ABSTRACT
MOTIVATION: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure. RESULTS: Here, we present phecodeX, an expanded version of phecodes with a revised structure and 1,761 new codes. PhecodeX adds granularity to phenotypes in key disease domains that are under-represented in the current phecode structure-including infectious disease, pregnancy, congenital anomalies, and neonatology-and is a more robust representation of the medical phenome for global use in discovery research. AVAILABILITY AND IMPLEMENTATION: phecodeX is available at https://github.com/PheWAS/phecodeX.
Subject(s)
Genome-Wide Association Study , Phenomics , Polymorphism, Single Nucleotide , PhenotypeABSTRACT
The herpesviruses are the most common infectious agents associated with both primary and secondary cytokine storm syndromes (CSS). While Epstein-Barr Virus (EBV) is most frequently reported in association with CSS, cytomegalovirus (CMV) and many other herpesviruses (e.g., herpes simplex virus, varicella zoster virus, and human herpesviruses 6 and 8) are clearly associated with CSS in children and adults. Immunocompromised hosts, whether due to primary immunodeficiency or secondary immune compromise (e.g., solid organ or stem cell transplantation), appear to be at particularly increased risk of herpesvirus-associated CSS. In this chapter, the association of the non-EBV herpesviruses with CSS will be discussed, including predisposing factors and treatment considerations.
Subject(s)
Cytokine Release Syndrome , Herpesviridae Infections , Herpesviridae , Humans , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Herpesviridae Infections/complications , Herpesviridae/immunology , Herpesviridae/pathogenicity , Herpesviridae/physiology , Immunocompromised HostABSTRACT
BACKGROUND: Musculoskeletal infections (MSKIs) are a major cause of morbidity in the pediatric population and account for nearly 1 in every 10 consultations with a pediatric orthopaedic provider at a tertiary care center. To prevent or deescalate the risk of adverse medical and musculoskeletal outcomes, timely medical intervention in the form of antibiotics and potential surgical debridement is required. While there have been numerous studies indicating the value of laboratory testing during the initial workup of a child with MSKI, few studies to date have examined the utility of longitudinal assessment of laboratory measures in the acute setting to monitor the efficacy of antibiotic therapy and/or surgical intervention. The purpose of this investigation was to retrospectively determine whether measuring changes in the inflammatory response could indicate the need for escalated care. Specifically, this study examined the hypothesis that serial measurements of C-reactive protein (CRP), immediately preoperatively and 2 days after surgical debridement, could predict the need for medical (change in antibiotics) or surgical (additional debridement) escalation. METHODS: Retrospective review of pediatric patients undergoing operative debridement for the treatment of MSKI between September 2009 and December 2015 from whom laboratory data (CRP) was obtained preoperatively and at postoperative day (POD) 2. Patient demographics, the need for escalated care, and patient outcomes were evaluated. RESULTS: Across 135 pediatric patients, preoperative CRP values >90 mg/L and a positive change in CRP at POD2 effectively predicted the need for escalation of care after initial surgical debridement (Area under the Receiver Operator Curve: 0.883). For each 10-unit increase in preoperative CRP or postoperative change in CRP, there was a 21% or 22% increased risk of needing escalated care, respectively. Stratification by preoperative CRP >90 mg/L and change in CRP postoperatively likewise correlated with increased rates of disseminated disease, percent tissue culture positivity, length of stay, and rate of adverse outcomes. CONCLUSIONS: This study demonstrates the utility of serial CRP to assess the need for escalated care in patients being treated for MSKI. As serial CRP measurements become standard of practice in the acute setting, future prospective studies are needed to optimize the timing of CRP reassessment during inpatient hospitalization to prognosticate patient outcomes, weighing both improvements of patient care and clinical burden. LEVEL OF EVIDENCE: Level III-retrospective comparative study.
