Additional Potential Risk Factors Research Articles

Four Cases of Sirolimus-Associated Interstitial Pneumonitis: Identification of Risk Factors

Sirolimus-associated interstitial pneumonitis is a severe side effect of sirolimus therapy; fatal outcomes have been described. We report 4 patients with sirolimus-associated interstitial pneumonitis and review the literature for risk factors for the development of disease. Until June 2005, 48 patients received either de novo sirolimus treatment (n = 7) or were switched from a calcineurin inhibitor-containing regimen to a sirolimus-based protocol for various indications (n = 41). Compared with the 44 patients on sirolimus therapy with no evidence of a disorder, the 4 patients (8.3%) who developed suspected sirolimus-associated interstitial pneumonitis showed no difference in gender, immunosuppressive therapy, days posttransplantation, comorbidity, or preexistent lung disease. Several points, however, are of interest. None of the de novo-treated patients except 4 patients (9.8%) with late administration of sirolimus developed interstitial pneumonitis. The 4 patients with interstitial pneumonitis tended to be older (58.7 ± 5.5 vs 46.9 ± 1.7 years) and received higher sirolimus doses (3.5 ± 0.5 vs 1.4 ± 0.2 mg/d) with greater trough levels (15.4 ± 2.9 vs 8.0 ± 1.2 μg/L) at the onset of symptoms. Most notably, all patients with interstitial pneumonitis had a loading dose at the start of therapy, and an increase in sirolimus dose (or trough level) within 3 weeks prior to the onset of symptoms. Additional potential risk factors identified from the literature include allograft dysfunction, hypervolemia, and male gender. With careful monitoring (or even exclusion from therapy) of patients at risk for the development of disease, we have had no case of sirolimus-associated interstitial pneumonitis since September 2004.

Genomic Identification of Potential Risk Factors during Acetaminophen-Induced Liver Disease in Susceptible and Resistant Strains of Mice

Drug-induced liver disease (DILD) continues to cause significant morbidity and mortality and impair new drug development. Mounting evidence suggests that DILD is a complex, multifactorial disease in which no one factor is likely to be an absolute indicator of susceptibility. As an approach to better understand the multifactorial basis of DILD, we recently compared the hepatic proteomes of mice that were resistant (SJL) and susceptible (C57Bl/6) to APAP-induced liver disease (AILD) wherein we identified potential risk factors and mechanistic pathways responsible for DILD. In this study, we have uncovered additional potential risk factors by comparing hepatic mRNA expression profiles of the same two strains of mice with that of SJLxB6-F1 hybrid (F1) mice, which were found to be of intermediate susceptibility to AILD. Global hepatic gene expression profiling over a 24 h period following APAP treatment revealed elevated patterns in the mRNA expression of cytoprotective genes in resistant SJL mice as compared to susceptible B6 mice, while F1 mice had intermediate mRNA expression levels of these genes. One of these genes encoded for heat shock protein (HSP) 70 whose relative protein expression among the three strains of mice was found to parallel that of their mRNA levels, suggesting that this protein had a protective role against AILD. However, there was no difference in the susceptibility of HSP70 knockout (KO) mice to AILD as compared to wild-type (WT) mice. There were also protoxicant genes, such as osteopontin (OPN), with elevated mRNA expression levels in the B6 mice as compared to the SJL mice and with intermediate levels in the F1 mice, suggesting that they may play a role in exacerbating liver injury after APAP treatment. In support of this hypothesis, OPN KO mice were found to be more resistant to AILD than WT mice. Additionally, the results from both the proteomic and the genomic studies were compared. The two approaches were found to be complementary to each other and not simply overlapping. Our findings suggest that comparative gene expression analysis of susceptible and resistant mouse strains may lead to the identification of factors that could have a role in determining the susceptibility of individuals to DILD.

Risk Factors for Extrapyramidal Symptoms During Treatment With Selective Serotonin Reuptake Inhibitors, Including Cytochrome P-450 Enzyme, and Serotonin and Dopamine Transporter and Receptor Polymorphisms

Extrapyramidal symptoms (EPS) are rare adverse drug reactions to selective serotonin reuptake inhibitors (SSRIs). This study aimed to investigate the potential risk factors for EPS associated with SSRIs including polymorphisms of cytochrome P-450 isoenzymes, and serotonin and dopamine transporters and receptors. All spontaneous adverse drug reaction reports received by the Swedish Medical Products Agency until December 1999 that were coded with EPS and judged to be at least possibly related to SSRI treatment were included in the study. Reporting physicians received a form for collection of relevant information including current and previous use of SSRIs and antipsychotics, alcohol or substance abuse, central nervous system damage, a history of epilepsy or EPS, and a family history of Parkinson disease. A blood sample was also requested for genotyping of selected cytochrome P-450, and serotonin and dopamine transporter and receptor mutations. A total of 64 cases of EPS were reported. Twenty-eight forms (46%) were returned, and 20 blood samples were obtained. Identified potential risk factors included age of 65 years or older and the presence of the A1 allele of the D2 dopamine receptor gene (DRD2) Taq1A polymorphism (relative risk, 2.4; 95% confidence interval, 1.2-4.5 vs literature controls). No relationship was apparent for sex, drug dose, or other genetic polymorphisms. At least 1 additional potential risk factor for EPS, such as a history of central nervous system damage, alcohol or substance abuse, epilepsy, Parkinson disease, previous or current exposure to antipsychotic drugs, concomitant treatment with other antidopaminergic or serotonergic agents, or a history of EPS, was found in 93% of the cases. The risk of EPS with SSRIs seems to increase with advanced age and with the presence of the A1 allele of DRD2 Taq1A polymorphism. Because of the small sample size of our study and the use of historical controls rather than patients who did not experience EPS during SSRIs treatment, the DRD2 finding is preliminary and needs to be replicated in other studies before firm conclusions can be drawn. At least 1 additional potential risk factor was found in almost all cases.

