Patients with chronic rhinosinusitis, CRS, consistently score lower in quality-of-life surveys than patients with asthma or heart disease, while up to 40% of CRS patients also suffer from depression1.
This emerged in a presentation on endotyping in chronic rhinosinusitis by Chris Quitter, Senior Specialist at the Department of Ear Nose and Throat and Head and Neck Surgery at the University of Pretoria’s Medical School.
He was speaking at the 25th centenary gathering of the South African Rhinitis Working Group, SAARWG, entitled “Allergic Rhinitus – Back to Basics and the Future,” held at a Magaliesberg venue from November 15th to 17th this year.
Quoting from a European position paper on rhinosinusitis and nasal polyps, Dr Quitter defined the condition as an inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/ congestion or nasal discharge (anterior/ posterior nasal drip).
He said treatment involved antibiotics, (short or long term), cortisone, oral, topical or other topical medications, Leukotriene receptor antagonists, or rinses.
Global prevalence
The percentage of population suffering from sinus disease ranged between 5% and 25% in different parts of the world while US and Canadian studies estimated the direct cost of treatment at $10000 per patient/year (up to $26000 in patients requiring surgery). Indirect costs (absenteeism, presenteeism, time spent on treatment and impact on quality of life) could add as much as $25000 per patient/year. Expanding on how this impacted on an individual’s quality of life, Dr Quitter said; “imagine the worst flu you’ve ever had and multiply that by 10. Depression with these patients is up to 40% higher than in the general population, which is hardly surprising.”
All these costs added up to an estimated $64,5 billion per annun in the US alone (2011 figures).
Dr Quitter drew clear distinctions between various ways of defining allergic rhinitis. He said phenotyping consisted of all the observable characteristics of an organism that resulted from the interaction of its genotype (total genetic inheritance) with the environment. Genotyping on the other hand was the process of determining differences in the genetic make-up of an individual by examining the individual’s DNA sequence using biological assays and comparing it to another individual’s sequence or a reference sequence.
He said endotyping was a subtype of a condition, defined by a distinct functional or pathobiological mechanism – and fell between the other two classifications.
“In principle we’re looking for what makes it so, and how it works,” he said, adding that cluster analysis of similar groupings in classification, facilitated treatment.
Clusters displayed regional differences, with African-Americans having the same patterns as Caucasians (and a much higher prevalence), but suffering more severe disease than Caucasians and Hispanics.
He said, “We have to ask; who do the Africans follow? Is it, African Americans – their (the Africans’ disease) may be driven by completely different inflammatory patterns.”
Neutrophilic disease was greater in Asians (Mainly Chinese and Koreans – not Japanese) while eosinophilic disease was different, with Asians in the US having a higher proportion of eosinophilic disease. While disease patterns were changing in Asia there was a glaring lack of data for Africa.
Discerning the repertoires of T-helper cells
Outlining the need for endotyping, Dr Quitter said endotypes had a distinct impact on treatment with the best markers to base them on being T-helper cells. However, T-cell repertoires were different in different populations. A Neutrophilic type would not develop asthma while 50% of Eosiniphilic types would. This had prompted a global move towards examining them. There was evidence that S. Aureus Ag drove more eosinophilic disease while evidence from Gent showed S. Aureus carriers in 30% of tested subjects. There was also S.Aureus in polyps in 95% of these. Surgery decreased Il-5 but increased Il-17 and INF-y. Il-5 helped S.Aureus survive intra-cellularly, as in polyps.
Dr Quitter listed exclusions (while posing the question of whether they were separate endotypes), as; Cystic Fibrosis, (CF), Non-steroidal exacerbated respiratory disease, (NERD), the extremely rare Churg-Strauss Syndrome (inflammation of the blood vessels), Ciliary dyskinesis, a rare, ciliopathic, autosomal recessive genetic disorder that causes defects in the action of cilia lining the respiratory tract (lower and upper, sinuses, Eustachian tube, middle ear), fallopian tube, and flagellum of sperm cells), Antro-choanal polyp, Allergic Fungal Rhinosinusitis, Eosonophilic, non-allergic fungal rhinosinusitis, local allergic rhinitis, central compartment disease and Rhinitis of the Aged.
The inflammatory marker jungle
He went on to describe the plethora of inflammatory markers in CRS and diagnostic markers, and their impact on treatment, rinses and cortisone, before elaborating on the influence of cortisone on the sinuses. Apart from their well described anti-inflammatory properties, intranasal steroids had been found to enhance mucosal innate immunity, improve patient symptoms, and result in significant reduction in culture rate in patients with refractory CRS. Topical cortisone showed the ability to break up biofilms, this being valid for sprays as well as drops and medicated rinses. Dr Quitter said there was speculation that molecule size of topical cortisone could influence the ability of the molecule to penetrate into a biofilm. Interestingly however, the same study shows saline rinses to also be effective in decreasing the volume of biofilms.
Revisiting annual treatment costs, he said that currently the cost of surgery every six months was less than treating with biologics over the lifetime of a patient. Per year, Omalizumab cost between US$ 13000 and 26000 (depending on dosage), Mepalizumab: US$ 32500 (also dose dependant), and Dupilumab: US$ 31000 – 37000 (dose dependant). He warned colleagues about Tetracyclines, saying they gave patients, “terrible headaches.”
Surgery a vital medication enabler
Dr Quitter said it appeared that that different types of rhinitis needed different types of surgery, the operation being essential to ‘get the medication into the sinuses – you have to drill out. The bigger the hole the better. We need to get the treatment into the noses – you have to tell patients this; they think that if they have surgery, they won’t need medication. That just won’t work,” he stressed.
Surgery in patients with polyps should be different to patients without polyps where a ‘gentler approach,’ was called for.
“For patients with polyps you remove all mucosa in sinuses you can get hold of, but not in the nose, where new epithelium grows in time,” Dr Quitter advised.
He said biofilms were the normal state of bacteria wherever there was mucosa. Bitter taste receptors were starting to come into their own (for example, Quinine). It was also recently shown that there could be partial expression of Cystic Fibrosis in patients with nasal polyps. Many asthma sufferers also had AR, “so there could be something in this,” he said.
Among the most pressing current issues were refining the definition of endotypes, developing treatment based on endotypes, clearly defining the role of surgery – and the role of cortisone and long-term antibiotics with anti-inflammatory activity (Macrolides, Doxycycline), recognising the risk factors for recurrence, defining predictors of recurrence, genetics, establishing viable targets, and perhaps most importantly; defining stop points for biologicals.
Dr Quitter concluded by offering some food for thought around a recent longitudinal cohort study across Korea which showed a link between CRS and cancer. He emphasised that the connection was only in neutrophilic disease, while a link to IL-17 was suspected.
- Burden of illness: A systematic review of depression in chronic rhinosinusitis. (Am J Rhinol Allergy 30, 250–256, 2016; doi: 10.2500/ajra. 2016.30.4343) – Rodney J. Schlosser, M.D., Selby E. Gage, B.S., Preeti Kohli, B.A., and Zachary M. Soler, M.D., M.Sc.