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Necrotiserende otitis externa – osteomyelitis schedelbasis

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Additional conditions and optimizing care

Beoordeeld: 25-09-2025

Uitgangsvraag

  1. What is the added value of intensifying diabetes regulation, or detecting/correcting deficiencies, in the treatment of necrotizing otitis externa?
  2. Which conditions should be met in the organization around patients with NOE?

Aanbeveling

Recommendation-1

Assess general blood values, including blood cell count, eGFR, liver function, HbA1c, CRP/ESR in every patient with necrotizing otitis externa at diagnosis (and during follow up if indicated).

 

Consider consulting an internal medicine specialist (or physician in charge of treatment underlying disease), in case of underlying (immuno)defiencies, dysregulated diabetes mellitus or a complicated course.

 

Recommendation-2

Consider outpatient parenteral antimicrobial therapy (OPAT) as a safe and efficient alternative for hospitalized intravenous therapy.

 

Overwegingen

Balance between desired and undesired effects

Necrotizing otitis externa is an infectious disease. Curation of disease therefore depends on the immune system of the patient, in combination with antimicrobial therapy. Deficiencies in the immune system thereforecould lead to worse outcomes in the treatment of NOE.

 

Diabetes mellitus

It is generally accepted that people with diabetes mellitus are at an increased risk of serious infections, representing a significant burden on public health. A large, matched cohort study on the risk of infection in general among patients with type 1 and type 2 diabetes showed that diabetic patients had higher rates of all infections, particularly bone and joint infections, sepsis, and cellulitis (Carey, 2018). The authors estimated that 6% of infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes.

 

The typical profile of a patient with NOE is an elderly man with diabetes mellitus. Diabetes is the most frequently reported risk factor for NOE and is present in 84% of patients (Takata, 2023). Poorly controlled glycemic status leads to decreased cellular innate immunity, worsened microcirculation (Geerlings, 1999), and impaired neutrophil function, including chemotaxis, adherence to vascular endothelium, opsonization, and phagocytosis. Cell-mediated immunity is also affected; the methylglyoxal-glycation pathway inhibits the production of inflammatory mediators such as IL-10, IFN-gamma, and TNF-alpha from T-cells. Microvascular complications, resulting in localized ischemia due to diabetes, may hinder the penetration and absorption of antibiotics at the infection site. In the external auditory canal, the origin of the infection, the pH levels of cerumen are significantly higher, creating a favorable environment for pathogens such as Pseudomonas aeruginosa (Driscoll, 1993).

 

It could be theorized that better control of diabetes, most often in the form of glycemic control, results in better outcomes for patients with necrotizing otitis externa. However, the literature shows conflicting results regarding this matter, and it is important to note that these studies often involve small numbers of patients. Some studies indicate that there is no correlation between HbA1c levels and outcomes such as cure rates or length of treatment (Loh, 2012; Lee, 2017). In one study, high HbA1c levels were not considered a risk factor, but the duration of diabetes was associated with worse outcomes (Lee, 2018). The authors concluded that the most likely explanation was the microvascular complications developed over time. On the other hand, other studies suggest a positive correlation between HbA1c levels and outcomes (Verim, 2014; Hudson, 2019). Joshua et al. is frequently cited in other studies for reporting a correlation between a history of diabetes-related complications and longer treatment durations, as well as reduced survival rates in NOE patients. One study intensified glucose regulation in hospitalized patients with NOE and diabetes and found that intensifying diabetes therapy significantly shortened the duration of hospital stays (Peled, 2022).

 

In conclusion, there is insufficient evidence to support clear recommendations on diabetes management with the goal to enhance the immune response during treatment for NOE. However, it is well-known that uncontrolled diabetes leads to a worse prognosis in infections overall. Given the potential severity of NOE, optimizing glycemic control should be encouraged. The guideline panel advises blood glucose tests to identify patients with undiagnosed diabetes mellitus. For patients with known diabetes, assessing glycemic control via HbA1c testing should be considered. In cases of moderately or severely uncontrolled diabetes, consultation with an internal medicine specialist for the optimization of diabetes management is recommended.

 

Other (immuno)defiencies

The literature shows that immunodeficiencies other than diabetes are found in less than 10% of NOE cases (Byun, 2020; Takata, 2023). In addition to diabetes mellitus, immune dysfunction can be caused by other conditions, such as uncontrolled HIV infection, the natural aging process, or the use of immunosuppressants (e.g., medications for transplantations, autoimmune diseases, or hematologic malignancies). In cases involving immunosuppressive medication, it is important to consider possible treatment adjustments in consultation with the physician managing the underlying condition. Depending on the situation, this may involve temporarily discontinuing (some) immunosuppressants, reducing the dosage, or postponing the initiation of immunosuppressive therapy.

 

Another category of vulnerable patients includes those with vitamin or iron deficiencies, malnutrition, significant unintentional weight loss, or alcoholism. People with nutritional deficiencies are generally considered more susceptible to infections. Over the past two decades, numerous articles have been published on the correlation between vitamin D deficiency and the risk of infections in general. Vitamin D plays an immunomodulatory role, among other functions (De Haan, 2014). Iron is involved in erythropoiesis and the proper functioning of the immune system, but it is also essential for microbial growth (Jonker, 2014). Chronic alcoholism interferes with the normal sequences of the immune response, including both cell-mediated and humoral responses. Additionally, it affects multiple organs, making these patients more susceptible to complicated disease courses or multiple side effects, especially when prolonged antibiotic treatment is required. Unintentional weight loss can be caused by various underlying conditions and warrants further investigation.

 

We did not identify articles looking for nutritional deficiencies as a risk factor for (complicated) NOE. However, given their established role in predisposing individuals to infections in general, the working group advises consultation of an internal medicine specialist and/or dietitian if any of the above-mentioned conditions are suspected. A search for nutritional deficiencies and subsequent treatment is encouraged at the time of diagnosis (anemia, vitamin B1, B12, D and folic acid deficiency).

 

Monitoring side effects of treatment

NOE requires long term antimicrobial therapy, during which allergic reactions or various side effects may occur. One of the most frequent adverse reactions are the following (not exhaustive): diarrea with Clostridium difficile, renal failure, long QT syndrome with possible torsades de pointes, liver test abnormalities, cytopenia. There are also more specifically adverse events: e.g., tendon rupture due to long-term ciprofloxacine-use. If there are many or severe side effects under voriconazole, it could be because of CYP2C19 polymorphism in slow metabolizers. Voriconazol is also known to have multiple drug-drug interactions as it is an inhibitor of CYP3A4, CYP2C19 and CYP2C9.).

