Claire E. Bocchini

Panton-valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children

BACKGROUND. Staphylococcus aureus strains carrying the genes encoding Panton-Valentine leukocidin (pvl-positive [pvl+]) are associated with more febrile days and higher complication rates of osteomyelitis in children than are pvl-negative (pvl−) strains. OBJECTIVES. Selected clinical, laboratory, and radiographic findings in children with osteomyelitis caused by pvl+ and pvl− S aureus strains were compared. METHODS. The demographics, selected clinical features, laboratory values, and radiographic findings of children with community-acquired S aureus osteomyelitis prospectively identified at Texas Childrens Hospital between August 2001 and July 2004 were reviewed. Polymerase chain reaction was performed to detect the genes for pvl (luk-S-PV and luk-F-PV) and fibronectin-binding protein (fnbB) in S aureus isolates. χ2, 2-sample t test, and multiple logistic regression were used for statistical analysis. RESULTS. Methicillin-susceptible and methicillin-resistant S aureus (MSSA and MRSA, respectively) caused osteomyelitis in 33 and 56 children, respectively. Twenty-six isolates were pvl− (26 MSSA), 59 were pvl+ (3 MSSA, 56 MRSA), and 4 were not available for analysis (4 MSSA). On univariate analysis, patients with pvl+ S aureus isolates had significantly higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level both at presentation and as a maximum value during hospitalization and were more likely to have a blood culture positive for S aureus during their admission. Patients with pvl+ S aureus isolates were significantly more likely to have concomitant myositis or pyomyositis compared with patients with pvl− S aureus isolates on MRI. In a multivariate analysis pvl remained significantly associated with ESR and CRP levels at presentation and blood culture positive for S aureus. pvl+ status and younger age were associated with myositis on MRI. CONCLUSIONS. Osteomyelitis caused by pvl+ S aureus strains were associated with more severe local disease and a greater systemic inflammatory response compared with osteomyelitis caused by pvl− S aureus.

Risk factors for development of endocarditis and reintervention in patients undergoing right ventricle to pulmonary artery valved conduit placement

OBJECTIVE To determine the incidence and risk factors for endocarditis and reintervention in patients undergoing placement of right ventricle-to-pulmonary artery valve conduits. METHODS All right ventricle-to-pulmonary artery valved conduits placed between 1995 and 2014 were included. Freedom from endocarditis, reintervention, and replacement were analyzed using the Kaplan-Meier method and parametric survival regression models. RESULTS A total of 586 patients underwent placement of a total of 792 valved conduits, including 289 (36%) pulmonary homografts, 121 (15%) aortic homografts, 245 (31%) bovine jugular grafts, and 137 (17%) porcine heterografts. There were 474 (60%) primary placements and 318 (40%) replacements. The median duration of conduit follow-up was 7 years; 23 conduits developed endocarditis at a median of 5 years after surgery. The use of bovine jugular grafts was the sole significant risk factor associated with endocarditis (hazard ratio, 9.05; 95% confidence interval, 2.6-31.8 compared with homografts). The hazard was greater for bovine jugular grafts compared with the other conduit types and increased with time; however, bovine jugular grafts were associated with a lower risk for reintervention (P < .0001) and replacement (P = .0002). Factors associated with greater risk of both reintervention and replacement were younger age and smaller conduit size. In addition, a diagnosis of truncus arteriosus was associated with a greater risk for replacement (P = .03). CONCLUSIONS Bovine jugular grafts are associated with a significantly greater risk of late endocarditis but with lower reintervention rates compared with other valved conduits. The risk of endocarditis and durability must be balanced during conduit selection. Antibiotic prophylaxis and a high index of suspicion for endocarditis are warranted in patients with bovine jugular grafts.

Recurrent Community-associated staphylococcus aureus Infections in Children Presenting to Texas Children’s Hospital in Houston, Texas

Background: There are limited data characterizing recurrent staphylococcal disease in children. We sought to define the clinical features and laboratory findings of children with recurrent community-associated Staphylococcus aureus infections presenting to Texas Children’s Hospital in Houston, TX. Methods: Medical records of children with recurrent, culture-proven community-associated S. aureus infections at Texas Children’s Hospital from 8/1/2001 to 7/29/2009 were reviewed, and antibiotic susceptibility patterns were obtained for all S. aureus isolates. Results: Six hundred ninety-four otherwise healthy patients presented to Texas Children’s Hospital with 2–7 episodes of community-associated S. aureus infection, accounting for 1495 encounters, 823 hospitalizations and 3337 inpatient days. In 90% of patients with ⩽12 months separating their initial and recurrent infections, the methicillin susceptibility of the initial and recurrent isolates was the same, compared with 79% of patients with > 12 months separating their infections. The overall antibiotic susceptibility pattern did not change between isolates in 71% of otherwise healthy children compared with only 33% of children with eczema. Ninety-two percent of otherwise healthy children had only recurrent skin and soft tissue infections; 8% had ≥1 non–skin and soft tissue infections. The location of skin and soft tissue infections varied by age, with children ⩽36 months of age being more likely to have ≥1 S. aureus infection located in the diaper area. Conclusions: Our study demonstrates that recurrent staphylococcal disease requiring emergency center or inpatient care is common, accounting for significant utilization of hospital resources. Children with recurrent staphylococcal infections are likely to have repeated infections from the same staphylococcal strain (by antibiotic susceptibility pattern), indicating that persistent colonization, frequent exposure to others who are chronically colonized, or environmental contamination is playing a role in recurrent disease. Finally, our study emphasizes the need for repeat cultures in children with recurrent disease, as 29% of healthy children and 67% of children with a predisposing risk factor (such as eczema) have a change in the antibiotic susceptibility pattern between S. aureus isolates.

