P49 The effects of oral cotrimoxazole upon neutrophil and monocyte activation in patients with pulmonary fibrosis and healthy controls; does this relate to its action in idiopathic pulmonary fibrosis?

Abstract

Sulfamethoxazole and dapsone share the same sulphonamide ring with similar antibacterial effects. Detailed studies of dapsone show extensive effects on the immune system with the reduced generation of oxygen free radicals (ROS) and inhibition of neutrophil (NΦ) myeloperoxidase. These effects reduce intra and extracellular ROS reducing endothelial damage, lipid peroxidation and apoptosis. The bacterial peptide N-formyl-met-leu-phe (fMLP) activates the NΦ via its formyl peptide receptor (FPR) generating ROS much of which is extracellular. The FPR receptor also induces cell migration, granule secretion and lysosomal activation. Dapsone very significantly reduces fMLP activation of NΦ, giving anti-inflammatory effects. Interestingly phorbol 12-myristate 13-acetate (PMA), a well characterised activator of protein kinase C is less inhibited by dapsone. There are no comparable studies with cotrimoxazole despite its structural similarity. UK clinical studies of cotrimoxazole in Idiopathic pulmonary fibrosis (IPF), suggest protection against sudden severe exacerbations. Cotrimoxazole is thought to act via its anti-bacterial properties with data showing pathogen carriage in a third of new IPF cases. Oxidative stress is increased in IPF and limited studies show that peripheral monocyte (MΦ) depletion via a charcoal column in IPF exacerbations has reduced the 30 day mortality. In fibrotic organ injury, recruitment of MΦ appears critical and blocking MΦ activation and recruitment arrests the fibrotic process. We have examined by flow cytometry the effects of oral cotrimoxazole upon NΦ and MΦ activation in IPF patients on long-term treatment and healthy controls at baseline and after 1 week of cotrimoxazole. The commercial kit PHAGOBURST (Glycotope Biotechnology) was used, which allows quantitative determination of leucocyte oxidative burst in whole blood following stimulation by opsonized E Coli, PMA and fMLP.FindingsDespite the small numbers to date, similar to dapsone there is a significant blocking of oxidative burst to fMLP in NΦ and MΦ pre- and post cotrimoxazole with a similar trend in IPF. There is also some reduction in PMA oxidative burst, but none to E.coli. The reduced MΦ stimulation may reflect the lower MΦ bloods counts. If NΦ and MΦ ROS generation are reduced by cotrimoxazole, this may stabilise the disease process protecting against severe exacerbations.Abstract P49 Table 1Neutrophils Mean fluorescence*±SEM of stimulated cells (arbitrary units)Healthy controls(HC) n=9 No treatmentsHealthy controls n=6 post-Cotrimoxazole 7 days (960 mgBD)Paired t test +significance at the 5% level (pre- and post Cotrimoxazole n=6)IPF on long-term Cotrimoxazole (mean treatment duration 23 months, Cotrimoxazole (960 mgBD) n=8Mann Whitney U test HC versus IPF +significance at the 5% level Mean neutrophil blood count 109/l (SEM)3.32±0.243.43±0.164.49±0.39PMA Nφ7014±16235903±1503p=0.6833866±823p=0.117fMLP Nφ989±242246±244p=0.015+448±407p=0.08E coli Nφ4417±4473302±815p=0.3313606±358p=0.189Monocytes Mean fluorescence*±SEM of stimulated ...

Improved Recovery and Survival with Trimethoprim or Cotrimoxazole in Patients with Severe COVID-19: A Retrospective Analysis

“…In this process, highly stressed neutrophils extrude their nuclear content as Neutrophil Extracellular Traps (or NETs) that form 'external nets' in an attempt to trap and kill infectious agents; but platelets, debris , fibrin and other cells can become trapped and block off the pulmonary alveolar bed as seen in post mortems from COVID-19 patients [20]. Neutrophil nets have a high procoagulant potential that could explain the microvascular thrombosis seen in lungs, heart and kidney and brain in COVID-19, leading to the risk of hypoxic injury and death Excessive neutrophil and platelet activation gives dysregulated immuno-thrombosis and microvascular thrombi with neutrophil NETosis now recognised in recent post-mortem data [16,[18][19][20][21].…”

“…ARDS is a lifethreatening complications of COVID-19 thought to be associated with a hyper-immune response to the virus. Co-trimoxazole and trimethoprim block stimulation of the formyl peptide receptors (FPR's) which are abundantly expressed on the surface of circulating neutrophils and monocytes and normally regulate their function [15][16][17][18][19]. When FPR's are stimulated, they trigger the release of both intracellular and extracellular Reactive Oxygen Series (ROS) which can in turn drive cytokine production both inside and outside the neutrophil.…”

Cotrimoxazole as adjuvant therapy in critical ill COVID 19 patients

“…Hence it should be reserved only for critically ill patients. Oxidative stress has an important aspect of the cytokine storm, which is also reduced by Cotrimoxazole [9]. Various side effects are mentioned in the literature.…”

The impact of high dose oral cotrimoxazole in patients with COVID-19 with hypoxic respiratory failure requiring non-invasive ventilation: A Case Control Study

“…In addition sulphamethaxazole inhibits neutrophil activation by inhibiting Phorbol 12-myristate 13-acetate (PMA) stimulation thereby preventing Protein Kinase C activation and reducing inflammation. 11,12 This offers a possible explanation for the observed clinical benefit by reducing neutrophil, monocyte and lymphocyte activation leading to a reduction in the risk of ARDS. [12][13][14][15][16][17] Case reports describing clinical recovery from acute respiratory distress sydrome after the addition of cotrimoxazole are seen in medical literature.…”