Currently, no biomarkers are known to predict the response of the patient to aspirin desensitization or biological therapy, but patient's characteristics can already point into a direction (1). For example, when co-morbidities like cardiovascular disease or inflammatory disorder are present, the medical need for tolerance to aspirin/cyclo-oxygenase 1 (COX-1) therapy is obvious and favours aspirin desensitization. This enables the N-ERD patient to take prophylactic daily aspirin as antiplatelet therapy or to take daily NSAIDs as painkillers to relief the pain associated with a rheumatologic condition (7).

On the other hand the patient's history can make aspirin desensitisation not the preferred option due to the presence of some absolute or relative contra-indications to aspirin, like a history of peptic ulcers, eosinophilic esophagitis (which can also be associated with N-ERD), renal impairment, taking anticoagulant/antiplatelet therapy and history of bleeding disorders (1, 12, 13). These patients are at elevated risk for aspirin-related adverse effects as long-term aspirin desensitization diminish synthesis of gastric prostaglandin (PGI2) formation and causes inadequate repopulation of gastric mucosal cells, leading to gastric pain or ulcer, and as aspirin inhibits platelet function by acetylating platelet cyclo-oxygenase (3). According to White et al. 2020 between 10% and 15% of the N-ERD patients will be unable to remain on aspirin therapy due to the gastrointestinal side effects or bleeding/bruising (1). Remarkably, black and Latino patients are more prone than white patients to fail to tolerate the initial aspirin desensitization due to persistent gastrointestinal symptoms (2).

The necessity to evaluate the risks and comorbidities in the choice for oral aspirin desensitisation, becomes more important when the N-ERD patient becomes older. Recent clinical research suggests that daily oral aspirin is associated with a very small but significantly higher risk of major bleeding and haemorrhage and possibly a higher all-cause mortality in older adults, suggesting biological therapy as alternative treatment, although data for biologics in advanced age are lacking (2, 14). The treating physician should therefore be continuously attentive for aspirin-related adverse effects and asses the benefit/risk ratio of aspirin desensitization regularly as patients' history can change.

In line with this, some contra-indications for oral aspirin desensitization are temporary, like for example pregnancy and planned sinus surgery. In pregnant N-ERD patients, the intake of aspirin doses larger than 81 mg daily can contribute to premature closure of the ductus arteriosus and increases the risk for maternal and foetal bleeding. Therefore, oral aspirin desensitization should not be initiated or discontinued during pregnancy (2, 13). There is some consensus amongst the Rhinology community that aspirin desensitization should be started after sinus surgery, because of the potential for increased intraoperative bleeding and associated decrease in intraoperative visualization after aspirin intake, but also because of better clinical outcomes of aspirin desensitization after debulking the inflammatory nasal polyp tissue (2). Until now, it is unclear whether initiating biologics immediately after surgery would have a better clinical effect, but in every case, however, surgery is not a contra-indication.

Another important factor to consider is the extent to which the patient can adhere to the treatment. Patients on aspirin treatment after aspirin desensitisation (ATAD) missing their dose for more than two days will gradually regain their intolerance and will need further desensitization (2, 15).

Finally, there are some prerequisites associated with the start of aspirin desensitization or biological therapy. For aspirin desensitization, it is recommended that the patient has stable/controlled asthma (FEV1 > 70% predicted) before initiating the therapy to prevent further exacerbation of patients’ asthma (13, 15). For biologics, governments define criteria that need to be met for reimbursement of biologics. Clinical criteria to start biological therapy include, but are not limited to, evidence of type 2 inflammation, need for systemic corticosteroids, impaired quality of life, previous sinus surgery, failure of treatment with nasal corticosteroids, significant loss of smell and co-morbid asthma (16, 17). In N-ERD patients, asthma is not always present from the start according to a distinctive pattern characterized by a sequence of symptoms with first persistent rhinosinusitis. Asthma can thus be non-existent at the time of diagnosis of N-ERD (18). Interestingly, research has shown that even patients without asthma can benefit from aspirin desensitization (19).