Subject(s)
Anti-Bacterial Agents , C-Reactive Protein , Humans , Child , C-Reactive Protein/analysis , Retrospective Studies , Biomarkers , Debridement , Anti-Bacterial Agents/therapeutic useABSTRACT
BACKGROUND: With limited severe acute respiratory syndrome coronavirus (SARS-CoV-2) testing capacity in the United States at the start of the epidemic (January-March 2020), testing was focused on symptomatic patients with a travel history throughout February, obscuring the picture of SARS-CoV-2 seeding and community transmission. We sought to identify individuals with SARS-CoV-2 antibodies in the early weeks of the US epidemic. METHODS: All of Us study participants in all 50 US states provided blood specimens during study visits from 2 January to 18 March 2020. Participants were considered seropositive if they tested positive for SARS-CoV-2 immunoglobulin G (IgG) antibodies with the Abbott Architect SARS-CoV-2 IgG enzyme-linked immunosorbent assay (ELISA) and the EUROIMMUN SARS-CoV-2 ELISA in a sequential testing algorithm. The sensitivity and specificity of these ELISAs and the net sensitivity and specificity of the sequential testing algorithm were estimated, along with 95% confidence intervals (CIs). RESULTS: The estimated sensitivities of the Abbott and EUROIMMUN assays were 100% (107 of 107 [95% CI: 96.6%-100%]) and 90.7% (97 of 107 [83.5%-95.4%]), respectively, and the estimated specificities were 99.5% (995 of 1000 [98.8%-99.8%]) and 99.7% (997 of 1000 [99.1%-99.9%]), respectively. The net sensitivity and specificity of our sequential testing algorithm were 90.7% (97 of 107 [95% CI: 83.5%-95.4%]) and 100.0% (1000 of 1000 [99.6%-100%]), respectively. Of the 24 079 study participants with blood specimens from 2 January to 18 March 2020, 9 were seropositive, 7 before the first confirmed case in the states of Illinois, Massachusetts, Wisconsin, Pennsylvania, and Mississippi. CONCLUSIONS: Our findings identified SARS-CoV-2 infections weeks before the first recognized cases in 5 US states.
Subject(s)
COVID-19 , Population Health , Antibodies, Viral , COVID-19/diagnosis , Enzyme-Linked Immunosorbent Assay , Humans , Immunoglobulin G , SARS-CoV-2 , Sensitivity and SpecificityABSTRACT
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased morbidity and mortality in solid organ transplant (SOT) recipients. Despite exclusion from SARS-CoV-2 vaccine clinical trials, these individuals were identified as high-risk and prioritized for vaccination in public health guidelines. METHODS: We prospectively evaluated humoral and cellular immune responses to two doses of the SARS-CoV-2 mRNA vaccine, BNT162b2, in 56 SOT recipients and 26 healthy controls (HCs). Blood specimens collected from participants prior to each dose and following the second dose were tested for SARS-CoV-2-specific antibodies, as well as CD4+ and CD8+ T-cell responses. RESULTS: SOT recipients demonstrated lower mean anti-SARS-CoV-2 antibody levels compared to HCs after each dose, and only 21.6% achieved an antibody response after the second dose within the range of HC responses. Similarly, the percentage of responsive CD4+ and CD8+ T cells in SOT recipients was lower than in HCs. While most HCs showed notable humoral and cellular responses, responses were less concordant in SOT recipients, with some showing evidence of either humoral or cellular response, but not both. CONCLUSION: Humoral and cellular immune responses to the BNT162b2 vaccine are markedly reduced in SOT recipients as compared to HCs, suggesting that SOT recipients may benefit from more tailored regimens such as higher dose and/or additional vaccinations.
Subject(s)
COVID-19 , Organ Transplantation , Antibodies, Viral , BNT162 Vaccine , COVID-19 Vaccines , Humans , Immunity, Cellular , SARS-CoV-2 , Transplant Recipients , Vaccines, Synthetic , mRNA VaccinesABSTRACT
A successful Staphylococcus aureus vaccine remains elusive, and one controversy in the field is whether humans generate a protective adaptive immune response to infection. We developed a bacterial challenge murine assay that directly assesses the protective capacity of adoptively transferred human serum samples. We first validated the model by showing that postpneumococcal vaccine serum samples from humans induced effective clearance of Streptococcus pneumoniae in mice. We then found that human serum samples adoptively transferred from children with invasive S. aureus infections exhibited protection from disease in a murine model, with some samples conferring near complete protection. These findings demonstrate that human serum samples are capable of conferring a protective adaptive response generated by humans during invasive staphylococcal disease, allowing for the study of protective factors in a murine model. Identification of the protective factors present in the most efficacious serum samples would be of high interest as potential staphylococcal vaccine candidates or passive therapeutics.
