Hana Hakim

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.

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.

Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults

BACKGROUND Influenza vaccination is recommended for immunocompromised patients. METHODS Children (6 months to 21 years) with cancer, HIV infection, or sickle cell disease (SCD) received 1 or 2 doses of pandemic 2009 H1N1 monovalent influenza vaccine (H1N1 MIV). Safety and tolerability, hemagglutination inhibition (HI) and microneutralization (MN) antibody titers were measured against 2009 H1N1 influenza A virus after each dose. Seroprotection (SP) and seroconversion (SC) rates were determined. RESULTS 103 participants were enrolled and 99 were evaluable (39 with HIV, 37 with cancer and 23 with SCD). Mean age (±SD) was 7.9 (±5.4) years for cancer participants, 18.0 (±3.5) for HIV, and 13.3 (±4.2) for SCD. 54% were males; 65% black; and 96% had received seasonal influenza vaccine. HIV-infected participants had a median CD4 count of 625 cells/mm(3) (range, 140-1260). 46% had an undetectable HIV viral load and 41% were perinatally infected. No participant had vaccine-related serious adverse events. None developed influenza A proven illness during the 6 months after the vaccine. Local injection reactions were reported in 29% and systemic reactions in 42% after the first dose of vaccine. SC and SP were achieved after the last dose in 48% and 52%, respectively, of participants with leukemia or lymphoma, 50% and 75% of participants with solid tumors, 63% and 92% of HIV-infected participants, and 74% and 100% of participants with SCD. CONCLUSION H1N1 MIV was safe and well tolerated. H1N1 MIV resulted in an adequate immune response in children with SCD. It was only modestly immunogenic in cancer or HIV participants.

Immunogenicity and safety of high-dose trivalent inactivated influenza vaccine compared to standard-dose vaccine in children and young adults with cancer or HIV infection

BACKGROUND Approaches to improve the immune response of immunocompromised patients to influenza vaccination are needed. METHODS Children and young adults (3-21 years) with cancer or HIV infection were randomized to receive 2 doses of high-dose (HD) trivalent influenza vaccine (TIV) or of standard-dose (SD) TIV. Hemagglutination inhibition (HAI) antibody titers were measured against H1, H3, and B antigens after each dose and 9 months later. Seroconversion was defined as ≥4-fold rise in HAI titer comparing pre- and post-vaccine sera. Seroprotection was defined as a post-vaccine HAI titer ≥1:40. Reactogenicity events (RE) were solicited using a structured questionnaire 7 and 14 days after each dose of vaccine, and adverse events by medical record review for 21 days after each dose of vaccine. RESULTS Eighty-five participants were enrolled in the study; 27 with leukemia, 17 with solid tumor (ST), and 41 with HIV. Recipients of HD TIV had significantly greater fold increase in HAI titers to B antigen in leukemia group and to H1 antigen in ST group compared to SD TIV recipients. This increase was not documented in HIV group. There were no differences in seroconversion or seroprotection between HD TIV and SD TIV in all groups. There was no difference in the percentage of solicited RE in recipients of HD TIV (54% after dose 1 and 38% after dose 2) compared to SD TIV (40% after dose 1 and 20% after dose 2, p=0.27 and 0.09 after dose 1 and 2, respectively). CONCLUSION HD TIV was more immunogenic than SD TIV in children and young adults with leukemia or ST, but not with HIV. HD TIV was safe and well-tolerated in children and young adults with leukemia, ST, or HIV.

Predicting microbiologically defined infection in febrile neutropenic episodes in children: global individual participant data multivariable meta-analysis.

Background:Risk-stratified management of fever with neutropenia (FN), allows intensive management of high-risk cases and early discharge of low-risk cases. No single, internationally validated, prediction model of the risk of adverse outcomes exists for children and young people. An individual patient data (IPD) meta-analysis was undertaken to devise one.Methods:The ‘Predicting Infectious Complications in Children with Cancer’ (PICNICC) collaboration was formed by parent representatives, international clinical and methodological experts. Univariable and multivariable analyses, using random effects logistic regression, were undertaken to derive and internally validate a risk-prediction model for outcomes of episodes of FN based on clinical and laboratory data at presentation.Results:Data came from 22 different study groups from 15 countries, of 5127 episodes of FN in 3504 patients. There were 1070 episodes in 616 patients from seven studies available for multivariable analysis. Univariable analyses showed associations with microbiologically defined infection (MDI) in many items, including higher temperature, lower white cell counts and acute myeloid leukaemia, but not age. Patients with osteosarcoma/Ewings sarcoma and those with more severe mucositis were associated with a decreased risk of MDI. The predictive model included: malignancy type, temperature, clinically ‘severely unwell’, haemoglobin, white cell count and absolute monocyte count. It showed moderate discrimination (AUROC 0.723, 95% confidence interval 0.711–0.759) and good calibration (calibration slope 0.95). The model was robust to bootstrap and cross-validation sensitivity analyses.Conclusions:This new prediction model for risk of MDI appears accurate. It requires prospective studies assessing implementation to assist clinicians and parents/patients in individualised decision making.

Clinical and demographic characteristics of seasonal influenza in pediatric patients with cancer.

