Receipt Of Corticosteroids Research Articles

Safety of thoracic radiotherapy in patients with prior immune-related adverse events from immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) and thoracic radiotherapy are increasingly used to treat advanced cancers. Despite data indicating exaggerated radiation toxicities in patients with autoimmune disease, the safety of thoracic radiotherapy in patients with prior ICI-associated immune-related adverse events (irAEs) is undefined. Patients treated from 2014 to 2020 with ICIs were queried for receipt of corticosteroids and radiotherapy. Patients who received thoracic radiation after symptomatic irAEs were assessed for ≥grade 2 radiation pneumonitis (RP). Characteristics predictive of RP were assessed using logistic regression and response relationships were modeled. Among 496 assessed patients, 41 with irAE history subsequently treated with thoracic radiotherapy were analyzed. Most irAEs were grade 2 (n= 21) and 3 (n= 19). Median time from irAE onset to radiotherapy was 8.1 months. Most patients received stereotactic body radiation therapy (n= 20) or hypofractionated radiotherapy (n= 18). In total, 25 patients (61%) developed ≥grade 2 RP at a median of 4 months from radiotherapy and 11 months from onset of irAEs. Three months from RP onset, 16 of 24 (67%) assessable patients had persistent symptoms. Among patients with prior ICI pneumonitis (n= 6), five patients (83%) developed ≥grade 2 RP (grade 2, n= 3; grade ≥3, n= 2). The mean lung radiation dose (MLD) predicted for RP (odds ratio: 1.60, P= 0.00002). The relationship between MLD and RP was strong (area under the receiver-operating characteristic curve: 0.85) and showed an exaggerated dose-response. Among patients with an MLD >5 Gy (n= 26), 21 patients (81%) developed ≥grade 2 RP. This is the first study assessing the toxicity of radiotherapy among patients with prior irAEs from ICIs. Patients with prior irAEs were found to be at very high risk for clinically significant and persistent RP from thoracic radiotherapy. Careful consideration should be given to the possibility of an increased risk of RP, and close monitoring is recommended in these patients.

Corticosteroid Use for Acute Respiratory Tract Infections in Direct-to-Consumer Telemedicine

BackgroundSystemic corticosteroids are not indicated for acute respiratory tract infections yet are nonetheless prescribed in outpatient care. Acute respiratory tract infections are the most common diagnosis in direct-to-consumer telemedicine. The objective of this study was to characterize use of corticosteroids for acute respiratory tract infections in this setting and to assess the association between corticosteroid receipt and patient satisfaction. MethodsEncounters with acute respiratory tract infection patients 18 years and older on a nationwide direct-to-consumer telemedicine platform were conducted by physicians between July 2016 and July 2018. Mixed-effects logistic regression was used to assess differences in the odds of corticosteroid prescription. A second mixed-effects model assessed differences in patient satisfaction by corticosteroid or antibiotic receipt. Adjusted prescribing rates for individual physicians were estimated. Models included diagnoses, patient age and geographic region, physician specialty and geographic region, and antibiotic prescription. ResultsOf the 85,972 encounters with 465 physicians, 11% resulted in the physician prescribing corticosteroids. The median physician prescribing rate was 4.0% (range: <1%-81%). Corticosteroid receipt was associated with higher satisfaction versus receiving nothing (odds ratio: 2.54; 95% confidence interval: 2.25-2.87). Patients who received both an antibiotic and a corticosteroid reported the highest satisfaction (odd ratio: 3.91; 95% confidence interval: 3.27-4.68). There was no correlation between individual physicians’ corticosteroid and antibiotic prescribing rates. ConclusionsCorticosteroid receipt was associated with patient satisfaction. Most physicians rarely prescribed corticosteroids, yet a small number prescribed them frequently. Identification of high-prescribing physicians for educational interventions could reduce use of corticosteroids for acute respiratory tract infections.

