Alicia K. Gerke

The Immunology of Sarcoidosis

Sarcoidosis continues to be a disease of research interest because of its complicated immune mechanisms and elusive etiology. So far, it has been established that granulomatous inflammation in sarcoidosis is predominantly a T-helper 1 immune response mediated by a complex network of lymphocytes, macrophages, and cytokines. The cause of progression to a chronic and potentially fibrotic form is unclear but may involve loss of apoptotic mechanisms, loss of regulatory response, or a persistent antigen that cannot be cleared. Recent genomic and proteomic technology has emphasized the importance of host susceptibility and gene-environment interaction in the expression of the disease.

Coordinated DNA methylation and gene expression changes in smoker alveolar macrophages: specific effects on VEGF receptor 1 expression

Cigarette smoking is implicated in numerous diseases, including emphysema and lung cancer. The clinical expression of lung disease in smokers is not well explained by currently defined variations in gene expression or simple differences in smoking exposure. Alveolar macrophages play a critical role in the inflammation and remodeling of the lung parenchyma in smoking‐related lung disease. Significant gene expression changes in alveolar macrophages from smokers have been identified. However, the mechanism for these changes remains unknown. One potential mechanism for smoking‐altered gene expression is via changes in cytosine methylation in DNA regions proximal to gene‐coding sequences. In this study, alveolar macrophage DNA from heavy smokers and never smokers was isolated and methylation status at 25,000 loci determined. We found differential methylation in genes from immune‐system and inflammatory pathways. Analysis of matching gene expression data demonstrated a parallel enrichment for changes in immune‐system and inflammatory pathways. A significant number of genes with smoking‐altered mRNA expression had inverse changes in methylation status. One gene highlighted by this data was the FLT1, and further studies found particular up‐regulation of a splice variant encoding a soluble inhibitory form of the receptor. In conclusion, chronic cigarette smoke exposure altered DNA methylation in specific gene promoter regions in human alveolar macrophages.

Acute myocardial infarctions, strokes and influenza: seasonal and pandemic effects.

The incidence of myocardial infarctions and influenza follow similar seasonal patterns. To determine if acute myocardial infarctions (AMIs) and ischaemic strokes are associated with influenza activity, we built time-series models using data from the Nationwide Inpatient Sample. In these models, we used influenza activity to predict the incidence of AMI and ischaemic stroke. We fitted national models as well as models based on four geographical regions and five age groups. Across all models, we found consistent significant associations between AMIs and influenza activity, but not between ischaemic strokes and influenza. Associations between influenza and AMI increased with age, were greatest in those aged >80 years, and were present in all geographical regions. In addition, the natural experiment provided by the second wave of the influenza pandemic in 2009 provided further evidence of the relationship between influenza and AMI, because both series peaked in the same non-winter month.

Association of hospitalizations for asthma with seasonal and pandemic influenza.

Although influenza has been associated with asthma exacerbations, it is not clear the extent to which this association affects health care use in the United States. The first goal of this project was to determine whether, and to what extent, the incidence of asthma hospitalizations is associated with seasonal variation in influenza. Second, we used influenza trends (2000–2008) to help predict asthma admissions during the 2009 H1N1 influenza pandemic.

Increased hospitalizations among sarcoidosis patients from 1998 to 2008: a population-based cohort study

BackgroundDiagnostic and treatment approaches for sarcoidosis have changed dramatically over the past decade. Yet, the most recent reports of trends in hospitalizations of sarcoidosis patients are over ten years old. The objectives of this study were to determine the incidence of sarcoidosis among hospitalized patients and to analyze recent trends and seasonality of hospitalizations in sarcoidosis patients.MethodsWe performed a retrospective cohort study of the Nationwide Inpatient Sample from 1998 through 2008. We identified all hospitalizations with a primary or secondary diagnosis of sarcoidosis (ICD-9-CM code 135). Incidence was modeled as a seasonal time series about a linear trend.ResultsTime series analysis of the monthly number of hospitalizations revealed a distinct positive linear trend. Over the study period, the number of hospitalized patients with sarcoidosis increased from 37,516 to 70,947 cases. Trends were most pronounced in patients older than 55 years (p < 0.0001), African Americans (p < 0.0001), females (p = 0.0289), and non-Medicaid populations (p < 0.0001). Hospitalizations are seasonal with highest incidence in January through March.ConclusionsHospitalizations among sarcoidosis patients have almost doubled during the past decade, with disproportionate rate increases in African Americans, women, and older patients. The rate also increases among patients with insurance other than Medicaid. This study indicates the need for heightened surveillance of sarcoidosis patients given the unknown consequences of evolving treatment approaches. Our results point to a need for research investigating risk factors for hospitalization, including medications, co-morbidities, demographics, and socioeconomic status.