Subject(s)
Adoptive Transfer , Antibodies, Bacterial/immunology , Sepsis , Staphylococcal Infections , Animals , Child , Disease Models, Animal , Humans , Mice , Sepsis/prevention & control , Staphylococcal Infections/prevention & control , Staphylococcus aureusABSTRACT
PURPOSE OF REVIEW: Staphylococcus aureus is the most common invasive bacterial pathogen infecting children in the U.S. and many parts of the world. This major human pathogen continues to evolve, and recognition of recent trends in epidemiology, therapeutics and future horizons is of high importance. RECENT FINDINGS: Over the past decade, a relative rise of methicillin-susceptible S. aureus (MSSA) has occurred, such that methicillin-resistant S. aureus (MRSA) no longer dominates the landscape of invasive disease. Antimicrobial resistance continues to develop, however, and novel therapeutics or preventive modalities are urgently needed. Unfortunately, several recent vaccine attempts proved unsuccessful in humans. SUMMARY: Recent scientific breakthroughs highlight the opportunity for novel interventions against S. aureus by interfering with virulence rather than by traditional antimicrobial mechanisms. A S. aureus vaccine remains elusive; the reasons for this are multifactorial, and lessons learned from prior unsuccessful attempts may create a path toward an effective preventive. Finally, new diagnostic modalities have the potential to greatly enhance clinical care for invasive S. aureus disease in children.
Subject(s)
Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Anti-Bacterial Agents/therapeutic use , Child , Humans , Microbial Sensitivity Tests , Staphylococcal Infections/diagnosis , Staphylococcal Infections/drug therapy , Staphylococcal Infections/epidemiology , Staphylococcus aureusABSTRACT
OBJECTIVES: To understand the epidemiology of acute hematogenous osteomyelitis and septic arthritis, including clinical and demographic features, microbiology, treatment approaches, treatment-associated complications, and outcomes. STUDY DESIGN: Retrospective cohort study of 453 children with acute hematogenous osteomyelitis and/or septic arthritis from 2009 to 2015. RESULTS: Among the 453 patients, 218 (48%) had acute hematogenous osteomyelitis, 132 (29%) had septic arthritis, and 103 (23%) had concurrent acute hematogenous osteomyelitis/septic arthritis. Treatment failure/recurrent infection occurred in 41 patients (9%). Patients with concurrent acute hematogenous osteomyelitis/septic arthritis had longer hospital stays, longer duration of antibiotic therapy, and were more likely to have prolonged bacteremia and require intensive care. Staphylococcus aureus was identified in 228 (51%) patients, of which 114 (50%) were methicillin-resistant S aureus. Compared with septic arthritis, acute hematogenous osteomyelitis and concurrent acute hematogenous osteomyelitis/septic arthritis were associated with higher odds of treatment failure (OR, 8.19; 95% CI, 2.02-33.21 [P = .003]; and OR, 14.43; 95% CI, 3.39-61.37 [P < .001], respectively). The need for more than 1 surgical procedure was also associated with higher odds of treatment failure (OR, 2.98; 95% CI, 1.18-7.52; P = .021). Early change to oral antibiotic therapy was not associated with treatment failure (OR, 0.64; 95% CI, 0.24-1.74; P = .386). Most (73%) medically attended treatment complications occurred while on parenteral therapy. CONCLUSIONS: Musculoskeletal infections are challenging pediatric infections. S aureus remains the most common pathogen, with methicillin-resistant S aureus accounting for 25% of all cases. Concurrent acute hematogenous osteomyelitis/septic arthritis is associated with more severe disease and worse outcomes. Fewer treatment-related complications occurred while on oral therapy. Early transition to oral therapy was not associated with treatment failure.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Arthritis, Infectious/epidemiology , Gram-Negative Bacterial Infections/epidemiology , Gram-Positive Bacterial Infections/epidemiology , Orthopedic Procedures , Osteomyelitis/epidemiology , Acute Disease , Administration, Oral , Adolescent , Arthritis, Infectious/diagnosis , Arthritis, Infectious/microbiology , Arthritis, Infectious/therapy , Child , Child, Preschool , Combined Modality Therapy , Female , Gram-Negative Bacterial Infections/diagnosis , Gram-Negative Bacterial Infections/microbiology , Gram-Negative Bacterial Infections/therapy , Gram-Positive Bacterial Infections/diagnosis , Gram-Positive Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/therapy , Humans , Infant , Logistic Models , Male , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Osteomyelitis/diagnosis , Osteomyelitis/microbiology , Osteomyelitis/therapy , Retrospective Studies , Staphylococcal Infections/diagnosis , Staphylococcal Infections/epidemiology , Staphylococcal Infections/microbiology , Staphylococcal Infections/therapy , Treatment Outcome , United States/epidemiologyABSTRACT
