From NSAID to NERD – a lethal possibility?

The link between asthma, nasal polyps and aspirin sensitivity, also referred to as Samter’s triad, has long been known. Aspirin belongs to the class of medications known as non-steroid anti-inflammatory drugs (NSAIDs). When chronic rhinosinusitis and other features such as hypereosinophilia and anosmia (loss of sense of smell) are added, then the combination is known as aspirin-exacerbated respiratory disease or AERD, which is often seen in patients with severe asthma.

Reactions to NSAIDs can occur in genetically predisposed individuals and can be expressed as respiratory (asthma), cutaneous (angioedema and urticaria) and even as anaphylactic. Reactions may be immediate or delayed and may be more severe in the elderly. This is partly due to the physiological changes that occur – decreased cardiac output, reduced kidney filtration rate, changes in body compositions and functions as well as response to drugs (including distribution and clearance of drugs) and an increased propensity for adverse reactions. Use of NSAIDs can and will exacerbate existing problems.1-3

The prevalence of AERD, determined by oral provocation testing, was found to be 5% in children and 21% in adults.4 Women who develop AERD tend to have a more severe form of the disease. However, AERD is seen in almost 15% of patients with severe asthma and in about 9% of individuals who have chronic rhinosinusitis with nasal polyps. (1) It is most often seen in males in adulthood. AERD occurs in 5% to 10% of patients with chronic rhinosinusitis but ranges between 15% and 40% in those with nasal polyposis.5

In individuals with asthma, reactions to aspirin generally occur 30 to 90 minutes or more after ingestion. Symptoms involve the respiratory tract and can include rhinitis, congestion, flushing, laryngospasm and asthma exacerbations.2,3

Treatment of AERD requires avoidance of aspirin and other NSAIDs.6 Intranasal steroids can be used to reduce inflammation and the formation of polyps.

A study of asthma patients with AERD found that one in three needed systemic steroids daily, while almost one in two needed short courses of systemic steroids.2,7 If necessary, aspirin de-sensitization can be done by an experienced specialist.

NERD and Asthma

AERD can be life-threatening and is considered a distinct syndrome. Cross-sensitivity in patients with AERD to other NSAIDS has been found to b4

  • 100 % to naproxen
  • 98 % to ibuprofen
  • 93 % to diclofenac

NSAIDs can and do exacerbate asthma. As such, NSAID-exacerbated respiratory disease is known as NERD. The prevalence of NERD is 9% in adults who have asthma.8 In a study involving adult asthma patients, the researchers found that in a comparison with NSAID-tolerant individuals, those who had NERD also had8

  • a two-fold increase in uncontrolled asthma
  • a 60% increase in both severe asthma and asthma exacerbations
  • an 80% increase in emergency room visits
  • a 40% increase in asthma hospitalizations

NSAIDS may be considered as cofactors in diseases other than asthma such as

  • food-related exercise-induced anaphylaxis
  • angiotensisn-converting enzyme inhibitors that result in angioedema
  • oral mite anaphylaxis.9

Children, NSAIDS and NERD

A review of publications pertaining to reactions to NSAIDS in preschool children found that while facial angioedema and urticaria were the most common reaction to NSAIDS, there were also cardiovascular, respiratory and systemic reactions.10 NERD reactions in children and adolescents are expressed in a variety of ways including angioedema, flushing, gastric pain, hives, hypotension and urticaria. In addition to cutaneous symptoms, lower respiratory reactions such as a 15% to 57% drop in FEV1 were also seen.11,12

A study of children with asthma in Taiwan found that the use of NSAIDS was associated with an increased risk of exacerbations. While ibuprofen, diclofenac, naproxen, ketoprofen were among the most- prescribed NSAIDs for children with asthma, ibuprofen and diclofenac were associated with an increased risk of hospitalisation for asthma.13 The European Safety of NSAIDs project also indicated a two-fold association between ibuprofen and asthma exacerbations.14

In adolescents with asthma NSAID reactions included hives or angioedema accompanied by respiratory symptoms. Of the ten adolescents included in this particular study, two developed chronic rhinosinusitis; and aspirin desensitization was need in two adolescents with recurrent nasal polyps. This study concluded that NERD in childhood was less severe than in adulthood and that the asthma could be well controlled.11

NERD and Asthma Control

Asthma control is affected in patients with NERD. A study15 of 201 AERD patients with asthma found

  • 20.4 % had controlled asthma
  • 34.3 % had partially controlled asthma
  • 45.3 % had uncontrolled asthma.