The biologics omalizumab, mepolizumab and dupilumab are approved for use in patients with severe, uncontrolled chronic rhinosinusitis as add-on therapy to nasal corticosteroids. Their effect sizes seem large enough to reflect a major reduction in symptom burden as experienced by patients suffering from refractory CRSwNP (11). Benralizumab is not yet approved, but the OSTRO Phase III trial which met both co-primary endpoints with a safety profile consistent with the known profile of the medicine, is completed (20). An important side note is that data for N-ERD patients are generated by post-hoc analysis as they constituted only a subgroup of the whole study population. The percentage of participants with N-ERD within the group of patients with CRSwNP was 27% for mepolizumab, 28% of the overall population for dupilumab, 30% in each treatment arm for benralizumab and between 17% and 39% for the two trials with omalizumab (15). A second site note is that diagnosis of N-ERD based on history alone is not always reliable (21), and that provocation tests are necessary to have a confirmed diagnosis of N-ERD. Extrapolated data show that patients with N-ERD responded equally well compared to the aspirin-tolerant subgroup on the treatment with reduction of polyp size. In addition, N-ERD patients responded equally well on the dupilumab treatment with improvement in sense of smell and equally well in nasal blockage score on the benralizumab treatment. Dupilumab is the only biological showing a difference between aspirin-tolerant and aspirin-intolerant CRSwNP patients. More specifically, N-ERD patients reported significantly greater improvement in nasal congestion and SNOT-22. The efficacy of mepolizumab, benralizumab and dupilumab in patients with N-ERD for the treatment of asthma is also to be expected at least equally and even potentially superior given the fact that outcomes improved with higher numbers of peripheral eosinophils (15).

Since the first introduction of aspirin desensitization by Widal and associates in 1992 (3), only 5 double-blind placebo-controlled trials were conducted to assess the efficacy and safety of ATAD, totalling only 163 patients. The low number of double-blinded placebo-controlled trials can be explained by the fact that blinding of desensitization is difficult since patients in the active arm will experience a worsening of their symptoms during desensitization while those patients in the placebo arm will not. Alternatively, true desensitization with aspirin can be performed in all patients before randomization in the active or placebo arm (2, 15). Furthermore, there is no interest of the pharmaceutical industry in the repurposing of such an old molecule as aspirin for a new indication besides pain, fever, and prevention of blood clots. In cross-over trials from the early 1980s, 67% of the 25 patients noted improvement in nasal symptoms, while only half of the patients experienced improvement in their asthma symptoms. In general, most patients reported not only improvement in upper but also in lower respiratory symptoms, as well as overall disease control. Taken together, including one meta-analysis focusing on ATAD, the American Academy of Asthma Allergy & Immunology considers aspirin treatment after aspirin desensitization a unique treatment option for patients with N-ERD. Interestingly, a new systemic review and meta-analysis compared the efficacy and safety of ATAD with 8 other mAbs. More specifically, besides the 5 RCTs about ATAD, they included 24 RCTs evaluating 7 different mAbs. Comparisons among biologics and aspirin desensitization show with moderate to high certainty that dupilumab is among the most beneficial for 7 of 7 patient-important and surrogate outcomes, omalizumab for 2 of 7 (HRQoL and sinusitis symptoms), mepolizumab for 1 of 7 (sinusitis symptoms), and aspirin desensitization for 1 of 7 (sinusitis symptoms) (22). Aggregation of the data about aspirin desensitization is difficult because of the differences in study protocol (total daily aspirin dose, length of treatment) and primary endpoints (14). Moreover, most of the studies performed have a retrospective study design. The longest retrospective study has shown that 85% of patients were still taking daily aspirin 10 years after desensitization because they felt that the aspirin was “very” or “extremely” helpful in controlling their sinonasal and asthma symptoms as well as in improving their quality of life (2, 13). Although study results about the effect of ATAD on the need for revision surgery are conflicting, there is a consensus that ATAD is beneficial in the prevention of regrowth of nasal polyps after debulking surgery, rather than in the reduction of existing polyp burden (15). Finally, not unimportantly, ATAD improves N-ERD patients’ intolerance to alcohol (13).

Long term safety data for the biologics are lacking, especially in the field of allergy and rhinology. In the short term, the use of biologics seems to be relatively safe, with a drop-out rate of less than 5% for most of the published phase 3 studies (15). According to the meta-analysis of Oykhman et al. comparing 24 RCTs, the occurrence of adverse events with dupilumab, omalizumab, mepolizumab, benralizumab and reslizumab differed little from placebo (22).

An issue associated with dupilumab treatment might be the risk of increased blood levels of eosinophils in roughly 10% of patients. At circa 16 to 20 weeks after starting the treatment, eosinophil levels were 10% higher compared with baseline. Several patients (<5%) needed a rescue treatment to continue on dupilumab for their asthma or chronic rhinosinusitis (15). Permanent discontinuation of dupilumab was needed in 7 adverse events of eosinophilia compared to 1 in the placebo arm (23). However, peripheral eosinophilia is also associated with high dose aspirin therapy in N-ERD (2).

