Acute Pulmonary Exacerbation Phenotypes in Patients with Cystic Fibrosis.

Rationale: The etiology of cystic fibrosis (CF) pulmonary exacerbations (PEx) is likely multifactorial with viral, bacterial, and non-infectious pathways contributing. Objectives: To determine whether viral infection status and CRP (C-reactive protein) can classify subphenotypes of PEx that differ in outcomes and biomarker profiles. Methods: Patients were recruited at time of admission for a PEx. Nasal swabs and sputum samples were collected and processed using the respiratory panel of the FilmArray multiplex polymerase chain reaction (PCR). Serum and plasma biomarkers were measured. PEx were classified using serum CRP and viral PCR: "pauci-inflammatory" if CRP < 5 mg/L, "non-viral with systemic inflammation" if CRP ⩾ 5 mg/L and no viral infection detected by PCR and "viral with systemic inflammation" if CRP ⩾ 5 mg/L and viral infection detected by PCR. Results: Discovery cohort (n = 59) subphenotype frequencies were 1) pauci-inflammatory (37%); 2) non-viral with systemic inflammation (41%); and 3) viral with systemic inflammation (22%). Immunoglobulin G, immunoglobulin M, interleukin-10, interleukin-13, serum calprotectin, and CRP levels differed across phenotypes. Reduction from baseline in forced expiratory volume in 1 second as percent predicted (FEV1pp) at onset of exacerbation differed between non-viral with systemic inflammation and viral with systemic inflammation (-6.73 ± 1.78 vs. -13.5 ± 2.32%; P = 0.025). Non-viral with systemic inflammation PEx had a trend toward longer duration of intravenous antibiotics versus pauci-inflammation (18.1 ± 1.17 vs. 14.8 ± 1.19 days, P = 0.057). There were no differences in percent with lung function recovery to <10% of baseline FEV1pp. Similar results were seen in local and external validation cohorts comparing a pauci-inflammatory to viral/non-viral inflammatory exacerbation phenotypes. Conclusions: Subphenotypes of CF PEx exist with differences in biomarker profile, clinical presentation, and outcomes.

Change in pain and its relation to change in activity in osteoarthritis.

Objective: Trials testing promising interventions in knee osteoarthritis (OA) often fail to show pain reductions. This may be due to change in activity whereby a person's pain decreases, leading them to increase their activity levels, in turn increasing pain back to baseline levels. Using data from a trial of a beneficial treatment for knee pain, we explored whether activity changes might mask a treatment's effect on pain, by looking at whether activity levels increased with effective treatment and whether change in activity level related to change in pain. Design: During the InRespond trial (ISRCTN55059760) participants wore an accelerometer for 7 days before and during treatments. We assessed change in pain on treatment using scores for overall knee pain and pain in a nominated pain-aggravating activity both in the last week and evaluated change in different types of activity using accelerometer data. Principal components analysis tested whether change in activity and pain outcomes were correlated and created composites combining them. We then tested whether activity, pain or the composites showed a treatment effect, and examined their responsiveness. Results: In the 61 participants (mean age 64.5 years, 38% women, mean overall knee pain score 5.08 (0-10)), activity levels mostly decreased during the trial. Principal component analyses suggested that pain and activity did not correlate highly, loading on different components. Treatment that showed significant effects on pain did not show similar effects on either activity (e.g. the active treatment had a slightly greater reduction in total steps taken than the control treatment (difference 1942.6 steps/week, p = 0.42) nor on composites combining activity and pain. Pain outcomes were the most responsive; static loading (standing) outcomes were the most responsive activity outcome. Conclusion: We found no evidence to support the hypothesis that activity levels increase during effective OA treatment and might account for the negligible pain effects of OA treatments.

Pharmacogenetics of cystic fibrosis treatment.

Cystic fibrosis (CF) is genetic autosomal recessive disease caused by reduced or absent function of CFTR protein. Treatments for patients with CF have primarily focused on the downstream end-organ consequences of defective CFTR. Since the discovery of the CFTR gene that causes CF in 1989 there have been tremendous advances in our understanding of the genetics and pathophysiology of CF. This has recently led to the development of new CFTR mutation-specific targeted therapies for select patients with CF. This review will discuss the characteristics of the CFTR gene, the CFTR mutations that cause CF and the new mutation specific pharmacological treatments including gene therapy that are contributing to the dawning of a new era in cystic fibrosis care.