 

Standard lab tests should be performed every 1-2 weeks. Consider contacting an internal medicine specialist in case of using glycopeptides, aminoglycosides or azoles for specific advice.

 

Outpatient healthcare (OPAT)

Given the long duration of systemic antibiotic treatment, outpatient parenteral antimicrobial therapy (OPAT) could be a useful option to reduce healthcare costs, decrease hospital bed occupancy, and improve patient comfort. OPAT has been already used for many infections in the daily practice in order to decrease the burden of the hospital without endangering the efficiency of the therapy.

 

OPAT is indicated when oral therapy is not suitable due to antimicrobial resistance, drug interactions, intolerance, poor adherence, or poor oral absorption. A recent study focused on NOE (Durojaiye, 2022) investigated factors associated with treatment response. OPAT failure and prolonged intravenous (IV) antimicrobial therapy were recorded in 9 (19.6%) and 23 (50.0%) episodes, respectively. OPAT failure (implied as failure of treatment or the impossibility/impracticality of treatment outside of the hospital)  was associated with facial nerve involvement, dementia, Charlson comorbidity score, and peak CRP levels. Prolonged duration of IV antimicrobial therapy was correlated with the extent of disease (based on imaging findings), facial nerve involvement, and peak CRP levels.

 

The guideline panel recommends the use of OPAT for patients requiring IV therapy, considering the long duration of NOE treatment and the positive outcomes observed in daily practice for various infections.

 

Quality of the evidence

As the systemic search of literature found no studies that reported the selected outcomes, considerations and recommendations were based on expert opinion and known literature. the overall quality of evidence is therefore very low.

 

Values and preferences of patients (and possibly their relatives/caregivers)

As previously mentioned, OPAT significantly decreases hospital stay and has therefore an often positive effect on patient comfort.

 

Costs

The opinion of internal medicine specialists (or other specialists who prescribe immunossupressive therapy or treat underlying diseases) could be asked for during multidisciplinary disscussions. A referral to such a specialist is not always necessary. Optimizing diabetes medication could be done sometimes by GP - general practioner.

 

No studies on cost-effectiveness were identified for NOE. However, extrapolating from experience with other infections, costs during OPAT are supposed to be lower than costs  during hospitalization.

 

Equity

The guideline panel expects no problems with health equity with regard to medical treatment of necrotizing otitis externa.

 

Acceptibility

Diabetes mellitus and other immunodeficiencies are reported to increase the susceptibility for infections in general.

OPAT has been already used for many infections in the daily practice.

 

Feasibility

The feasibility of OPAT depends on outpatient healthcare system in each country.

 

Rationale of recommendation-1: weighing arguments for and against the interventions

Every patient should have baseline bloodtests, inclusively blood cell count, eGFR, liver tests, CRP/ESR and an HbA1c check performed at diagnosis. The cost of these tests are low especially in the context of difficult to treat infections, with potential life-threatening course. Periodical bloodtests every 1-2 weeks for side effects or evolution of disease and awareness of possible complications are needed. If the infection parameters are elevated at the start of treatment, it appears advisable to monitor them throughout the course of the treatment as an additional indicator of treatment success.

 

A suboptimal control of diabetes could jeopardize the good course of NOE because diabetes leads to microangiopathy and impaired polymorphonuclear and T cell function. Because of the poor microcirculation secondary to small vessel obliteration, the antibiotics penetrate less in these areas. Various forms of immunosupression are generally accepted as risk factors for complicated evolutions of infections.

 

Seeing the possible severe complications of NOE, e.g., skull base osteomyelitis with life threatening course, a special attention should be given both to immediate diagnosis and management of NOE itself and also to controlling associated diseases (diabetes, immunosuppression).

 

Referral to internal medicine or other specialties could generate higher costs. It is still encouraged mostly if  underlying disease is not under control or if bloodtests identifies new underlying clinical entity (important side effects, nutritional deficiencies, other diseases) In case of immunosuppressants, it is adviced to evaluate the pros en cons of adjusting this treatment with the responsible treating physicianuntil the resolution of NOE.

 

Rationale of recommendation-2: weighing arguments for and against the interventions

Outpatient parenteral antimicrobial therapy (OPAT) has been shown to be a safe and effective alternative to hospitalisation for treatment of a wide range of infections, but there are little studies on NOE patients. Selected patients can receive oral antibiotica. If is not feasible, OPAT could be taken into consideration in order to decrease healthcare burden (costs, occupancy of beds) and to increase the quality of life of these patients.

 

OPAT requires close monitoring by a specialized team of nurses and also patients who can recognize alarm symptoms. Periodical bloodtests every 1-2 weeks for side effects or evolution of disease and proactive questions to detect the these issues are needed. Some antibiotical or antifungal regimens impose controle bloodtests more frequently. A personalized plan should be discussed depending on medical history of patients and extension of NOE.

Onderbouwing

The development of necrotizing otitis externa is the result of a combination of factors. In the majority of patients, comorbidities are present. The most well-known and common of those is diabetes mellitus, which in itself leads to immune dysfunction, especially if poorly regulated. There are also other causes of immune dyfunction, some of which may be easily correctable such as iron or vitamin defiencies, which may increase the likelihood of developing NOE. Because treatment of NOE can be challenging and outcomes are often poor, addressing the potentially underlying causes should be considerered. This approach could also help prevent potential relapses.

 

Many patients will often already receive treatment for these underlying causes. Additionally, there is an added burden on healthcare systems to detect relevant deficiencies. The question is whether optimizing the treatment of known comorbidities, as well as detecting and treating new conditions, will lead to better patient outcomes and whether this justifies the additional use of healthcare resources.

 

The diagnosis and management of NOE implies a multidisciplinary approach. Taking into consideration a long trajectory of the patient with NOE until recovery, it is essential to discuss the possibility of therapy  in an ambulatory setting. This could have a positive influence on the associated healthcare costs and occupancy of beds.

There were no studies found in the systemic search of literature that complied with the PICO. Therefore, no systemic review of literature could be performed. However, relevant studies were found, wich will be discussed within the considerations.

What is the effect of intensifying diabetes treatment and/or detecting and correcting deficiencies.

