When should one suspect necrotizing otitis externa, to limit doctor’s delay?

More specifically, the following subquestions were formulated by the working group:

1. When should (non healing) otitis externa be suspected for necrotizing otitis externa?
2. Which patient factors are important in the recognition of necrotizing otitis externa?
3. Which are alarm symptoms for necrotizing otitis externa?

Balance between desired and undesired effects

Definition of necrotizing otitis externa and skull base osteomyelitis

The definition and staging of the disease have been a longstanding discussion. In earlier days, the disease was firstly called malignant otitis externa (Chandler, 1968). Later, the term necrotizing otitis externa (NOE) was introduced to confirm the severity, but to avoid confusion with a malignancy (Kohut, 1979).

Necrotizing otitis externa (NOE) clearly indicates that the condition originates in the ear canal. It is an epithelial infection of the external auditory canal which has spread into the temporal bone affecting soft tissue and bone structures of the skull base.

The term skull base osteomyelitis is also used in this context and may be more accurate when the infection extends beyond the temporal bone to involve the skull base. This represents a form of osteomyelitis secondary to otitis externa. However, the term misleadingly implies a purely bony pathology. It does not fully capture the condition, as soft tissue infiltration beneath the skull base is invariably present. This variant is termed typical skull base osteomyelitis.

Central skull base osteomyelitis, resulting from sinonasal infections, is also classified as typical skull base osteomyelitis. Finally, skull base osteomyelitis may also occur secondary to trauma, iatrogenic causes, or hematogenous spread, though these fall outside the scope of the condition addressed in this guideline.

We consider the term skull base osteomyelitis to be correct in this context, but for consistency throughout this guideline, we will invariably use the term necrotizing otitis externa.

Clinical application of the definition

The abovementioned discussion concerns the semantics of this type of infection. The clinical implementation and its implications are also not straightforward. For this matter, the guideline committee refers to a recently published, high-quality UK consensus paper in which agreement on key principles was achieved following a systematic literature review. This was performed through a Delphi study involving multidisciplinary specialists (Hodgson, 2023). Primarily, establishing a clear definition, which had varied significantly in earlier literature, serves two important purposes: 1) facilitating the diagnosis as well as the exclusion of NOE (necrotizing otitis externa), and 2) standardizing study populations in future robust research. The criteria required that agreement was reached by at least 70% of respondents and that disagreement on a particular condition or statement was less than 15%.

We also mention the goals that were set in the consensus paper, as they align with the scope of this guideline. While the consensus paper focuses on defining the disease and treatment outcomes, this guideline concentrates on the diagnosis and treatment itself. Given that the target population and type of healthcare system are very similar, the two papers appear to be complementary.

The following aims were defined in terms of the conditions/statements in the consensus paper:

1. They should be implementable in all centres across the UK, from a small district general hospital to tertiary referral centres.
2. They should be highly specific (ie, describe a typical definite case of NOE and minimise the chances of misclassifying another condition), but not necessarily describe all potential presentations of NOE.
3. They are for guidance only and not prescriptive in terms of practice.
4. They should allow standardised description of cases to facilitate recruitment to clinical trials and comparison of cases across different cohorts.
5. They mark the start of an iterative process—as more, and better quality evidence becomes available these definitions/statements will be revisited and revised.

The results outlined below are proposed with regard to definition and with regard to treatment outcomes:

Definite NOE according to UK consensus paper

NOE is diagnosed if ALL of the following are present:

• Otalgia and otorrhoea OR otalgia and a history of otorrhoea.

• Granulation OR inflammation of the external auditory canal.

• Histological exclusion of malignancy in cases where this is suspected.

• Radiological features consistent with NOE:

• CT imaging findings of bony erosion of the external auditory canal, together with soft tissue inflammation of the external auditory canal OR
• MRI with changes consistent with NOE (eg, bone marrow oedema of the temporal bone with soft tissue inflammation of the external auditory canal).

Possible NOE according to UK consensus paper

A severe infection of the external ear canal which does not show bony erosion of the external auditory canal on CT scan OR does not show changes consistent with NOE on MRI if this is performed (eg, bone marrow oedema of the temporal bone) AND which has ALL of the following characteristics:

• Otalgia and otorrhoea OR otalgia and a history of otorrhoea AND

• Granulation OR inflammation of the external auditory canal AND

• Any of the following features:

• Immunodeficiency.
• Night pain.
• Raised inflammatory markers (erythrocyte sedimentation rate/C reactive protein) in absence of other plausible cause.
• Failure to respond to >2 weeks of topical anti-infectives and aural care.

