Publications

RATIONALE

Airway eosinophilia is typical of asthma, and many controller treatments target eosinophilic disease. Asthma is clinically heterogeneous, however, and a subgroup of people with asthma do not have airway eosinophilia. The size of this subgroup is uncertain because prior studies have not examined repeated measures of sputum cytology to determine when people with asthma have intermittent versus persistent sputum eosinophila and when they are persistently noneosinophilic.

OBJECTIVES

To determine the prevalence and clinical characteristics of the noneosinophilic asthma phenotype.

METHODS

We analyzed sputum cytology data from 995 subjects with asthma enrolled in clinical trials in the Asthma Clinical Research Network where they had undergone sputum induction and measures of sputum cytology, often repeatedly, and assessment of responses to standardized asthma treatments.

MEASUREMENTS AND MAIN RESULTS

In cross-sectional analyses, sputum eosinophilia (≥2% eosinophils) was found in only 36% of subjects with asthma not taking an inhaled corticosteroid (ICS) and 17% of ICS-treated subjects with asthma; an absence of eosinophilia was noted frequently, even in subjects with asthma whose disease was suboptimally controlled. In repeated measures analyses of people with asthma not taking an ICS, 22% of subjects had sputum eosinophilia on every occasion (persistent eosinophilia); 31% had eosinophilia on at least one occasion (intermittent eosinophilia); and 47% had no eosinophilia on every occasion (persistently noneosinophilic). Two weeks of combined antiinflammatory therapy caused significant improvements in airflow obstruction in eosinophilic asthma, but not in persistently noneosinophilic asthma. In contrast, bronchodilator responses to albuterol were similar in eosinophilic and noneosinophilic asthma.

CONCLUSIONS

Approximately half of patients with mild-to-moderate asthma have persistently noneosinophilic disease, a disease phenotype that responds poorly to currently available antiinflammatory therapy.

The majority of data on risk factors (RFs) for hepatocellular carcinoma (HCC) comes from studies involving populations without underlying liver disease. It is important to evaluate RFs for HCC in patients with chronic liver disease since HCC rarely occurs in those without underlying liver disease. We conducted a hospital-based case-control study of 259 incident HCC cases and 781 controls by convenience sampling between 02/2001 and 12/2009 from the liver clinic at Stanford University Medical Center. The study population was 41% White, 14% Hispanic, 3% African American, 40% Asian American, and 2% other race/ethnicity. RFs were examined through medical records and an in-person questionnaire. Alcohol and tobacco use was calculated by cumulative grams of alcohol or cumulative pack(s) of cigarette consumed over one's lifetime. Diabetes mellitus (DM) was defined by random glucose level of ≥200 mg/dL. RFs were evaluated using multivariate logistic regression. Independent predictors of HCC risk, after mutual adjustment and additional control for alcohol use, etiology of liver diseases, and DM, included age >40 (OR = 8.5 [2.6-28.3]), male gender (OR = 3.5 [2.2-5.8]), presence of cirrhosis (OR = 2.8 [1.6-4.9]), Asian ethnicity (OR = 2.8 [1.8-4.6]), AFP > 50 (OR = 4.2 [2.6-6.8]), and cumulative lifetime tobacco use of >11,000 packs (OR = 1.7 [1.0-2.9]). Heavy prolonged cigarette smoking, but not alcohol use, was a significant independent predictor for HCC in patients with underlying liver disease. Besides older age, male gender, presence of cirrhosis, and elevated AFP, Asian ethnicity and heavy cumulative tobacco use are strong independent predictors of HCC.

Mycobacterium tuberculosis promotes its replication by inhibiting the apoptosis of infected macrophages. A proapoptotic M. tuberculosis mutant lacking nuoG, a subunit of the type I NADH dehydrogenase complex, exhibits attenuated growth in vivo, indicating that this virulence mechanism is essential. We show that M. tuberculosis also suppresses neutrophil apoptosis. Compared to wild-type, the nuoG mutant spread to a larger number of lung phagocytic cells. Consistent with the shorter lifespan of infected neutrophils, infection with the nuoG mutant resulted in fewer bacteria per infected neutrophil, accelerated bacterial acquisition by dendritic cells, earlier trafficking of these dendritic cells to lymph nodes, and faster CD4 T cell priming. Neutrophil depletion abrogated accelerated CD4 T cell priming by the nuoG mutant, suggesting that inhibiting neutrophil apoptosis delays adaptive immunity in tuberculosis. Thus, pathogen modulation of apoptosis is beneficial at multiple levels, and enhancing phagocyte apoptosis promotes CD4 as well as CD8 T cell responses.