Matthew D. Eberly

Increased IL-15 Production Is Associated with Higher Susceptibility of Memory CD4 T Cells to Simian Immunodeficiency Virus during Acute Infection

Acute SIV infection is characterized by explosive infection of memory CD4 T cells in peripheral and mucosal tissues. Interestingly, relatively few memory CD4 T cells are infected until as late as days 7–8 after challenge. However, by day 10 postinfection, most of the memory CD4 T cells are infected and carry viral DNA. The rapidity with which infection expands within 2–3 days to encompass virtually the entire memory CD4 T cell compartment suggests significant alterations in the susceptibility of memory CD4 T cells to infection during this period. The mechanism(s) underlying this increased permissiveness to infection is not known. In this study, we show that IL-15 secretion significantly correlates with the up-regulated expression of CD4 on memory CD4 T cells that is associated with increased permissiveness to SIV infection. Activation and proliferation of memory CD8, but not memory CD4 T cells, preceded the amplification of viral infection. Although memory CD4 T cells did not express normal activation markers, they displayed a significant up-regulation in the density of CD4 but not CCR5 expression between days 7 and 10 postinfection that correlated with increased plasma IL-15 levels and infection in these cells. Culture of purified CD4 T cells with IL-15 and/or SIV was associated with a significant increase in the expression of CD4 and infection of these sorted cells. Our results demonstrate that IL-15 contributes to the increased susceptibility of memory CD4 T cells to SIV during the early phase of acute SIV infection.

Azithromycin in Early Infancy and Pyloric Stenosis

BACKGROUND AND OBJECTIVE: Use of oral erythromycin in infants is associated with infantile hypertrophic pyloric stenosis (IHPS). The risk with azithromycin remains unknown. We evaluated the association between exposure to oral azithromycin and erythromycin and subsequent development of IHPS. METHODS: A retrospective cohort study of children born between 2001 and 2012 was performed utilizing the military health system database. Infants prescribed either oral erythromycin or azithromycin as outpatients in the first 90 days of life were evaluated for development of IHPS. Specific diagnostic and procedural codes were used to identify cases of IHPS. RESULTS: A total of 2466 of 1 074 236 children in the study period developed IHPS. Azithromycin exposure in the first 14 days of life demonstrated an increased risk of IHPS (adjusted odds ratio [aOR], 8.26; 95% confidence interval [CI], 2.62–26.0); exposure between 15 and 42 days had an aOR of 2.98 (95% CI, 1.24–7.20). An association between erythromycin and IHPS was also confirmed. Exposure to erythromycin in the first 14 days of life had an aOR of 13.3 (95% CI, 6.80–25.9), and 15 to 42 days of life, aOR 4.10 (95% CI, 1.69–9.91). There was no association with either macrolide between 43 and 90 days of life. CONCLUSIONS: Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing IHPS. This association is strongest if the exposure occurred in the first 2 weeks of life, but persists although to a lesser degree in children between 2 and 6 weeks of age.

Antiretroviral Therapy prior to Acute Viral Replication Preserves CD4 T Cells in the Periphery but Not in Rectal Mucosa during Acute Simian Immunodeficiency Virus Infection

ABSTRACT The rectal mucosa is a major site for human immunodeficiency virus entry and CD4 T-cell depletion. The early and near-total loss of these cells from the rectal mucosa severely compromises the ability of the mucosal immune system to control various opportunistic infections. Protecting these cells from infection and destruction can delay disease progression, leading to a better long-term outcome. Here we show that effective suppression of viral infection in memory CD4 T cells from the rectal mucosa and peripheral blood to a very low level with antiretroviral therapy (ART) initiated prior to the peak of infection is associated with opposite outcomes in these tissues. A near-total loss of CD4 T cells in the rectal mucosa contrasted with preservation of most memory CD4 T cells in peripheral blood during the course of treatment. Interestingly, ART significantly reduced viral infection in memory CD4 T cells from both rectal mucosa and peripheral blood. Although early ART was of limited value in protecting the CD4 T cells in the rectal mucosa, the significant preservation of peripheral CD4 T cells could contribute to maintaining immune competence, leading to a better long-term outcome.