Optimal timing of antenatal corticosteroid administration and preterm neonatal and early childhood outcomes

Antenatal corticosteroids reduce morbidity and mortality among preterm neonates. However, the optimal timing of steroid administration with regards to severe neonatal and early childhood morbidity is uncertain. To evaluate the association between the timing of antenatal corticosteroid adminstration and preterm outcomes. We hypothesized that neonates exposed to antenatal corticosteroids 2 to <7 days before delivery would have the lowest risks of neonatal and childhood morbidity. Secondary analysis of two prospective multicenter studies enriched for spontaneous preterm birth, Genomics and Proteomics Network for Preterm Birth Research (11/2007-1/2011) and Beneficial Effect of Antenatal Magnesium (12/1997-5/2004). We included women with singleton gestations who received antenatal corticosteroids and delivered at 23 0/7-33 6/7 weeks' gestation. Women who received ≥1 course of corticosteroids were excluded. Neonatal outcomes were compared by the timing of the first dose of antenatal corticosteroids in relation to delivery: <2 days, 2 to <7 days, 7 to <14 days, and ≥14 days. The primary outcome was respiratory distress syndrome. Secondary outcomes included composite neonatal morbidity (death, intraventricular hemorrhage grade III or IV, periventricular leukomalacia, bronchopulmonary dysplasia, or necrotizing enterocolitis), and early childhood morbidity (death or moderate to severe cerebral palsy at age 2). Multivariable logistic regression estimated the association between timing of antenatal corticosteroid administration and study outcomes. A total of 2,259 subjects met inclusion criteria: 622 (27.5%) received antenatal corticosteroids <2 days before delivery, 821 (36.3%) 2 to <7 days, 401 (17.8%) 7 to <14 days, and 415 (18.4%) ≥14 days. The majority (78.1%) delivered following idiopathic spontaneous preterm labor or preterm premature rupture of membranes at a mean gestational age of 29.5 +/-2.8 weeks. Neonates exposed to antenatal corticosteroids 2 to <7 days before delivery were the least likely to develop respiratory distress syndrome (51.3%), compared to those receiving antenatal corticosteroids <2 days, 7 to <14 days, and ≥14 days before delivery (62.7%, 55.9%, and 57.6%, respectively, p<0.001). Compared to receipt 2 to <7 days before delivery, there was an increased odds of respiratory distress syndrome with receipt of antenatal corticosteroids <2 days (aOR 2.07, 95%CI 1.61-2.66), 7 to <14 days (aOR 1.40, 95% CI 1.07-1.83), and ≥14 days (aOR 2.34, 95%CI 1.78-3.07). Neonates exposed to antenatal corticosteroids ≥14 days before delivery were at increased odds for severe neonatal morbidity (aOR 1.57, 95%CI 1.12-2.19) and early childhood morbidity (aOR 1.74, 95%CI 1.02-2.95), compared to those exposed 2 to <7 days before delivery. There was no significant association between antenatal corticosteroid receipt <2 days or 7 to <14 days and severe neonatal morbidity or severe childhood morbidity. Preterm neonates exposed to antenatal corticosteroids 2 to <7 days before delivery had the lowest odds of respiratory distress syndrome, compared to shorter and longer time intervals between steroid administration and delivery. Antenatal corticosteroid administration ≥14 days before delivery is associated with an increased odds of severe neonatal and childhood morbidity, compared to 2 to <7 days before delivery. These results emphasize the importance of optimally timed antenatal corticosteroids to improve both short- and long-term outcomes.

Genetic variation and fungal infection risk: State of the art.

Fungal infections cause significant mortality in patients with acquired immunodeficiencies including AIDS, hematological malignancies, transplantation, and receipt of corticosteroids, biologics or small-molecule kinase inhibitors that impair key immune pathways. The contribution of several such pathways in antifungal immunity has been uncovered by inherited immunodeficiencies featuring profound fungal susceptibility. Furthermore, the risk of fungal infection in patients with acquired immunodeficiencies may be modulated by single nucleotide polymorphisms (SNPs) in immune-related genes. This review outlines key features underlying human genetic fungal predisposition. The discovery of monogenic disorders that cause fungal disease and the characterization of immune-related gene SNPs that may regulate fungal susceptibility have provided important insights into how genetic variation affects development and outcome of fungal infections in humans. Recognition of individualized genetic fungal susceptibility traits in humans should help devise precision-medicine strategies for risk assessment, prognostication and treatment of patients with opportunistic fungal infections.