Patients Patients with proven necrotizing otitis externa
Intervention Optimization of the immune system (referral to an internist for diabetes control/referral to a doctor who can address deficiencies)
Control No referral/standard of care
Outcomes Remission, length of treatment, mortality
Other selection criteria

Study design: systematic reviews and randomized controlled trials, cohort studies and other comparative research

[Minimal follow-up: 3 months]

Relevant outcome measures

The guideline panel considered remission, length of treatment and mortality as critical outcome measures for decision making;

The guideline panel defined the outcome measures as follows:

  • Remission: rate of curation of disease. Defined after prolonged disappearance of the signs and symptoms of a disease.
  • Length of treatment: Days/weeks until the treatment for NOE was stopped.
  • (Disease specific) Mortality: number of deaths, caused by the effects of necrotizing otitis externa.

The guideline panel defined the following as a minimal clinically important difference:

  • Remission: GRADE standard limits*.
  • Length of treatment: GRADE standard limits*.
  • Mortality: GRADE standard limits*.

Search and select (Methods)

The databases [Medline (via OVID) and Embase (via Embase.com)] were searched with relevant search terms until 30 september 2024. The detailed search strategy is listed under the tab ‘Literature search strategy’. The systematic literature search resulted in 982 hits. Studies were selected based on the following criteria: Systematic reviews, RCTs, observational and other studies on the added value of intensifying diabetes regulation, or detecting/correcting deficiencies, in the treatment of malignant otitis externa. One hundred and twenty-eight studies were initially selected based on title and abstract screening. After reading the full text, 128 studies were excluded (see the exclusion table under the tab ‘Evidence tabellen’), and no studies were included.

  1. Bhandary S, Karki P, Sinha BK. Malignant otitis externa: a review. Pac Health Dialog. 2002 Mar;9(1):64-7. PMID: 12737420.
  2. Carey IM, Critchley JA, DeWilde S, Harris T , Hosking FJ , Cook DG. Risk of Infection in Type 1 and Type 2 Diabetes Compared With the General Population: A Matched Cohort Study. Diabetes Care. 2018 Mar;41(3):513-521. PMID: 29330152.
  3. Danjou W, Chabert P, Perpoint T, Pradat P, Miailhes P, Boibieux A, Becker A, Fuchsmann C, Laurent F, Tringali S, Roux S, Triffault-Fillit C, Valour F, Ferry T; Lyon Bone and Joint Infection Study Group. Necrotizing otitis externa: analysis of relapse risk factors in 66 patients managed during a 12 year period. J Antimicrob Chemother. 2022 Aug 25;77(9):2532-2535. doi: 10.1093/jac/dkac193. PMID: 35696322.
  4. Driscoll PV, Ramachandrula A, Drezner DA, Hicks TA, Schaffer SR. Characteristics of cerumen in diabetic patients: a key to understanding malignant external otitis? Otolaryngol Head Neck Surg. 1993 Oct;109(4):676-9. doi: 10.1177/019459989310900407. PMID: 8233503.
  5. Durojaiye OC, Slucka A, Kritsotakis EI. Retrospective analysis of outcomes of outpatient parenteral antimicrobial therapy (OPAT) for necrotising otitis externa. Eur J Clin Microbiol Infect Dis. 2022 Jun;41(6):941-949. DOI: 10.1007/s10096-022-04455-y. PMID: 35556187.
  6. Eveleigh MO, Hall CE, Baldwin DL. Prognostic scoring in necrotising otitis externa. J Laryngol Otol. 2009 Oct;123(10):1097-102. DOI: 10.1017/S0022215109990491. PMID: 19586581.
  7. Geerlings SE, Hoepelman AI. Immune dysfunction in patients with diabetes mellitus (DM). FEMS Immunol Med Microbiol. 1999 Dec;26(3-4):259-65. doi: 10.1111/j.1574-695X.1999.tb01397.x. PMID: 10575137.
  8. de Haan K, Groeneveld AB, de Geus HR, Egal M, Struijs A. Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Crit Care. 2014 Dec 5;18(6):660. doi: 10.1186/s13054-014-0660-4. PMID: 25475621; PMCID: PMC4277653.
  9. Hutson KH, Watson GJ. Malignant otitis externa, an increasing burden in the twenty-first century: review of cases in a UK teaching hospital, with a proposed algorithm for diagnosis and management. J Laryngol Otol. 2019 May;133(5):356-362. doi: 10.1017/S0022215119000604. Epub 2019 Apr 12. PMID: 30975233.
  10. Jonker FA, Boele van Hensbroek M. Anaemia, iron deficiency and susceptibility to infections. J Infect. 2014 Nov;69 Suppl 1:S23-7. doi: 10.1016/j.jinf.2014.08.007. Epub 2014 Sep 26. PMID: 25264159.
  11. Joshua BZ, Sulkes J, Raveh E, Bishara J, Nageris BI. Predicting outcome of malignant external otitis. Otol Neurotol. 2008 29(3):339–343. DOI: 10.1097/MAO.0b013e3181661879. PMID: 18317396.
  12. Lee SK, Lee SA, Seon SW, Jung JH, Lee JD, Choi JY, Kim BG. Analysis of Prognostic Factors in Malignant External Otitis. Clin Exp Otorhinolaryngol. 2017 Sep;10(3):228-235. doi: 10.21053/ceo.2016.00612. Epub 2016 Sep 27. PMID: 27671716; PMCID: PMC5545692.
  13. Loh S, Loh WS. Malignant otitis externa: an Asian perspective on treatment outcomes and prognostic factors. Otolaryngol Head Neck Surg. 2013 Jun;148(6):991-6. doi: 10.1177/0194599813482107. Epub 2013 Apr 4. PMID: 23558287.
  14. Peled C, Sadeh R, El-Saied S, Novack V, Kaplan DM. Diabetes and glycemic control in necrotizing otitis externa (NOE). Eur Arch Otorhinolaryngol. 2022 Mar;279(3):1269-1275. doi: 10.1007/s00405-021-06772-y. Epub 2021 Apr 1. PMID: 33792784.
  15. Singh A, Al Khabori M, Hyder MJ. Skull base osteomyelitis; diagnostic and therapeutic challenges in atypical presentation. Otolaryngol Head Neck Surg 2005;133:121–5. DOI: 10.1016/j.otohns.2005.03.024. PMID: 16025065.
  16. Takata J, Hopkins M, Alexander V, Bannister O, Dalton L, Harrison L, Groves E, Kanona H, Jones GL, Mohammed H, Andersson MI, Hodgson SH. Systematic review of the diagnosis and management of necrotising otitis externa: Highlighting the need for high-quality research. Clin Otolaryngol. 2023 May;48(3):381-394. doi: 10.1111/coa.14041. Epub 2023 Feb 22. PMID: 36759416.
  17. Verim A, Naiboğlu B, Karaca Ç, Seneldir L, Külekçi S, Oysu Ç. Clinical outcome parameters for necrotizing otitis externa. Otol Neurotol. 2014 Feb;35(2):371-6. doi: 10.1097/MAO.0000000000000249. PMID: 24448298.

