NSAID-exacerbated respiratory disease (NERD). Selectivity of
NSAIDs
NERD, also called AERD-aspirin exacerbated respiratory disease or
AIA-aspirin-intolerant asthma, is a phenotype of asthma recognized in 5
to 25% asthmatics. It is characterized by a non-immunological
hypersensitivity to low doses of NSAIDs and a cross-reactivity (a
multi-responder phenotype). Profound changes in biosynthesis of
eicosanoids comprise overproduction of cysteinyl-LTs, excreted in urine
as LTE4.173,174 Some patients have
higher excretion of LTE4 also during a stable period of
NERD.74,175-177 It is debatable, which cells produce
cysteinyl-LTs in NERD. Since overproduction of PGD2 and
increase of histamine concentration accompanies symptoms of NERD, these
could be mast cells. However, eosinophils in NERD overexpress
leukotriene C4 synthase (LTC4S), thus can contribute to the symptoms and
concurrent release of eosinophils cationic protein was observed.
PGE2 plays a key role in NERD, where both decreased
production of PGE2 and reduced EP2expression were observed.174,178 When
PGE2 is further decreased, it leads to mast cell
activation and bronchoconstriction because it removes the stabilising
effect of PGE2 on mast cell mediator
release131. Accordingly, inhalation of
PGE2 before aspirin challenge prevented reduction in
pulmonary function and mast cell activation.179However, inhibition of PGE2 biosynthesis by NSAIDs is
difficult to measure, since this prostaglandin is produced by most cells
of the body. Interestingly, patients with NERD have also an imbalance in
pro-resolving lipoxin A4 (LXA4) that may
contribute to the increased severity of this particular asthma
endotype.180 The minimal dose triggering bronchial
constriction and extra bronchial symptoms (cutaneous flush, nasal
obstruction, irritations of conjunctiva) varies across patients, but
generally it reflects NSAID potency to inhibit cyclooxygenase-1
isoenzyme (COX-1).181,182 Highly selective inhibitors
of COX-2 like coxibs (e.g. celecoxib, etoricoxib)183are well tolerated in most NERD patients, whereas preferential COX-2
inhibitors (nimesulide, meloxicam) can trigger symptoms at high
doses184 (Table 1) . Diclophenac, ketorolac,
ibuprofen, naproxen, indomethacin or pyrazolone derivatives inhibits
both COX-2 and COX-1,185 therefore are contraindicated
in NERD. Acetylsalicylic acid is more potent inhibitor of COX-1 than
COX-2.183,186 This was the first NSAID ever reported
to trigger symptoms in asthmatics. Paracetamol (acetaminophen), with an
unclear effects on prostanoids biosynthesis including possible
inactivation of brain cyclooxygenases by a non-substrate mechanism, is
tolerated by the vast majority of NERD patients unless given in very
high doses.39