<figure><img src="image_1.png" /></figure>

# Head-to-Head Comparison Between
¹⁸F-FDG PET and Leukocyte Scintigraphy
to Monitor Treatment Responses in
Necrotizing Otitis Externa

Journal of Otolaryngology - Head &
Neck Surgery

Volume 53: 1-9

© The Author(s) 2024

Article reuse guidelines:
sagepub.com/journals-permissions

DOI: 10.1177/19160216241288810

journals.sagepub.com/home/ohn

Sage

Moïra Hurstel, MD¹*, Alice Vasseur, MD²* ID, Saifeddine Melki, MD¹ ID,
Nicolas Veran, PharmD¹, Laetitia Imbert, PhD¹,⁴,
Duc Trung Nguyen, MD², Cécile Rumeau, MD, PhD²,³*,
and Antoine Verger, MD, PhD¹,⁴*

## Abstract

**Background.** Necrotizing otitis externa (NOE) is a rare disease associated with high morbidity and mortality, and there is currently no available accurate biomarker to assess treatment responses. The aim of the current study was to evaluate and directly compare the diagnostic performances of 18-Fluoro-deoxyglucose positron emission tomography (¹⁸F-FDG PET) and labeled leukocyte scintigraphy (LS) to monitor treatment responses in NOE.

**Methods.** Consecutive patients with NOE who underwent ¹⁸F-FDG PET at the end of antibiotic therapy and planar as well as single photon emission computed tomography-labeled leukocyte scintigraphy after completing the initial antibiotic treatment were retrospectively included. Semiquantitative analyses were performed to determine the ratios of affected/nonaffected sides for PET and 4-hour and 24-hour LS acquisitions as well as the kinetic PET ratios (at diagnosis and post-treatment) and LS (4 and 24hours). The final treatment responses were assessed by 2 experienced ENT physicians based on clinical, otoscopic, and biological data and subsequent 3-month follow-up.

**Results.** Seventeen patients (74.0 ± 10.6 years old, 5 women) were included. The best diagnostic performances were obtained with the PET maximum standardized uptake value (SUVmax)-lesion-to-background ratio and the tomographic LS lesion-to-background ratio at the 4-hour acquisition timepoint (thresholds of 4.1 and 1.19, yielding accuracies of 100% and 88%, respectively). In the multivariate analysis, the PET SUVmax-lesion-to-background ratio was the only predictive factor of recovery when associated with all clinical parameters (P < .001).

**Conclusion.** ¹⁸F-FDG PET is the first-line imaging modality for evaluating NOE treatment responses, with excellent diagnostic performances. LS with only 4-hour acquisitions appeared to suffice to evaluate NOE treatment responses. Both biomarkers constitute early prognostic biomarkers for predicting antibiotic treatment response in patients with NOE.

**Trial registration.** The institutional ethics committee (Comité d'Ethique du CHRU de Nancy) approved the evaluation of retrospective patient data, and the trial was registered at ClinicalTrials.gov (n°2023PI003-404).

## Keywords

¹⁸F-FDG PET, labeled leukocyte, necrotizing, otitis

Received March 1, 2024; accepted June 5, 2024.

<figure><img src="image_2.png" /></figure>

Creative Commons CC-BY-NC-ND: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 License (https://creativecommons.org/licenses/by-nc-nd/4.0/) which permits non-commercial use, reproduction and distribution of the work as published without adaptation or alteration, without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
**Graphical Abstract**

# HEAD-TO-HEAD COMPARISON OF 18F-FDG PET AND LEUCOCYTE SCINTIGRAPHY TO MONITOR TREATMENT RESPONSES IN NECROTIZING OTITIS EXTERNA

Hurstel M, Vasseur A, Melki S, Veran N, Imbert L, Nguyen D, Verger A

## OBJECTIVES

To evaluate and directly compare the
diagnostic performances of 18F-FDG
PET and labeled leucocyte
scintigraphy (LS) to monitor
treatment responses in Nectrotizing
otitis externa

<figure><img src="image_3.png" /></figure>

## METHODS

Longitudinal
case series of
17 patients

## RESULTS

Best diagnostic performances were
with the PET SUVmax-lesion-to-
background ratio and the
tomographic LS lesion-to-background
ratio at the 4-hour acquisition
timepoint

accuracies of 100% and 88%,
respectively.