Children with Down Syndrome Are High-Risk for Severe Respiratory Syncytial Virus Disease

OBJECTIVE To assess Down syndrome as an independent risk factor for respiratory syncytial virus (RSV) hospitalization in children younger than 3 years of age and to evaluate illness severity. STUDY DESIGN A retrospective cohort study of children enrolled in the military health system database was conducted. The effect of Down syndrome on RSV hospitalization was assessed by Cox proportional hazards model, while we controlled for risk factors. Disease severity was assessed by length of hospital stay, need for respiratory support, and age at hospitalization. RESULTS The study included 633 200 children and 3 209 378 person-years. Children with Down syndrome had a hospitalization rate of 9.6% vs 2.8% in children without Down syndrome. Down syndrome had a greater adjusted hazard ratio (HR) for RSV hospitalization than most risk factors, 3.46 (95% CI 2.75-4.37). A sensitivity analysis demonstrated HR 3.21 (95% CI 2.51-4.10) for patients with Down syndrome ages 0-23 months and HR 5.07 (95% CI 2.21-11.59) ages 24-36 months. The median (IQR) length of stay of children with and without Down syndrome was 4 days (2-7) and 2 days (1-4) (P < .001). Patients with Down syndrome had a greater risk of requiring respiratory support (relative risk 5.5; 95% CI, 2.5-12.3). The median (IQR) ages at admission for children with and without Down syndrome were 9.8 months (5.5-17.7) and 3.5 months (1.7-8.7) (P < .001). CONCLUSIONS Down syndrome is independently associated with an increased risk for RSV hospitalization. Children with Down syndrome are older at time of RSV hospitalization and have more severe RSV illness than children without Down syndrome. This increased risk for hospitalization continues beyond 24 months.

Healthy Late-preterm infants born 33–36 + 6 weeks gestational age have higher risk for respiratory syncytial virus hospitalization

BACKGROUND Respiratory syncytial virus (RSV) is a leading cause of hospitalization for children <1year old and is more severe in premature infants. OBJECTIVE To assess whether late preterm (LPT) birth is an independent risk factor for RSV hospitalization and more severe RSV disease in children less than 24months old. METHODS We conducted a retrospective cohort study of children enrolled in the military health system. LPT birth was defined as 33+0 through 36+6weeks gestation. Patients who received palivizumab or had known risk factors for RSV were excluded. Adjusted hazard ratios (HR) for LPT birth were calculated using a Cox proportional hazard model, while controlling for sex and RSV season. Severity of illness was assessed by comparing the need for respiratory support, length of stay, and age at RSV hospitalization between LPT and term children. RESULTS A total of 599,535 children for 1,216,382 person-years were studied, of which 7597 children were admitted for RSV infection. LPT infants accounted for 643 (8.5%) of these RSV hospitalizations. The incidence density for RSV hospitalization of LPT infants was higher than term children (12.1 vs 7.8 per 1000 person-years). LPT infants had an increased adjusted risk for RSV hospitalization; specifically, those born 33+0 through 34+6weeks (HR 2.45; 95% confidence interval (CI) 1.96-3.07), and 35+0 through 36+6weeks (HR, 1.92; 95% CI, 1.66-2.22). LPT infants had longer hospital stays and required more respiratory support than term children. CONCLUSIONS LPT birth is an independent risk factor for severe RSV disease and need for hospitalization.

The effect of rotavirus immunization on rotavirus gastroenteritis hospitalization rates in military dependents

We conducted a retrospective review of all U.S. military dependents less than 5 years old hospitalized with rotavirus-associated gastroenteritis from July 2003 to June 2009. The two post-vaccine seasons showed a significant reduction of 62.4% (95% CI, 58.6-65.8, P<0.001) in rotavirus gastroenteritis hospitalization rate compared to the three pre-vaccine seasons. Infants less than 12 months old showed the greatest reduction in incidence at 75.3%. A substantial decrease was also seen in unvaccinated children as well. Vaccine efficacy against hospitalization was 86.0% (95% CI, 77.7-91.3) after just a single dose. The overwhelming majority of children hospitalized for rotavirus since the introduction of the vaccine (ranging from 91.8 to 100% per season) had not received any of the rotavirus vaccine series.

