NSAIDs in asthma and viral asthma exacerbations
Aside from NSAIDs-exacerbated respiratory disease (NERD), NSAIDs are
usually well tolerated by patients with asthma and therefore they are
often used in real life during asthma exacerbations together with
intensified asthma treatment in children and adults.2Current Global Initiative for Asthma (GINA) guidelines are stating with
evidence level A, that aspirin and other NSAIDs are generally not
contraindicated in patients with asthma, unless there is a history of
previous reactions to those medications. Nevertheless, it is still not
very well studied whether NSAIDs facilitate or inhibit achievement of
asthma control following exacerbations, and if they affect the speed of
resolution of airway inflammation. Exacerbations of asthma are most
often induced by common respiratory viruses including rhinovirus (RV),
respiratory syncytial virus (RSV), bocavirus, influenza viruses,
adenovirus and others.3-5 RV is responsible for up to
76% of exacerbations of wheeze in children and up to 83% of asthma
attacks in adults.3-5 Recurrent viral infections do
not only cause acute disease and exacerbations of established disease,
but they also contribute to the pathophysiology of early wheezing in
children and the development of asthma. Prophylaxis of RSV-induced
bronchiolitis with palivizumab, an anti-RSV monoclonal antibody, in late
pre-term infants decreased the risk of recurrent infant wheeze and the
rate of parent reported asthma symptoms at 6 years of age, however
without any effect on lung function or doctor-diagnosed
asthma.6,7 The majority of respiratory viruses are
known to modify several major eicosanoid pathways, including the COX and
the LOX pathways8 (Fig. 2) . RV infection
increases expression of 5-lipoxygenase (5-LOX), 5-lipoxygenase
activating protein (FLAP), and cyclooxygenase-2 (COX-2), as well as the
production of prostaglandins E2 (PGE2)
and PGD2 by the respective isomerases in human bronchial
epithelial cells, with higher levels in asthmatic patients than in
controls.9 In addition, cysteinyl leukotriene
(cysteinyl-LT) levels, 5-LOX positive cells and FLAP-positive cells in
bronchoalveolar lavage fluid are increased in humans upon RV infection
and correlate with the emergence of upper respiratory
symptoms.10 Infection with RV affects airway mucosal
barriers and also the peripheral blood and distant tissues.
PGE2 plays an important role in optimal antibody
synthesis, as COX inhibitors reduce antibody release by plasma cells,
also in case of viral infections.11,12 Healthy
individuals experimentally infected with RV showed a suppressed serum
neutralizing antibody response when treated with aspirin or
acetaminophen.13 Significant increase in COX-2 (PTGS2)
expression and in COX-derived metabolites is a hallmark of
RSV14 and influenza virus
infection.15 Pharmacologic inhibition of the COX
pathway decreased RSV-induced lung pathology, although this was not
linked to a specific metabolite.14,16 At a later stage
of RSV infection there is an increase in LOX metabolites, which might
promote appropriate resolution of infection-induced
inflammation.17 This resolution is impaired in 5-LOX
and 15-LOX knockout mice upon RSV or pathogenic influenza strain
infection. Moreover, in mice lacking 5-LOX there is an upregulation of
COX2 expression and aggravation of infection-induced lung
pathology.14,16 During influenza A infection, newly
generated PGE2 leads to the inhibition of type I
interferon (IFN) production, inhibition of macrophage apoptosis and
subsequent increase in virus replication.Ptges -/- knockout mice, which do not produce
PGE2, or wild type mice treated with
PGE2 type 2 (EP2) and type 4 receptor (EP4) antagonists
demonstrated enhanced protection against lethal influenza
infection.18 PGE2 also inhibits
activation of the Nod like receptor family pyrin domain containing 3
(NLRP3) inflammasome in human monocytes and macrophages, and COX pathway
blocking increases inflammasome activation and mature Il-1β release.
NLRP3 inflammasome activation can contribute to limiting viral
replication at the early stages of infection, but in some instances, it
may also lead to harmful hyperinflammation during late-stage
infection.19 Much less is known about
PGD2 and antiviral responses. However, it was shown that
in aging mice there is an increase in PGD2 in the lungs
which correlates with the impaired migration of respiratory dendritic
cells (DC) to lymph nodes, diminished T cell responses and more severe
clinical disease in older mice infected with respiratory viruses, such
SARS-CoV-1 and influenza.20 Blocking
PGD2 function enhances DC migration, T cell responses,
and survival in the infected animals.20 In summary,
prostaglandins and other COX-dependent metabolites are involved in a
complex way in the pathogenesis of respiratory viral infections and thus
in virus-induced exacerbation of asthma. Therefore, the use of NSAIDs to
alleviate symptoms of viral infections in general population and in
patients with asthma should be re-evaluated with assessment of the
effects of the timing of the administration, their selectivity and the
long-term effects.