Comparative effectiveness of colony-stimulating factors in febrile neutropenia prophylaxis: how results are affected by research design.

AIMS: To examine the impact of research design on results in two published comparative effectiveness studies. METHODS: Guidelines for comparative effectiveness research have recommended incorporating disease process in study design. Based on the recommendations, we develop a checklist of considerations and apply the checklist in review of two published studies on comparative effectiveness of colony-stimulating factors. Both studies used similar administrative claims data, but different methods, which resulted in directionally different estimates. RESULTS: Major design differences between the two studies include: whether the timing of intervention in disease process was identified and whether study cohort and outcome assessment period were defined based on this temporal relationship. CONCLUSION: Disease process and timing of intervention should be incorporated into the design of comparative effectiveness studies.

Technical evaluation of methods for identifying chemotherapy-induced febrile neutropenia in healthcare claims databases.

BACKGROUND: Healthcare claims databases have been used in several studies to characterize the risk and burden of chemotherapy-induced febrile neutropenia (FN) and effectiveness of colony-stimulating factors against FN. The accuracy of methods previously used to identify FN in such databases has not been formally evaluated. METHODS: Data comprised linked electronic medical records from Geisinger Health System and healthcare claims data from Geisinger Health Plan. Subjects were classified into subgroups based on whether or not they were hospitalized for FN per the presumptive "gold standard" (ANC <1.0×10(9)/L, and body temperature ≥38.3°C or receipt of antibiotics) and claims-based definition (diagnosis codes for neutropenia, fever, and/or infection). Accuracy was evaluated principally based on positive predictive value (PPV) and sensitivity. RESULTS: Among 357 study subjects, 82 (23%) met the gold standard for hospitalized FN. For the claims-based definition including diagnosis codes for neutropenia plus fever in any position (n=28), PPV was 100% and sensitivity was 34% (95% CI: 24-45). For the definition including neutropenia in the primary position (n=54), PPV was 87% (78-95) and sensitivity was 57% (46-68). For the definition including neutropenia in any position (n=71), PPV was 77% (68-87) and sensitivity was 67% (56-77). CONCLUSIONS: Patients hospitalized for chemotherapy-induced FN can be identified in healthcare claims databases--with an acceptable level of mis-classification--using diagnosis codes for neutropenia, or neutropenia plus fever.

Costs and outcomes associated with hospitalized cancer patients with neutropenic complications: A retrospective study.

The average total hospitalization costs for adult cancer patients with neutropenic complications were quantified and the average length of hospital stay (LOS), all-cause mortality during hospitalization and reimbursement rates were determined. This observational retrospective cohort study identified adult patients with cancer who were hospitalized from January 2005 through June 2008 using a large private US health care database (>342 inpatient facilities). ICD-9-CM diagnosis codes identified patients by cancer type and who had neutropenic complications. The utilization and accounting systems of the hospitals were used to calculate mean (±95% confidence interval) hospitalization costs and LOS and percent all-cause mortality and reimbursement. Costs were adjusted to 2009 US dollars. There were 3,814 patients who had cancer and neutropenia, 1,809 (47.4%) also had an infection or fever and 1,188 (31.1%) had infection. Mean hospitalization costs were $18,042 (95% CI 16,997-19,087) for patients with neutropenia, $22,839 (95% CI 21,006-24,672) for patients with neutropenia plus infection or fever and $27,587 (95% CI 24,927-30,247) for patients with neutropenia plus infection. Mean LOS were 9 days (95% CI 8.7-9.3), 10.7 days (95% CI 10.2-11.2) and 12.6 days (95% CI 11.9-13.3), respectively. Mortality followed a similar trend; 8.3, 13.7 and 19.4%, respectively. By cancer type, hematologic malignancies had the highest average hospitalization costs and longest mean LOS of $52,579 (95% CI 42,183-62,975) and 20.3 days (95% CI 17.4-23.2), and a high mortality rate of 20.0%, while primary breast cancer patients had the lowest cost of $8,413 (95% CI 6,103-10,723), shortest LOS of 5.5 days (95% CI 4.2-6.8) and lowest mortality (0%). Mean reimbursement rates were 100.0, 101.5 and 95.4% for patients with neutropenia, neutropenia plus infection or fever and neutropenia plus infection, respectively. Hospitalized cancer patients with neutropenic complications had a higher all-cause mortality rate and higher inpatient hospitalization costs than those previously published. Results from this study suggest that costs for inpatient hospitalized cancer patients with neutropenic complications are principally reimbursed by payers.

Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up.

BACKGROUND: We hypothesized that subset classification of Epstein-Barr virus (EBV) in chronic fatigue syndrome (CFS) is required. At first, a blinded-random placebo-controlled trial of valacyclovir in EBV CFS subset was performed (Group 1), and this EBV subset was followed for thirty-six months (Group 2). Patients were given valacyclovir at 14.3 mg/kg every 6 hours. The validated Energy Index (EI) point score assessing physical functional capacity, Holter monitor, multigated (radionuclide) MUGA rest/stress ventriculographic examination, EBV serum IgM viral capsid antibodies (VCA), and EBV early antigen diffuse (EA) were followed. After six-months, Group 1 CFS patients receiving valacyclovir experienced an increased mean least square EI point score +1.12 units (122 kcal/day), while the placebo cohort increased +0.42 EI units (65 kcal/day). EI point scores at Group 2 increased progressively. Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities.

Prevalence of abnormal cardiac wall motion in the cardiomyopathy associated with incomplete multiplication of Epstein-barr Virus and/or cytomegalovirus in patients with chronic fatigue syndrome.

We reported unique incomplete herpesvirus (Epstein-Barr Virus (EBV) and/or nonstructural (HCMV) cytomegalovirus) multiplication in 2 distinct subsets of CFS patients. The CFS subsets were identified by: a) presence of IgM serum antibodies to HCMV nonstructural gene products p52 and CM2 (UL44 and UL57), and/or b) IgM serum antibodies to Epstein-Barr virus viral capsid antigen (EBV, VCA IgM). Diagnostic IgM serum antibodies were found in two independent blinded studies involving 49 CFS patients, but the same antibodies were absent in 170 control patients (p<0.05). Abnormal 24 Hr-electrocardiographic monitoring, tachycardias at rest and, in severe chronic cases, abnormal cardiac wall motion (ACWM) were seen in these same CFS patients. We now report a prospective consecutive case control study from 1987--1999 of cardiac dynamics as measured by radionuclide ventriculography in 98 CFS patients from 1987--1999. Controls were patients with various malignancies who were evaluated in protocols requiring radionuclide ventriculography before initiation of cardiotoxic chemotherapeutic agents. The prevalence of abnormal cardiac wall motion (ACWM) at rest in CFS patients was 10 out of 87 patients (11.5%). With stress exercise, 21 patients (24.1%) demonstrated ACWM. Cardiac biopsies in 3 of these CFS patients with ACWM showed a cardiomyopathy. Among the controls, ACWM at rest was present in 4 out of 191 patients (2%) (p=0.0018). A progressive cardiomyopathy caused by incomplete virus multiplication of EBV and/or HCMV in CFS patients is present.

IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome.