We used the FilmArray meningitis/encephalitis panel for evaluation of sepsis in febrile neonates. We detected human herpesvirus 6, a virus we did not routinely test for previously, in the cerebrospinal fluid of 7 neonates. In all 7 cases, detection of the virus did not warrant antiviral treatment.
Subject(s)
DNA, Viral/analysis , Encephalitis/complications , Herpesvirus 6, Human/genetics , Meningitis/diagnosis , Roseolovirus Infections/diagnosis , Sepsis/virology , Tertiary Care Centers , Encephalitis/diagnosis , Encephalitis/virology , Female , Humans , Infant , Infant, Newborn , Male , Meningitis/complications , Multiplex Polymerase Chain Reaction , Roseolovirus Infections/complications , Roseolovirus Infections/virology , Sepsis/diagnosis , Sepsis/etiologyABSTRACT
The nutrient metal iron plays a key role in the survival of microorganisms. The iron-regulated surface determinant (Isd) system scavenges heme-iron from the human host, enabling acquisition of iron in iron-deplete conditions in Staphylococcus aureus during infection. The cell surface receptors IsdB and IsdH bind hemoproteins and transfer heme to IsdA, the final surface protein before heme-iron is transported through the peptidoglycan. To define the human B-cell response to IsdA, we isolated human monoclonal antibodies (mAbs) specific to the surface Isd proteins and determined their mechanism of action. We describe the first isolation of fully human IsdA and IsdH mAbs, as well as cross-reactive Isd mAbs. Two of the identified IsdA mAbs worked in a murine septic model of infection to reduce bacterial burden during staphylococcal infection. Their protection was a result of both heme-blocking and Fc-mediated effector functions, underscoring the importance of targeting S. aureus using diverse mechanisms.
Subject(s)
Antibodies, Monoclonal/immunology , Antigens, Bacterial/immunology , Hemeproteins/immunology , Staphylococcal Infections/immunology , Staphylococcus aureus/immunology , Animals , Bacterial Proteins , Disease Models, Animal , Female , Humans , Hydrogen Deuterium Exchange-Mass Spectrometry , Mice , Mice, Inbred BALB C , Receptors, Cell Surface/immunologyABSTRACT
OBJECTIVES: To characterize Staphylococcus aureus isolates recovered from hospitalized children and to determine the concordance between colonizing and invasive isolates. STUDY DESIGN: Children with culture-confirmed, community-onset, invasive S aureus infections were enrolled in this prospective case series from a large children's hospital over a 5-year period. Colonization isolates were obtained from the anterior nares, oropharynx, and inguinal folds and were compared with invasive isolates via repetitive-element, sequence-based polymerase chain reaction testing. Isolates with a ≥96% genetic match were characterized as concordant. RESULTS: A total of 86 S aureus isolates (44 invasive, 42 colonization) were collected from 44 children with invasive infections. Clinical isolates were genetically diverse, 64% of invasive isolates were methicillin-susceptible S aureus (MSSA), and 59% of cases had a colonizing S aureus isolate at the time of hospitalization. Of those who were colonized, at least 1 of their colonization isolates was indistinguishable from the infecting isolate in 88% of cases. Patients with invasive MSSA were significantly more likely to have a concordant MSSA colonization isolate present compared with patients with invasive methicillin-resistant S aureus (MRSA) (61% vs 38%, P < .05). CONCLUSIONS: Invasive MSSA infection was more common than MRSA infection in this pediatric cohort, and patients with MSSA infection were significantly more likely than those with MRSA infection to have concordant colonizing isolates across multiple anatomic sites. These findings warrant larger scale validation and may have important infection control and epidemiologic implications, as unlike MRSA, transmissibility of MSSA largely is ignored in healthcare settings.
