Aditya H. Gaur

Risk factors for severe respiratory syncytial virus disease in children with cancer: the importance of lymphopenia and young age.

OBJECTIVE. We sought to determine the epidemiologic features of respiratory syncytial virus infection in immunocompromised pediatric patients and to identify the risk factors for severe disease. METHODS. We designed a retrospective study examining the experience with respiratory syncytial virus infection in pediatric patients with underlying malignancies and hematopoietic stem cell transplant recipients seen between 1997 and 2005. Clinical and laboratory data were extracted from patient records, and independent predictors of disease severity were investigated. RESULTS. Fifty-eight patients met the study criteria. Twenty-three patients (40%) had underlying diagnoses of acute lymphoblastic leukemia, 11 (19%) had solid tumors, and 24 (41%) were hematopoietic stem cell transplant recipients, had acute myeloid leukemia, or had severe combined immunodeficiency syndrome. Seventeen patients (29%) were <2 years of age. Overall, 16 patients (28%) developed lower respiratory tract infections. The frequency of lower respiratory tract infections was highest in patients with hematopoietic stem cell transplants, acute myeloid leukemia, or severe combined immunodeficiency syndrome (42%). Independent predictors of lower respiratory tract infections were profound lymphopenia, with absolute lymphocyte counts of <100 cells per mm3, and age of ≤2 years. Of all patients with lower respiratory tract infections, 31% died as a result of respiratory syncytial virus infection. The overall mortality rate was low (5 of 58 patients; 8.6%). All deaths occurred in patients with lower respiratory tract infections who were before or after hematopoietic stem cell transplants or were <2 years of age and receiving treatment for acute myeloid leukemia. Neutropenia was not a predictor of respiratory syncytial virus lower respiratory tract infection or death. CONCLUSIONS. This study identified profound lymphopenia and young age as independent predictors of respiratory syncytial virus-related lower respiratory tract infections in immunocompromised children. No association between neutropenia and respiratory syncytial virus-related morbidity or death was found. These findings can guide interventions for respiratory syncytial virus infection in high risk hosts.

Bacillus cereus Bacteremia and Meningitis in Immunocompromised Children

Two cases of Bacillus cereus meningitis in immunocompromised children at our hospital within a 2-month period prompted us to review B. cereus--related invasive disease. We identified 12 patients with B. cereus isolated in blood cultures from September 1988 through August 2000 at our institution. Three of these patients also had B. cereus isolated from CSF specimens; 1 additional patient had possible CNS involvement (33%, group A), whereas 8 patients had no evidence of CNS involvement (67%, group B). Patients in group A were more likely to have neutropenia at the onset of sepsis and were more likely to have an unfavorable outcome. They were also more likely to have received intrathecal chemotherapy in the week before the onset of their illness. Two patients from group A died. One survived with severe sequelae. The fourth patient had mild sequelae at follow-up. No sequelae or deaths occurred among patients in group B. In patients with unfavorable outcomes, the interval from the time of recognition of illness to irreversible damage or death was short, which demonstrates a need for increased awareness, early diagnosis, and more-effective therapy, particularly that which addresses B. cereus toxins.

PG4KDS: A model for the clinical implementation of pre‐emptive pharmacogenetics

Pharmacogenetics is frequently cited as an area for initial focus of the clinical implementation of genomics. Through the PG4KDS protocol, St. Jude Childrens Research Hospital pre‐emptively genotypes patients for 230 genes using the Affymetrix Drug Metabolizing Enzymes and Transporters (DMET) Plus array supplemented with a CYP2D6 copy number assay. The PG4KDS protocol provides a rational, stepwise process for implementing gene/drug pairs, organizing data, and obtaining consent from patients and families. Through August 2013, 1,559 patients have been enrolled, and four gene tests have been released into the electronic health record (EHR) for clinical implementation: TPMT, CYP2D6, SLCO1B1, and CYP2C19. These genes are coupled to 12 high‐risk drugs. Of the 1,016 patients with genotype test results available, 78% of them had at least one high‐risk (i.e., actionable) genotype result placed in their EHR. Each diplotype result released to the EHR is coupled with an interpretive consult that is created in a concise, standardized format. To support‐gene based prescribing at the point of care, 55 interruptive clinical decision support (CDS) alerts were developed. Patients are informed of their genotyping result and its relevance to their medication use through a letter. Key elements necessary for our successful implementation have included strong institutional support, a knowledgeable clinical laboratory, a process to manage any incidental findings, a strategy to educate clinicians and patients, a process to return results, and extensive use of informatics, especially CDS. Our approach to pre‐emptive clinical pharmacogenetics has proven feasible, clinically useful, and scalable.

