Rising prevalence of diabetes

Diabetes mellitus is a well-known risk factor for developing necrotising otitis externa.^{Reference Chandler1} A study of 88 patients from 1990 to 2013 by Stern Shavit et al.^{Reference Stern, Soudry, Hamzany and Nageris10} revealed that 75 per cent of patients had a pre-existing diagnosis of diabetes. Other necrotising otitis externa case series have reported diabetes in more than 50 per cent of patients.^{Reference Carlton, Perez and Smouha11–Reference Ali, Meade, Anari, ElBadawey and Zammit-Maempel13}

Studies have shown that, compared with non-diabetics, diabetic patients have: impaired polymorphonuclear leukocyte function, diminished chemotactic and phagocytic activity, and poor oxidative and bactericidal function.^{Reference Marhoffer, Stein, Maeser and Federlin14–Reference Gallacher, Thomson, Fraser, Fisher, Gemmell and MacCuish16} Coupled with the associated endarteritis, microangiopathy and small vessel obliteration that occur in diabetics, these patients are thus uniquely susceptible to P aeruginosa infections. The higher pH of cerumen in diabetics may also be a contributing factor to infection rates.^{Reference Driscoll, Ramachandrula, Drezner, Hicks and Schaffer17} It is therefore not surprising to observe an increase in the prevalence of diabetes mellitus coinciding with the rise in incidence of necrotising otitis externa. The Quality Outcome Framework from which our diabetes prevalence data were acquired is a primary care initiative and therefore a reliable measure of population health.

For future prospective studies, ascertaining the relative risk of diabetes in predisposing patients to necrotising otitis externa, or indeed the involvement of diabetic control in the management and prognosis of patients with necrotising otitis externa, will be essential avenues to research.

Antibiotic resistance trends

There is currently no national database for antibiotic resistance trends, and our data are therefore based on analysis of over 4000 ear swab culture and sensitivity results within our NHS Trust. A limitation of this analysis is that P aeruginosa is not the only causative organism in necrotising otitis externa, though it remains the most commonly isolated pathogen in necrotising otitis externa worldwide, accounting for a positive microbiological culture in a substantial majority of cases.^{Reference Mahdyoun, Pulcini, Gahide, Raffaelli, Savoldelli and Castillo18}

There has been no significant change in the proportion of P aeruginosa swabs demonstrating antibiotic resistance during the matched time period. These data are comparable to findings at other UK centres (based on informal discussion with other UK centres), though they demonstrate a lower pseudomonal resistance rate than that described in published case series from other countries.^{Reference Mahdyoun, Pulcini, Gahide, Raffaelli, Savoldelli and Castillo18} Pseudomonal resistance has been attributed to an overuse of fluoroquinolones and delays in diagnosis, which can facilitate biofilm formation.^{Reference Loh and Loh19,Reference Berenholz, Katzenell and Harell20}

Staphylococcus aureus has been cultured in a minority of reported case series, with its methicillin-resistant S aureus (MRSA) strain reportedly more prevalent in non-diabetics.^{Reference Hobson, Moy, Byers, Raz, Hirsch and McCall21} Resistant pseudomonal strains and MRSA have been linked to poor prognostic indicators.^{Reference Hobson, Moy, Byers, Raz, Hirsch and McCall21,Reference Clerc, Verillaud, Duet, Guichard, Herman and Kania22} Fungal necrotising otitis externa is an increasingly recognised phenomenon, having an increased incidence in the severely immunosuppressed.^{Reference Marchionni, Parize, Lefevre, Vironneau, Bougnoux and Poiree23}

As a fluoroquinolone, ciprofloxacin eradicates bacteria by inhibiting bacterial DNA replication. It does this by inhibiting the two bacterial enzymes that are key to DNA synthesis.^{Reference Hooper24} Studies demonstrating its efficacy in the treatment of necrotising otitis externa have been well documented.^{Reference Lew and Waldvogel25} However, there are published reports of pseudomonal resistance to ciprofloxacin,^{Reference Berenholz, Katzenell and Harell20} and one reported case of pseudomonal resistance to ceftazidime, gentamicin and ciprofloxacin.^{Reference Bernstein, Holland, Porter and Maw26} The two recognised mechanisms for ciprofloxacin resistance are target site modification and upregulation of efflux pumps.^{Reference Rehman, Patrick and Lamont27} Mutations in target-encoding genes, gyrAB and parCE, reduce the affinity of DNA gyrase and topoisomerase to ciprofloxacin. Over-expression of efflux pumps, which occurs via mutations in regulatory efflux genes, reduces the intracellular concentration of ciprofloxacin.^{Reference Rehman, Patrick and Lamont27} Such mutations in efflux regulatory genes can lead to broad antimicrobial resistance. For example, over-expression of the MexAB-OprM efflux system has been linked to intrinsic resistance of P aeruginosa to quinolones, tetracycline, chloramphenicol, macrolides and B-lactams.^{Reference Li, Nikaido and Poole28}

Whilst it is reassuring that our local case series of over 4000 ear swabs does not demonstrate an increase in antibiotic resistance, this may not represent the environment present in patients with necrotising otitis externa, who are almost inevitably diabetic or immunosuppressed, and are likely to have had a number of courses of topical and systemic antibiotics prior to diagnosis. Future research could usefully clarify these points, ascertain the relevance of antibiotic-resistant bacterial strains in necrotising otitis externa, and optimise antibiotic choice and administration.