Impact of Corticosteroid Administration on Outcomes Following Stereotactic Ablative Radiotherapy for Non–small-cell Lung Cancer

IntroductionRadiotherapy produces immune-promoting effects, which may be blunted by the delivery of corticosteroids (CS). We thus aimed to evaluate the impact of CS use on recurrence and survival outcomes of patients with early stage non–small-cell lung cancer treated with stereotactic ablative radiotherapy (SABR). Materials and MethodsA prospectively registered database of patients with stage I to II (T1-3N0M0) stage non–small-cell lung cancer treated with SABR from 2004 to 2015 was queried. Concurrent CS administration was defined as receipt of CS within 2 days of the SABR course. Statistics included Kaplan-Meier survival analysis, Cox proportional hazards modeling, and cumulative incidence analysis utilizing death as a competing risk. ResultsOf 912 patients, 87 (9.5%) received CS with their SABR course. The most common agent was prednisone (64.4%). Indications for CS use were chronic obstructive pulmonary disease in 53 cases (60.9%), chemotherapy in 7 (8.0%), arthritis in 7 (8.0%), chronic pain in 4 (4.6%), transplant-related in 3 (3.4%), and “others” in 13 (14.9%; pneumonia, asthma, anemia, etc.). The median follow-up time was 59.3 months. Compared with patients who did not receive CS, receipt of CS was associated with poorer overall survival (P = .004). However, CS administration was not associated with worse time to progression (P = .766) or any recurrence when using death as a competing risk (local P = .119, regional P = .449, distant P = .847, and any recurrence P = .708). Toxicity rates were not statistically different between cohorts. ConclusionsThese data do not suggest increased recurrence rates when patients undergoing SABR are administered corticosteroids. However, owing to limitations of retrospective analyses, individualized judgment is still recommended.

Serious Infections in Patients Receiving Ibrutinib for Treatment of Lymphoid Cancer.

Ibrutinib is a Bruton tyrosine kinase inhibitor that is used for the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma. Several case series have described opportunistic infections among ibrutinib recipients, but the full extent of these infections is unknown. We sought to determine the spectrum of serious infections associated with ibrutinib treatment. We reviewed the electronic medical records of patients with lymphoid cancer at Memorial Sloan Kettering Cancer Center who received ibrutinib during a 5-year period from 1 January 2012 to 31 December 2016. Serious infections were identified by review of the relevant microbiology, clinical laboratory, and radiology data. Risk factors for infection were determined by means of univariate and multivariate analyses. We analyzed findings in 378 patients with lymphoid cancer who received ibrutinib. The most common underlying cancers were chronic lymphocytic leukemia and mantle cell lymphoma. 84% of patients received ibrutinib as monotherapy. Serious infection developed in 43 patients (11.4%), primarily during the first year of ibrutinib treatment. Invasive bacterial infections developed in 23 (53.5%) of these patients, and invasive fungal infections (IFIs) in 16 (37.2%) .The majority of patients with IFIs during ibrutinib therapy (62.5%) lacked classic clinical risk factors for fungal infection (ie, neutropenia, lymphopenia, and receipt of corticosteroids). Infection resulted in death in 6 of the 43 patients (14%). Patients with lymphoid cancer receiving ibrutinib treatment are at risk for serious infections, including IFIs.

Anxiety Contributes to Poorer Asthma Outcomes in Inner-City Black Adolescents

The factors associated with poor asthma control, exacerbations, and health care utilization in black adolescents are complex and not well understood. Although psychological comorbidities such as anxiety are common in patients with asthma, these have not been studied in this population. This study characterized anxiety and associated asthma features in a cohort of black inner-city adolescents with persistent asthma and determined the association between anxiety symptoms, persistent uncontrolled asthma, and prospective health care utilization over 1 year. Eighty-six black adolescents were enrolled, phenotyped, and screened for anxiety symptoms with the Hospital Anxiety and Depression Scale anxiety subscale (HADS-A). Participants were telephoned every 2 months and a second study visit was completed at 1 year. Primary outcomes included persistent uncontrolled asthma, asthma exacerbations requiring systemic corticosteroids, and unscheduled health care utilization during the 1-year study period. A total of 31% (n= 27) of adolescents had probable anxiety (ie, HADS-A score >7) and 27% (n= 23) had possible anxiety (ie, HADS-A score 5-7) at the baseline visit. Anxiety symptoms were associated with poorer asthma control, more impaired quality of life, and more insomnia symptoms. Adolescents with probable anxiety disorders also had increased odds of persistent uncontrolled asthma and emergency department utilization, with no differences in physician visits or systemic corticosteroid receipt. Inner-city black adolescents with persistent asthma have a high prevalence of anxiety symptoms associated with poorer asthma control, impaired quality of life, insomnia, and increased prospective emergency department utilization for asthma. Routine screening for anxiety disorders may be useful in the clinical management of adolescents with asthma.