It has been noted that atopy is a risk factor for NERD.16 In a comparison with NSAID-tolerant adults with asthma and adults with both asthma and NERD, the following increases were noted in the latter group8

  • double for uncontrolled asthma (RR 1.96)
  • 60% for severe asthma (RR 1.58)
  • 60% ofasthma exacerbations (RR 1.59)
  • 80% of emergency room visits (RR 1.79)
  • 40% of asthma hospitalizations (RR 1.37)

It is clear that asthma morbidity is substantially increased in individuals with asthma and NERD. Hence, more careful monitoring and follow-up of these patients is essential to maintain control of the asthma. In individuals who are prescribed low-dose aspirin, its protective benefits must be balanced with the known toxic effects of NSAIDS on the GI tract. Lack of attention to gastrointestinal events associated with NSAIDScan result in death with associated mortality rates around 5.6%.17 “Up to one-third of all NSAID/aspirin deaths can be attributed to low-dose aspirin use.”17

NSAIDS then, have the potential to be lethal, particularly in individuals agedover 75and particularly those with associated comorbid conditions such as heart failure, kidney or respiratory diseases.18

Abbreviations
AERD    aspirin-exacerbated respiratory disease
NERD    NSAID-exacerbated respiratory disease
NSAID   non-steroid anti-inflammatory drug(s)
RR         relative risk

References

  1. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. J Allergy Clin Immunol. 2015 ; 135 (3): 676-81.e1.
  2. Kennedy JL, Stoner AN, Borish L. Aspirin-exacerbated respiratory disease: Prevalence, diagnosis, treatment, and considerations for the future. Am J Rhinol Allergy. 2016 Nov 1;30(6):407-413. doi: 10.2500/ajra.2016.30.4370.
  3. Durrance SA. Older adults and NSAIDS: avoiding adverse teactions. Geriatr Nurs. 2003; 24(6).
  4. Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice. BMJ 2004; 328:434. Doi:  10.1136/bmj.328.7437.434
  5. Ledford DK, Lockey RF. Aspirin or Nonsteroidal Anti-inflammatory Drug-Exacerbated Chronic Rhinosinusitis. J Allergy Clin Immunol Pract. 2016 Jul-Aug;4(4):590-8. doi: 10.1016/j.jaip.2016.04.011.
  6. Stevenson DD, Szczeklik A. Clinical and pathologic perspectives on aspirin sensitivity and asthma. J Allergy Clin Immunol. 2006 Oct; 118(4):773-86; quiz 787-8.
  7. Berges-Gimeno MP, Simon RA, Stevenson DD. The natural history and clinical characteristics of aspirin-exacerbated respiratory disease. Ann Allergy Asthma Immunol. 2002 Nov; 89(5):474-8.
  8. Morales DR, Guthrie B et al. NSAID-exacerbated respiratory disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity. Allergy. 2015 Jul;70(7):828-35. doi: 10.1111/all.12629.
  9. Sánchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A. Cofactors and comorbidities in patients with aspirin/NSAID hypersensitivity. Allergol Immunopathol (Madr). 2016 Nov 16. pii: S0301-0546(16)30121-5. doi: 10.1016/j.aller.2016.08.010.
  10. Kidon MI, Kang LW, Chin CW et al. Nonsteroidal anti-inflammatory drug hypersensitivity in preschool children. Allergy Asthma Clin Immunol. 2007 Dec 15;3(4):114-22. doi: 10.1186/1710-1492-3-4-114.
  11. Ertoy Karagol HI, Yilmaz O et al. Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease in adolescents. Int Forum Allergy Rhinol. 2015 May;5(5):392-8. doi: 10.1002/alr.21494
  12. Debley JS, Carter ER et al. The prevalence of ibuprofen-sensitive asthma in children: a randomized controlled bronchoprovocation challenge study. J Pediatr. 2005; 147(2): 233–8.
  13. Lo PC, Tsai YT, Lin SK, Lai JN.  Risk of asthma exacerbation associated with nonsteroidal anti-inflammatory drugs in childhood asthma: A nationwide population-based cohort study in Taiwan. Medicine (Baltimore). 2016 Oct;95(41):e5109. Doi:  10.1097/MD.0000000000005109
  14. Valkhoff VE, Schade R, W‘t Jong G, et al. Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues? BMC Pediatr 2013; 13:1.  Doi:  10.1186/ 1471-2431-13-192
  15. Bochenek G, Szafraniec K et al. Factors associated with asthma control in patients with aspirin-exacerbated respiratory disease. Respir Med. 2015 May;109(5):588-95. doi: 10.1016/j.rmed.2015.02.015.
  16. Sanchez-Borges M, Capriles-Hulett A. Atopy is a risk factor for non-steroidal anti-inflammatory drug sensitivity. Ann Allergy Asthma Immunol. 2000;84:101–6. doi: 10.1016/S1081-1206(10)62748-2.
  17.  Lanas A, Perez-Aisa MA et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol 2005; 100(8): 1685-93. DOI: 10.1111/j.1572-0241.2005.41833.x
  18. Merel SE, Paauw DS.  Common drug side effects and drug-drug interactions in elderly adults in primary care. J Am Geriatr Soc. 2017;65(7):1578-1585.

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