No abstract

Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept.

We describe the first confirmed person-to-person transmission of oseltamivir-resistant pandemic influenza A(H1N1) 2009 virus that occurred in a hematology unit in the United Kingdom. Eleven cases of (H1N1) 2009 virus infection were identified, of which, ten were related as shown by sequence analysis of the hemagglutinin and neuraminidase genes. H275Y analysis demonstrated that 8 of 10 case patients had oseltamivir-resistant virus, with 4 of 8 case patients infected by direct transmission of resistant virus. Zanamivir should be considered as first-line therapy for influenza in patients with lymphopenic hematological conditions and uptake of influenza vaccination encouraged to further reduce the number of susceptible individuals.

Background Patients with primary antibody deficiency (PAD) are at increased risk of respiratory tract infections but our understanding of their nature and consequences remains limited. Objective To define the symptomatic and microbial burden of upper airway infection in adults with PAD relative to age-matched controls. Methods Prospective 12-month observational study consisting of a daily upper and lower airway symptom score alongside fortnightly nasal swab with molecular detection of 19 pathogen targets. Results 44 patients and 42 controls (including 34 household pairs) were recruited, providing over 22,500 days of symptom scores and 1,496 nasal swabs. Swab and questionnaire compliance exceeded 70%. At enrolment, 64% of patients received prophylactic antibiotics with a 34% prevalence of bronchiectasis. On average, PAD patients experienced symptomatic respiratory exacerbations every 6 days compared to 6 weeks for controls, associated with significant impairment of respiratory-specific quality of life scores. Viral detections were associated with worsening of symptom scores from a participant’s baseline. PAD patients had increased odds ratio (OR) for pathogen detection, particularly viral (OR 2.73; 95% CI: 2.09 to 3.57), specifically human rhinovirus HRV (OR 3.60; 2.53-5.13), and parainfluenza (OR 3.06; 1.25-7.50). H. influenzae and S. pneumonia were also more frequent in PAD. Young child exposure, IgM deficiency, and presence of bronchiectasis were independent risk factors for viral detection. Prophylactic antibiotic use was associated with a lower risk of bacterial detection by PCR. Conclusion PAD patients have a significant respiratory symptom burden associated with increased viral infection frequency despite immunoglobulin replacement and prophylactic antibiotic use. This highlights a clear need for future therapeutic trials in the PAD-population, and informs future study design.

Summary:The use of zanamivir in seven patients with influenza (three A and four B) post allograft is described. Inhaled zanamivir (10 mg twice daily) was continued from the diagnosis of influenza until excretion of virus ceased (median duration 15 days, range 5 to 44 days). There was no toxicity attributable to zanamivir and rapid resolution of influenza symptoms was seen. There was no mortality due to influenza in the seven patients. The good outcome of 30 previous patients with influenza post transplant is described. A randomised multicentre study would be required to demonstrate efficacy.