynamically changed during persistent M. tuberculosis infection. CD8+ T cells used differential effector functions during acute and chronic phases of the immune response, where CD8+ T cells produced negligible amounts of IFN-γ early in infection, but switched to cytokine production during the chronic stage of infection. Using limiting dilution analysis, CD8+ T cells isolated during the initial phase of infection demonstrated lytic potential, but this waned in the chronic stage. The apparent loss of cytotoxic activity was not associated with the lack of perforin. Ag dose could potentially govern the functional program of CD8+ T cells. Collectively, these results depict a host immune response mounted against M. tuberculosis of a significantly more dynamic nature than previously recognized.

The Mycobacterium tuberculosis Phagosome Is a HLA-I Processing Competent Organelle

Mycobacterium tuberculosis (Mtb) resides in a long-lived phagosomal compartment that resists maturation. The manner by which Mtb antigens are processed and presented on MHC Class I molecules is poorly understood. Using human dendritic cells and IFN-γ release by CD8+ T cell clones, we examined the processing and presentation pathway for two Mtb–derived antigens, each presented by a distinct HLA-I allele (HLA-Ia versus HLA-Ib). Presentation of both antigens is blocked by the retrotranslocation inhibitor exotoxin A. Inhibitor studies demonstrate that, after reaching the cytosol, both antigens require proteasomal degradation and TAP transport, but differ in the requirement for ER–golgi egress and new protein synthesis. Specifically, presentation by HLA-B8 but not HLA-E requires newly synthesized HLA-I and transport through the ER–golgi. Phenotypic analysis of the Mtb phagosome by flow organellometry revealed the presence of Class I and loading accessory molecules, including TAP and PDI. Furthermore, loaded HLA-I:peptide complexes are present within the Mtb phagosome, with a pronounced bias towards HLA-E:peptide complexes. In addition, protein analysis also reveals that HLA-E is enriched within the Mtb phagosome compared to HLA-A2. Together, these data suggest that the phagosome, through acquisition of ER–localized machinery and as a site of HLA-I loading, plays a vital role in the presentation of Mtb–derived antigens, similar to that described for presentation of latex bead-associated antigens. This is, to our knowledge, the first description of this presentation pathway for an intracellular pathogen. Moreover, these data suggest that HLA-E may play a unique role in the presentation of phagosomal antigens.

Spectrum of clinical manifestations of West Nile virus infection in children.

Reports of clinical manifestations of West Nile virus (WNV) infections in children have been relatively rare. Four cases of WNV infection in children are described: the first report of prolonged encephalitis and fulminant hepatitis caused by WNV, and 3 other presentations of WNV, including the first report of ocular involvement in a child.

Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis

ABSTRACT Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i) IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8+, CD4+, and NK cells) in the lungs of infected mice and (ii) IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis.

Recommendations for serogroup B meningococcal vaccine for persons 10 years and older

This policy statement provides recommendations for the prevention of serogroup B meningococcal disease through the use of 2 newly licensed serogroup B meningococcal vaccines: MenB-FHbp (Trumenba; Wyeth Pharmaceuticals, a subsidiary of Pfizer, Philadelphia, PA) and MenB-4C (Bexsero; Novartis Vaccines, Siena, Italy). Both vaccines are approved for use in persons 10 through 25 years of age. MenB-FHbp is licensed as a 2- or 3-dose series, and MenB-4C is licensed as a 2-dose series for all groups. Either vaccine is recommended for routine use in persons 10 years and older who are at increased risk of serogroup B meningococcal disease (category A recommendation). Persons at increased risk of meningococcal serogroup B disease include the following: (1) persons with persistent complement component diseases, including inherited or chronic deficiencies in C3, C5–C9, properdin, factor D, or factor H or persons receiving eculizumab (Soliris; Alexion Pharmaceuticals, Cheshire, CT), a monoclonal antibody that acts as a terminal complement inhibitor by binding C5 and inhibiting cleavage of C5 to C5A; (2) persons with anatomic or functional asplenia, including sickle cell disease; and (3) healthy persons at increased risk because of a serogroup B meningococcal disease outbreak. Both serogroup B meningococcal vaccines have been shown to be safe and immunogenic and are licensed by the US Food and Drug Administration for individuals between the ages of 10 and 25 years. On the basis of epidemiologic and antibody persistence data, the American Academy of Pediatrics agrees with the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention that either vaccine may be administered to healthy adolescents and young adults 16 through 23 years of age (preferred ages are 16 through 18 years) to provide short-term protection against most strains of serogroup B meningococcal disease (category B recommendation).

Influenza immunization for all health care personnel: Keep it mandatory

The purpose of this statement is to reaffirm the American Academy of Pediatrics’ support for a mandatory influenza immunization policy for all health care personnel. With an increasing number of organizations requiring influenza vaccination, coverage among health care personnel has risen to 75% in the 2013 to 2014 influenza season but still remains below the Healthy People 2020 objective of 90%. Mandatory influenza immunization for all health care personnel is ethical, just, and necessary to improve patient safety. It is a crucial step in efforts to reduce health care–associated influenza infections.