Complex necrotising otitis externa (NOE) according to UK consensus paper

Patients meeting the criteria for ‘definite’ NOE may be classified as ‘complex’ (or severe) if the following are present:

• Facial nerve or other lower cranial nerve palsy.

• Cerebral venous thrombosis on MRI or contrast enhanced CT.

• Extensive bone involvement as demonstrated by any of the following:

• CT showing bone erosion in other skull base locations in addition to the external ear canal wall (eg, around stylomastoid foramen, clivus, petrous apex, temporomandibular joint).
• MRI showing bone marrow oedema extending to central skull-base.
• CT or MRI showing extensive soft tissue oedema or inflammation or fluid collection below the skull base.
• Intracranial spread of the disease (eg, dural thickening, extradural or subdural empyema, cerebral/cerebellar abscess).

Cure

A case of necrotising otitis externa (NOE) is considered treated and cured if a patient has no pain or otorrhoea for a minimum period of 3 months after completing antibiotic therapy.

Relapse

Relapse is recurrence of disease after the patient has been treated and cured, at least 3 months after stopping antibiotic therapy. A relapsed case of NOE is a serious, invasive infection which occurs after the initial infection was considered to be treated and cured and is characterised by:

• Recurrence of local disease
  • Recurrent otalgia OR recurrent otorrhoea AND
  • Recurrent granulation OR inflammation AND
  • Unchanged or progression of bony erosion of the external auditory canal on CT OR unchanged or progression of MRI changes such as bone marrow oedema of the temporal bone and soft tissue changes of the external auditory canal.

                AND/OR

• Development or recurrence of complex disease

Development or worsening of a lower cranial nerve palsy, base of skull osteomyelitis or development or worsening of other intracranial complication deemed a consequence of NOE and supported by radiological imaging.

Non-response to therapy

A case of NOE is defined as non-responsive to therapy if there is no improvement in otalgia or otorrhoea or inflammation or granulation tissue in the external auditory canal after 14 days of optimum analgesia, anti-infective therapy, aural care and optimisation of immune state.

Use of definitions

The guideline committee agrees with the definitions and criteria published by Hogdson (2023), with the exception of possible NOE. In the opinion of the committee these criteria are more indicative of severe external otitis. The boundary between severe otitis externa and necrotizing otitis externanecrotizing otitis externa are sometimes hard to distinguish and might be seen as a fluid spectrum. However, as this guideline focuses on disease defined as necrotizing otitis externanecrotizing otitis externa, it was decided not to use the definition possible NOE within the scope of this guideline.

When should (non healing) otitis externa be suspected for necrotizing otitis externa?

Necrotizing otitis externa is a complication of (persisting) external otitis. The presentation of patients with necrotizing otitis externa predominantly starts with symptoms of external otitis. The management of otitis externa should therefore be evaluated at first. In the Netherlands, ways of effective diagnosis and treatment otitis externa are carefully formulated in guidelines, both available for primary and secondary (or tertiary) care.

This actual guideline, however, is made for medical professionals in secondary (or tertiary) care. Therefore, recommendations and considerations are mainly addressed to them. However, considering the topic limiting doctor’s delay, the recommendations are applicable to both primary and secondary care settings.

Guideline for otitis externa in primary care

Guidelines for primary care are summarized in the NHG standard (Dutch College of General Practicioners) (Otitis externa | NHG-Richtlijnen). Recommendations for referring to secondary care setting are the following:

• No remission of symptoms after 5 to 6 weeks of treatment, based on microbial cultures and concordant resistance patterns.
• If acceptable treatment results are not met, regarding patients with multiple recurrences of otitis externa.
• Otitis externa, with pain, swelling of the ear, fever or sickness, in (elderly) patients with diabetes or immunodeficiency.
• Otitis externa, with fever and sickness, with no improvement of symptoms after administration of 48 hours of oral flucloxacillin.

Although this primary care guideline is primarily developed for the diagnosis and treatment (evaluation) of otitis externa, it is the opinion of the guideline committee that this algorithm sufficiently covers precautionary measures to select those patients at risk for development of necrotizing otitis externa. However, it is recommended to specifically mention the disease entity necrotizing otitis externa within the primary care guideline to improve awareness.