Preadmission Oral Corticosteroids Are Associated With Reduced Risk of Acute Respiratory Distress Syndrome in Critically Ill Adults With Sepsis.

To determine the association between preadmission oral corticosteroid receipt and the development of acute respiratory distress syndrome in critically ill patients with sepsis. Retrospective observational study. Medical, surgical, trauma, and cardiovascular ICUs of an academic medical center. A total of 1,080 critically ill patients with sepsis. None. The unadjusted occurrence rate of acute respiratory distress syndrome within 96 hours of ICU admission was 35% among patients who had received oral corticosteroids compared with 42% among those who had not (p = 0.107). In a multivariable analysis controlling for prespecified confounders, preadmission oral corticosteroids were associated with a lower incidence of acute respiratory distress syndrome in the 96 hours after ICU admission (odds ratio, 0.53; 95% CI, 0.33-0.84; p = 0.008), a finding that persisted in multiple sensitivity analyses. The median daily dose of oral corticosteroids among the 165 patients receiving oral corticosteroids, in prednisone equivalents, was 10 mg (interquartile range, 5-30 mg). Higher doses of preadmission oral corticosteroids were associated with a lower incidence of acute respiratory distress syndrome (odds ratio for 30 mg of prednisone compared with 5 mg 0.53; 95% CI, 0.32-0.86). In multivariable analyses, preadmission oral corticosteroids were not associated with in-hospital mortality (odds ratio, 1.41; 95% CI, 0.87-2.28; p = 0.164), ICU length of stay (odds ratio, 0.90; 95% CI, 0.63-1.30; p = 0.585), or ventilator-free days (odds ratio, 1.06; 95% CI, 0.71-1.57; p = 0.783). Among ICU patients with sepsis, preadmission oral corticosteroids were independently associated with a lower incidence of early acute respiratory distress syndrome.

The Spectrum of Serious Infections Among Patients Receiving Immune Checkpoint Blockade for the Treatment of Melanoma.

The risk of infection among patients receiving immune checkpoint blockade is unknown. We retrospectively reviewed medical records of 740 patients with melanoma who received immune checkpoint blockers. Serious infection occurred in 54 patients (7.3%). The main risk factors were receipt of corticosteroids and/or infliximab.

Discontinuation of empirical antifungal therapy in ICU patients using 1,3-β-d-glucan.

Empirical antifungal therapy in high-risk ICU patients is an attractive strategy, but overuse of antifungal agents is a potential problem. We evaluated if ICU patients at high risk to develop candidaemia identified by a prediction rule could discontinue empirical antifungal therapy on the basis of repeatedly negative 1-3-β-d-glucan (BDG) tests. We conducted a multicentre cohort study in 85 ICU patients receiving antibiotics or with central venous catheter plus two additional factors (dialysis, parenteral nutrition, surgery, pancreatitis or receipt of corticosteroids or other immunosuppressive agents) plus either fever, hypothermia, hypotension, acidosis, elevated C-reactive protein or leucocytosis. Blood cultures (days 1 and 2) and BDG (days 1-3, baseline period) were performed and anidulafungin was given. On day 4, patients with negative blood cultures and BDG discontinued antifungal therapy. Registered in ClinicalTrials.gov (NCT01734525). The incidence of candidaemia was 8.2% in patients selected versus 0.5% in patients without entry criteria (16.9 times higher). Sixty-four patients (75.3%) had baseline positive BDG, including 7 with candidaemia. All 21 patients with baseline negative BDG discontinued anidulafungin on day 4. None developed candidaemia until day 30. Early discontinuation of empirical echinocandin therapy in high-risk ICU patients based on consecutive negative BDG tests may be a reasonable strategy, with great potential to reduce the overuse of echinocandins in ICU patients. Prospective studies with a higher number of patients are needed.