BACKGROUND: A unique subset of patients with chronic fatigue syndrome (CFS) and IgM serum antibodies to cytomegalovirus (HCMV) non-structural gene products p52 and CM2 (UL 44 and UL 57) has been described. PATIENTS AND METHODS: Fifty-eight CFS patients and 68 non-CFS matched controls were studied. Serum antibodies to EBV viral capsid antigen (VCA) IgM and EBV Early Antigen, diffuse (EA, D) as well HVCMV(V), IgM and IgG; VP (sucrose, density purified V); p52 and CM2 IgM serum antibodies were assayed. RESULTS: Mean age of CFS patients was 44 years (75% women). Control patients were 9 years older (73% women). Serum EBV VCA IgM positive antibody titers were identified in 33 CFS patients (Group A subset EBV VCA IgM 62.3+/-8.3, neg. <20), but were not present in other CFS patients, (Group B subset EBV VCA IgM 6.8+/-0.7) controls (p<0.0001). EBV VCA IgM titers remained positive in CFS patients from Group A for 24-42 months. CONCLUSION: Serum antibody to EBV VCA IgM may be a specific diagnostic test for a second subset of CFS patients.

IgM serum antibodies to human cytomegalovirus nonstructural gene products p52 and CM2(UL44 and UL57) are uniquely present in a subset of patients with chronic fatigue syndrome.

Human cytomegalovirus (HCMV) IgM serum antibodies to two nonstructural gene products UL44 and UL57 (p52 and CM2) were assayed in patients with the diagnosis of the chronic fatigue syndrome (CFS) according to criteria established by the US Centers for Disease Control and Prevention. A subset of 16 CFS patients demonstrated HCMV IgG, but no HCMV IgM serum antibodies to conformational structural HCMV antigens (designated, V). By convention, these findings are interpreted to indicate only a remote HCMV infection. However, HCMV IgM p52 and CM2 antibodies were uniquely present in these 16 CFS patients. Other CFS patients with similar HCMV (V) IgG antibodies (18 patients), non-fatigued HCMV (V) IgG-positive control patients (18 patients), random HCMV (V) IgG-positive control patients from a clinical laboratory (26 patients), and non-fatigued HCMV (V) IgG-negative control patients (15 patients) did not have HCMV, IgM p52 or CM2 serum antibodies (p < 0.05). Control HCMV (V) IgG-positive patients had no serum IgM HCMV (V) antibodies to conventional structural HCMV (V) antigen. Thus, 77 various control patients did not contain IgM p52 or CM2 serum antibodies. The presence of IgM p52 and/or CM2 HCMV serum antibodies in this subset of CSF-specific patients may detect incomplete HCMV multiplication in which a part of the HCMV protein-coding content of the HCMV genome is processed, but remains unassembled. These findings suggest that the presence of HCMV IgM p52 and CM2 serum antibodies may be a specific diagnostic test for the diagnosis of a subset of CFS patients. Further, these data suggest an etiologic relationship for HCMV infection in this group of CFS patients.

A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function.

This study was designed to determine safety and efficacy of a 6-month trial of valacyclovir in single-virus Epstein-Barr virus (EBV) persistent infection. Phase I of this study used four specific criteria to define a subset of patients with chronic fatigue syndrome (CFS). In the second phase, myocardial dynamics were measured by MUGA rest/stress radionuclide ventriculographic (RVG) examinations pre- and posttreatment with valacyclovir. In phase I, a trial was performed in 19 consecutive CFS patients with the following diagnostic conditions: patients met criteria for diagnosis of CFS; they had had CFS for less than 1 year. They demonstrated repetitively abnormal oscillating T waves (ischemic or flat) at 24-h Holter monitoring; and they had elevated serum IgM antibody titers to EBV viral capsid antigen and/or total diffuse early antigen as measured by the enzyme-linked immunosorbent assay method. The treatment group comprised 10 CFS patients with no serum antibodies to human cytomegalovirus, but the control group (nine CFS patients) had, additionally, high titers of serum antibodies (IgG) to conformational structural antigens of human cytomegalovirus. Both the parallel treatment and control CFS groups received valacyclovir 1.0-1.5 gm q.6.h. for 6 months. This valacyclovir dose achieved serum acyclovir C(max) of > 7 microm and high antiviral activity versus EBV (IC(50) of 4.4-13.3 m). In phase II, six additional CFS patients met the same four criteria as the 19 CFS patients in phase I. They had, however, been ill for a mean of 55.8 months. Thus, 25 CFS patients comprise this study. The studies were carried out at a single outpatient practice in Birmingham, MI, U.S.A. Before initiating valacyclovir, and after 6 months of treatment, clinical and laboratory observations were made. The CFS Energy Index point score (Table I) was used to record each CFS patient's functional capacity at baseline and after 1, 3 and 6 months of valacyclovir. Energy Index point scores, as well as EBV and human cytomegalovirus serum antibody titers were assessed. In the second phase, left ventricular dynamics were repeated after 6 months of treatment with valacyclovir. We concluded that the 16 CFS patients (included in both phases of this study) with EBV-persistent infection (EBV single-virus subset) are improved after 6 months of continuous pharmacokinetic dosing with valacyclovir. Nine CFS patients with EBV/human cytomegalovirus co-infection did not benefit from 6 months of similar treatment. Valacyclovir is not an effective anti-human cytomegalovirus antiviral drug. Unimproved CFS patients with co-infections EBV and human cytomegalovirus may require combined treatment with valacyclovir and another drug more active against human cytomegalovirus. This preliminary trial, with a small number of patients, may be critical to an appropriately designed larger, double-blind, placebo-controlled trial.