Guideline for otitis externa in secondary (and tertiary) care

Guidelines for secondary (and tertiary) care are stated in the Dutch guideline Otitis Externa (Dutch Society of Otolaryngology/Head-Neck Surgery). Treatment includes microscopic debridement of the ear canal (or the placement of an ear wick for a few days in the case of ear canal obstruction), followed by topical treatment with antiseptic (and corticosteroid) drops. If the patient was already treated with this topical treatment, or in case it is ineffective after 48-72 hours, it is recommended to treat with a topical corticosteroid with an antibiotic/antimycotic agent, preferably guided by the results of an ear canal swab. The guideline states in its recommendations that one should re-evaluate the differential diagnosis of external otitis, after 3 weeks of recommended treatment, as most symptoms should resolve within 2 weeks of correct treatment (van Balen, 2003).

When should necrotizing otitis externa be suspected?

Several factors play a role here to secure the accurate and prompt diagnosis.

• The working group agrees with the aforementioned guidelines and encourages the strict use. There is no exact cut-off in literature after how many weeks of (correct) treatment necrotizing otitis externa should be considered. The consideration of the diagnosis itself is of utmost importance, as this is often described as an important delaying factor (Jacobson, 2010; Rubin, 1988). Awareness of the diagnosis seems to be a key factor in the diagnosis.
• Partial response of the initial treatment of otitis externa. Both guidelines provide adequate recommendations in how to treat, or when to refer a patient with external otitis. However, as a panel treating patients with necrotizing otitis externa, it is observed that the diagnosis can be significantly delayed due to the lack of prompt referral. Patients are often seemingly treated according the guidelines, do have partial response and are considered recovered. Then, there is an interval without directed treatment, as pain has decreased, the ear canal skin has improved (or at least not deteriorated) and sometimes even healed. The infection may linger in deeper tissues, whereas the symptoms of the patients are not understood. Subclinically the condition might progress into necrotizing otitis externa.

Which patient factors are important in the recognition of necrotizing otitis externa?

Briefly, the major important factors that raise the suspicion of NOE are patients with diabetes mellitus, advanced age, or immunocompromised status who present with severe, refractory otalgia and otorrhea. Early diagnosis and aggressive treatment are essential to prevent complications such as cranial nerve palsies, uncontrollable spread in general, and even death. However, there are more factors, which are associated with NOE. All factors are elaborated below.

1. Advanced age: Elderly patients are at higher risk for NOE due to age-related changes in immunity and microvascular circulation (Byun, 2020; Soudry, 2007). Also, the decrease of cerumen production at higher age is thought to contribute to an environment at risk (Kelly, 1996). Cerumen creates an acidic coat containing lysozymes and other substances that are thought to inhibit bacterial and fungal growth. The lipid-rich cerumen is also hydrophobic and prevents water from penetrating througho the skin and causing maceration. 
2. Diabetes mellitus: In a comprehensive systematic review (Takata et al., 2023), the most reported risk factor was diabetes mellitus, reported in 84% (1400/1668) of patients. This significantly exceeds the general prevalence of diabetes, considered 9.3% (Saeedi 2019). Hyperglycemia impairs immune function and microvascular perfusion, creating an environment prone to infection and tissue necrosis (Kelly, 1996; Darwitz 2024). Some clinicians state that any otitis externa in a patient with diabetes, presenting with otalgia and otorrhoea, should be presumed to have necrotizing externa until proven otherwise (Lambor, 2013).
3. Immunocompromised status: Patients with conditions or treatments that weaken the immune system, such as HIV/AIDS, chemotherapy, long-term corticosteroid use, or organ transplantation, are at increased risk for NOE (Byun, 2020). In the review of Takata (2023), it was stated that six percent (61/994) of patients were immunosuppressed for reasons other than age or diabetes and only 10% (109/1130) had no immunosuppressive risk factor.
4. Radiation therapy: Patients who have undergone radiation therapy to the head and neck region may have compromised local tissue integrity and blood supply, increasing the risk of NOE (Treviño González, 2020). This should not be confused with osteoradionecrosis. This is a distinct entity, a chronic condition characterized by radiotherapy-induced avascular necrosis, mainly of the tympanic part of the temporal bone. Patients with osteoradionecrosis are thought to have an increased risk of NOE.
5. Chronic kidney disease: While references linking kidney disease directly to NOE are absent, the association can be inferred from the broader literature on infections in immunocompromised patients. Impaired renal function leads to immune dysfunction and metabolic imbalances, contributing to a higher risk of severe infections like NOE (Rubin Grandis, 2004; Sarnak, 2000) . The study of Sarnak highlights the increased risk of severe infections, including those caused by Pseudomonas aeruginosa, in patients with end-stage renal disease.
6. Malnutrition or poor general health: Poor nutritional status or chronic debilitating conditions can weaken the immune system and delay wound healing, increasing susceptibility to NOE (Carfrae, 2009; Chandra, 1997)
7. Warm, humid climate is associated with a higher prevalence of NOE (Nadol, 1980; Yang, 2020).