Etiology and Clinical Course of Febrile Neutropenia in Children with Cancer

Background The etiology, clinical course, and outcome of fever and neutropenia (FN) in children with cancer using the current FN guidelines and diagnostic resources in the United States have not been well described. Patients and Methods Medical records of a randomly selected FN episode per patient during 2004-2005 at a pediatric oncology center were reviewed. Patients were managed as per institutional FN guidelines and blood cultures collected in continuously read BACTEC bottles. Results Of 337 FN episodes, infection was proven in 86 (25%) and probable in 75 (22%). In all, 177 episodes (53%) were judged fever of unknown origin (FUO). Bacteremia accounted for most (41) of the proven bacterial episodes, with viridans streptococci (13), Pseudomonas spp. (6) and Escherichia coli (6) the most frequently isolated organisms. The median time to positivity of blood cultures was 12 hours (range, 5.4-143.7) with 93% positive within 24 hours of incubation. Viral pathogens were identified in 29 (34%) episodes. Compared with other patients, those with FUO had shorter median duration of fever (0.5 vs. 2.0 d; P<0.0001) and hospitalization (3 vs. 6 d; P<0.0001), longer median duration since last chemotherapy (6.0 vs. 4.0 d; P=0.01), and were less likely to have a diagnosis of acute myelogenous leukemia (11% vs. 22%; P=0.009) or develop a clinical complication (5.1% vs. 24.4%; P<0.0001). Conclusions Despite currently available diagnostic resources, the majority of patients with FN have FUO marked by a low rate of clinical complications and no infection-related mortality. Emergence of viridans streptococci as the most common blood isolate has affected FN treatment recommendations. Study findings will help further development of strategies for risk stratified management of fever with neutropenia in pediatric patients.

Practice of Feeding Premasticated Food to Infants: A Potential Risk Factor for HIV Transmission

OBJECTIVES: Although some caregivers are known to premasticate food for infants, usually during the weaning period, HIV transmission has not been linked to this practice. We describe 3 cases of HIV transmission in the United States possibly related to this practice. PATIENTS AND METHODS: Three cases of HIV infection were diagnosed in children at ages 9, 15, and 39 months; clinical symptomatology prompted the testing. A thorough investigation to rule out alternative modes of transmission was conducted. In addition, phylogenetic comparisons of virus from cases and suspected sources were performed by using the C2V3C3 or gp41 region of env and the p17 coding region of gag. RESULTS: In 2 cases, the mothers were known to be infected with HIV, had not breastfed their children, and perinatal transmission of HIV had previously been ruled out following US HIV testing guidelines. In the third case, a great aunt who helped care for the child was infected with HIV, but the childs mother was not. All 3 children were fed food on multiple occasions that had been premasticated by a care provider infected with HIV; in 2 cases concurrent oral bleeding in the premasticating adult was described. Phylogenetic analyses supported the epidemiologic conclusion that the children were infected through exposure to premasticated food from a caregiver infected with HIV in 2 of the 3 cases. CONCLUSIONS: The reported cases provide compelling evidence linking premastication to HIV infection, a route of transmission not previously reported that has important global implications including being a possible explanation for some of the reported cases of “late” HIV transmission in infants, so far attributed to breastfeeding. Until the risk of premastication and modifying factors (eg, periodontal disease) are better understood, we recommend that health care providers routinely query childrens caregivers and expecting parents who are infected with HIV or at risk of HIV infection about this feeding practice and direct them to safer, locally available, feeding options.

