Viral safety of human plasma-derived medicinal products: impact of regulation requirements.

The viral safety of plasma-derived medicinal products is of paramount importance. This article aims to provide insight into the relative impact of different safety measures on achieving viral safety of finished products, derived from human plasma. Virus removal and/or inactivation during the production process is the most important safety measure, and model-based risk estimates show that with current safety measures, the risk of transmission of known blood-borne pathogens to plasma product recipients is extremely low. However, because the residual risk of virus transmissions is also influenced by the incidence rate of infection in the donor population, it makes sense to control these incidence rates, as well. The current measures are aiming in the right direction, but integration of guidelines is required to adequately address their common goal: controlling the risk of infectious disease transmission by plasma-derived medicinal products. By integration of guidelines, the combination of various types of safety measures to prevent virus transmission-donor selection, donation screening, quarantining, and virus removal and/or inactivation during production-may be consistently interpreted and adequately assessed.

Testing bias in clinical databases: methodological considerations.

BACKGROUND: Laboratory testing in clinical practice is never a random process. In this study we evaluated testing bias for neutrophil counts in clinical practice by using results from requested and non-requested hematological blood tests. METHODS: This study was conducted using data from the Utrecht Patient Oriented Database. This clinical database is unique, as it contains physician requested data, but also data that are not requested by the physician, but measured as result of requesting other hematological parameters. We identified adult patients, hospitalized in 2005 with at least two blood tests during admission, where requests for general blood profiles and specifically for neutrophil counts were contrasted in scenario analyses. Possible effect modifiers were diagnosis and glucocorticoid use. RESULTS: A total of 567 patients with requested neutrophil counts and 1,439 patients with non-requested neutrophil counts were analyzed. The absolute neutrophil count at admission differed with a mean of 7.4 x 109/l for requested counts and 8.3 x 109/l for non-requested counts (p-value < 0.001). This difference could be explained for 83.2% by the occurrence of cardiovascular disease as underlying disease and for 4.5% by glucocorticoid use. CONCLUSION: Requests for neutrophil counts in clinical databases are associated with underlying disease and with cardiovascular disease in particular. The results from our study show the importance of evaluating testing bias in epidemiological studies obtaining data from clinical databases.

Medication changes prior to hospitalization for obstructive lung disease: a case-crossover study.

BACKGROUND: Hospitalizations have always been seen as a solid outcome parameter in pharmacoepidemiology. However, the period leading to hospitalization and prehospital management of the patient are equally important. OBJECTIVE: To evaluate medication changes in the period prior to hospitalization for obstructive lung disease and to quantify the association between medication use and the risk of hospitalization. METHODS: We conducted a case-crossover study using the PHARMO record linkage system, which contains drug dispensing data from community pharmacies and hospital admission data. Patients included in the study were adults hospitalized for obstructive lung disease between 2005 and 2007. The index date of the case period was the date of hospitalization, and control moments were set at 3, 6, 9, and 12 months before admission. For each patient, all prescriptions prior to the date of hospitalization were identified. Medication use was ascertained in a 90-day time window prior to each case or control moment. RESULTS: We identified 1481 patients who were hospitalized for obstructive lung disease. It appeared that respiratory medication use increased in the 90 days prior to hospitalization. Hospitalization was associated with the use of 3 or more respiratory drugs (OR 2.2; 95% CI 1.8 to 2.8), systemic glucocorticoids (OR 4.5; 95% CI 3.8 to 5.4), and antibiotics (OR 3.1; 95% CI 2.7 to 3.6). CONCLUSIONS: The use of systemic glucocorticoids, antibiotics, and other respiratory drugs increased prior to hospitalization for obstructive lung disease. These results could be indicative of the development and/or treatment of an exacerbation. There is a need for markers to detect exacerbations in an early phase in order to start treatment as early as possible and possibly prevent hospitalizations for obstructive lung disease.

Effects of corticosteroid use on readmission in obstructive lung disease.

OBJECTIVE: Obstructive lung disease is a leading cause of morbidity and mortality worldwide. Some patients are readmitted, but currently predicting parameters for identifying these patients are lacking. The aim of this study was to quantify the incidence of readmission in chronic obstructive lung disease and to identify determinants for hospital readmission. METHODS: We conducted a cohort study using the PHARMO record linkage system, including demographic details and complete medication histories of more than two million community-dwelling residents in the Netherlands from 1985 onwards. Eligible patients were adult users of inhaled corticosteroids (ICS) with an admission for obstructive lung disease. The outcome parameter was readmission within a follow-up period of one year. RESULTS: We identified 605 ICS users with an admission for chronic obstructive lung disease, 132 of these patients were readmitted. Readmission was associated with a high Chronic Disease Score (adjusted HR 2.4; 95% CI 1.1-5.3). Patients using short courses of systemic corticosteroids only (adjusted HR 0.5; 95% CI 0.4-0.8) or combined with antibiotics (adjusted HR 0.4; 95% CI 0.2-0.6) were at decreased risk of readmission. The effect of high-dose ICS use varied over time. CONCLUSIONS: Treatment of exacerbations out of the hospital was associated with a decreased risk of readmission, while patients with multiple chronic diseases are at increased risk of readmission for obstructive lung disease. These patients should be educated and should be invited to consultation more often to be able to detect exacerbation in an early phase and start treatment as early as possible.

Effects of glucocorticoids on the neutrophil count: a cohort study among hospitalized patients.