What are alarm symptoms for necrotizing otitis externa?

As stated in the previously mentioned review (Takata, 2023), the most common presenting symptom was otalgia (96%, 1249/1307) followed by otorrhoea (78%, 972/1255). Fever was infrequently reported. (7%, 28/416). Granulation tissue (69%, 918/1332) and oedema/swelling (76%, 754/987) were the commonest clinical signs. These symptoms can be identical to the presentation other otological conditions, making differentiation virtually impossible without knowing the course of the symptoms, without knowing previous treatment and without knowing the (clinical) context of the patient.

Severe and increasing otalgia which is discongruent to the extent of ear canal abnormalities in a patient previously diagnosed with and/or treated for otitis externa should be considered high-risk for (development of) necrotizing otitis externa. Pain is a very important symptom in normal otitis externa as well, but is then accompanied with congruent findings upon physical examination.

Granulation tissue. (Bacterial) Otitis externa arises from a skin infection due to discontinuity of the epithelial lining of the ear canal. An epithelial defect can also occur iatrogenically, for example due to the use of hearing aids or ear syringing. The porte d’entrée can usually not be seen in acute otitis externa, due to swelling of the canal skin. This infectious process might also involve (inflammatory) granulation tissue, formationof small abscesses or furuncles. These abnormalities disappear during the healing course upon correct treatment. Although not pathognomonic for necrotizing otitis externa, persisting granulation tissue of the external auditory canal should raise suspicion, especially if co-existent with other symptoms. This can be a sign of a lingering infection beneath the ear canal skin. Moreover, abnormal tissue in the ear canal after the time window of acute otitis externa can also be caused by cancer of the ear canal.

Another alarm symptom that can occur in necrotizing otitis externa, is cranial nerve palsy, in case of progression of the skull base osteomyelitis. In theory, all cranial nerves can be involved, depending on the spreading pattern. However, the nerves that are mostly affected are the facial nerve and other lower cranial nerves (glossopharyngeal, vagus, accessory, hypoglossal). In the study by Takata (2023), 21% (371/1741) of patients had a facial nerve palsy and 5% (73/1447) had two or more affected cranial nerves. Athough cranial nerve palsy can also occur in other otological diseases (e.g., chronic otitis media/cholesteatoma), it generally urges the need for futher diagnostic imaging.

Precautions upon referral

• Patients with untractable acute otitis externa treated according the guidelines and patients suspected for necrotizing otitis externa should be referred as an urgency. It is advised to assess these patients within two weeks. 
• In case of clinical suspicion of NOE and waiting time for a a specialist consultation, it can be wise to discuss the treatment course with the referring doctor. This may lead to meaningful treatment or diagnostic steps upfront the specialist consultation or cessation of treatment on purpose in order to have an unbiased situation at the time of the specialist consultation (also for taking a culture).    
• Generally patients are referred to an ENT-specialist. However, if the symptoms are not primarily otologic but neurologic, a patient can end up being referred to a neurologist, geriatric or internal medicine ward. Decreased consciousness, metabolic issues due to infection, dysregulated diabetes and decreased intake can shift the attention off the otologic problem. Again awareness, not only for the general practitioners, but also for medical specialists, is key.  

Values and preferences of patients (and family/caretakers)

Patients with necrotizing otitis externa benefit from an early diagnosis, as it can shorten their length of therapy. It also minimalises the chance of complications of the disease, which can be extensive (permanent hearing loss and other neurological damage). This also includes mortality. All cause mortality within one year is estimated a 7%, while disease specific survival within 1 year is estimated at 2%. Furthermore, symptoms such as severe pain and illness often takes a toll on the patients and family/caregivers. Early recognition reduces the length of these symptoms.

Costs

No cost efficiency studies have been performed on this subject. However, the treatment of the disease can take up to several weeks, even months (described in module Antimicrobial treatment and module Duration of treatment), which can lead to health care costs such as prolonged admissions to the hospital. The working group promotes further diagnostics in case of suspicion, to rule out the disease or for an early diagnosis. This does not outweigh the potential additional costs of (the complications of) a delayed diagnosis.

Health equity/equitable

Not applicable.

Acceptability and feasibility

It is important that there is adequate access to medical professionals involved. First, medical professionals in primary care for referral to secondary (or tertiary) care: this includes an ENT specialist, radiologist, medical microbiologist and infectious disease specialist. Means for accurate diagnosis and management of disease, such as aforementioned specialists, microbial cultures, imaging facilities and antibiotic treatment should be available in most health care systems.