Protein stabilization improves STAT3 function in autosomal dominant hyper-IgE syndrome

Autosomal dominant hyper-IgE syndrome (AD-HIES) is caused by dominant-negative mutations in STAT3; however, the molecular basis for mutant STAT3 allele dysfunction is unclear and treatment remains supportive. We hypothesized that AD-HIES mutations decrease STAT3 protein stability and that mutant STAT3 activity can be improved by agents that increase chaperone protein activity. We used computer modeling to characterize the effect of STAT3 mutations on protein stability. We measured STAT3 protein half-life (t1/2) and determined levels of STAT3 phosphorylated on tyrosine (Y) 705 (pY-STAT3) and mRNA levels of STAT3 gene targets in Epstein-Barr virus-transformed B (EBV) cells, human peripheral blood mononuclear cells (PBMCs), and mouse splenocytes incubated without or with chaperone protein modulators-HSF1A, a small-molecule TRiC modulator, or geranylgeranylacetone (GGA), a drug that upregulates heat shock protein (HSP) 70 and HSP90. Computer modeling predicted that 81% of AD-HIES mutations are destabilizing. STAT3 protein t1/2 in EBV cells from AD-HIES patients with destabilizing STAT3 mutations was markedly reduced. Treatment of EBV cells containing destabilizing STAT3 mutations with either HSF1A or GGA normalized STAT3 t1/2, increased pY-STAT3 levels, and increased mRNA levels of STAT3 target genes up to 79% of control. In addition, treatment of human PBMCs or mouse splenocytes containing destabilizing STAT3 mutations with either HSF1A or GGA increased levels of cytokine-activated pY-STAT3 within human CD4+ and CD8+ T cells and numbers of IL-17-producing CD4+ mouse splenocytes, respectively. Thus, most AD-HIES STAT3 mutations are destabilizing; agents that modulate chaperone protein function improve STAT3 stability and activity in T cells and may provide a specific treatment.

Contribution of chaperones to STAT pathway signaling.

Aberrant STAT signaling is associated with the development and progression of many cancers and immune related diseases. Recent findings demonstrate that proteostasis modulators under clinical investigation for cancer therapy have a significant impact on STAT signaling, which may be critical for mediating their anti-cancer effects. Chaperones are critical for protein folding, stability and function and, thus, play an essential role in the maintenance of proteostasis. In this review we discuss the role of chaperones in STAT and tyrosine kinase (TK) protein folding, modulation of STAT and TK activity, and degradation of TKs. We highlight the important role of chaperones in STAT signaling, and how this knowledge has provided a framework for the development of new therapeutic avenues of targeting STAT signaling related pathologies.

A Case of an 11-year-old With Cough, Diarrhea, and Findings of Concern in His Lungs and Spleen.

This is the case of a previously healthy, 11-year-old male of Indian descent who presented to the emergency department with a 2-month history of nausea, vomiting, diarrhea, fatigue, cough, and 7-lb weight loss. Acutely, he developed 5 days of fever as high as 39.4°C. He had a remote travel history to the Middle East. On physical examination, he was febrile and tachycardic, was thin but otherwise had a normal examination. His inflammatory markers were elevated: erythrocyte sedimentation rate was 93 mm/hour and his C-reactive protein was 25.4 mg/L. A complete blood count revealed a white blood cell count of 17 000 × 103/µL with increased bands. His hemoglobin level was 8.8 g/dL with a mean corpuscular volume of 81 fl. Platelets were 556 × 103/µL. A chest radiograph was concerning for a cavitary lung lesion and an abdominal ultrasound revealed multiple hypoechoic lesions in his spleen. Our panel of experts reviews his case and examines the workup of this patient with diverse symptoms and focal findings on chest radiograph and abdominal ultrasound.

Infected Congenital Neck Lesions

Congenital neck lesions can present as asymptomatic neck masses, but they also frequently get infected and present as deep neck infections that are important to distinguish from suppurative lymphadenitis or infections along fascial planes. Congenital neck lesions frequently involved in infectious processes include thyroglossal duct cysts, branchial cleft cysts, sinuses and fistulae, dermoid cysts, preauricular sinuses, thymic cysts, laryngoceles and lymphatic malformations. The types of infectious pathogens found in each lesion, as well as their medical and surgical management, vary depending on their embryology. Diagnostic and therapeutic approaches to the most common congenital neck lesions are presented here and discussed in the context of various infectious processes.