BACKGROUND: Systemic glucocorticoids are often used in clinical practice for a large variety of indications. Clinical observations have shown that patients using glucocorticoids often have higher neutrophil counts. Debate remains whether this observed neutrophilia is associated with glucocorticoid use or that other factors, like disease and severity of disease, should be considered. The objective of this study was to investigate the effect of systemic glucocorticoids on the absolute neutrophil count in hospitalized patients. METHODS: A cohort study was conducted using data from the Utrecht Patient Oriented Database which comprises clinical data of patients of the University Medical Center Utrecht. We identified all adult patients, hospitalized in 2005 with at least two blood samples for hematological testing during admission and compared in-hospital glucocorticoid use with non-use. RESULTS: A total of 809 glucocorticoid users and 2658 non-users were included in the study with comparable neutrophil counts at admission (8.2.10(9)/l for glucocorticoid users and 8.0.10(9)/l for non-users). Overall analysis showed a slight association between glucocorticoid use and an increase in neutrophil count (RR 1.3; 95% CI 1.1-1.5). However, within diagnostic subgroups there was no increase in neutrophil count in glucocorticoid users. Furthermore, among all no dose response relationship, no effect of time between the two samples, and no effect of anti-inflammatory/sodium retaining potency was found. CONCLUSION: Observed neutrophilia in users of systemic glucocorticoids is probably associated with underlying disease, rather than glucocorticoid use itself.

Measuring exacerbations in obstructive lung disease.

PURPOSE: Using hospitalization always has been seen as a solid measurement for exacerbation in pharmacoepidemiology, but might lead to an underestimation of disease exacerbation because of a trend towards outpatient care. The aim of this study was to quantify the incidence of different exacerbation markers in obstructive lung disease and to identify predictors for these exacerbation markers. METHODS: We conducted a cohort study using the PHARMO record linkage system, including demographic details and complete medication histories of more than two million community-dwelling residents in the Netherlands from 1985 onwards. Eligible patients were adult users of inhaled corticosteroids (ICS). Outcome parameters were hospitalization and short courses of systemic corticosteroids. Patients were allowed to have multiple exacerbations during follow-up. RESULTS: We identified 5327 patients. During follow-up, 8635 exacerbations occurred in 2332 patients with a trend in time towards treating exacerbations out of the hospital (p-value 0.003). Of all patients with exacerbations, 73% was not hospitalized during follow-up. Exacerbations were associated with high-dose ICS use (adjusted RR 1.4; 95% CI 1.2-1.7) and chronic systemic corticosteroid use (adjusted RR 1.9; 95%CI 1.6-2.2). CONCLUSIONS: Using hospitalization only as exacerbation marker leads to underestimating the exacerbation rate, because of exacerbation treatment out of the hospital. Patients with obstructive lung disease using chronic systemic corticosteroids or high-dose ICS use are more prone to exacerbations. This implies that these patients should be monitored carefully to prevent recurrent exacerbations which are detrimental for their prognosis and quality of life.

Identification of exacerbations in obstructive lung disease through biomarkers.

Inflammation has been identified as an important factor for disease exacerbation in obstructive lung disease. In this study, we used neutrophil and eosinophil counts as biomarkers for exacerbation in obstructive lung disease. We conducted a case-control study within a cohort of patients frequenting an outpatient clinic of Respiratory Medicine using data from the Utrecht Patient Oriented Database (UPOD). Cases were patients with a hospital admission for obstructive lung disease in 2005. For each case, one control patient was sampled from the same study base. We identified 143 cases (118 patients with chronic obstructive pulmonary disease and 25 asthma patients) and 143 controls. Admission was associated with both neutrophilia (adjusted odds ratio (OR) 4.3; 95% confidence interval (CI) 2.2-8.5), and eosinophilia (adjusted OR 2.6; 95% CI 1.1-6.2). The association with eosinophilia was only seen in asthma patients. In conclusion, neutrophil and eosinophil counts seem to be useful biomarkers for identifying exacerbations in pharmacoepidemiological studies on obstructive lung disease.

Hematocytometry analysis as discriminative marker for asthma phenotypes.

BACKGROUND: There is an increasing demand for easy to measure biomarkers in clinical practice. We created the relational database Utrecht Patient Oriented Database (UPOD) to develop tools for identifying new biomarkers for disease. In this study, we used UPOD to identify better biomarkers for discriminating different asthma phenotypes. METHODS: We performed a prospective study at the University Medical Center (UMC) Utrecht using blood from patients with asthma and a healthy reference group. Since asthma is an inflammatory disease, absolute leukocyte counts and leukocyte differential parameters were analyzed using raw data files and a logistic regression model. RESULTS: We compared 17 difficult-to-treat asthma (DTA) cases, 13 non-difficult-to-treat asthma cases, and 19 healthy volunteers. Absolute leukocyte counts and differential parameters for leukocytes were able to discriminate asthma patients from healthy volunteers. However, among patients with asthma, difficult-to-treat cases could be more accurately defined with a neutrophil morphology change (OR 8.0; 95% CI 1.5-42.0), compared to the absolute neutrophil count (OR 4.0; 95% CI 0.8-21.0). CONCLUSIONS: In this asthma patient population, we were able to define asthma phenotypes more precisely using neutrophil morphology parameters, compared to absolute counts. Using UPOD with differential parameters, it is possible to conduct larger scale biomarker studies, combining clinical, laboratory medicine, and epidemiological techniques.