Ageing population

The presented Hospital Episode Statistics data (Figures 2 and 3) clearly demonstrate that an increasingly aged population is being admitted to hospital in England, and that the proportion of patients aged over 75 years admitted with necrotising otitis externa is increasing year on year. These are population-level data and do not tell us whether this simply reflects an ageing population or perhaps an increasing trend for the older adult to be admitted to hospital. Census data in England²⁹ tell us that people aged over 75 years made up 7.5 per cent of the population in 2001, and this almost doubled to 14.7 per cent in 2011. The ageing population in England is therefore very real, and will have an increasing impact on the provision of health and social care in coming years.

It is not possible to use this population-level data to draw a conclusion regarding the apparent rising incidence of necrotising otitis externa amongst the same population, but only to observe that, in a similar manner to diabetes prevalence, the increasing older adult population means that a larger proportion of the population have an additional risk factor for developing necrotising otitis externa – immunosenescence. Immunosenescence refers to the gradual deterioration of the immune system by the ageing process. Age, like diabetes mellitus, has always been a recognised predisposing risk factor for developing necrotising otitis externa.^{Reference Chandler1} As the immune system ages, the ability to protect oneself from infections and cancer decreases. Conversely, inflammatory responses mediated by the innate immune system increase in intensity and duration, rendering older adults susceptible to tissue-damaging inflammatory reactions.^{Reference Weyand and Goronzy30} Specific age-related changes leading to susceptibility to infections include: impairment of the respiratory burst of macrophages and neutrophils, hindering their ability to destroy bacteria;^{Reference Weyand and Goronzy30} decreased stimulatory ability of antigen-presenting dendritic cells;²⁹ and decreased neutrophil chemotactic and phagocytic abilities.^{Reference Corberand, Ngyen, Laharrague, Fontanilles, Gleyzes and Gyrard31} With such a deterioration in the host's defences, opportunistic bacteria such as P aeruginosa can easily infect ear canal tissue and establish a chronic infection, likely having a synergistic effect with diabetes and other causes of immunosuppression.

Increased physician awareness

The theory of increased physician awareness of necrotising otitis externa is one that is exceptionally difficult to explore. We could consider the alternative diagnoses that necrotising otitis externa patients might have been mistakenly diagnosed with in the past, but this would be almost impossible to investigate retrospectively. It is not beyond the realms of imagination, though, that as physicians learn about a rare condition first described only two generations earlier, they are more likely to recognise it, diagnose it and document it. It is also not beyond the realms of imagination that increased awareness of necrotising otitis externa may have led to more widespread use of accurate clinical terminology and increasingly accurate clinical coding for centralised diagnosis registration. One of the limitations of epidemiological data is that it relies on diagnosis documentation and may not reflect accurate necrotising otitis externa case numbers. At the time of writing, there are no published clinical cohort studies that demonstrate a rise in necrotising otitis externa incidence, this phenomenon being limited to epidemiological studies.

We used a proxy measure of peer-reviewed publications to ascertain whether there has been an increase in physician awareness of necrotising otitis externa. This is a very flawed measure, as it may be a self-fulfilling prophecy. If the incidence of a rare condition increases, it makes sense that the frequency of publications on the topic and physician awareness of the condition will also increase. Between 2002 and 2017, there were 61 papers published on necrotising otitis externa in major ENT journals (with an impact factor greater than 1). The level of evidence within these papers was poor, with most being single-centre case series with low patient numbers. One systematic review by Mahdyoun et al.^{Reference Mahdyoun, Pulcini, Gahide, Raffaelli, Savoldelli and Castillo18} was published in the 16-year time period. The number of peer-reviewed published studies per year was small, and whilst it demonstrates a gradual increase over the time period, it is impossible to draw a conclusion from these numbers.

Delayed diagnosis of necrotising otitis externa is associated with poorer outcomes, and increased physician awareness would enable earlier recognition of this rare and dangerous infection. Increasing physician awareness of necrotising otitis externa is therefore a topic that warrants further attention.

This study has not resolved the issue of an apparent rising incidence of necrotising otitis externa in England, whilst the condition is stable or declining in incidence in other countries. What we do know, however, is that the increased at-risk population means that physician awareness, and rapid diagnosis and management of necrotising otitis externa, is more important than ever.