Subject(s)
Staphylococcal Infections/epidemiology , Staphylococcus aureus/genetics , Staphylococcus aureus/isolation & purification , Adolescent , Carrier State , Child , Child, Preschool , Community-Acquired Infections/epidemiology , DNA, Bacterial/genetics , Female , Groin/microbiology , Humans , Infant , Infant, Newborn , Male , Molecular Epidemiology , Nasal Cavity/microbiology , New York/epidemiology , Oropharynx/microbiology , Polymerase Chain Reaction , Prospective StudiesABSTRACT
INTRODUCTION: Musculoskeletal infection (MSI) is a common cause of morbidity and hospital resource utilization in the pediatric population. Many physicians prefer to withhold antibiotics until tissue cultures can be taken in an effort to improve culture yields. However, there is little evidence that this practice improves culture results or outcomes in pediatric MSI. Therefore, investigating the effects of antibiotic timing may lead to improved clinical practice guidelines for treating children with MSI. METHODS: An IRB-approved retrospective review was conducted that identified 113 patients aged 0 to 18 who presented to the pediatric emergency room at a tertiary care children's hospital with MSI from 2008 to 2013. Demographic data, culture results, severity markers, and intervention timing were obtained from the medical record. Logistic regression and Cox survival analysis were performed to determine the relationship of antibiotic timing with culture sensitivity and time to discharge. RESULTS: No difference was seen in culture sensitivity antibiotic administration in either the local (55% culture before antibiotics vs. 89% after antibiotics) or disseminated group (76% before vs. 79% after), which persisted when further accounting for disease severity with C-reactive protein. However, later administration of antibiotics in the local infection group correlated with a decreased likelihood of discharge (3.91 d when cultured before antibiotics vs. 2.93 d when cultured after antibiotics; hazard ratio, 0.53; P<0.05). In patients with disseminated infection, antibiotic administration was not shown to correlate with any difference in time to discharge (hazard ratio, 1.08). CONCLUSIONS: The authors were surprised to find that tissue culture sensitivities were not decreased by antibiotic administration in either local or disseminated MSI, suggesting that antibiotic administration should not be delayed to obtain tissue cultures. The correlation of earlier antibiotic administration with shorter length of stay in children with local MSI led the authors to conclude that antibiotics should be initiated as quickly as possible. Further study is necessary to confirm these findings and establish clinical practice guidelines. LEVEL OF EVIDENCE: Level III-retrospective cohort.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Infections , Microbial Sensitivity Tests , Microbiological Techniques/methods , Musculoskeletal Diseases , Time-to-Treatment , Adolescent , Biomarkers , Child, Preschool , Female , Humans , Infant, Newborn , Infections/diagnosis , Infections/drug therapy , Male , Microbial Sensitivity Tests/methods , Microbial Sensitivity Tests/statistics & numerical data , Musculoskeletal Diseases/classification , Musculoskeletal Diseases/diagnosis , Musculoskeletal Diseases/drug therapy , Outcome and Process Assessment, Health Care , Retrospective Studies , Severity of Illness Index , Time-to-Treatment/standards , Time-to-Treatment/statistics & numerical dataABSTRACT
BACKGROUND: The rate of venous thromboembolism in children with musculoskeletal infections (MSKIs) is markedly elevated compared with hospitalized children in general. Predictive biomarkers to identify high-risk patients are needed to prevent the significant morbidity and rare mortality associated with thrombotic complications. We hypothesize that overactivation of the acute phase response is associated with the development of pathologic thrombi and we aim to determine whether elevations in C-reactive protein (CRP) are associated with increased rates of thrombosis in pediatric patients with MSKI. METHODS: A retrospective cohort study measuring CRP in pediatric MSKI patients with or without thrombotic complications. RESULTS: The magnitude and duration of elevation in CRP values correlated with the severity of infection and the development of pathologic thrombosis. In multivariable logistic regression, every 20 mg/L increase in peak CRP was associated with a 29% increased risk of thrombosis (P<0.001). Peak and total CRP were strong predictors of thrombosis with area under the receiver-operator curves of 0.90 and 0.92, respectively. CONCLUSIONS: Future prospective studies are warranted to further define the discriminatory power of CRP in predicting infection-provoked thrombosis. Pharmacologic prophylaxis and increased surveillance should be strongly considered in patients with MSKI, particularly those with disseminated disease and marked elevation of CRP. LEVEL OF EVIDENCE: Level III.