Predictors of Circulating Insulin-Like Growth Factor-1 and Insulin-Like Growth Factor-Binding Protein-3 in Critical Illness.

To characterize predictors of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 in acute critical illness with the hypothesis that acute factors associated with critical illness will more strongly predict circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 than chronic clinical or genetic factors. Observational study nested within a large prospective study using multivariable linear regression to model circulating insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 with acute and chronic clinical variables, and genotype from five polymorphisms in insulin-like growth factor pathway genes. ICUs from two large academic medical centers. Five hundred forty-three Caucasian patients with risk factors for acute respiratory distress syndrome and available plasma from early in critical illness. None. Total insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 were measured in plasma using IMMULITE assays (Siemens, Malvern, PA). We examined age, gender, body mass index, cirrhosis, and diabetes, as well as Acute Physiology, Age, and Chronic Health Evaluation III score, acute hepatic dysfunction, pneumonia and aspiration, sepsis/septic shock, acute respiratory distress syndrome, and receipt of corticosteroids. Body mass index, cirrhosis, and acute respiratory distress syndrome were strongly associated with insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 levels; Acute Physiology, Age, and Chronic Health Evaluation III was strongly associated with insulin-like growth factor-1 levels; and age was strongly associated with insulin-like growth factor-binding protein-3. Five polymorphisms (IGF1: rs1520220, rs35767, rs2946834; IGFBP1: rs4619; IGFBP3: rs2854746) were analyzed for associations with plasma levels. When genotypes were added to models, rs2854746 was significantly associated with plasma insulin-like growth factor-binding protein-3. Genotype explained an additional 2% of variability with an overall adjusted R-square of 0.18. Despite the acute derangements of critical illness, both acute and chronic health factors significantly influence circulating levels of insulin-like growth factor-1 and insulin-like growth factor-binding protein-3 early in critical illness. rs2854746 is also significantly associated with insulin-like growth factor-binding protein-3 levels in this ICU cohort. Overall, phenotypic and genotypic factors explained only a modest amount of variability in insulin-like growth factor-1 and insulin-like growth factor-binding protein-3. Further research is needed to understand how to apply these findings to patient care.

Subcutaneous Abscess as a Single Manifestation of Candidiasis

Candida is yeast responsible for the majority of the systemic invasive fungal infections in humans. The incidence of systemic Candida infections has increased, probably due to a rising number of patients with comorbidities and risk factors for invasive candidiasis. Candidemia is a life-threatening infection with high morbidity and mortality especially in individuals at greatest risk of fungal infection, such as patients receiving cancer chemotherapy, immunosuppressive therapy, prolonged antibiotic therapy, neutropenia, recent abdominal surgery, hematological malignancies, central venous catheter, receipt of corticosteroids, parenteral nutrition, etc. In patients infected with the human immunodeficiency virus (HIV) the predominant clinical forms of candidiasis include the mucosal involvement as oral candidiasis, oesophageal candidiasis, Candida vaginitis and Candida balinitis [1]. Although subcutaneous abscess due to Candida species is frequent in non-neutropenic patients after transient candidemia, it is a rare complication in immunocomprimised patients due to HIV/AIDS disease. The few cases reported in the medical literature occur as a complication of bacterial cellulitis, iatrogenic injury, trauma or intravenous drug abuse [2]. We present the clinical history of an HIV patient who developed a subcutaneous abscess due to Candida albicans without fungemia or other focal manifestation of this mycosis.