<figure><img src="image_4.png" /></figure>

In the multivariate
analysis, the PET SUVmax-
lesion-to-background ratio
was the only predictive
factor of recovery when
associated with all clinical
parameters (p<0.001).

18F-FDG PET is the first-line imaging modality for evaluating NOE treatment responses, with excellent diagnostic performances. LS with only 4-hour acquisitions appeared to suffice to evaluate NOE treatment responses. Both biomarkers constitute early prognostic biomarkers for predicting antibiotic treatment response in NOE patients.

<figure><img src="image_5.png" /></figure>

CANADIAN SOCIETY OF
OTOLARYNGOLOGY -
HEAD & NECK SURGERY

THE OFFICIAL JOURNAL OF THE CANADIAN SOCIETY OF OTO-HNS

## Background

Necrotizing otitis externa (NOE), formerly known as malig-
nant otitis externa, is a rare but severe pathology. NOE is an

osteitis that predominantly affects diabetic, elderly, or immu-
nocompromized patients and may progress to osteomyelitis. Its
severity predominantly stems from complications: nerve palsy,
meningitis, venous sinus thrombosis and extensive basicranial

<footnote n="1">¹Department of Nuclear Medicine and Nancy Cyclotep, University Hospital of Nancy, Hospitals of Brabois, Vandoeuvre-lès-Nancy, France</footnote>

<footnote n="2">²ENT Department, CHRU-Nancy, Université de Lorraine, Nancy, France</footnote>

<footnote n="3">³DevAH, Université de Lorraine, Nancy, France</footnote>

<footnote n="4">⁴IADI, INSERM, UMR 1254, Université de Lorraine, Nancy, France</footnote>

<footnote>*These authors contributed equally to this work.</footnote>

<footnote>**Corresponding Author:**</footnote>

<footnote>Saifeddine Melki, MD, Department of Nuclear Medicine and Nancy Cyclotep, University Hospital of Nancy, Hospitals of Brabois, Vandoeuvre-lès-Nancy 54035, France.</footnote>

<footnote>Email: s.melki@chru-nancy.fr</footnote>
infection,¹ with the latest studies reporting a mortality rate of approximately 8%.² Cohen and Friedman proposed the first diagnosis criteria for NOE in 1987.³ These included clinical signs such as otalgia, otorrhea, granulation tissue, or edema and radiobiological signs such as a positive technetium-99 m bone scan or signs suggestive of a localized *Pseudomonas aeruginosa* infection. The optimal treatment modality remains unclear in terms of the type, route (oral or intravenous), and duration of antibiotherapy. Most of the recent studies opt for a 6-week, combining oral and intravenous treatments⁴,⁵ to obtain a quick auditory canal recovery. Biological signs of infection also promptly return to normal, but osteitis may take longer to resolve. Due to its well-known radio-clinical delay, the computed tomography (CT) bone scan is a flawed choice to establish complete healing. Signs of osteolysis persist weeks after osteitis.⁶ Consequently, clinical and biological markers should not be used in isolation to evaluate full recovery and need follow-up in clinical practice to ascertain full recovery. There is currently a lack of accurate biomarkers to identify good treatment responders early, limiting the prescription of noneffective prolonged antibiotic therapies and selecting patients at risk of nontreatment response, requiring a close follow-up.

Nuclear medicine techniques such as technetium-99 m bone scan and gallium-67 or, more recently, leukocyte scintigraphy (LS) have been proposed as imaging biomarkers.⁷⁻¹⁰ LS has shown good results in terms of sensitivity and specificity for osteitis and is now regularly used for bone and prosthesis infections.¹¹

Interestingly, positron emission tomography with a 2-deoxy-2-fluoro-D-glucose CT (¹⁸F-FDG-PET/CT) has been proposed as a reliable imaging modality for treatment cessation in NOE.¹² ¹⁸F-FDG-PET/CT has the advantage of being more accessible and less expensive than LS. However, to the best of our knowledge, no study has to date evaluated and directly compared the performances of LS and ¹⁸F-FDG-PET/CT for providing the rationale of when to stop antibiotic treatment.