Subject(s)
Abscess/complications , Arthritis, Infectious/complications , C-Reactive Protein/analysis , Myositis/complications , Osteomyelitis/complications , Venous Thromboembolism/etiology , Abscess/blood , Arthritis, Infectious/blood , Biomarkers/blood , Child , Child, Preschool , Cohort Studies , Female , Humans , Male , Myositis/blood , Osteomyelitis/blood , Retrospective Studies , Risk , Severity of Illness IndexABSTRACT
BACKGROUND: Musculoskeletal infections (MSKIs) are a common cause of pediatric hospitalization. Children affected by MSKI have highly variable hospital courses, which seem to depend on infection severity. Early stratification of infection severity would therefore help to maximize resource utilization and improve patient care. Currently, MSKIs are classified according to primary diagnoses such as osteomyelitis, pyomyositis, etc. These diagnoses, however, do not often occur in isolation and may differ widely in severity. On the basis of this, the authors propose a severity classification system that differentiates patients based on total infection burden and degree of dissemination. METHODS: The authors developed a classification system with operational definitions for MSKI severity based on the degree of dissemination. The operational definitions were applied retrospectively to a cohort of 202 pediatric patients with MSKI from a tertiary care children's hospital over a 5-year period (2008 to 2013). Hospital outcomes data [length of stay (LOS), number of surgeries, positive blood cultures, duration of antibiotics, intensive care unit LOS, number of days with fever, and number of imaging studies] were collected from the electronic medical record and compared between groups. RESULTS: Patients with greater infection dissemination were more likely to have worse hospital outcomes for LOS, number of surgeries performed, number of positive blood cultures, duration of antibiotics, intensive care unit LOS, number of days with fever, and number of imaging studies performed. Peak C-reactive protein, erythrocyte sedimentation rate, white blood cell count, and temperature were also higher in patients with more disseminated infection. CONCLUSIONS: The severity classification system for pediatric MSKI defined in this study correlates with hospital outcomes and markers of inflammatory response. The advantage of this classification system is that it is applicable to different types of MSKI and represents a potentially complementary system to the previous practice of differentiating MSKI based on primary diagnosis. Early identification of disease severity in children with MSKI has the potential to enhance hospital outcomes through more efficient resource utilization and improved patient care. LEVEL OF EVIDENCE: Level II-prognostic study.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Osteomyelitis , Pyomyositis , Adolescent , Biomarkers/blood , Blood Sedimentation , C-Reactive Protein/analysis , Child , Child, Preschool , Female , Hospitals, Pediatric/statistics & numerical data , Humans , Length of Stay/statistics & numerical data , Leukocyte Count/methods , Male , Osteomyelitis/classification , Osteomyelitis/diagnosis , Osteomyelitis/epidemiology , Outcome Assessment, Health Care/methods , Pyomyositis/classification , Pyomyositis/diagnosis , Pyomyositis/epidemiology , Retrospective Studies , Severity of Illness Index , United States/epidemiologyABSTRACT