Agreement Between Fixed-Ratio and Lower Limit of Normal Spirometry Interpretation Protocols Decreases With Age Is There a Need for a New GOLD Standard?

Objectives: To assess concordance between the fixed 70% ratio cutoff point with the fixed percent predicted values (Fixed-ratio) and the lower limit of normal (LLN) algorithms in interpreting spirometry results in an older population. Methods: Spirometries were interpreted using Third National Health and Nutrition Examination Survey reference equations for 2319 workers. Results: The Fixed-ratio algorithm characterized 34.5% (n = 801) results as abnormal, compared with 29.7% (n = 689) by the LLN. There were almost twice as many obstructive and mixed airways spirometries identified under the Fixed-ratio compared to LLN. Rates of restrictive pattern physiology were virtually the same under each algorithm. Overall agreement between the algorithms decreased with age from “almost perfect” for those younger than 60 years to “substantial” for those older than 80 years. Conclusions: This study found age-related discordance between two algorithms possibly related to the lack of reference equations and standards for individuals older than 80 years.

Disease Burden and Variability in Sarcoidosis

&NA; Sarcoidosis is a systemic inflammatory disease with substantial morbidity and increasing mortality. As part of the National Heart, Lung, and Blood Institutes workshop to better understand this disease and improve the outcomes of patients with sarcoidosis, we reviewed the available data on health care burden and outcomes of this disease in the United States. Disparities in outcomes exist by race, ethnicity, sex, and socioeconomic groups, with African Americans having disproportionately more severe disease. Mortality rates are highest in African Americans, but may be increasing in white individuals. The health care burden of sarcoidosis is defined not only by its somatic manifestations, but is also greatly impacted by psychosocial, economic, and comorbid conditions associated with this disease. Fatigue, depression, cognitive dysfunction, treatment side effects, and pain syndromes are highly prevalent in this population and contribute to poor outcomes. The direct and indirect economic costs to patients and society are likely also substantial, although not well defined. We recommend leveraging existing and future technology and infrastructure to more accurately define and monitor the overall total sarcoidosis‐attributable health care burden and patient outcomes in the United States.

Predicting chronic obstructive pulmonary disease hospitalizations based on concurrent influenza activity

Abstract Although influenza has been associated with chronic obstructive pulmonary disease (COPD) exacerbations, it is not clear the extent to which this association affects healthcare use in the United States. The first goal of this project was to determine to what extent the incidence of COPD hospitalizations is associated with seasonal influenza. Second, as a natural experiment, we used influenza activity to help predict COPD admissions during the 2009 H1N1 influenza pandemic. To do this, we identified all hospitalizations between 1998 and 2010 in the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project (HCUP) during which a primary diagnosis of COPD was recorded. Separately, we identified all hospitalizations during which a diagnosis of influenza was recorded. We formulated time series regression models to investigate the association of monthly COPD admissions with influenza incidence. Finally, we applied these models, fit using 1998–2008 data, to forecast monthly COPD admissions during the 2009 pandemic. Based on time series regression models, a strong, significant association exists between concurrent influenza activity and incidence of COPD hospitalizations (p-value < 0.0001). The association is especially strong among older patients requiring mechanical ventilation. Use of influenza data to predict COPD admissions during the 2009 H1N1 pandemic reduced the mean-squared prediction error by 29.9%. We conclude that influenza activity is significantly associated with COPD hospitalizations in the United States and influenza activity can be exploited to more accurately forecast COPD admissions. Our results suggest that improvements in influenza surveillance, prevention, and treatment may decrease hospitalizations of patients diagnosed with COPD.