Treating CF patients – ignore the nose at your peril

While South Africa has a cystic fibrosis, (CF), registry of 442 patients drawn from four centres of excellence, more data is urgently needed to begin making further inroads on the disease.

This was said by Dr Carla Els, a paediatric pulmonologist from Linksfield Hospital and past chairperson of the Cystic Fibrosis Association of South Africa.  She 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.

Dr Els was presenting on cystic fibrosis and the upper airway, her central focus being on identifying and managing a patient with a blocked nose and allergic rhinitis after they failed initial therapy. Elaborating on the SA CF Registry Initiative, she said it was launched in April 2018 and embraced the Charlotte Maxeke Academic Hospital (Adult and Paediatric), linked to Mill Park Private Hospital, a combination of Groote Schuur Hospital, UCT Private Hospital, Red Cross Children’s Hospital and Tygerberg Hospital, Durban’s Albert Luthuli Academic Hospital, and the Port Elizabeth Hospital.

The data showed that the biggest CF population registered (62%) was white and six to 18 years old, with 54% of all patients’ female, 27% mixed-race and just five percent black. The median diagnosis age was six months old while 15% had meconium ileus – a bowel obstruction that occurs when the meconium in a child’s intestine is thicker and stickier than normal meconium, creating a blockage in a part of the small intestine called the ileum. Most infants with meconium ileus have CF. She added that at least one sweat test had been conducted in 201 patients (61%) while there was missing diagnosis information in 35 patients (11%), mostly adults or those how moved practices or clinics. A cross sectional annual review data was available in 306 people, with chronic pseudomonas infection in 97 (32%), ‘unable to establish pseudomonas status’ in 61 (20%), one death and no transplants in that year (2017). Ten were not seen for F/U that year and the status of one patient was unknown.

Dr Els listed key events for notifying regional CF co-ordinators and centres of excellence as new diagnoses or referrals, deaths, transplants and pregnancies or births.

CF ‘right under our noses’

Stressing the critical importance of the nose in the link between CF and AR, she said that she told her patients that the nose was the ‘start of all evil.”.

“We need to treat the nose to keep the chest healthy. We should all be thinking about CF in allergic rhinitis. CF patients who don’t want to eat always have mucous in their mouth. We also underestimate their psychological mechanisms of coping. In my practice if I can’t control the chest, I look at the nose. We don’t do that often enough. They (CF patients), hardly ever complain about their noses,” she added.

Dr Els said that while presenting symptoms were numerous, they were not always indicative. Often when the nose was good, lung function was better. However, the biggest problem she encountered among her CF patients was that they seldom treated themselves if they had a runny nose or were coughing. She said a combination of treatment strategies and surgery was often worth considering. Nasal saline irrigations were the mainstay in her practice. Antibiotics helped improve quality of life while nasal steroids were also very helpful. Decongestants helped with the absorption of medicines while all patients seemed to love mucolytics. However only topical steroids were proven to work and should be continued, with high-dose rinses very effective, especially when combined with surgery. Dr Els warned against referring patients to surgeons who had no experience in CF and said the 11-18-year-old group was a proven target cohort. Follow-up 10 years after endoscopic surgery showed that there was no different in their facial measurements, emphasizing how safe it was to use such procedures in children. As in other areas of disease, low socio-economic groups fared worse, especially where there was limited access to safe running water and healthcare facilities. She stressed that more aggressive treatment of the nose was required in 11 to 17 years-old’s, adding that post-surgical medical treatment was vital.

Tell CF patients to manage their noses

She added, ‘sinusitis is not a curable aspect of CF but if CF patients can just be persuaded to manage their noses, it will make a world of difference,”

A combination of many therapies made a difference for CF patients, but endoscopic surgery was a ‘must,’ she emphasized. There was a significant correlation between the health of paranasal sinuses and lungs. Interestingly, non-CF, CRS patients had distinct niches of micro-organisms in their upper versus lower airways and CF-CRS patients had indistinguishable niches at both anatomic sites.  The evidence was that the sino-nasal cavity acted as a reservoir for bacterial translocation to the lower airway, she added.

Chronic rhinosinusitis – no easy walk to treatment

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.

  1. 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.

SA allergy testing a ‘work in progress’

A comprehensive review of testing for allergies from a major South African pathology laboratory since 2007 shows that health practitioners still have some way to go when it comes to consistently and accurately diagnosing allergies.