Early Archiving and Predominance of Nonnucleoside Reverse Transcriptase Inhibitor—Resistant HIV-1 among Recently Infected Infants Born in the United States

BACKGROUND The extent to which drug-resistant human immunodeficiency virus type 1 (HIV-1) acquired through mother-to-child transmission (MTCT) or failed chemoprophylaxis populates viral reservoirs and limits responses to antiretroviral treatment in infants is unknown. METHODS We evaluated the presence, type, and persistence of drug-resistant HIV-1 in pretreatment plasma and resting CD4(+) T cells from US infants enrolled in a multicenter, open-label, phase 1/2 treatment trial of lopinavir/ritonavir (Pediatric AIDS Clinical Trials Group Protocol 1030) in young infants. RESULTS Twenty-two consecutively enrolled infants initiating highly active antiretroviral therapy at a median age of 9.7 weeks and treated for up to 96 weeks were studied. Drug-resistant HIV-1 was present in 5 (23.8%) of 21 infants analyzed; 4 (80.0%) had nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant HIV-1, only 1 of whom had a history of receiving nevirapine chemoprophylaxis. All 4 infants had NNRTI-resistant variants other than the K103N mutation. The fifth infant had the M184V mutation. Drug-resistant virus was archived in the resting CD4(+) T cell latent reservoir in all 5 infants. CONCLUSIONS The high rate, types, and early archiving of drug-resistant HIV-1 suggests that resistance testing be considered for infants, especially when an NNRTI-based regimen is planned. Furthermore, drug-resistance outcomes in infants should be an important secondary end point in MTCT trials.

Motivating factors for high rates of influenza vaccination among healthcare workers.

BACKGROUND Recent guidance from related regulatory agencies and medical societies supports mandatory vaccination of healthcare workers (HCW) against influenza. At St. Jude Childrens Research Hospital, a pediatric oncology referral center, more than 90% of HCWs receive vaccine each year without a policy mandating immunization. Factors associated with HCW uptake of influenza vaccines have not previously been evaluated in a high compliance rate setting. METHODS A structured, anonymous, electronic questionnaire was distributed in August 2010 to employees (HCW and non-HCW). Demographics, prior receipt of influenza vaccines, reasons for acceptance or refusal of seasonal and 2009 H1N1 pandemic vaccine, and attitudes on mandatory vaccination were assessed. RESULTS 95.0% of 925 HCWs and 63.1% of all 3227 qualifying employees responded to the survey. 93.8% and 75.2% of HCW reported receiving seasonal and 2009 H1N1 influenza vaccines, respectively, in the 2009-2010 season. Benefits to self and/or patients were cited as the most frequent reasons for accepting seasonal (83.5% and 78.3%, respectively) and 2009 H1N1 (85.9% and 81.1%, respectively) vaccination. 36.6% of HCWs opposed mandating influenza vaccination; 88.2% and 59.9% of whom reported receiving the seasonal and 2009 H1N1 influenza vaccines, respectively. Violation of freedom of choice and personal autonomy were the most frequently reported reasons for opposition. CONCLUSION In this cohort of HCWs with a high influenza vaccination rate, realistic assessments of the potential benefits of vaccination appear to have driven the choice to accept immunization. Despite this, mandating vaccination was viewed unfavorably by a significant minority of vaccinated individuals. Employee concerns over autonomy should be addressed as institutions transition to mandatory vaccination policies.