The current study therefore aimed to evaluate and directly compare the diagnostic performances of ¹⁸F-FDG-PET/CT and LS for monitoring NOE treatment responses.

# Methods

## Study Population

All patients with NOE referred to our department between December 2020 and March 2023 for planar and SPECT/CT ⁹⁹mTc-HMPAO-LS as well as an 18-Fluoro-deoxyglucose positron emission tomography (¹⁸F-FDG PET) scan to monitor antibiotic therapy responses within 1 month of completing treatment were retrospectively included in the study. ¹⁸F-FDG PET scans were performed at least 1 week after the end of antibiotic therapy, as recommended.¹³⁻¹⁵ The institutional ethics committee (Comité d'Ethique du CHRU de Nancy) approved the evaluation of retrospective patient data, and the trial was registered at [ClinicalTrials.gov (n°2023PI003-404)](https://ClinicalTrials.gov). This research complied with the principles of the Declaration of Helsinki. Informed consent was obtained from all individuals included in the study.

# ENT Consultations

Patients attended at least 3 ENT specialist consultations, the first at the initial diagnosis (V1), the second at the end of the antibiotic treatment (V2) (6 weeks), and the third at 3 months from the end of the antibiotic therapy (V3). Patients requiring external ear calibration had additional consultations for otologic care. The initial consultation considered comorbidities such as diabetes, kidney failure, and immunosuppressive therapy. Standard inflammatory diagnostics included blood count, C-reactive protein, renal function, and tests to confirm that diabetes was well controlled. NOE was suspected based on clinical (fever, otalgia, cranial nerve palsy) and otoscopic criteria (otorrhea, inflammation of the external auditory canal, osseous exposition, granulation tissue). The NOE diagnosis was confirmed by the detection of osteitis, with/without external ear edema or middle-ear opacities, on the CT scan. MRI is not systematic for NOE diagnosis in our practice and has been realized only in 3 patients: in 1 case to confirm osteitis, due to the absence of clear osseous erasure on CT scan and in 2 cases because of neurological impairments associated with NOE at the diagnosis with extended osteitis, an association that makes malignancy more credible as an alternative diagnosis. Bacteriological ear canal samples were systematically analyzed. Biopsies were only taken for the pathological examination of granulation tissue as a potential differential diagnosis for tumors. After the definitive NOE diagnosis, an antibiotic treatment combining intravenous ceftazidime and oral ciprofloxacin was prescribed for a duration of 6 weeks. The second and third consultations were scheduled at the end of the antibiotic therapy (V2) and at 3 months from the end of this therapy (V3) to search for the resolution of the infection (based constantly on clinical and otoscopic parameters and biological parameters at V2). Patients were considered to be still infected if any one of the previously defined clinical or otoscopic signs persisted. The recovery of each individual patient was assessed by the combination of clinical, otoscopic, and biological recovery at V2 associated with the persistence of recovery during the V3 consultation. Biological recovery was assessed as the normalization of C-reactive protein (CRP) at the end of the treatment if it was high at diagnosis, or the persistence of CRP's negativity. At these points, the criteria for scoring a recovery were solely based on the clinical and otoscopic signs previously described, and ENT specialists were blinded to the imaging results, including morphological imaging such as CT or MRI scans.