That’s the conclusion of Professor Eftyhia Vardas, a medical doctor and clinical virologist who heads up the allergy and immunology laboratory at Lancet Laboratories. Her wide-ranging review of allergy testing including skin prick tests (SPT’s), total IgE and of specific IgE tests (previously known as “radioallergosorbent” test or RAST tests) which detect specific immunoglobulin E (IgE) antibodies that determine which substances individual patients are allergic to. The process of how these tests work differs, skin allergy testing measures the reactions of cells in the skin in response to allergens. Both skin tests and specific IgE allergy tests are useful for the diagnosis of allergy and have different pros and cons, the most important pro for specific IgE tests done on a blood sample is that the patient does not need to stop their antihistamine medications before testing as in the case of skin tests.

She told a mid-November 2019 gathering of ENT surgeons, allergy  specialists, paediatricians  and general physicians who met under the banner of the South African Allergic Rhinitis Working Group, SAARWG, that the review of allergy testing patterns and positive results, patient demographics and doctors types asking for these tests had evolved into the current testing laboratory diagnostic algorithm  for Allergic Rhinitis, (AR).

Diagnostic shortfall

Reviewing the implementation of these recommendations 4 years later, including the costs of allergy tests, her short answer as to whether allergic rhinitis laboratory testing had triumphed diagnostically was a simple ‘no – I don’t think we’re quite there yet’.

While the clinical and economic burden of AR continues to grow in South Africa, lab testing is still marked by confusion, the consensus only recently reached in 2016 – now needs further revision.  She said allergy testing was critical for patient management as well as directing appropriate specific pharmacotherapy and immunotherapy. Getting testing for allergies right, also allows early identification of patients that may be at increased risk for development of asthma or severe allergic disease.

Consensus continually evolving

Professor Vardas said that in between 2012-14 the SAARWG set out to audit laboratory-based allergy data to determine if this information could provide regular allergy surveillance, including the regional pollens for South Africa. Over a 5-year period, all allergy tests were reviewed from a single private laboratory, including trends in testing requests, types of doctors ordering allergy tests, patient demographics and seasonal trends in positive results to inform guidelines and testing policy.

The vast majority of both specific IgE tests and skin prick tests (SPT’s) were negative (69%), showing that allergy testing is being applied in patients with a low probability of allergic disease. Selecting the correct patient for allergy testing is therefore very important before embarking on expensive allergy testing. She listed the factors that pointed to successful testing – a high pre-test probability of allergy – as a history of anaphylaxis after exposure to a particular allergen, a history related in time to a particular substance suggesting an allergic reaction, a reliable witness to the reaction and measurable objective signs of an allergic reaction.

The top positive allergens identified, regardless of geographical localisation were dust mites, , followed by grass  Plane tree pollen, indoor and outdoor moulds (Altenaria and Cladosporium, Eucalyptus tree pollen and oak tree pollen.  

GP’s and Specialists order different types of Allergy tests

GP’s, paediatricians and ENT’s formed the bulk of those ordering allergy tests. But they ordered different types of tests, with GP’s favouring total IgE (t-IgE) as an entry point allergy screen, whereas paediatricians preferred specific IgE (s-IgE) tests and ENT’s used mainly SPT’s.  Conclusions drawn from the laboratory allergen data analysis shows that this type of data is a good indicator of prevailing clinical practice, and this information can be used to provide guidance for directed allergy testing and custom-made aero-allergen screens. Prof Vardas emphasised that seasonal variability and geographical pollen audits were not possible via lab data review.

Medical aids out of step

When it comes to costs of allergy tests, although the consensus algorithm for allergic rhinitis adopted in 2016 halved the costs of allergy testing, she said that medical aids appeared to be unaware of and not endorsing hard-won consensus recommendations. She also noted that GP’s seldom indicate to their patients that screening allergy tests with pooled tests necessitates identification of which allergen in the pool is causing positivity, thus making a positive screening test very expensive. Pooled screening tests should therefore be used cautiously, the patient informed of the implications of a positive result which would necessitate further testing to be meaningful clinically. A full 55% of positive Phadiotope and 70% of positive FX5 did not get a breakdown because of cost restriction, which Prof Vardas described as ‘tragic” – these patients have spent money to get a positive pooled result but still don’t know what exactly is causing their allergy. She said t-IgE had thankfully now had been abandoned by paediatricians because it is not an appropriate screening test for allergy, while GP’s however continued to use it.

Further attempts from laboratories to decrease the confusion with allergy testing would mean new revisions to allergy request forms and changes in the recommended consensus based on the new data available.