Risk of Bias tables

Not applicable.

 

Table of excluded studies

Reference

Reason for exclusion

Chen CN, Chen YS, Yeh TH, Hsu CJ, Tseng FY. Outcomes of malignant external otitis: survival vs mortality. Acta Otolaryngol. 2010;130(1):89-94. doi: 10.3109/00016480902971247. PMID: 19466617.

Observational study, without intervention (No comparison made)

 

Chin R, Roche P, Sigston E, Valance N. Malignant otitis externa: an Australian case series. Surgeon. 2012 Oct;10(5):273-7. doi: 10.1016/j.surge.2011.09.004. Epub 2011 Oct 26. PMID: 22032882.

Observational study, without intervention (No comparison made)

 

Hutson KH, Watson GJ. Malignant otitis externa, an increasing burden in the twenty-first century: review of cases in a UK teaching hospital, with a proposed algorithm for diagnosis and management. J Laryngol Otol. 2019 May;133(5):356-362. doi: 10.1017/S0022215119000604. Epub 2019 Apr 12. PMID: 30975233.

Observational study, without intervention (No comparison made)

 

Jamshidi A, Zonnour A, Dabiri S, Hasibi M, Tajdini A, Karrabi N, Yazdani N. Predictive role of facial nerve palsy improvement in malignant external otitis. Eur Arch Otorhinolaryngol. 2024 Mar;281(3):1253-1258. doi: 10.1007/s00405-023-08230-3. Epub 2023 Sep 19. PMID: 37725133.

Observational study, without intervention (No comparison made)

 

Krawiec E, Brenet E, Truong F, Nguyen Y, Papthanassiou D, Labrousse M, Dubernard X. Epidemiology and risk factors for extension of necrotizing otitis externa. Eur Arch Otorhinolaryngol. 2024 May;281(5):2383-2394. doi: 10.1007/s00405-024-08549-5. Epub 2024 Mar 18. Erratum in: Eur Arch Otorhinolaryngol. 2024 Jun;281(6):3317-3318. doi: 10.1007/s00405-024-08638-5. PMID: 38499694.

Wrong outcome

Lee SK, Lee SA, Seon SW, Jung JH, Lee JD, Choi JY, Kim BG. Analysis of Prognostic Factors in Malignant External Otitis. Clin Exp Otorhinolaryngol. 2017 Sep;10(3):228-235. doi: 10.21053/ceo.2016.00612. Epub 2016 Sep 27. PMID: 27671716; PMCID: PMC5545692.

Observational study, without intervention (No comparison made),

 

Loh S, Loh WS. Malignant otitis externa: an Asian perspective on treatment outcomes and prognostic factors. Otolaryngol Head Neck Surg. 2013 Jun;148(6):991-6. doi: 10.1177/0194599813482107. Epub 2013 Apr 4. PMID: 23558287.

Wrong outcome

Mahdyoun P, Pulcini C, Gahide I, Raffaelli C, Savoldelli C, Castillo L, Guevara N. Necrotizing otitis externa: a systematic review. Otol Neurotol. 2013 Jun;34(4):620-9. doi: 10.1097/MAO.0b013e3182804aee. PMID: 23598690.

Observational study, without intervention (No comparison made)

 

MULLAPUDI, H., and S. AV. “MALIGNANT OTITIS EXTERNA – OUR EXPERIENCE”. Asian Journal of Pharmaceutical and Clinical Research, vol. 15, no. 4, Apr. 2022, pp. 61-62, doi:10.22159/ajpcr.2022.v15i4.43974.

Observational study, without intervention (No comparison made)

 

Peled C, Sadeh R, El-Saied S, Novack V, Kaplan DM. Diabetes and glycemic control in necrotizing otitis externa (NOE). Eur Arch Otorhinolaryngol. 2022 Mar;279(3):1269-1275. doi: 10.1007/s00405-021-06772-y. Epub 2021 Apr 1. PMID: 33792784.

Observational study, without intervention (No comparison made)

 

Saidha PK, Kakkar V, Das P, Kapoor S. Malignant Otitis Externa: Association of Biochemical Markers with Staging of the Disease and Emergence of Methicillin Resistant Staphylococcus aureus as a Causative Agent. Int J Otorhinolaryngol Clin 2023; 15 (1):14-18.

Wrong outcome

Saxena A, Paul BS, Singh G, Ahluwalia A, Paul G. Predicting Outcome in Skull Base Osteomyelitis: An Assessment of Demographic, Clinical, and Pathological Attributes. J Neurosci Rural Pract. 2021 Sep 28;12(4):751-757. doi: 10.1055/s-0041-1735324. PMID: 34737511; PMCID: PMC8559086.

Observational study, without intervention (No comparison made)

 

Sekar R, Raja K, Ganesan S, Alexander A, Saxena SK. Clinical and Current Microbiological Profile with Changing Antibiotic Sensitivity in Malignant Otitis Externa. Indian J Otolaryngol Head Neck Surg. 2022 Dec;74(Suppl 3):4422-4427. doi: 10.1007/s12070-021-03068-9. Epub 2022 Jan 22. PMID: 36742648; PMCID: PMC9895493.

Observational study, without intervention (No comparison made)

 

Tsilivigkos C, Avramidis K, Ferekidis E, Doupis J. Malignant External Otitis: What the Diabetes Specialist Should Know-A Narrative Review. Diabetes Ther. 2023 Apr;14(4):629-638. doi: 10.1007/s13300-023-01390-9. Epub 2023 Mar 10. PMID: 36897495; PMCID: PMC10064349.

Observational study, without intervention (No comparison made)

 

Upreti G, Thomas R, Sundaresan R, Rebekah G, Rupali P, Jasper A. Clinico-Radiological Evaluation for Longitudinal Assessment in Central Skull Base Osteomyelitis: Proposal of Novel Scoring System. Indian J Otolaryngol Head Neck Surg. 2023 Dec;75(4):3553-3564. doi: 10.1007/s12070-023-03956-2. Epub 2023 Jul 4. PMID: 37974699; PMCID: PMC10646027.

Overview of literature

Verim A, Naiboğlu B, Karaca Ç, Seneldir L, Külekçi S, Oysu Ç. Clinical outcome parameters for necrotizing otitis externa. Otol Neurotol. 2014 Feb;35(2):371-6. doi: 10.1097/MAO.0000000000000249. PMID: 24448298.