⁹⁹mTc-HMPAO leukocyte scintigraphy. A ⁹⁹mTc-HMPAO LS was planned for each patient at the end of the antibiotic therapy as for the ¹⁸F-FDG PET scan. As recommended for LS, autologous leukocytes were isolated from peripheral blood and radiolabeled ex vivo and then reinjected back into the same patient for imaging. Leukocytes were labeled with Technetium-99 m-hexamethylpropyle-neamineoxime (⁹⁹mTc-HMPAO) as recommended by the European guidelines for the labeling of leukocytes with ⁹⁹mTc-HMPAO.¹⁶ ⁹⁹mTc-HMPAO-labeled leukocytes (200-500 Mbq) were injected into the patient intravenously.
LS acquisitions included both planar and single photon emission computed tomography (SPECT) associated with a CT scan. A 5-minute planar acquisition was performed 30 minutes after the injection of radiolabeled leukocytes for quality control purposes to determine the lung, liver, and spleen uptake and calculate the liver-to-spleen ratio (normal range greater than 0.5). Planar and SPECT/CT images centered on the head and neck were subsequently obtained 4 and 24 hours after the injection of ⁹⁹mTc-HMPAO-labeled leukocytes using a gamma camera (Symbia Siemens®, Germany, MUNICH) with low-energy high-resolution collimators (centered on the peak of 140 keV using a 15% window). Fixed time and fixed duration planar and SPECT/CT acquisitions were performed using a 128 × 128 matrix. Planar images were acquired for 240 seconds at 4 hours post-IV and 1200 seconds at 24 hours post-IV. SPECT images consisted of 32 projections over 360° for 30 seconds per projection at 4 hours post-IV and 45 seconds per projection at 24 hours postinjection. Three-dimensional (3D) images were reconstructed using the ordered subset expectation maximization algorithm. CT scans were performed immediately after SPECT. Scanning parameters were 130 kV, 90 mAs, and 6 × 1 mm collimation. For CT scans, bone-weighted (B70, Medium Sharp) reconstructions were performed to obtain 1.25 mm slices.

## ¹⁸F-FDG PET

¹⁸F-FDG PET scans were performed at the time of the initial diagnosis and at the end of the antibiotic therapy. All ¹⁸F-FDG-PET/CT scans were performed at least 1 week after the completion of the antibiotic therapy to limit the risk of false-negative results.¹³⁻¹⁵ PET acquisitions were performed on a digital camera (Vereos, Philips®, Amsterdam) after the intravenous injection of 3 MBq/kg of ¹⁸F-FDG. All participants had fasted at least 6 hours before the injection and had a fasting blood glucose level less than 11 mmol/L, as recommended.¹⁷ PET scans extended from the vertex to the liver with the patient's hands down. PET images were obtained from 90-second acquisitions per bed position. PET images were reconstructed using an iterative algorithm (4 iterations, 8 subsets, Gaussian postfilter 5 mm full width at half maximum [FWHM] and 9.6 mm slices), corrected for scattering, random coincidences, and CT-based attenuation and resulted in 2 mm slices displayed in a 512 × 512 matrix. The CT scanning parameters were 120 kV, 100 mAs with mA modulation, and 0.625 mm collimation.

## Image Analysis

The semiquantitative LS analysis was performed by a specialist nuclear medicine physician using an 80 mm region of interest (ROI) in the anterior planar projection and a 15 mm volume of interest (VOI) on SPECT/CT images of both affected and nonaffected sides. For SPECT/CT images, the VOIs were applied on 4 different anatomical locations: the external auditory canal, the temporo-mandibular joint, the mastoid, and the base of the skull, as previously reported.¹² Semiquantitative analyses were performed by calculating the

ratios of the number of counts for planar images and the concentrations in kBq/mL for SPECT images of the affected/non-affected sides within the most severely affected anatomical location and its respective contralateral region at 4 and 24 hours acquisitions. Changes in these ratios between the 4 and 24 hours acquisitions were also determined.

The semiquantitative analysis of the ¹⁸F-FDG PET scans was performed by a specialist nuclear physician using a 15 mm VOI applied to the same anatomical location as the one most affected in LS (checking that it was also the anatomical location most affected in the PET scan). Standardized uptake values (SUVs), defined as the ratio of the radioactive concentration in the respective VOIs and the product of the injected dose and the body volume, were determined from the maximal and mean values of the VOIs on the affected side and the mean values of the VOIs on the unaffected side. Semiquantitative analyses were performed based on the ratios of affected/nonaffected sides for both ¹⁸F-FDG PET at the initial diagnosis and at the end of treatment. Changes between these ratios from the 2 PET scans were also calculated.

