Development of a Large Pneumatocele in a Patient Recovering from COVID-19 Pneumonitis.

A 39-year-old man presented with severe COVID-19 pneumonitis requiring hospital admission. He represented three days following discharge with sudden onset breathlessness and chest pain. Initial imaging suggested the presence of a left pneumothorax. Following further clinical decline a plan was made to insert a CT guided chest drain. However, imaging in the prone position for the procedure unexpectedly revealed a large left lower lobe pneumatocele with only a very small pneumothorax. Events and appearances suggest that this is a rare case of delayed COVID-19 pneumonitis-related pneumatocele formation. We will discuss the clinical significance of this entity. LEARNING POINTS: Pneumatocele formation should be considered in patients presenting with new respiratory symptoms after completing therapy for COVID-19 pneumonitis.Performing CT examinations with patients in different positions may be required to help exclude the possibility of pneumatocele formation when a loculated pneumothorax is suspected on the supine CT images.

Serum Iron Level Is Associated with Time to Antibiotics in Cystic Fibrosis.

BACKGROUND: Serum levels of hepcidin-25, a peptide hormone that reduces blood iron content, are elevated when patients with cystic fibrosis (CF) develop pulmonary exacerbation (PEx). Because hepcidin-25 is unavailable as a clinical laboratory test, we questioned whether a one-time serum iron level was associated with the subsequent number of days until PEx, as defined by the need to receive systemic antibiotics (ABX) for health deterioration. METHODS: Clinical, biochemical, and microbiological parameters were simultaneously checked in 54 adults with CF. Charts were reviewed to determine when they first experienced a PEx after these parameters were assessed. Time to ABX was compared in subgroups with and without specific attributes. Multivariate linear regression was used to identify parameters that significantly explained variation in time to ABX. RESULTS: In univariate analyses, time to ABX was significantly shorter in subjects with Aspergillus-positive sputum cultures and CF-related diabetes. Multivariate linear regression models demonstrated that shorter time to ABX was associated with younger age, lower serum iron level, and Aspergillus sputum culture positivity. CONCLUSIONS: Serum iron, age, and Aspergillus sputum culture positivity are factors associated with shorter time to subsequent PEx in CF adults.

Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.

Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients with chronic inflammatory lung diseases, such as cystic fibrosis (CF), results in improved outcomes. Paradoxically, a recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM). Here, we confirm that long-term azithromycin use by adults with CF is associated with the development of infection with NTM, particularly the multi-drug-resistant species Mycobacterium abscessus, and identify an underlying mechanism. We found that in primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM in mice. Our findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.

Gout and hyperuricaemia in adults with cystic fibrosis.

Gout has not been described previously as a complication in cystic fibrosis (CF). Here we present data on nine CF patients who have presented with symptoms of acute gout. This gives an estimated prevalence of gout of around 2.5% in our adult CF population, compared to a previously described prevalence in the non-CF population of just over 1%. Serum urate is measured routinely at the annual review in our unit. Mean (SD) serum urate was 0.40 (0.09) mmol/L in male CF patients (n = 108) and 0.31 (0.08) mmol/L in female patients (n = 74). This was significantly greater than in historical controls. Thirty-seven percent of male CF patients and 36% of female patients had serum urate levels above the upper limit of normal.

Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells.