Background: Changes in oncology care and the diagnosis and management of influenza over the past several decades may have altered the epidemiology and outcomes of influenza in pediatric oncology patients. Methods: The clinical features and outcomes of 102 pediatric patients undergoing cancer therapy during 107 episodes of influenza between January 2002 and April 2009 were retrospectively ascertained. Results: Median age at the time of influenza was 7.2 years (interquartile range: 3.8–11.2 years); 46% of patients were male. Nineteen patients (18%) were recipients of hematopoietic stem cell transplants. Patients’ median absolute neutrophil and lymphocyte counts were 1300/&mgr;L (interquartile range: 500–2967/&mgr;L) and 360/&mgr;L (interquartile range: 180–836/&mgr;L), respectively. Twelve patients (11%) had coinfections with influenza and one or more other respiratory pathogens. Influenza prompted patients’ hospitalization during 64% of episodes, and 75% received antiviral therapy. Complications occurred in 30% of infections and serious complications occurred in 7%. Three patients died, but no deaths were directly attributable to influenza. Most patients had delays in cancer therapy; the median delay was 5 days. Neutropenia, concurrent infection, increasing age and having received hematopoietic stem cell transplant increased the risk of serious complications. Conclusions: Advances in the management of pediatric cancer and influenza have not altered the epidemiology and outcome of influenza in oncology patients. Clinical features identify subgroups of patients with influenza who are at risk of poor outcomes and those with a good prognosis.

Levofloxacin Prophylaxis During Induction Therapy for Pediatric Acute Lymphoblastic Leukemia

Background Infection is the most important cause of treatment-related morbidity and mortality in pediatric patients treated for acute lymphoblastic leukemia (ALL). Although routine in adults with leukemia, antibacterial prophylaxis is controversial in pediatrics because of insufficient evidence for its efficacy or antibiotic choice and concerns about promoting antibiotic resistance and Clostridium difficile infection. Methods This was a single-center, observational cohort study of patients with newly diagnosed ALL, comparing prospectively collected infection-related outcomes in patients who received no prophylaxis, levofloxacin prophylaxis, or other prophylaxis during induction therapy on the total XVI study. A propensity score-weighted logistic regression model was used to adjust for confounders. Results Of 344 included patients, 173 received no prophylaxis, 69 received levofloxacin prophylaxis, and 102 received other prophylaxis regimens. Patients receiving prophylaxis had longer duration of neutropenia. Prophylaxis reduced the odds of febrile neutropenia, likely bacterial infection, and bloodstream infection by ≥70%. Levofloxacin prophylaxis alone reduced these infections, but it also reduced cephalosporin, aminoglycoside, and vancomycin exposure and reduced the odds of C. difficile infection by >95%. No increase in breakthrough infections with antibiotic-resistant organisms was seen, but this cannot be excluded. Conclusions This is the largest study to date of antibacterial prophylaxis during induction therapy for pediatric ALL and the first to include a broad-spectrum fluoroquinolone. Prophylaxis prevented febrile neutropenia and systemic infection. Levofloxacin prophylaxis also minimized the use of treatment antibiotics and drastically reduced C. difficile infection. Although long-term antibiotic-resistance monitoring is needed, these data support using targeted prophylaxis with levofloxacin in children undergoing induction chemotherapy for ALL. Clinical Trials Registration NCT00549848.

Correlation Between the Interval of Influenza Virus Infectivity and Results of Diagnostic Assays in a Ferret Model

BACKGROUND The relationship between influenza virus infectivity and virus shedding, based on different diagnostic methods, has not been defined. METHODS Three donor ferrets infected with 2009 pandemic influenza A(H1N1) underwent daily quantitative culture, antigen-detection testing, and real-time reverse transcription-polymerase chain reaction (RT-PCR). Eight contacts were sequentially cohoused with each of the donors for 24 hours during days 3-10 after inoculation. RESULTS Transmission was observed until day 5 after inoculation, corresponding to high culture titers and positive results of antigen-detection tests. Real-time RT-PCR showed no relation to the cessation of transmission. CONCLUSIONS Antigen-detection testing and virus culture but not real-time RT-PCR identified the end of the infectious period.

Acute respiratory infections in children and adolescents with acute lymphoblastic leukemia

Knowledge regarding the incidence, clinical course, and impact of respiratory viral infections in children with acute lymphoblastic leukemia (ALL) is limited.

Gut Microbiome Composition Predicts Infection Risk During Chemotherapy in Children With Acute Lymphoblastic Leukemia

Background Myelosuppression-related infections remain important causes of morbidity and mortality in children with acute lymphoblastic leukemia (ALL). Methods By analyzing fecal samples collected at diagnosis and after each of the initial 3 phases of chemotherapy, we evaluated the role of gut microbiota in predicting infections in 199 children with newly diagnosed ALL. The bacterial 16S rRNA gene was analyzed by high-depth sequencing to determine the diversity and composition of the microbiome. Results After the induction and reinduction I phases of chemotherapy, microbial diversity decreased significantly relative to the prechemotherapy value. After chemotherapy, the relative abundance of certain bacterial taxa (eg, Bacteroidetes) decreased significantly, whereas that of other taxa (eg, Clostridiaceae and Streptococcaceae) increased. A baseline gut microbiome characterized by Proteobacteria predicted febrile neutropenia. Adjusting for the chemotherapy phase and ALL risk level, Enterococcaceae dominance (relative abundance ≥30%) predicted significantly greater risk of subsequent febrile neutropenia and diarrheal illness, whereas Streptococcaceae dominance predicted significantly greater risk of subsequent diarrheal illness. Conclusions In children undergoing therapy for newly diagnosed ALL, the relative abundance of Proteobacteria before chemotherapy initiation predicts development of febrile neutropenia, and domination of the gut microbiota by Enterococcaceae or Streptococcaceae at any time during chemotherapy predicts infection in subsequent phases of chemotherapy. Clinical Trial Registration NCT00549848.