Oral and intranasal aspirin desensitisation for non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease.
NSAID-exacerbated respiratory disease (N-ERD) is a hypersensitivity to non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, accompanied by chronic rhinosinusitis (with or without nasal polyps) or asthma. The prevalence of hypersensitivity to NSAIDs is estimated to be 2%. The first line of treatment is the avoidance of NSAIDs. Another treatment option is aspirin treatment after desensitisation (ATAD). Desensitisation can be induced by repeated administration of aspirin at fixed time intervals. The clinical benefit of aspirin might occur through inhibition of interleukin 4 and a reduction in prostaglandin D2. This therapy can be useful for people who have progressive airway disease and are in great need of medical intervention (mostly systemic corticosteroids) or surgery. An up-to-date Cochrane review is vital to investigate the effects of this therapy.
To assess the effectiveness of oral or intranasal aspirin desensitisation, as monotherapy or as adjunctive therapy, in adults with NSAID-exacerbated respiratory disease.
The Cochrane Ear Nose and Throat (ENT) Information Specialist searched the Cochrane ENT and Airways Trials Registers; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; International Clinical Trials Registry Platform and additional sources for published and unpublished trials. The date of the search was 10 February 2023.
Randomised controlled trials that compared ATAD with placebo were eligible. We included studies of adults with NSAID-exacerbated respiratory disease (i.e. intolerance to NSAID established, e.g. by aspirin challenge test), with chronic rhinosinusitis or asthma, or both. Participants had to be followed up for at least three months.
We used standard Cochrane methods. The primary outcomes were health-related quality of life, asthma control, and significant serious and non-serious adverse events. The secondary outcomes were changes in airway assessments, nasal endoscopy score, medication use, symptom scores, and chronic rhinosinusitis and asthma exacerbations (description of exacerbation for which systemic corticosteroid or sinus surgery was needed). We used the GRADE approach to rate the certainty of the evidence.
We included five studies with a total of 211 participants (146 analysed). All studies compared oral ATAD at different dosages with placebo and were performed in tertiary care centres. All participants had a diagnosis of chronic rhinosinusitis with nasal polyps. In four studies, participants also had a confirmed diagnosis of asthma and two studies reported that participants had previous surgery for nasal polyps. Outcomes were analysed at six and 36 months follow-up. However, only one study reported data for 36 months follow-up. All but one study reported source of funding. Mid-term follow-up (six months, ATAD versus placebo) ATAD may improve health-related quality of life, assessed with Sino-Nasal Outcome Test (SNOT) scores (mean difference (MD) -0.54, 95% confidence interval (CI) -0.76 to -0.31; 3 studies, 85 participants; minimum clinically important difference (MCID) 9.0 points for total score; low-certainty evidence). In this analysis, SNOT-22 scores were divided by 22 and SNOT-20 scores were divided by 20. The mean reduction (11.9 points) in SNOT score (based on SNOT-22) is larger than the MCID. It is uncertain if asthma control may be improved after ATAD. Asthma control was measured using the Asthma Control Test (ACT) in one study and the Asthma Control Questionnaire (ACQ) in another study, so data were not pooled. The MD on the ACQ was -2.00 (total score 0 to 6) (95% CI -4.30 to 0.30; 1 study, 15 participants; MCID 0.5 points; very low-certainty evidence). The MD on the ACT was 5.90 (total score 5 to 25) (95% CI 2.93 to 8.87; 1 study, 30 participants; MCID 3 points; very low-certainty evidence). All but one study reported on adverse events. Seven participants in the active treatment group developed a gastrointestinal disorder and dropped out (129 participants, very low-certainty evidence). We are uncertain of the effect of ATAD on nasal airflow, measured by peak nasal inspiratory flow scores (MD 32.90 L/min, 95% CI -12.44 to 78.24; 1 study, 15 participants; very low-certainty evidence). It is uncertain if the dosage of intranasal or inhaled corticosteroids may be reduced with ATAD (inhaled corticosteroids: -1197.60 µg, 95% CI -1744.93 to -650.27; intranasal corticosteroids: -120.50 µg, 95% CI -206.49 to -34.51; 1 study; 15 participants; very low-certainty evidence). Symptom scores may not differ between ATAD and placebo, but the evidence is very uncertain (sneezing: MD -0.70, 95% CI -1.45 to 0.05; smell: MD -2.20, 95% CI -4.74 to 0.34; nasal blockage: MD -0.90, 95% CI -1.90 to 0.10; 1 study, very low-certainty evidence). No study assessed nasal endoscopy at this time point. Long-term follow-up (36 months, ATAD versus placebo) ATAD may improve quality of life, as measured with the Rhinosinusitis Disability Index (RSDI) score (MD-18.10, 95% CI -32.82 to -3.38; 1 study; 31 participants; low-certainty evidence). ATAD may result in little to no difference in the size of nasal polyps (MD -1.20, 95% CI -2.72 to 0.32; 1 study, 31 participants; very low-certainty evidence). No adverse events were reported in either group over the total study period of 36 months (1 study; 31 participants; very low-certainty evidence). Data on peak nasal inspiratory flow, changes in dosage of inhalation or intranasal corticosteroids and symptom scores were not reported at this time point.
Aspirin treatment after desensitisation may improve health-related quality of life for people with N-ERD with a follow-up of six months. With respect to asthma control, adverse events, peak nasal inspiratory flow score, nasal endoscopy scores, changes in dosage of inhaled or intranasal corticosteroids, nasal and bronchial symptom scores, exacerbations or worsening of asthma and chronic rhinosinusitis (including the need for surgery), the evidence is inconclusive for the short-term and long-term. We did not find data on peak expiratory flow. It is difficult to interpret the results adequately, due to the potential influence of the use of any co-medications for chronic rhinosinusitis or asthma. Future research should emphasise longer duration of follow-up, report baseline disease characteristics and report on compliance and exacerbations for which additional medication or surgery is warranted.
Lourijsen E
，Avdeeva K
，Gan KL
，Fokkens W
... -
《Cochrane Database of Systematic Reviews》
Cervical mucus patterns and the fertile window in women without known subfertility: a pooled analysis of three cohorts.
What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age?
The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (<30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle.
The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns.
This study is a secondary data analysis, combining data from three cohorts of women: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year.
Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding.
The majority of women were <30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age <30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P < 0.01). Compared to nulliparous women age <30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by cycle were examined as follows: most minus fewest days of peak type mucus >3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus >4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score >4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days >8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters.
We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings.
Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies.
Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest.
N/A.
Najmabadi S
，Schliep KC
，Simonsen SE
，Porucznik CA
，Egger MJ
，Stanford JB
... -
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ResearchGate
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