## Statistical Analysis

Categorical variables are expressed as percentages, and continuous variables are expressed as medians (first and third quartiles). Receiver operating curves of LS and PET semiquantitative parameters were determined to quantify the rate of recovery. Decision cutoffs were selected when the product of sensitivity and specificity reached its maximum. Multivariate binary logistic regression analyses were performed to test for associations between recovery and LS and PET semiquantitative parameters as well as clinical parameters such as age, sex, comorbidities, treatment, type, and duration of symptoms as well as pathological microorganisms involved as confounding factors. A *P* value <.05 was considered significant. Statistical analyses were performed using IBM, USA, New York SPSS Statistics (Version 25).

## Results

### Population

A total of 17 patients with a median age of 72.0 [62.5-78] years were included in this longitudinal study. Patient characteristics are summarized in Table 1. The most prevalent NOE risk factors were diabetes (n=10, 59%) and renal failure (n=6, 35%), with 5 patients (29%) showing both diabetes and renal failure risk factors. *Pseudomonas aeruginosa* was the most prevalent etiological agent identified (n=6, 35%). The median duration of symptoms prior to the first consultation in our tertiary center was 70 [28-108.5] days. At the initial ENT consultation, most patients presented symptoms such as otalgia (n=12, 70%), otillithia (n=13, 76%), inflammation of the external auditory canal (n=12, 70%), and cranial nerve paralysis (n=5, 12%). The final ¹⁸F-FDG PET scans were performed at 9 [7;13] days after the end of the antibiotic therapy. LS was performed at 1 [1;5] day from the final ¹⁸F-FDG PET
<table><caption>**Table 1.** Patient Characteristics.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Age (years)</td><td>72.0 [62.5-78]</td></tr><tr><td>Sex (female)</td><td>5 (29%)</td></tr><tr><td>Risk factors</td><td></td></tr><tr><td>Diabetes</td><td>11 (65%)</td></tr><tr><td>Renal failure</td><td>6 (35%)</td></tr><tr><td>None</td><td>6 (35%)</td></tr><tr><td>Causative agents</td><td></td></tr><tr><td>Pseudomonas aeruginosa</td><td>6 (35%)</td></tr><tr><td>Staphylococcus aureus</td><td>2 (12%)</td></tr><tr><td>Others</td><td>7 (41%)</td></tr><tr><td>Not identified</td><td>3 (18%)</td></tr><tr><td>Symptoms</td><td></td></tr><tr><td>Otalgia</td><td>12 (70%)</td></tr><tr><td>Otorrhea</td><td>13 (76%)</td></tr><tr><td>Inflammation of the external auditory canal</td><td>12 (70%)</td></tr><tr><td>Cranial nerve paralysis</td><td>5 (12%)</td></tr><tr><td>Duration of symptoms before treatment (days)</td><td>70 [28-108.5]</td></tr><tr><td>Duration of antibiotic treatment (days)</td><td>45.5 [42-62.5]</td></tr></tbody></table>

Thirteen patients were considered to have recovered according to the clinical and otoscopic criteria and follow-ups defined. Four patients were deemed not to have recovered: 2 continued the combined ceftazidime + ciprofloxacin antibiotic treatment for at least an additional 6 weeks, 1 was prescribed voriconazole for fungal osteitis, and the last patient had a relapse shortly after discontinuing the initial antibiotic treatment. In our practice, patients are followed for at least 3 months after establishing recovery and then are considered healed. They are not asked to come back again for systematic control. But in practice, patients often ask for further controls, to be reassured. For this particular series, we have now data for a mean delay of 19 months [9-37]. As 100% of healed patients did not relapse in this delay, our data obtained nevertheless in a small series of patients seems to validate our clinical practice.

