Screening Practices for Latent Tuberculosis Infection in Clinical Trials Evaluating Treatments for Chronic Hepatitis B Virus Infection.

Latent tuberculosis infection (LTBI) prevalence among adults with chronic hepatitis B (CHB) is two times higher than LTBI prevalence in the general adult population. Although newer CHB treatments evaluated in clinical trials modulate the immune system and potentially increase LTBI reactivation risk, it is unknown whether CHB clinical trials are screening for LTBI. We describe LTBI screening practices in CHB clinical trials. We utilized the ClinicalTrials.gov website to identify clinical trials that evaluated CHB treatments. CHB treatments were categorized according to LTBI reactivation risk as unknown, low, moderate, and high-risk. Tuberculosis burden among countries in which CHB clinical trials were conducted were defined using World Health Organization definitions. Of 651 CHB clinical trials identified, 452 (69%) were included in the final cohort, among which 337 (75%), 108 (24%), and 7 (1%) evaluated CHB medications with a low, unknown, and moderate LTBI reactivation risk, respectively. A total of 330 (73.0%) CHB clinical trials reviewed were conducted in high TB burden countries. Three (0.6%) CHB trials reviewed screened for LTBI; one each among CHB treatments with low, moderate, and high LTBI reactivation risk. Although nearly 75% of all CHB clinical trials were conducted in high TB burden countries and 25% of trials evaluated CHB treatments with an unknown LTBI reactivation risk, less than 1% of trials screened for LTBI. Consideration should be given to screen for LTBI among CHB clinical trials given high prevalence of co-infection and potential for increased LTBI reactivation risk with CHB treatments evaluated.

Citrullination of extracellular histone H3.1 reduces antibacterial activity and exacerbates its proteolytic degradation.

BACKGROUND: Cystic fibrosis (CF), involves excessive airway accumulation of neutrophils, often in parallel with severe infection caused by Pseudomonas aeruginosa. Free histones are known to possess bactericidal properties, but the degree of antibacterial activity exerted on specific lung-based pathogens is largely unknown. Neutrophils have a high content of peptidyl deiminase 4 (PADI4), which citrullinate cationic peptidyl-arginines. In histone H3.1, several positions in the NH2-terminal tail are subject to citrullination. METHODS: Full-length and segmented histone subunit H3.1 was investigated for bactericidal activity towards P. aeruginosa (strain PAO1). PADI4-induced citrullination of histone H3.1 was assessed for antibacterial activity towards P. aeruginosa. Next, the effect of neutrophil elastase (NE)-mediated proteolysis of histone H3.1 was investigated. Finally, PADI4, H3.1, and citrullinated H3.1 were examined in healthy control and CF patient lung tissues. RESULTS: Full-length histone H3.1 and sections of the histone H3.1 tail, displayed bactericidal activity towards P. aeruginosa. These antibacterial effects were reduced following citrullination by PADI4 or proteolysis by NE. Interestingly, citrullination of histone H3.1 exacerbated NE-mediated degradation. In CF lung tissue, citrullinated histone H3.1 and PADI4 immunoreactivity was abundant. Degraded histone H3.1 was detected in the sputum of CF patients but was absent in the sputum of healthy controls. CONCLUSIONS: Citrullination impairs the antibacterial activity of histone H3.1 and exacerbates its proteolytic degradation by NE. Citrullination is likely to play an important role during resolution of acute inflammation. However, in chronic inflammation akin to CF, citrullination may dampen host defense and promote pathogen survival, as exemplified by P. aeruginosa.