Pharmacokinetics and safety of valaciclovir in children with Epstein-Barr virus illness.

OBJECTIVE: Valaciclovir has in vitro activity against Epstein-Barr virus (EBV) and, because of improved absorption with higher achievable serum concentrations, may be more effective than aciclovir in the treatment of EBV. No studies to date have evaluated the efficacy, safety or proper dosing of valaciclovir in children for the treatment of EBV infection. The objectives of this study were to determine the pharmacokinetics and safety of valaciclovir tablets and suspension in children with EBV illness. METHODS: 24 children with EBV illness were randomised to receive valaciclovir suspension 10 mg/kg or 20 mg/kg; eight children subsequently were crossed over and also received valaciclovir 500 mg tablets. Doses of either suspension or tablets were administered every 8 hours for four doses, and pharmacokinetic studies were performed to determine aciclovir serum concentrations. Samples for drug assay were obtained at 0, 0.5, 1, 2, 4, 6, 8 and 24 hours. Samples were assayed by high performance liquid chromatography (HPLC) methods and aciclovir pharmacokinetics determined using non-compartmental analysis. RESULTS: Valaciclovir pharmacokinetic parameters (mean +/- SD) in children who received tablets and suspension (normalised to 500 mg dose) were: maximum serum concentration (C(max)) 3.16 +/- 1.30 and 2.42 +/- 0.74 mg/L, time to maximum serum concentration (t(max)) 1.88 +/- 0.99 and 1.31 +/- 0.53 hours, half-life (t 1/2) 1.72 +/- 0.41 and 1.94 +/- 0.60 hours, apparent total systemic clearance (CL/F) 20.01 +/- 6.61 and 15.58 +/- 3.34 ml/min/kg, volume of distribution/bioavailability (Vd/F) 3.04 +/- 1.26 and 2.58 +/- 0.81 L/kg, and area under the concentration-time curve (AUC) 10.13 +/- 3.47 and 8.59 +/- 2.52 mg x h/L, respectively. There were no statistically significant differences in the pharmacokinetics of valaciclovir tablets versus suspension. The relative bioavailability of the valaciclovir tablets compared with the suspension was 115 +/- 32%. Valaciclovir was well tolerated, with gastrointestinal disturbances and headache being the most common adverse effects in a small number of subjects. CONCLUSIONS: Valaciclovir is absorbed and achieves concentrations in children that appear to be effective for the treatment of herpes lesions. The pharmacokinetics of valaciclovir suspension and tablets are similar, and the pharmacokinetics of aciclovir after administration of valaciclovir to children are similar to historical observations of aciclovir pharmacokinetics in adults. Valaciclovir has a good safety profile and was well tolerated after oral administration in this group of children.