Risk Factors for Community-Associated Clostridium difficile Infection in Children

Objective To characterize the medication and other exposures associated with pediatric community‐associated Clostridium difficile infections (CA‐CDIs). Study design We performed a case‐control study using billing records from the US military health system database. CA‐CDI cases included children 1‐18 years of age with an outpatient International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code for Clostridium difficile infection (CDI) from 2001 to 2013. Each case was matched to 3 controls without CDI by age and sex. Children hospitalized at any time before their CDI were excluded. Outpatient pharmacy records were used to identify medication exposures in the preceding 12 weeks. In addition, we evaluated recent outpatient healthcare exposure, exposure to a sibling younger than 1 year of age, or to a family member with CDI. Results A total of 1331 children with CA‐CDI were identified and 3993 controls were matched successfully. Recent exposure to fluoroquinolones, clindamycin (OR 73.00; 95% CI 13.85‐384.68), third‐generation cephalosporins (OR 16.32; 95% CI 9.11‐29.26), proton pump inhibitors (OR 8.17; 95% CI 2.35‐28.38), and to multiple classes of antibiotics, each was associated strongly the subsequent diagnosis of CA‐CDI. Recent exposure to outpatient healthcare clinics (OR 1.35; 95% CI 1.31‐1.39) or to a family member with CDI also was associated with CA‐CDI. Conclusions CA‐CDI is associated with medications regularly prescribed in pediatric practice, along with exposure to outpatient healthcare clinics and family members with CDI. Our findings provide additional support for the judicious use of these medications and for efforts to limit spread of CDI in ambulatory healthcare settings and households.

Development of pneumococcal mastoiditis due to multidrug-resistant serotype 19A despite three doses of 13-valent pneumococcal vaccine

Acute mastoiditis is a potential complication of acute otitis media (AOM), with Streptococcus pneumoniae historically the most common pathogen isolated. Following the release of the 7-valent pneumococcal conjugate vaccine in 2000, a marked decline in invasive pneumococcal disease and a smaller reduction in pneumococcal AOM were observed, but data regarding its impact on acute mastoiditis are limited. With the recent introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), it is anticipated that pneumococcal AOM and invasive disease will further diminish. We report a case of acute mastoiditis from a multidrug-resistant serotype 19A S. pneumoniae in an immunocompetent child who had received three PCV13 vaccinations.

A Localized Macular Rash in an Immunocompromised Patient with Pneumonia and Necrotizing Enterocolitis

A 21-year-old male with T-cell acute lymphoblastic leukemia (ALL) was admitted for fever and neutropenia. Despite 72 h of antibiotic therapy, he remained febrile and developed new abdominal and pleuritic chest pain. His antimicrobial regimen was broadened to meropenem and voriconazole. On hospital day 5, a new asymptomatic rash appeared on his left face consisting of erythematous macules that blanched with pressure Within 24 h, the skin lesions expanded and developed a central, non-blanching violaceous hue. Liposomal amphotericin B was added and a biopsy of the rash was obtained. Mucor spp was confirmed by skin culture. Repeat imaging showed interval development of diffusely scattered and innumerable hypodense lesions throughout the liver and spleen, as well as diffuse myositis and lesions within the brain and spine. Care was withdrawn and the patient expired on hospital day 11. Risk factors for developing invasive aspergillosis and mucormycosis are similar. This case illustrates similarities in their clinical presentations, highlights potential gaps in coverage by antifungal agents that are commonly used for empiric coverage, and reviews treatment options.

West Nile Encephalitis in a previously healthy child: Evaluation for CCR5 Chemokine receptor mutation

Neuroinvasive disease seldom follows infection with West Nile virus, but is particularly rare in children. Most reported cases of West Nile virus encephalitis have occurred in older adults or the immunocompromised. Although individuals who are homozygous for a 32 base pair deletion in the chemokine receptor CCR5 have been shown to be resistant to infection with HIV-1, they have been reported to have in increased risk of developing severe disease following West Nile virus infection. Analysis of the presence of the CCR5 deletion has not been previously examined in children with West Nile neuroinvasive disease. We present a case of West Nile encephalitis in a previously healthy young child whom we evaluated for the presence of the CCR5Δ32 mutation.