BACKGROUND: Intermittent viral exacerbations in patients with cystic fibrosis (CF) with chronic Pseudomonas aeruginosa (PA) infection are associated with increased bacterial load. A few clinical studies suggest that rhinoviruses (RV) are associated with the majority of viral-related exacerbations in CF and require prolonged intravenous antibiotic treatment. These observations imply that acute RV infection may increase lower respiratory symptoms by increasing planktonic bacterial load. However, the underlying mechanisms are not known. METHODS: Primary CF airway epithelial cells differentiated into mucociliary phenotype were infected with mucoid PA (MPA) followed by RV and examined for bacterial density, biofilm mass, levels of chemokines and hydrogen peroxide (H2O2). The need for dual oxidase 2, a component of NADPH oxidase, in RV-induced generation of H2O2 in CF cells was assessed using gene-specific siRNA. RESULTS: Superinfection with RV increased chemokine responses in CF mucociliary-differentiated airway epithelial cells with pre-existing MPA infection in the form of biofilm. This was associated with the presence of planktonic bacteria at both the apical and basolateral epithelial cell surfaces. Further, RV-induced generation of H2O2 via dual oxidase 2 in CF cells was sufficient for dispersal of planktonic bacteria from the biofilm. Inhibition of NADPH oxidase reduced bacterial transmigration across mucociliary-differentiated CF cells and the interleukin-8 response in MPA- and RV-infected cells. CONCLUSION: This study shows that acute infection with RV liberates planktonic bacteria from biofilm. Planktonic bacteria, which are more proinflammatory than their biofilm counterparts, stimulate increased chemokine responses in CF airway epithelial cells which, in turn, may contribute to the pathogenesis of CF exacerbations.

Emerging treatments in cystic fibrosis.

There are a number of potential drugs for the treatment of cystic fibrosis (CF) currently undergoing clinical studies. A number of antibacterials formulated for delivery by inhalation are at various stages of study; these include dry-powder inhaler versions of colistin, tobramycin and ciprofloxacin, and formulations of azteonam, amikacin, levofloxacin, ciprofloxacin and fosfomycin/tobramycin for nebulization. Clinical trials of anti-inflammatory agents, including glutathione, phosphodiesterase-5 inhibitors such as sildenafil, oral acetylcysteine, simvastatin, methotrexate, docosahexaenoic acid, hydroxychloroquine, pioglitazone and alpha1-antitrypsin, are ongoing. Ion channel modulating agents, such as lancovutide (Moli1901, duramycin) and denufosol, which activate alternate (non-CF transmembrane regulator [CFTR]) chloride channels, and GS 9411, a sodium channel antagonist, are now at the stages of clinical study and if successful, will offer a new category of therapeutic agent for the treatment of CF. Correction of the underlying gene effect, either by agents that help to correct the dysfunctional CFTR, such as ataluren, VX-770 and VX-809, or by gene transfer (gene therapy), is a particularly exciting prospect as a new therapy for CF and clinical studies are ongoing. This article reviews the exciting potential drug treatments for CF currently being evaluated in clinical studies, and also highlights some of the challenges faced by research and clinical teams in assessing the efficacy of potential new therapies for CF.

Comparison of high specificity with standard versions of a quantitative latex D-dimer test in the assessment of community pulmonary embolism: HaemosIL D-dimer HS and pulmonary embolism.

BACKGROUND: D-dimer assays are sensitive but have poor specificity. False positive results lead to extra imaging and hospital admissions. OBJECTIVES: To make a pilot comparison of the diagnostic accuracy of the standard quantitative latex HemosIL D-dimer assay with a newer HemosIL D-dimer HS version designed to have improved specificity. PATIENTS / METHODS: Consecutive patients presenting from the community to an Emergency Department that were investigated for suspected pulmonary embolism using a D-dimer test were included in the study. Standard and D-dimer HS tests were performed. Pulmonary Embolism was diagnosed on the basis of imaging studies or post-mortem at any time from presentation to 90 days thereafter. RESULTS: The prevalence of Pulmonary Embolism was 4.5% (18/402). The sensitivity, specificity, negative predictive value, and positive predictive value for the standard quantitative D-dimer test was 100% (81.5 - 100.0), 49.2% (44.1 - 54.3),100% (98.1 - 100.0), and 8.5% (5.1 - 13.0), respectively, and 100% (81.5 - 100.0), 58.3% (53.2 - 63.3),100% (98.4 - 100.0), and 10.1% (6.1 - 15.5), for the D-dimer HS test. There were 35 (16%) fewer 'false positives' using the D-dimer HS assay compared with the standard assay. CONCLUSIONS: D-dimer HS has superior specificity to the standard quantitative D-dimer test without any loss of sensitivity. The generation of fewer false positive results should lead to less unnecessary diagnostic imaging; the use of which is associated with increased hospital admissions and length of stay. The HS assay may therefore have significant health economic benefits.