Prevalence, screening and treatment of latent tuberculosis among oral corticosteroid recipients

To the Editor: Tuberculosis guidelines identify individuals receiving the corticosteroid drug prednisone (or its equivalent) at a dose of >15 mg·day−1 for 2–4 weeks or more as a group at risk of tuberculosis if infected with Mycobacterium tuberculosis [1, 2]. There is an eight-fold increased risk of developing active tuberculosis with such drugs at this dose [3]. However, there is no information on the epidemiology of latent tuberculosis infection (LTBI), screening and treatment among oral corticosteroid users. Tuberculosis guidelines recommend using a threshold of ≥5 mm induration to identify latent infection among oral corticosteroid recipients [1, 2] but this recommendation is not evidence-based. The purpose of this study was to describe the prevalence, screening and treatment of LTBI among oral corticosteroid recipients in the USA. This was a cross-sectional study using US nationally representative, population-level data from the 1999–2000 National Health and Nutrition Examination Survey (NHANES). A description of the survey design and methodology appears elsewhere [4]. Self-reported medication receipt within the past month that required a prescription was collected by NHANES. Medication receipt was confirmed in 83.3% of participants through examiner inspection of prescription containers [5]. Survey participants who received any corticosteroid in an oral formulation within the past month were considered “recipients”. Survey participants who did not receive any oral corticosteroids within the past month were considered “nonrecipients”. Topical, inhaled or intra-articular corticosteroids were not included in this study. Information on total duration of corticosteroid receipt was collected but not dose. A single-step tuberculin skin test (TST) …

Improvement in the outcome of invasive fusariosis in the last decade

Invasive fusariosis (IF) has been associated with a poor prognosis. Although recent series have reported improved outcomes, the definition of optimal treatments remains controversial. The objective of this study was to evaluate changes in the outcome of IF. We retrospectively analysed 233 cases of IF from 11 countries, comparing demographics, clinical findings, treatment and outcome in two periods: 1985–2000 (period 1) and 2001–2011 (period 2). Most patients (92%) had haematological disease. Primary treatment with deoxycholate amphotericin B was more frequent in period 1 (63% vs. 30%, p <0.001), whereas voriconazole (32% vs. 2%, p <0.001) and combination therapies (18% vs. 1%, p <0.001) were more frequent in period 2. The 90-day probabilities of survival in periods 1 and 2 were 22% and 43%, respectively (p <0.001). In period 2, the 90-day probabilities of survival were 60% with voriconazole, 53% with a lipid formulation of amphotericin B, and 28% with deoxycholate amphotericin B (p 0.04). Variables associated with poor prognosis (death 90 days after the diagnosis of fusariosis) by multivariable analysis were: receipt of corticosteroids (hazard ratio (HR) 2.11, 95% CI 1.18–3.76, p 0.01), neutropenia at end of treatment (HR 2.70, 95% CI 1.57–4.65, p <0.001), and receipt of deoxycholate amphotericin B (HR 1.83, 95% CI 1.06–3.16, p 0.03). Treatment practices have changed over the last decade, with an increased use of voriconazole and combination therapies. There has been a 21% increase in survival rate in the last decade.

Active Surveillance of Candidemia in Children from Latin America

Active surveillance is necessary for improving the management and outcomes of patients with candidemia. The aim of this study was to describe the epidemiologic and clinical features of candidemia in pediatric patients in Latin America. Prospective, multicenter, surveillance study of candidemia in a pediatric population from 23 hospitals in 8 Latin America countries between November 2008 and October 2010. Three hundred and two cases of candidemia were reported with a median incidence of 0.81/1000 admissions. Eighty nine (29%) were neonates. The main risk factors were prematurity, intensive care unit (ICU) admission, parenteral nutrition, respiratory disease and mechanical ventilation in neonates and malignancy, neutropenia, neurological disease and previous use of corticosteroids in children. The main species isolated in neonates and children were Candida albicans (43.8% and 35.7%), Candida parapsilosis (27.0% and 26.3%) and Candida tropicalis (14.6% and 14.6%), respectively. The most frequent antifungal therapy used in neonates and children was deoxycholate-amphotericin-B (43.8% and 29.1%) and fluconazole (28.1% and 53.1%). Seventeen neonates (19.1%) and 20 children (9.4%) did not receive antifungal therapy. The 30-day survival rate was 60% in neonates and 72% in children (P = 0.02). Survival was significantly higher in treated than in nontreated neonates (72% vs. 24%; P < 0.001). A multivariate analysis showed that independent predictors for 30-day mortality in children were renal disease (odds ratio: 4.38, 95% confidence interval: 1.92-10.1, P < 0.001) and receipt of corticosteroids (odds ratio: 2.08, 95% confidence interval: 1.04-4.17, P = 0.04). To our knowledge, this is the first prospective, multicenter surveillance study of candidemia in children in Latin America. This epidemiologic information may provide us with methods to improve preventive, diagnostic and therapeutic strategies in our continent.