Preventing CLABSIs Among Pediatric Hematology/Oncology Inpatients: National Collaborative Results

OBJECTIVES: Central lines (CLs) are essential for the delivery of modern cancer care to children. Nonetheless, CLs are subject to potentially life-threatening complications, including central line–associated bloodstream infections (CLABSIs). The objective of this study was to assess the feasibility of a multicenter effort to standardize CL care and CLABSI tracking, and to quantify the impact of standardizing these processes on CLABSI rates among pediatric hematology/oncology inpatients. METHODS: We conducted a multicenter quality improvement collaborative starting in November 2009. Multidisciplinary teams at participating sites implemented a standardized bundle of CL care practices and adopted a common approach to CLABSI surveillance. RESULTS: Thirty-two units participated in the collaborative and reported a mean, precollaborative CLABSI rate of 2.85 CLABSIs per 1000 CL-days. Self-reported adoption of the CL care bundle was brisk, with average compliance approaching 80% by the end of the first year of the collaborative and exceeding 80% thereafter. As of August 2012, the mean CLABSI rate during the collaborative was 2.04 CLABSIs per 1000 CL-days, a reduction of 28% (relative risk: 0.71 [95% confidence interval: 0.55–0.92]). Changes in self-reported CL care bundle compliance were not statistically associated with changes in CLABSI rates, although there was little variability in bundle compliance rates after the first year of the collaborative. CONCLUSIONS: A multicenter quality improvement collaborative found significant reductions in observed CLABSI rates in pediatric hematology/oncology inpatients. Additional interventions will likely be required to bring and sustain CLABSI rates closer to zero for this high-risk population.

Diagnosis of catheter-related bloodstream infections among pediatric oncology patients lacking a peripheral culture, using differential time to detection.

Background: Current methods for in situ diagnosis of catheter-related bloodstream infections require concurrent collection of central venous catheter (CVC) and peripheral vein (PV) blood cultures. Both the pain and inconvenience of PV cultures are undesirable. Methods: A prospective study was conducted (August 2002 to March 2004) to assess the accuracy of diagnosing catheter-related bloodstream infections based on the difference in time to detection of blood cultures drawn concurrently from 2 lumens of a multilumen CVC. This difference in time to detection between 2 lumens was compared with results of the standard criterion with paired CVC and PV blood cultures. Results: Twenty-one infectious episodes were categorized as catheter-related bloodstream infections and 38 as non-catheter-related bloodstream infections. With a cutoff in difference in time to detection between 2 lumens of ≥180 minutes, the sensitivity of this test to diagnose a catheter-related bloodstream infection was 61% (95% confidence interval, 39–80%) and the specificity was 94% (95% confidence interval, 82–99%). In 4 of 7 episodes with false-negative results, the colony counts in cultures from both lumens were >400 colony-forming units/mL (maximal value reported), indicating the limitation of this method when both lumens of the catheter are colonized. With the pretest probability of catheter-related bloodstream infections ranging from 28% to 54%, the positive predictive value of a difference in time to detection between 2 lumens of ≥180 minutes for diagnosis of catheter-related bloodstream infections ranged from 81% to 93% and the negative predictive value ranged from 67% to 86%. Conclusion: Within the context of its limitations, this novel method provides an alternative for diagnosing catheter-related bloodstream infections among patients with a CVC, without PV cultures.

The use and abuse of antibiotics and the development of antibiotic resistance

The growing problem of antibiotic resistance has made the formerly routine therapy of many infectious diseases challenging, and, in rare cases, impossible. The widespread nature of the problem has led some experts to speculate about a “post-antibiotic era.” Furthermore, though antibiotic resistance occurs in nature and is an inevitable consequence of even the most prudent antibiotic use, it is clear that our overuse and misuse of antibiotics is responsible for most of the recent increases in antibiotic resistance (McGowan, 1983; Austin et al., 1999; Arnold and Straus, 2005). Judicious and rational antibiotic use has the potential to limit the emergence of clinically important antibiotic resistance and may be able to reduce the impact of resistance that has already developed, effectively prolonging the shelf life of today’s (and tomorrow’s) antibiotics (Dowell et al., 1988). Nonetheless, the threat posed by antibiotic-resistant pathogens has been a wakeup call for modern medicine – developing new antibiotics is important but strategies to prevent infectious diseases (by immunization or other public health measures) will always be preferable when feasible.