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Title:   Author  item
                                            WALSH, PAUL - Sutter Medical Centeritem
                                            BEHRENS, NICOLE - University Of Californiaitem
                                            CRVALLO CHAIGNEAU, FRANCISCO - California Animal Health & Food Laboratoryitem
                                            MCELLIGOT, HEATHER - University Of Californiaitem
                                            AGRAWAL, KARAN - University Of Californiaitem
                                            Newman, Johnitem
                                            ANDERSEN, MARK - California Animal Health & Food Laboratoryitem
                                            GERSHWIN, LAUREL - University Of California
  Submitted to: PLOS ONE
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 3/22/2016
                                    Publication  Date: 4/13/2016
                                    Citation: Walsh, P., Behrens, N., Crvallo Chaigneau, F.R., Mcelligot, H., Agrawal, K., Newman, J.W., Andersen, M., Gershwin, L.J. 2016. A randomized placebo controlled trial of ibuprofen for respiratory syncytial infection in a bovine model study. PLoS One. 11(4):e0152913. doi: 10.1371/journal.pone.0152913.Interpretive Summary: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity through adverse host responses to the virus including acute lung inflammation.  RSV infection leads to a type of white blood cell mediated inflammation that is sensitive to drugs like ibuprofen.  This study tested the hypothesis that treating bovine RSV with ibuprofen would decrease inflammation, clinical illness, and pathological changes in the lung. We further hypothesized that viral replication would be unaffected.  To accomplish this, we performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, a suite of lipid mediators of immune function in plasma and lymph nodes, and cytokines (i.e. peptide mediators of inflammation) in mediastinal lymph nodes. Viral shedding was measured daily and nasal cytokines every other day. The calves were necropsied on Day 10 post inoculation and histology performed. One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Overall however, clinical scores and weight gain improved in the ibuprofen group. Ibuprofen decreased lipid mediators derived from cyclooxygenase, lipoxygenase, and cytochrome P450 metabolism, and increased monoacylglycerols in lung lymph nodes. Ibuprofen also narrowed the range of observed interleukin-13, interleukin-17 and interferon gamma gene expression in lymph tissue, further suggesting dampening of the immune response.  Lung histology was not different between groups, while viral shedding was increased in calves randomized to ibuprofen.  In summary, ibuprofen decreased lipid immune mediator levels, modulated the immune response, and improved clinical outcomes. However lung histopathology was not affected and viral shedding was increased, suggesting that combining antivirals with cyclooxygenase inhibitors should be investigated as a therapy for RSV infection.
                                Technical Abstract: Background: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and hospital admission in infants. An analogous disease occurs in cattle and costs US agriculture a billion dollars a year. RSV causes much of its morbidity indirectly via adverse effects of the host response to the virus.  RSV is accompanied by elevated prostaglandin E2 (PGE2) which is followed by neutrophil led inflammation in the lung. Ibuprofen is a prototypical non-steroidal anti-inflammatory drug that decreases PGE2 levels by inhibiting cyclooxygenase.

Hypotheses: We hypothesized that treatment of RSV with ibuprofen would decrease PGE2 levels, modulate the immune response, decrease clinical illness, and decrease the histopathological lung changes in a bovine model of RSV. We further hypothesized that viral replication would be unaffected.

Methods:  We performed a randomized placebo controlled trial of ibuprofen in 16 outbred Holstein calves that we infected with RSV. We measured clinical scores, cyclooxygenase, lipoxygenase and endocannabinoid products in plasma and mediastinal lymph nodes and interleukin (Il)-4, Il-13, Il-17 and interferon-' in mediastinal lymph nodes. RSV shedding was measured daily and nasal Il-6, Il-8 and Il-17 every other day. The calves were necropsied on Day 10 post inoculation and histology performed. 

Results: One calf in the ibuprofen group required euthanasia on Day 8 of infection for respiratory distress. Overall however clinical scores and weight gain were better in the ibuprofen group. Ibuprofen decreased cyclooxygenase, lipoxygenase, and cytochrome P450 products and increased monoacylglycerols in lung lymph nodes. Ibuprofen modulated the immune response as measured by narrowed range of observed Il-13, Il-17 and IFN-' gene expression in mediastinal lymph nodes.  Lung histology was not different between groups, and viral shedding was increased in calves randomized to ibuprofen.

Conclusions: Ibuprofen decreased PGE2, modulated the immune response, and improved clinical outcomes. However lung histopathology was not affected and viral shedding was increased.


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