Although ATAD was central to the management of N-ERD for the past 3 decades, safety data on high dose aspirin are limited due to the small size trials and the short study duration (14). One retrospective study was formally analysed to determine the rate of major complications associated with aspirin desensitization and maintenance therapy that resulted in discontinuation (24). Of the 109 N-ERD patients, included from July 2016 to February 2019, who underwent ESS with subsequent ATAD, 18 patients discontinued the therapy due to gastritis (9, 8.2%), GI bleeding (1, 0.92%), anaphylaxis (1, 0.92%), exacerbation of upper airway symptoms (1, 0.92%), recurrent epistaxis (1, 0.92%), exacerbation of lower airway symptoms (4, 3.7%) and cutaneous reaction (nummular rash) (1, 0.92%). These results are in line with the report of the working group of the American Academy of Allergy, Asthma & Immunology, stating that gastritis is the most common reason for discontinuation of maintenance therapy. Although the bleeding risk while taking high doses of aspirin has not specifically been studied in N-ERD, data extrapolated from its cardiovascular use shown a 50% increased risk of (gastro-intestinal) bleeding (2, 14). It is therefore of utmost importance to continuously monitor patients for aspirin-related side effects.

One alternative safer possibility is the use of topical intranasal lysine aspirin (LAS, the only soluble form) for both nasal challenge to diagnose N-ERD and subsequently as therapy, with gradual dose increase performed at home by the patient under close virtual supervision. Although a small blinded crossover trial with 16 mg did not improve symptoms (25), it did show a reduction in leukotriene receptors in the nasal mucosa. Open studies do suggest efficacy (26–29). The latest audit found higher nasal airflow and smell scores at each follow-up in N-ERD patients taking LAS (p < 0.001 and p = 0.048 respectively) compared tho those who were positive on challenge but did not continue therapy (30). No influence of LAS on pulmonary function measurements was observed in this study. Patient on intranasal LAS showed a lower rate of revision sinus surgery when compared to those who discontinued the treatment (p < 0.001). In addition, the doses now used are lower, at under 100 mg, than with oral ATAD, cause fewer gastric problems (3.8%) (31), and are more compatible with cardiac care since oral doses of over 100 mg (as necessary for oral ATAD) are associated with poor cardiovascular outcomes (32).

From the perspective of the health care system, less costly treatment options should be considered and tested before switching to complex and more expensive biological therapies. Aspirin is inexpensive, costing about $0,05 per tablet. The price for daily therapy is thus less than $100 per year. For the one-time cost of a desensitisation procedure, the price ranges from $1.700 to $3.000 (3, 33). In contrast, the cost of Th2 biological therapy is estimated to be $30.000 to $40.000 per patient per year. Given the fact that the age of onset of N-ERD is around 30 years and N-ERD is not remitting spontaneously, biological therapy cost multimillion dollars per patient per year (3, 13, 33).

Furthermore, there are currently no biosimilars for dupilumab, mepolizumab and omalizumab on the market to stimulate market competitiveness and to reduce the costs for the health care system. In Belgium, depending on the turnover threshold of the original biological, the price of a biosimilar can be up to maximum 47,18% lower than the original price of the original biological. Focusing only on the cost is, however, too short-sighted. The costs must be weighed against effectiveness, expressed by “quality-adjusted life year” (QALY), which stands for one year in perfect health.

In 2008, Shaker et al. investigated the cost-effectiveness of aspirin desensitization with subsequent aspirin therapy in moderate-to-severe N-ERD (34). According to their findings ambulatory desensitization for N-ERD could save $6.768 per QALY and across a wide range of assumptions, aspirin desensitization remained cost-effective with less than $50,000 per QALY saved. In their modelling of costs of asthma therapy, they did not include the potential of aspirin desensitization to reduce the need for omalizumab. Therefore, the abovementioned amounts are probably underestimating the cost saving effect of aspirin. Lysine aspirin is more expensive than aspirin tablets, but the process of challenge and initial desensitization is faster, taking half a day rather than 2–3 days of inpatient care, so the end result is cost-similar, very significantly lower than that of any biologic. A full-scale double- blind trial is needed.

Regarding the biologics, not surprisingly, cost-effective analyses are lacking, given their only recent approval for chronic rhinosinusitis. Anderson et al. reviewed in 2019 the current literature for asthma and the cost-efficacy of omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. The authors concluded that the prices should be reduced by a minimum of approximately 60% to achieve the cost-effectiveness threshold prices (35). In conclusion, there is something to be said for both biologics and aspirin desensitization. However, as the costs of aspirin desensitization are nothing compared to biologics, aspirin desensitization should be tried first when no clear contra-indication exists.