The 2-component leukotoxin LukAB is critical for Staphylococcus aureus targeting and killing of human neutrophils ex vivo and is produced in the setting of human infection. We report 3 LukAB-specific human monoclonal antibodies (mAbs) with distinct mechanisms of toxin neutralization and in vivo efficacy. Three hybridomas secreting mAbs with anti-LukAB activity (designated SA-13, -15, and -17) were generated from B cells obtained from a 12-year-old boy with S. aureus osteomyelitis. Each of the 3 mAbs neutralized LukAB-mediated neutrophil toxicity, exhibited differing levels of potency, recognized different antigenic sites on the toxin, and displayed at least 2 distinct mechanisms for cytotoxic inhibition. SA-15 bound exclusively to the dimeric form of the toxin, suggesting that human B cells recognize epitopes on the dimerized form of LukAB during natural infection. Both SA-13 and SA-17 bound the LukA monomer and the LukAB dimer. Although all 3 mAbs potently neutralized cytotoxicity, only SA-15 and SA-17 significantly inhibited toxin association with the cell surface. Treatment with a 1:1 mixture of mAbs SA-15 and SA-17 resulted in significantly lower bacterial colony counts in heart, liver, and kidneys in a murine model of S. aureus sepsis. These data describe the isolation of diverse and efficacious antitoxin mAbs.
Subject(s)
Antibodies, Bacterial/blood , Antibodies, Monoclonal/blood , Bacterial Proteins/immunology , Leukocidins/immunology , Neutrophils/immunology , Staphylococcal Infections/microbiology , Animals , B-Lymphocytes/immunology , Child , Female , Humans , Hybridomas , Male , Mice , Mice, Inbred BALB C , Regression Analysis , Staphylococcus aureusABSTRACT
The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB. A secondary aim was to examine the lot-to-lot variability of IVIg in the binding and neutralization of LukAB. We studied 24 distinct lots of IVIg and compared them to serum from children with invasive S. aureus infection (in the acute and convalescent phases) and from healthy, uninfected controls. We found that all lots of IVIg contained functional antibodies targeting LukAB. After adjusting for total antibody content per sample, we found that the amount of anti-LukAB antibody in IVIg was similar to that seen with healthy controls and less than that seen with patients with invasive S. aureus infection. IVIg samples had lower neutralization capacity than samples from healthy controls and children with invasive infection. IVIg had remarkably little lot-to-lot variation in LukAB binding but had significantly more variation in toxin neutralization. These results represent the first report of functional antibodies against the important S. aureus leukocidin LukAB in IVIg. Given the frequent clinical use of IVIg for severe S. aureus infections, improving our understanding of functional antibody properties exhibited by this therapeutic is essential.
Subject(s)
Antibodies, Neutralizing/immunology , Bacterial Proteins/immunology , Immunoglobulins, Intravenous/immunology , Leukocidins/immunology , Staphylococcal Infections/pathology , Staphylococcus aureus/pathogenicity , Antibodies, Neutralizing/blood , Antibody Affinity/immunology , Child , Child, Preschool , Humans , Staphylococcal Infections/immunology , Staphylococcal Infections/therapy , Staphylococcus aureus/immunology , Virulence Factors/immunologyABSTRACT
OBJECTIVES: Clostridium difficile, a common cause of antibiotic-associated diarrhea, has been reported to recur in high rates in adults. The rates and risk factors for recurrent C difficile infection (rCDI) in children have not been well established. METHODS: We conducted a retrospective cohort study of 186 pediatric patients seen at a tertiary care referral center for a 5-year period diagnosed as having a primary C difficile infection. Children with recurrent disease, defined as return of symptoms of C difficile infection and positive testing ≤60 days after the completion of therapy, were compared with children who did not experience an episode of recurrence. RESULTS: Of the 186 pediatric patients included in this study, 41 (22%) experienced rCDI. On univariable analysis, factors significantly associated with rCDI included malignancy, recent hospitalization, recent surgery, antibiotic use, number of antibiotic exposures by class, acid blocker use, immunosuppressant use, and hospital-acquired disease. On multivariable analysis, malignancy (odds ratio [OR] 3.39, 95% confidence interval [CI] 1.52-7.85), recent surgery (OR 2.40, 95% CI 1.05-5.52), and the number of antibiotic exposures by class (OR 1.33, 95% CI 1.01-1.75) were significantly associated with recurrent disease in children. CONCLUSIONS: The rate of rCDI in children was 22%. Recurrence was significantly associated with the risk factors of malignancy, recent surgery, and the number of antibiotic exposures by class.