Predictors of significant worsening of patient-reported fatigue over a 1-month timeframe in ambulatory patients with common solid tumors.

Understanding the determinants of fatigue worsening may help distinguish between different fatigue phenotypes and inform clinical trial designs. Patients with invasive cancer of the breast, prostate, colon/rectum, or lung were enrolled from multiple sites. At enrollment during an outpatient visit and 4 or 5 weeks later, patients rated their symptoms on a numerical rating scale from zero to 10. A 2-point change on that scale was considered clinically significant for a change in fatigue. Effects of demographic and clinical factors on patient-reported fatigue were examined using logistic regression models. In total, 3123 patients were enrolled at baseline, and 3032 patients could be analyzed for fatigue change. At baseline, 23% of patients had no fatigue, 35% had mild fatigue, 25% had moderate fatigue, and 17% had severe fatigue. Key parameters in a model of fatigue worsening included fatigue at baseline (odds ratio [OR], 0.75), disease status (OR, 1.99), performance status (OR, 1.38), history of depression (OR, 1.28), patient perception of bother because of comorbidity (OR, 1.26), and treatment exposures, including recent cancer treatment (OR, 1.77) and receipt of corticosteroids (OR, 1.37). The impact of sex was examined only in patients with colorectal and lung cancer, and it was a significant factor, with men most likely to experience worsening of fatigue (OR, 1.46). Predictors of fatigue worsening included multiple factors that were difficult to modify, including the baseline fatigue level, sex, disease status, performance status, recent cancer treatment, bother because of comorbidity, and history of depression. Future fatigue prevention and treatment trial designs should account for key predictors of worsening fatigue.

Effect of corticosteroid interval on markers of inflammation in spontaneous preterm birth

The objective of the study was to evaluate whether the time interval from corticosteroid administration to delivery is associated with variations in inflammatory/infectious markers in women with spontaneous preterm birth (SPTB). We conducted a secondary analysis of a prospectively collected cohort of women experiencing SPTB from 23(0/7) to 31(6/7) weeks. Patients were categorized by corticosteroid receipt and time interval until delivery. Prevalence of markers of inflammation and colonization/infection (cord blood interleukin [IL]-6 levels; Ureaplasma urealyticum [UU], Mycoplasma hominis [MH], and other anaerobic/aerobic cultures; histology of the placental disc, membranes and cord) were compared between groups using χ(2) and Mantel-Haenszel tests. Two hundred seventy-three patients had SPTB. Prevalence of elevated IL-6 (P= .028) and positive UU/MH cultures (P= .019) were highest in women not receiving corticosteroids and those delivering more than 7 days from receipt. The prevalence of both decreased in groups with delivery delayed at least 12 hours but increased as the interval lengthened to more than 48 hours. Overall positive placental cultures also nadired among those delivering at 12-24 hours after corticosteroids (P= .049). As the interval increased, prevalence of acute inflammation at the rupture site increased (P= .017). There were similar, but nonsignificant, increases in chorionic plate inflammation and funisitis. The relationship between time interval from corticosteroids and evidence of inflammation in women experiencing SPTB is U shaped, suggesting earlier stages of inflammation in women with delayed delivery or transient decreases of inflammation in response to corticosteroids. This warrants further investigation to elucidate the natural history of SPTB and its modulation by corticosteroids.

Lack of prompt expansion of cytomegalovirus pp65 and IE-1-specific IFNγ CD8+ and CD4+ T cells is associated with rising levels of pp65 antigenemia and DNAemia during pre-emptive therapy in allogeneic hematopoietic stem cell transplant recipients