Observational study, without intervention (No comparison made)

 

Zonnour A, Jamshidi A, Dabiri S, Hasibi M, Tajdini A, Karrabi N, Yazdani N. Predictive factors in treatment response of malignant external otitis. Eur Arch Otorhinolaryngol. 2023 Jan;280(1):159-166. doi: 10.1007/s00405-022-07478-5. Epub 2022 Jun 25. PMID: 35751693.

Observational study, without intervention (No comparison made)

 

Al-Noury K, Lotfy A. Computed tomography and magnetic resonance imaging findings before and after treatment of patients with malignant external otitis. Eur Arch Otorhinolaryngol. 2011 Dec;268(12):1727-34. doi: 10.1007/s00405-011-1552-8. Epub 2011 Mar 15. PMID: 21400256.

Wrong outcome

Beoordelingsdatum en geldigheid

Laatst beoordeeld  : 25-09-2025

Initiatief en autorisatie

Initiatief:
  • Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
Geautoriseerd door:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied
  • Nederlandse Vereniging voor Medische Microbiologie
  • Nederlandse Vereniging voor Nucleaire geneeskunde
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging van Ziekenhuisapothekers
  • Hoormij / Nederlandse Vereniging voor Slechthorenden

Algemene gegevens

For more details on the guideline methodology used, we refer you to the Werkwijze. Relevant information for the development of this guideline is presented below.

 

The revision of this guideline module was supported by the Knowledge Institute of the Federation of Medical Specialists (www.demedischspecialist.nl/kennisinstituut) and was funded by the Quality Funds for Medical Specialists (SKMS).

Samenstelling werkgroep

For the development of the guideline, a multidisciplinary guideline development group was established in 2022, consisting of representatives from all relevant specialties (see Composition of the working group) involved in the care of patients with necrotizing otitis externa.

 

Werkgroep

  • Dr. J.J. (Jérôme) Waterval (chairman), Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied, otorhinolaryngologist, Maastricht University Medical Center, Maastricht; Academic Alliance Skull Base Pathology Maaastricht University Medical Center – Radboud University Medical Center
  • Dr. M.J. (Mark) van Tilburg, Nederlandse Vereniging voor Keel-Neus-Oorheelkunde en Heelkunde van het Hoofd-Halsgebied, otorhinolaryngologist, Elistabeth-TweeSteden Ziekenhuis, Tilburg
  • Drs. S.A.H. (Sjoert) Pegge, Nederlandse Vereniging voor Radiologie, radiologist, Radboud University Medical Center, Nijmegen; Academic Alliance Skull Base Pathology Maaastricht University Medical Center – Radboud University Medical Center
  • Prof. Dr. A.W.J.M. (Andor) Glaudemans, Nederlandse Vereniging voor Nucleaire Geneeskunde, nuclear physicist UMCG, Groningen
  • Dr. M. (Moniek) Heusinkveld, Nederlandse Vereniging voor Medische Microbiologie, medical microbiologist, Gelderse Vallei Hospital, Ede
  • Dr. E.J.G. (Edgar) Peters, Nederlandse Internisten Vereniging, infectious disease specialist, Amsterdam University Medical Center (tot oktober 2022)
  • Dr. J.J. (Jonne) Sikkens, Nederlandse Internisten Vereniging, infectious disease specialist, Amsterdam University Medical Center (vanaf october 2022)
  • Dr. I.R. (Raluca) Mihailescu, Nederlandse Internisten Vereniging, infectious disease specialist, Onze Lieve Vrouwe Gasthuis, Amsterdam (vanaf juli 2024)
  • Dr. S.H. (Selwyn) Lowe, Nederlandse Internisten Vereniging, infectious disease specialist, Maastricht University Medical Center, Maastricht (vanaf juli 2024)

 Klankbordgroep

  • Dr. N.G.L. (Nynke) Jager, NVZA, hospital pharmacist Radboud University Medical Center, Nijmegen
  • Drs. F.S. (Fleur) Sinkeler, NVZA, hospital pharmacist Radboudumc Nijmegen

Ondersteuning

  • Drs. J.M.H. (Jasper) Janssen, NVKNO, otorhinolaryngologist in training, Maastricht University Medical Center, Maastricht
  • Dr. A. (Anja) van der Hout, advisor Knowledge Institute of the Dutch Association of Medical Specialists

Belangenverklaringen

An overview of the conflicts of interests of the guideline development group members and the assessment of how potential conflicts of interest were addressed can be found in the table below. The signed declarations of interest are available upon request from the Secretariat of the Knowledge Institute of the Dutch Federation of Medical Specialists at secretariaat@kennisinstituut.nl.

Werkgroeplid

Functie

Nevenfuncties

Gemelde belangen

Ondernomen actie

Waterval (voorzitter)

KNO-arts MUMC

Accreditatiecommissie Stichting Audiciensregister

Geen

Geen

Glaudemans

Nucleair geneeskundige UMCG

 

Voorzitter NVNG (onbetaald)

We hebben als ziekenhuis en afdeling een samenwerking met Siemens (UMCG-Siemens PUSH collaboration/Partnership of UMCG-Siemens for building the future of Health). Hieruit vloeit uit voort dat de nieuwste camera’s bij ons komen (bv UMCG neemt nieuwe Whole-Body PET/CT-scanner in gebruik) en dat er gezamenlijk onderzoek gedaan wordt. Hierbij heb ik een aantal promovendi die door Siemens betaald worden (niet op het gebied van osteomyelitis schedelbasis)

Geen restricties. Extern gefinancierd onderzoek valt buiten bestek richtlijn

 

Heusinkveld

Arts-microbioloog in ziekenhuis Gelders Vallei

Richtlijn otitis externa

 

Bestuur SKML sectie infectieserologie (onbetaald)

Geen

Geen

Peters (tot oktober 2022)

Internist-infectioloog-acute geneeskundige, Amsterdam UMC

richtlijnontwikkeling: Covid-19 FMS, diabetische voet NIV, diabetische voet IWGDF, alle onbetaald
Organisatie internationaal congres diabetische voet. Onbetaald

 

afdeling krijgt geld van Roche voor biomarker onderzoek bij diabetische voet osteomyelitis
Voorzitter gewrichtsprothese geassocieerde infectie richtlijn.