Subject(s)
Clostridioides difficile/isolation & purification , Enterocolitis, Pseudomembranous/epidemiology , Adolescent , Anti-Bacterial Agents/therapeutic use , Child , Child, Preschool , Clostridioides difficile/drug effects , Clostridioides difficile/growth & development , Cohort Studies , Comorbidity , Enterocolitis, Pseudomembranous/drug therapy , Enterocolitis, Pseudomembranous/microbiology , Enterocolitis, Pseudomembranous/prevention & control , Follow-Up Studies , Hospitals, Pediatric , Humans , Infant , Recurrence , Retrospective Studies , Risk Factors , Tennessee/epidemiology , Tertiary Care CentersABSTRACT
OBJECTIVE: The characteristics of staphylococcal skin and soft tissue infections (SSTIs) are poorly understood in northern South America and the Caribbean. The objectives of this study were to determine the frequency of methicillin resistance among Staphylococcus aureus isolates in an emergency department (ED) in Guyana and to identify specific molecular characteristics of these methicillin-resistant Staphylococcus aureus (MRSA) strains. METHODS: This was a cross-sectional study conducted at the main teaching hospital in Georgetown, Guyana. Eligible subjects included patients of all ages with SSTIs with obtainable purulent material. Purulent material was cultured, and S. aureus isolates were evaluated for antibiotic susceptibilities by disc diffusion. Molecular characterisation of MRSA isolates included identification of SCCmec type, assignment of genetic relatedness by rep-PCR and determination of the presence of two exotoxins, Panton-Valentine Leukocidin (PVL) and LukAB. RESULTS: Eighty-five samples were collected; of these, 47 grew S. aureus. 24 of the 47 S. aureus samples were MRSA (51%; 95% CI 37% to 65%), representing 28% of all samples. All MRSA isolates were SCCmec type IV, PVL positive, LukAB positive and were highly related to the current epidemic clone in the USA, USA300. CONCLUSIONS: Here, we demonstrate a clinically significant proportion of methicillin resistance in SSTI-associated staphylococcal isolates. Guyanese isolates were highly related to the most common community-associated strain seen in the USA, USA300. These results have important implications for empiric antibiotic therapy and infection control policies in Guyana and similar settings.
Subject(s)
Emergency Service, Hospital/statistics & numerical data , Methicillin-Resistant Staphylococcus aureus/genetics , Soft Tissue Infections/epidemiology , Staphylococcal Skin Infections/epidemiology , Adolescent , Adult , Aged , Bacterial Proteins/genetics , Bacterial Toxins/genetics , Child , Child, Preschool , Cross-Sectional Studies , DNA, Bacterial/genetics , Exotoxins/genetics , Female , Guyana/epidemiology , Humans , Infant , Leukocidins/genetics , Male , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Middle Aged , Prevalence , Sequence Analysis, DNA , Soft Tissue Infections/microbiology , Staphylococcal Skin Infections/microbiology , Young AdultABSTRACT
IMPORTANCE: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines. OBJECTIVE: To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015. INTERVENTIONS: The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site. MAIN OUTCOMES AND MEASURES: Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7. RESULTS: Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001). CONCLUSIONS AND RELEVANCE: The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01942265.