Rising levels of cytomegalovirus (CMV) DNAemia and/or pp65 antigenemia have been observed during pre-emptive ganciclovir therapy in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT). We assessed the incidence of this event in our series, and investigated whether its occurrence was associated with an impairment in the CMV-specific T-cell response. A total of 36 allo-SCT recipients experienced one or more episodes of active CMV infection (n=68) that were pre-emptively treated with val(ganciclovir). Rising levels of antigenemia and DNAemia, and an isolated increase in antigenemia, were observed in 39.7 and 2.9% of all episodes, respectively. Receipt of corticosteroids was associated with rising levels of antigenemia and DNAemia. Median increases of 12- and 6.8-fold of IFNgamma CD8(+) T and IFNgamma CD4(+) T cells, respectively, were observed at a median of 16.5 days after initiation of therapy in episodes with decreasing levels in antigenemia and DNAemia. In contrast, the numbers of both T-cell subsets at a median of 13.5 days after initiation of therapy did not differ significantly from those of pre-treatment samples in episodes with rising levels of antigenemia and DNAemia. Lack of prompt expansion of CMV pp65 and IE-1-specific IFNgamma CD8(+) and CD4(+) T cells is associated with rising levels in antigenemia and DNAemia during pre-emptive therapy.

Invasive Aspergillosis following Hematopoietic Cell Transplantation: Outcomes and Prognostic Factors Associated with Mortality

Invasive aspergillosis (IA) is a leading cause of infection-related mortality following hematopoietic cell transplantation (HCT). The aim of this study was to determine the probability of survival and prognostic factors associated with outcomes over a long period of time. Cases of proven and probable IA diagnosed in HCT recipients at the Fred Hutchinson Cancer Research Center from 1 January 1990 through 31 December 2004 were included. Patient data were collected from a prospectively maintained database and by retrospective clinical chart review. Survival was estimated using Kaplan-Meier curves, and Cox regression models were used for multivariable analyses. Four hundred five cases were identified. The probability of survival at 90 days after diagnosis was higher for patients identified as having IA between 2002 and 2004 than for patients whose IA was diagnosed in preceding years (45% vs. 22%; P<.001). Risk factors independently associated with all-cause mortality include impairment in pulmonary function before HCT, receipt of human leukocyte antigen-mismatched stem cells, neutropenia, elevated bilirubin and creatinine levels, receipt of corticosteroids at > or =2 mg/kg per day, disseminated and proven IA, and IA occurring >40 days after HCT. Factors associated with a decreased risk of all-cause mortality included receipt of nonmyeloablative conditioning and peripheral blood stem cells. In a subanalysis of attributable mortality restricted to patients receiving antifungal therapy, receipt of voriconazole was independently associated with protection from IA-related death. There has been a significant decrease in mortality in patients with a diagnosis of IA following HCT in recent years, coinciding with multiple changes in transplantation practices, including use of nonmyeloablative conditioning regimens, receipt of peripheral blood stem cells, more prompt diagnosis of IA, and use of voriconazole.

Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors

The incidence of postengraftment invasive aspergillosis (IA) in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. We determined risks for IA and outcomes among 1682 patients who received HSCTs between January 1993 and December 1998. Risk factors included host variables (age, underlying disease), transplant variables (stem cell source), and late complications (acute and chronic graft-versus-host disease [GVHD], receipt of corticosteroids, secondary neutropenia, cytomegalovirus [CMV] disease, and respiratory virus infection). We identified risk factors associated with IA early after transplantation (<or= 40 days) and after engraftment (41-180 days). Older patient age was associated with an increased risk during both periods. Chronic myelogenous leukemia (CML) in chronic phase was associated with low risk for early IA compared with other hematologic malignancies, aplastic anemia, and myelodysplastic syndrome. Multiple myeloma was associated with an increased risk for postengraftment IA. Use of human leukocyte antigen (HLA)-matched related (MR) peripheral blood stem cells conferred protection against early IA compared with use of MR bone marrow, but use of cord blood increased the risk of IA early after transplantation. Factors that increased risks for IA after engraftment included receipt of T cell-depleted or CD34-selected stem cell products, receipt of corticosteroids, neutropenia, lymphopenia, GVHD, CMV disease, and respiratory virus infections. Very late IA (> 6 months after transplantation) was associated with chronic GVHD and CMV disease. These results emphasize the postengraftment timing of IA; risk factor analyses verify previously recognized risk factors (GVHD, receipt of corticosteroids, and neutropenia) and uncover the roles of lymphopenia and viral infections in increasing the incidence of postengraftment IA in the 1990s.