Diabetische voet onderzoek (extern gefinancierd)

 

Geen restricties. Extern gefinancierd onderzoek valt buiten bestek richtlijn

 

Pegge

Radioloog (Neuro/Hoofdhals)

Radboud UMC Nijmegen

Geen

Geen

Geen

Van Tilburg

KNO-arts ETZ

 

Geen

Geen

Geen

Sikkens

Internist acute geneeskunde & infectioloog, Amsterdam UMC

post-doc onderzoeker Amsterdam UMC, onbetaald

 

Ja, via ZonMw (onderzoek naar COVID bij een medewerkerscohort, onderwerp infectiepreventie en vaccin-immunologie)

 

Geen restricties. Extern gefinancierd onderzoek valt buiten bestek richtlijn

 

Lowe

 

Internist-infectioloog. Afdeling Medische Microbiologie, Infectieziekten en Infectiepreventie (MMI), Maastricht UMC+

 

Geen

Geen

Geen

Mihailescu

 

Internist-infectioloog

OLVG

Amsterdam

Geen

Geen

Geen

Jasper Janssen

 

KNO-arts in opleiding bij het MUMC+ (0,8 FTE), promovendus (0,2 FTE).

Geen

Geen

Geen

Sinkeler

 

Ziekenhuisapotheker AmsterdamUMC

 

Geen

Geen

Geen

Jager

Ziekenhuisapotheker

 

Geen

Geen

Geen

Inbreng patiëntenperspectief

Attention was paid to the patient perspective by inviting Stichting Hoormij and Patiëntenfederatie Nederland for the invitational conference, and close contact with Stichting Hoormij during the development of the guideline. The report of this [see related products] was discussed in the guideline development group. The input obtained was taken into account when formulating the key questions, selecting the outcome measures, and drafting the considerations. The draft guideline was also submitted for comments to Stichting Hoormij and Patiëntenfederatie Nederland, and any comments received were reviewed and processed.

 

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule voerde de werkgroep conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uit om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).

Module

Uitkomst raming

Toelichting

Additional conditions and optimizing care

geen financiële gevolgen

Uit de toetsing volgt dat de aanbeveling(en) niet breed toepasbaar zijn (<5.000 patiënten) en daarom naar verwachting geen substantiële financiële gevolgen zal hebben voor de collectieve uitgaven.

Zoekverantwoording

Algemene informatie

Cluster/richtlijn: Osteomyelitis schedelbasis - UV9 Medicamenteuze behandeling

Uitgangsvraag/modules: Wat is de meerwaarde van intensiveren van diabetesregulatie, danwel opsporen/ aanvullen van deficiënties, in de behandeling maligne otitis externa?   

Database(s): Embase.com, Ovid/Medline

Datum: 30 september 2024

Periode: geen restrictie

Talen: geen restrictie

Literatuurspecialist: Esther van der Bijl

Rayyan review: https://rayyan.ai/reviews/1173104

BMI-zoekblokken: voor verschillende opdrachten wordt (deels) gebruik gemaakt van de zoekblokken van BMI-Online https://blocks.bmi-online.nl/

Deduplication: voor het ontdubbelen is gebruik gemaakt van http://dedupendnote.nl/

Toelichting:

Voor deze vraag is gezocht op de elementen maligne otitis externa EN optimalisatie immuunsysteem (verwijzing naar internist voor diabetes controle/verwijzing naar arts die deficiënties op kan lossen).

 

Er waren geen sleutelartikelen voor deze search opgegeven.

Te gebruiken voor richtlijntekst:

In de databases Embase.com en Ovid/Medline is op 30 september 2024 systematisch gezocht naar systematische reviews, RCTs, observationele - en overige studies over de meerwaarde van intensiveren van diabetesregulatie, danwel opsporen/ aanvullen van deficiënties, in de behandeling maligne otitis externa. De literatuurzoekactie leverde 982 unieke treffers op.

Zoekopbrengst

 

EMBASE

OVID/MEDLINE

Ontdubbeld

SR

40

25

41

RCT

32

7

36

Observationele studies

224

69

240

Overige studies

573

446

665

Totaal

869

547

982*

*in Rayyan

 

Zoekstrategie

Embase.com

No.

Query

Results

#1

'malignant otitis externa'/exp OR (((maligna* OR necroti* OR necrosis) NEAR/3 ('otitis externa' OR 'external otitis')):ti,ab,kw) OR ('otitis externa' AND (maligna*:ti,ab,kw OR necroti*:ti,ab,kw OR necrosis:ti,ab,kw)) OR (('osteomyelitis'/exp OR 'osteomyelitis':ti,ab,kw) AND ('skull'/exp OR 'skull disease'/exp OR skull*:ti,ab,kw OR cranial:ti,ab,kw OR cranium:ti,ab,kw))

6958

#2

'patient referral'/exp OR 'internal medicine'/exp OR 'internist'/exp OR 'diabetes mellitus'/exp OR 'insulin dependent diabetes mellitus'/exp OR 'non insulin dependent diabetes mellitus'/exp OR 'glycated hemoglobin'/exp OR 'hemoglobin a1c'/exp OR 'hemoglobin a1c test kit'/exp OR 'glycemic control'/exp OR ((dm NEAR/3 (1 OR 'type 1' OR 'type i' OR 2 OR 'type 2' OR 'type ii')):ti,ab,kw) OR (((doctor* OR physician* OR practitioner* OR clinical*) NEAR/3 (visit* OR exam*)):ti,ab,kw) OR (((haemoglobin* OR hb OR hba OR hemoglobin*) NEAR/3 (a1c OR 'a1' OR 1c OR aic OR 'alpha 1')):ti,ab,kw) OR (((clia OR a1c OR 1c) NEAR/3 (kit* OR test*)):ti,ab,kw) OR ((('blood glucose*' OR glycemic*) NEAR/3 (control* OR test* OR level*)):ti,ab,kw) OR (((glycated OR glycosyl OR glycosylated OR glycosylised OR glycoside OR glycosylation) NEAR/1 (haemoglobin* OR hemoglobin*)):ti,ab,kw) OR gatekeep*:ti,ab,kw OR referral*:ti,ab,kw OR consultation*:ti,ab,kw OR 'internal* medicine*':ti,ab,kw OR 'internist*':ti,ab,kw OR diabetes:ti,ab,kw OR diabetic*:ti,ab,kw OR diabets:ti,ab,kw OR iddm:ti,ab,kw OR iddm1:ti,ab,kw OR iddmi:ti,ab,kw OR t1dm:ti,ab,kw OR tidm:ti,ab,kw OR t2dm:ti,ab,kw OR tiidm:ti,ab,kw OR niddm:ti,ab,kw OR niddm2:ti,ab,kw OR niddmii:ti,ab,kw OR hba1c:ti,ab,kw OR 'dca vantage analy*':ti,ab,kw OR glycohaemoglobin*:ti,ab,kw OR glycohemoglobin*:ti,ab,kw OR glycosylhaemoglobin*:ti,ab,kw OR glycosylhemoglobin*:ti,ab,kw