Prevalence and risk factors for human immunodeficiency virus–associated neurocognitive impairment, 1996 to 2002: Results from an urban observational cohort

To assess prevalence and risk factors for human immunodeficiency virus (HIV)-related neurocognitive impairment (NCI), the authors performed a 7-year survey in the period 1996 to 2002. A total of 432 patients were examined. HIV-related NCI was diagnosed in 238 patients (55.1%), meeting the HIV dementia (HIV-D) criteria in 45 (10.4%). The prevalence of both NCI and HIV-D did not change significantly during the study period. Compared with patients without NCI, patients with NCI were older (40.4 versus 38.2 years; P = .003), had a higher prevalence of positive HCV serology (61.1% versus 38.9%; P = .003), and a lower nadir CD4 cell count (156 versus 222 cells/microl; P < .001). Compared with patients seen during 1996 to 1999, patients with NCI seen during 2000 to 2002 were older (40.7 versus 38.8 years; P = .004), had a less advanced disease stage (previous acquired immunodeficiency syndrome [AIDS] 28.8% versus 65.7%; P < .001) and a higher nadir CD4 count (174 versus 132 cells/microl; P = .026). This study showed an unchanged prevalence of both HIV-related NCI and HIV-D in the period 1996 to 2002. The authors found evidences for new additional potential risk factors for HIV-related NCI (older age, lower nadir CD4 count, positive hepatitis C virus [HCV] serology), and for a change of risk factors for NCI in the late highly active antiretroviral therapy (HAART) era (older age, less advanced disease, higher nadir CD4 count).

BUILDING-RELATED SYMPTOMS AMONG U.S. OFFICE WORKERS AND RISK FACTORS FOR MOISTURE AND CONTAMINATION

Introduction Moisture and other risks for indoor microbiologic growth have been associated with increased prevalence of symptoms in many studies. We assessed relationships between health symptoms in office workers and risk factors related to moisture and contamination, using data collected from a representative sample of 100 U.S. office buildings in the U.S. EPA BASE study. Methods Analyses assessed associations between three types of buildingrelated symptoms (defined as occurring at least weekly and improving when away from the building)-lower respiratory, mucous membrane, and neurologic-and risk factors for moisture or contamination in these office buildings. Multivariate logistic regression models were used to estimate the strength of associations for these risk factors as odds ratios (ORs) adjusted for personal-level potential confounding variables related to demographics, health, job, and workspace. Results A number of risk factors were associated significantly (e.g., 95% confidence limits excluded 1.0) in adjusted models with small to moderate increases in one or more symptom outcomes. Significantly elevated ORs for mucous membrane symptoms were associated with the following risk factors: presence of humidification system in good condition versus no system present (OR = 1.4); air handler inspection annually versus daily (OR = 1.6); current water damage in the building (OR = 1.2); and less than daily vacuuming in study space (OR = 1.2). Significantly elevated ORs for lower respiratory symptoms were associated with: air handler inspection annually versus daily (OR = 2.0); air handler inspection less than daily but at least semi-annually (OR = 1.6); less than daily cleaning of offices (1.7); and less than daily vacuuming of the study space (OR = 1.4). Only two statistically significant risk factors for neurologic symptoms were identified: presence of any humidification system versus none (OR = 1.3); and less than daily vacuuming of the study space (OR = 1.3). Dirty cooling coils, dirty or poorly draining drain pans, and standing water near outdoor air intakes were not identified as risk factors in these analyses, despite predictions based on previous findings elsewhere, except that very dirty cooling coils were associated with a statistically nonsignificant increase (OR = 1.3, 95% confidence interval = 0.9–2.1) in lower respiratory symptoms Conclusions These preliminary findings suggest that some factors indicating risks for moisture or contamination in office buildings may have adverse effects on respiratory or neurologic health of office workers. Expanded analyses are underway that will include in multivariate models additional potential confounders and risk factors, such as ventilation rate and indoor temperature. Future analyses will also assess risk in susceptible sub-groups such as previously diagnosed asthmatics.

Heightened risk of hypertension among black males: the masking effects of covariables.

This study examines the extent to which a set of 10 demographic, behavioral, and medical risk factors explain black/white differences in hypertension. Data are from a cross-sectional examination of San Francisco transit drivers aged 25-65 years surveyed during 1983-1985 as part of an occupational health study. The inherent restriction of the study population to bus drivers and the further restriction to males in this population (764 blacks and 224 whites) controlled for factors related to occupation and sex. Control of 10 additional potential risk factors, including age, education, body mass index, smoking, and intake of caffeine and alcohol was possible in the analytic phase of the study. The unadjusted prevalence of hypertension (systolic blood pressure greater than or equal to 140 mmHg, diastolic blood pressure greater than or equal to 90 mmHg, or current use of antihypertensive medications) was 36.1 per cent for black males compared with 30.8 per cent for white males. The greatest difference in prevalence was observed for black males aged 55-64 years, for whom the prevalence was 46 per cent higher than for white males the same age. Despite higher rates of hypertension, blacks in all age groups exhibited lower levels of most major risk factors for hypertension. As a result, the independent effect of race on hypertension was increased rather than attenuated when the 10 covariables were taken into account (odds ratio of 1.27 in the unadjusted analysis, increasing to 1.54 in the adjusted, multivariate analysis). That this set of risk factors did not explain the higher rates of hypertension among blacks suggests that racial differences may arise from as yet unrecognized environmental and/or individual factors. The results also indicate that the association between race and blood pressure may have been underestimated in past studies that have relied on unadjusted analyses, in which negative confounding or masking effects of covariables have not been considered.