xRead - Nasal Obstruction (September 2024) Full Articles

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Orlandi et al.

IX.C.15.a. Genetics in CRS The first identified genetic disorders were discovered because they showed a clear pattern of heritability, with well-defined disease phenotype. These well-characterized genetic disorders implicated a single gene with a high pen etrance and strong effects. In contrast, CRS is considered to be a more complex disease process with multiple genes all having weak effects and therefore contributing vary ing degrees of penetrance. This has made the identifica tion of candidate genes in CRS much more difficult. In the late 1990s, the goal of the Human Genome Project was to revolutionize medicine by sequencing the genome, iden tifying single nucleotide polymorphisms (SNPs) to allow identification of the genetic basis of diseases, and future treatments to be based on personalized genetic makeup. 957 Experience since has shown that while associations can be identified, interpreting these and transposing them for clinical use can be difficult. For a number of genetic find ings, biological plausibility may not be evident, as the role these genes play in normal function may not yet be described. Alternatively, identified genetic factors may not so much modify the structure of a cellular organelle, but may instead increase susceptibility to an environmental influence, such as infection with undesirable bacteria like Staphylococcus aureus. 958 Lastly, clinical phenotype does not necessarily originate from a unique genetic variation, but may instead reflect differently located variations in a single gene, or any number of key genes in a pathway. Also problematic for genetic association studies in CRS is the high risk of spurious association from multiple testing. Studies thus require large populations, explaining the high costs of such studies. For these reasons, caution must be used when interpreting CRS genetic studies in the litera ture. Strong evidence supports a hereditary (genetic) compo nent to CRS. Known genetic diseases that have a demon strated association with CRS indicate the presence of a genetic component to CRS. These include cystic fibrosis (CF), where homozygous mutations in the CFTR gene lead to defects in chloride transport, and the ciliary dyskinesias, where a mutation in 1 of 31 different genes coding for a dif ferent portion of the structural arm of the cilia causes cil iary dysfunction. 959 Recent work demonstrates the heritability of CRSwNP and CRSsNP. In a study by Oakley et al. of 1638 patients with CRSwNP and 24,200 CRSsNP patients, first-degree relatives of affected subjects are 4.1 times more likely to develop CRSwNP and 2.4 times more likely to develop CRSsNP. 960 This is complemented by work from Sweden in which 13.4% of relatives of patients with nasal polypo sis had CRSwNP compared to 2.7% in a Swedish control group, yielding a relative risk of the first-degree relatives having nasal polyps of 4.9. 961

The studies in this literature review demonstrate the sig nificance of PID in the development of chronic sinus dis ease, with up to 50% of those with recalcitrant CRS found to have primary immune dysfunction. 938 Conclusions drawn from the included studies are somewhat limited given the relatively inferior aggregate grade of evidence. Areas of further study include the degree to which the sever ity of hypogammaglobulinemia results in clinically signif icant RS, the cross-interaction of immunodeficiency and CRS endotypes, and the identification of CRS patients who would benefit most from further diagnostic investigation and treatment of immunodeficiency. Additional research may also define optimal medical and immune supplemen tation therapy in those with PID and CRS. Immunodeficiency as a Contributing Factor forCRSsNP Aggregate Grade of Evidence: C (Level 3: 1 study; level 4: 34 studies; Table IX-18). Benefit: Identifying patients with PID allows for the opportunity to treat a subset of patients who will respond to Ig replacement therapy. Morbidity associated with CRS may be minimized. Harm: There is a potential for increased cost asso ciated with unnecessary or premature testing. Cost: Associated costs consist of the direct costs of laboratory testing; high costs of Ig replacement therapy. Benefits-Harm Assessment: The benefits of identi fying patients with immune dysfunction outweigh any associated risks. Value Judgments: Otolaryngologists are often the first providers to see these patients given the fre quent co-existence of immunodeficiency and RS. This provides the opportunity to identify patients with a treatable underlying disorder. “Refractory CRS” is not well defined. Policy Level: Recommendation in cases of refrac toryCRS. Intervention: PID should be considered in patients with refractory CRS.

IX.C.15 Contributing Factors for CRS: Genetics and Epigenetics Because of limited data, CRSsNP and CRSwNP are com bined in this analysis.