2641309

#3

#1 AND #2

1171

#4

#3 NOT ('conference abstract'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it) NOT (('animal'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'nonhuman'/exp) NOT 'human'/exp)

869

#5

'meta analysis'/exp OR 'meta analysis (topic)'/exp OR metaanaly*:ti,ab OR 'meta analy*':ti,ab OR metanaly*:ti,ab OR 'systematic review'/de OR 'cochrane database of systematic reviews'/jt OR prisma:ti,ab OR prospero:ti,ab OR (((systemati* OR scoping OR umbrella OR 'structured literature') NEAR/3 (review* OR overview*)):ti,ab) OR ((systemic* NEAR/1 review*):ti,ab) OR (((systemati* OR literature OR database* OR 'data base*') NEAR/10 search*):ti,ab) OR (((structured OR comprehensive* OR systemic*) NEAR/3 search*):ti,ab) OR (((literature NEAR/3 review*):ti,ab) AND (search*:ti,ab OR database*:ti,ab OR 'data base*':ti,ab)) OR (('data extraction':ti,ab OR 'data source*':ti,ab) AND 'study selection':ti,ab) OR ('search strategy':ti,ab AND 'selection criteria':ti,ab) OR ('data source*':ti,ab AND 'data synthesis':ti,ab) OR medline:ab OR pubmed:ab OR embase:ab OR cochrane:ab OR (((critical OR rapid) NEAR/2 (review* OR overview* OR synthes*)):ti) OR ((((critical* OR rapid*) NEAR/3 (review* OR overview* OR synthes*)):ab) AND (search*:ab OR database*:ab OR 'data base*':ab)) OR metasynthes*:ti,ab OR 'meta synthes*':ti,ab

1065368

#6

'clinical trial'/exp OR 'randomization'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp OR 'placebo'/exp OR 'prospective study'/exp OR rct:ab,ti OR random*:ab,ti OR 'single blind':ab,ti OR 'randomised controlled trial':ab,ti OR 'randomized controlled trial'/exp OR placebo*:ab,ti

4115353

#7

'major clinical study'/de OR 'clinical study'/de OR 'case control study'/de OR 'family study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'prospective study'/de OR 'comparative study'/de OR 'cohort analysis'/de OR ((cohort NEAR/1 (study OR studies)):ab,ti) OR (('case control' NEAR/1 (study OR studies)):ab,ti) OR (('follow up' NEAR/1 (study OR studies)):ab,ti) OR (observational NEAR/1 (study OR studies)) OR ((epidemiologic NEAR/1 (study OR studies)):ab,ti) OR (('cross sectional' NEAR/1 (study OR studies)):ab,ti)

8424623

#8

'case control study'/de OR 'comparative study'/exp OR 'control group'/de OR 'controlled study'/de OR 'controlled clinical trial'/de OR 'crossover procedure'/de OR 'double blind procedure'/de OR 'phase 2 clinical trial'/de OR 'phase 3 clinical trial'/de OR 'phase 4 clinical trial'/de OR 'pretest posttest design'/de OR 'pretest posttest control group design'/de OR 'quasi experimental study'/de OR 'single blind procedure'/de OR 'triple blind procedure'/de OR (((control OR controlled) NEAR/6 trial):ti,ab,kw) OR (((control OR controlled) NEAR/6 (study OR studies)):ti,ab,kw) OR (((control OR controlled) NEAR/1 active):ti,ab,kw) OR 'open label*':ti,ab,kw OR (((double OR two OR three OR multi OR trial) NEAR/1 (arm OR arms)):ti,ab,kw) OR ((allocat* NEAR/10 (arm OR arms)):ti,ab,kw) OR placebo*:ti,ab,kw OR 'sham-control*':ti,ab,kw OR (((single OR double OR triple OR assessor) NEAR/1 (blind* OR masked)):ti,ab,kw) OR nonrandom*:ti,ab,kw OR 'non-random*':ti,ab,kw OR 'quasi-experiment*':ti,ab,kw OR crossover:ti,ab,kw OR 'cross over':ti,ab,kw OR 'parallel group*':ti,ab,kw OR 'factorial trial':ti,ab,kw OR ((phase NEAR/5 (study OR trial)):ti,ab,kw) OR ((case* NEAR/6 (matched OR control*)):ti,ab,kw) OR ((match* NEAR/6 (pair OR pairs OR cohort* OR control* OR group* OR healthy OR age OR sex OR gender OR patient* OR subject* OR participant*)):ti,ab,kw) OR ((propensity NEAR/6 (scor* OR match*)):ti,ab,kw) OR versus:ti OR vs:ti OR compar*:ti OR ((compar* NEAR/1 study):ti,ab,kw) OR (('major clinical study'/de OR 'clinical study'/de OR 'cohort analysis'/de OR 'observational study'/de OR 'cross-sectional study'/de OR 'multicenter study'/de OR 'correlational study'/de OR 'follow up'/de OR cohort*:ti,ab,kw OR 'follow up':ti,ab,kw OR followup:ti,ab,kw OR longitudinal*:ti,ab,kw OR prospective*:ti,ab,kw OR retrospective*:ti,ab,kw OR observational*:ti,ab,kw OR 'cross sectional*':ti,ab,kw OR cross?ectional*:ti,ab,kw OR multicent*:ti,ab,kw OR 'multi-cent*':ti,ab,kw OR consecutive*:ti,ab,kw) AND (group:ti,ab,kw OR groups:ti,ab,kw OR subgroup*:ti,ab,kw OR versus:ti,ab,kw OR vs:ti,ab,kw OR compar*:ti,ab,kw OR 'odds ratio*':ab OR 'relative odds':ab OR 'risk ratio*':ab OR 'relative risk*':ab OR 'rate ratio':ab OR aor:ab OR arr:ab OR rrr:ab OR ((('or' OR 'rr') NEAR/6 ci):ab)))

15424750

#9

#4 AND #5 - SR

40

#10

#4 AND #6 NOT #9 - RCT

32

#11

#4 AND (#7 OR #8) NOT (#9 OR #10) - Observationeel

224

#12

#4 NOT (#9 OR #10 OR #11) - Overig

573

#13

#9 OR #10 OR #11 OR #12 - Totaal

869

Ovid/Medline

#

Searches

Results

1

((maligna* or necroti* or necrosis) adj3 ('otitis externa' or 'external otitis')).ti,ab,kf. or (exp *Otitis Externa/ and (maligna* or necroti* or necrosis).ti,ab,kf.) or ((exp *Osteomyelitis/ or 'osteomyelitis'.ti,ab,kf.) and (exp Skull/ or skull*.ti,ab,kf. or cranial.ti,ab,kf. or cranium.ti,ab,kf.))