Diagnosis, treatment, and prevention of congenital toxoplasmosis in the United States

* Abbreviations: AC/HS — : differential agglutination (test) AF — : amniotic fluid CI — : confidence interval CNS — : central nervous system CSF — : cerebrospinal fluid CT — : congenital toxoplasmosis ELISA — : enzyme-linked immunosorbent assay EMSCOT — : European Multicenter Study of Congenital Toxoplasmosis EUROTOXO — : European Toxoprevention Study FDA — : US Food and Drug Administration GRADE — : Grading of Recommendations Assessment, Development, and Evaluation HR — : hazard ratio Ig — : immunoglobulin ISAGA — : immunosorbent agglutination assay MTCT — : mother-to-child transmission NCCCT — : National Collaborative Chicago-Based Congenital Toxoplasmosis Study NPV — : negative predictive value OR — : odds ratio PAMF-TSL — : Palo Alto Medical Foundation Toxoplasma Serology Laboratory PCR — : polymerase chain reaction PPV — : positive predictive value P/S — : pyrimethamine/sulfadiazine RCT — : randomized controlled trial SNHL — : sensorineural hearing loss SNSD — : serious neurologic sequelae or death SYROCOT — : Systematic Review on Congenital Toxoplasmosis Congenital toxoplasmosis (CT) is a parasitic disease that can cause significant fetal and neonatal harm. Coordinated efforts by pregnant women, researchers, physicians, and health policy makers regarding potential primary and secondary preventive measures for CT and their implementation may lead to a lower incidence of CT as well as lower morbidity and mortality rates associated with CT. In the United States, the age-adjusted seroprevalence of Toxoplasma gondii among women of childbearing age (15–44 years) has declined over time (15%, 11%, and 9% in 1988–1994, 1999–2004, and 2009–2010, respectively; among US-born women only, the seroprevalence rates during these time periods were 13%, 8%, and 6%, respectively). Thus, approximately 91% of women of childbearing age in the United States are susceptible to Toxoplasma infection. Should these women become infected during pregnancy and remain undiagnosed and untreated, they could deliver an infant with CT. However, the incidence of acute primary infection is likely very low in the current era and is probably much lower than the 1.1 in 1000 pregnant women originally reported in 1960s. There are 3 ways CT can occur. First, CT can develop through transmission of T gondii to the fetus from a previously seronegative, immunocompetent mother who acquired acute primary infection during pregnancy or within 3 months before …

Preventive antibiotics in pediatric patients with acute myeloid leukemia (AML)

Treatment of acute myeloid leukemia (AML) comes with a significant risk of life‐threatening infection during periods of prolonged severe neutropenia. We studied the impact of preventive intravenous (IV) antibiotic administration at onset of absolute neutropenia on the incidence and outcome of life‐threatening infections during treatment of childhood AML.

Parental Presence During Treatment of Ebola or Other Highly Consequential Infection.

This clinical report offers guidance to health care providers and hospitals on options to consider regarding parental presence at the bedside while caring for a child with suspected or proven Ebola virus disease (Ebola) or other highly consequential infection. Options are presented to help meet the needs of the patient and the family while also posing the least risk to providers and health care organizations. The optimal way to minimize risk is to limit contact between the person under investigation or treatment and family members/caregivers whenever possible while working to meet the emotional support needs of both patient and family. At times, caregiver presence may be deemed to be in the best interest of the patient, and in such situations, a strong effort should be made to limit potential risks of exposure to the caregiver, health care providers, and the community. The decision to allow parental/caregiver presence should be made in consultation with a team including an infectious diseases expert and state and/or local public health authorities and should involve consideration of many factors, depending on the stage of investigation and management, including (1) a careful history, physical examination, and investigations to elucidate the likelihood of the diagnosis of Ebola or other highly consequential infection; (2) ability of the facility to offer appropriate isolation for the person under investigation and family members and to manage Ebola; (3) ability to recognize and exclude people at increased risk of worse outcomes (eg, pregnant women); and (4) ability of parent/caregiver to follow instructions, including appropriate donning and doffing of personal protective equipment.

Medical versus nonmedical immunization exemptions for child care and school attendance

Routine childhood immunizations against infectious diseases are an integral part of our public health infrastructure. They provide direct protection to the immunized individual and indirect protection to children and adults unable to be immunized via the effect of community immunity. All 50 states, the District of Columbia, and Puerto Rico have regulations requiring proof of immunization for child care and school attendance as a public health strategy to protect children in these settings and to secondarily serve as a mechanism to promote timely immunization of children by their caregivers. Although all states and the District of Columbia have mechanisms to exempt school attendees from specific immunization requirements for medical reasons, the majority also have a heterogeneous collection of regulations and laws that allow nonmedical exemptions from childhood immunizations otherwise required for child care and school attendance. The American Academy of Pediatrics (AAP) supports regulations and laws requiring certification of immunization to attend child care and school as a sound means of providing a safe environment for attendees and employees of these settings. The AAP also supports medically indicated exemptions to specific immunizations as determined for each individual child. The AAP views nonmedical exemptions to school-required immunizations as inappropriate for individual, public health, and ethical reasons and advocates for their elimination.