3370

2

exp "Referral and Consultation"/ or exp Internal Medicine/ or exp Diabetes Mellitus/ or exp Glycated Hemoglobin/ or exp Glycemic Control/ or (dm adj3 ("1" or type 1 or type i or "2" or type 2 or type ii)).ti,ab,kf. or ((doctor* or physician* or practitioner* or clinical*) adj3 (visit* or exam*)).ti,ab,kf. or ((haemoglobin* or hb or hba or hemoglobin*) adj3 (a1c or a1 or 1c or aic or alpha 1)).ti,ab,kf. or ((clia or a1c or 1c) adj3 (kit* or test*)).ti,ab,kf. or ((blood glucose* or glycemic*) adj3 (control* or test* or level*)).ti,ab,kf. or ((glycated or glycosyl or glycosylated or glycosylised or glycoside or glycosylation) adj1 (haemoglobin* or hemoglobin*)).ti,ab,kf. or gatekeep*.ti,ab,kf. or referral*.ti,ab,kf. or consultation*.ti,ab,kf. or internal* medicine*.ti,ab,kf. or internist*.ti,ab,kf. or diabetes.ti,ab,kf. or diabetic*.ti,ab,kf. or diabets.ti,ab,kf. or iddm.ti,ab,kf. or iddm1.ti,ab,kf. or iddmi.ti,ab,kf. or t1dm.ti,ab,kf. or tidm.ti,ab,kf. or t2dm.ti,ab,kf. or tiidm.ti,ab,kf. or niddm.ti,ab,kf. or niddm2.ti,ab,kf. or niddmii.ti,ab,kf. or hba1c.ti,ab,kf. or dca vantage analy*.ti,ab,kf. or glycohaemoglobin*.ti,ab,kf. or glycohemoglobin*.ti,ab,kf. or glycosylhaemoglobin*.ti,ab,kf. or glycohemoglobin*.ti,ab,kf. or glycosylhaemoglobin*.ti,ab,kf. or glycosylhemoglobin*.ti,ab,kf.

1492419

3

1 and 2

563

4

3 not (comment/ or editorial/ or letter/) not ((exp animals/ or exp models, animal/) not humans/)

547

5

meta-analysis/ or meta-analysis as topic/ or (metaanaly* or meta-analy* or metanaly*).ti,ab,kf. or systematic review/ or cochrane.jw. or (prisma or prospero).ti,ab,kf. or ((systemati* or scoping or umbrella or "structured literature") adj3 (review* or overview*)).ti,ab,kf. or (systemic* adj1 review*).ti,ab,kf. or ((systemati* or literature or database* or data-base*) adj10 search*).ti,ab,kf. or ((structured or comprehensive* or systemic*) adj3 search*).ti,ab,kf. or ((literature adj3 review*) and (search* or database* or data-base*)).ti,ab,kf. or (("data extraction" or "data source*") and "study selection").ti,ab,kf. or ("search strategy" and "selection criteria").ti,ab,kf. or ("data source*" and "data synthesis").ti,ab,kf. or (medline or pubmed or embase or cochrane).ab. or ((critical or rapid) adj2 (review* or overview* or synthes*)).ti. or (((critical* or rapid*) adj3 (review* or overview* or synthes*)) and (search* or database* or data-base*)).ab. or (metasynthes* or meta-synthes*).ti,ab,kf.

778200

6

exp clinical trial/ or randomized controlled trial/ or exp clinical trials as topic/ or randomized controlled trials as topic/ or Random Allocation/ or Double-Blind Method/ or Single-Blind Method/ or (clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or multicenter study or clinical trial).pt. or random*.ti,ab. or (clinic* adj trial*).tw. or ((singl* or doubl* or treb* or tripl*) adj (blind$3 or mask$3)).tw. or Placebos/ or placebo*.tw.

2783743

7

Epidemiologic studies/ or case control studies/ or exp cohort studies/ or Controlled Before-After Studies/ or Case control.tw. or cohort.tw. or Cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or Longitudinal.tw. or Retrospective*.tw. or prospective*.tw. or consecutive*.tw. or Cross sectional.tw. or Cross-sectional studies/ or historically controlled study/ or interrupted time series analysis/ [Onder exp cohort studies vallen ook longitudinale, prospectieve en retrospectieve studies]

4839638

8

Case-control Studies/ or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or comparative study/ or control groups/ or controlled before-after studies/ or controlled clinical trial/ or double-blind method/ or historically controlled study/ or matched-pair analysis/ or single-blind method/ or (((control or controlled) adj6 (study or studies or trial)) or (compar* adj (study or studies)) or ((control or controlled) adj1 active) or "open label*" or ((double or two or three or multi or trial) adj (arm or arms)) or (allocat* adj10 (arm or arms)) or placebo* or "sham-control*" or ((single or double or triple or assessor) adj1 (blind* or masked)) or nonrandom* or "non-random*" or "quasi-experiment*" or "parallel group*" or "factorial trial" or "pretest posttest" or (phase adj5 (study or trial)) or (case* adj6 (matched or control*)) or (match* adj6 (pair or pairs or cohort* or control* or group* or healthy or age or sex or gender or patient* or subject* or participant*)) or (propensity adj6 (scor* or match*))).ti,ab,kf. or (confounding adj6 adjust*).ti,ab. or (versus or vs or compar*).ti. or ((exp cohort studies/ or epidemiologic studies/ or multicenter study/ or observational study/ or seroepidemiologic studies/ or (cohort* or 'follow up' or followup or longitudinal* or prospective* or retrospective* or observational* or multicent* or 'multi-cent*' or consecutive*).ti,ab,kf.) and ((group or groups or subgroup* or versus or vs or compar*).ti,ab,kf. or ('odds ratio*' or 'relative odds' or 'risk ratio*' or 'relative risk*' or aor or arr or rrr).ab. or (("OR" or "RR") adj6 CI).ab.))

5796137

9

4 and 5 - SR

25

10

(4 and 6) not 9 - RCT

7

11

(4 and (8 or 9)) not (9 or 10) - Observationeel

69

12

4 not (9 or 10 or 11) - Overig

446

13

9 or 10 or 11 or 12 - Totaal

547