## Semiquantitative Analyses

For ¹⁸F-FDG PET at initial diagnosis, the maximum standardized uptake value (SUV<sub>max</sub>)-lesion-to-background ratio was 5.37 [3.44;5.87], and the mean standardized uptake value (SUV<sub>mean</sub>)-lesion-to-background ratio was 3.20 [1.98;3.56]. These values did not correlate with age, sex, comorbidities, whether images were acquired under treatment, the type/duration of symptoms, or the type of microorganism detected (*P* > .15).

When comparing the initial PET with the final PET and the kinetics between the 2 time points, the ¹⁸F-FDG PET scans as well as planar or tomographic LS performed at 4 and 24 hours and the respective kinetics between these 2

time points, the SUV<sub>max</sub>-lesion-to-background of the final ¹⁸F-FDG PET scan showed a maximal area under the curve (AUC) of 1.0 [1.0;1.0] to predict patient recovery. Other significant imaging parameters to predict patient recovery were the SUV<sub>max</sub>-lesion-to-background of the initial ¹⁸F-FDG PET scan, the SUV<sub>mean</sub>-lesion-to-background ratio values of the final ¹⁸F-FDG PET scan, and the 4-hour tomographic LS lesion-to-background ratios with respective AUCs of 0.85 [0.63;1.0], 0.96 [0.87;1.0] and 0.90 [0.76;1.0] (*P* < .05). All the AUC results are presented in Supplemental Table 1. When restricting the analysis to the 14 patients who had discontinued antibiotic therapy at least 1 week prior to LS (Supplemental Table 2), the SUV<sub>max</sub>-lesion-to-background of the final ¹⁸F-FDG PET scan remained the best parameter, showing a maximal AUC of 1.0 [1.0;1.0] to predict patient recovery, and both 4 hours planar and tomographic LS lesion-to-background ratios showed significant AUCs to predict recovery.

When comparing the diagnostic performances of different cutoffs, as expected, an SUV<sub>max</sub>-lesion-to-background ratio of 4.1 for ¹⁸F-FDG PET resulted in an accuracy of 100% in predicting patient recovery. The 4-hour tomographic LS lesion-to-background ratio of 1.19 presented an accuracy of 88% (sensitivity of 85%, specificity of 100%) to predict patient recovery. Box plots of SUV<sub>max</sub>-lesion-to-background ratios in PET and 4-hour tomographic LS lesion-to-background ratios are depicted in Figure 1. Interestingly, an SUV<sub>max</sub>-lesion-to-background ratio of the initial ¹⁸F-FDG PET scan of 4.73 was associated with a specificity of 100% for predicting patient recovery. The diagnostic performances of cutoff values for parameters showing significant AUCs are given in Table 2.

The multivariate analysis only identified the SUV<sub>max</sub>-lesion-to-background ratio of the ¹⁸F-FDG PET as a predictive factor of recovery when combined with age, sex, comorbidities, the type/duration of symptoms, and the type of microorganism involved (*P* < .001).

Figure 2 shows representative ¹⁸F-FDG PET and LS images of patients with NOE who had and had not recovered.

## Discussion

Our current study demonstrates the outstanding diagnostic performances of ¹⁸F-FDG PET and, to a lesser extent, LS for monitoring antibiotic therapy in NOE based on the threshold ratios evaluated and focalizing on the 4 hour postinjection acquisitions for LS. Nuclear medicine could thus be pivotal in monitoring NOE therapy by providing compelling prognostic biomarkers of patient recovery. These imaging biomarkers would allow us to limit the prescription of prolonged noneffective antibiotic therapy in patients or to identify poor treatment responders who require close clinical follow-ups early.

After 6 to 8 weeks of antibiotic treatment, ¹⁸F-FDG PET showed very high diagnostic performances for predicting recovery from NOE, with an accuracy of 100% based on an SUV<sub>max</sub>-lesion-to-background ratio threshold of 4.1 (Table 2, Supplemental Table 1, Figure 1). Using a high ¹⁸F-FDG PET
<table><caption>**Table 2.** Diagnostic Performances of Cutoff Values for Parameters Showing Significant AUCs.</caption><thead><tr><th>PET and scintigraphy parameters</th><th>Threshold</th><th>Sensitivity (%)</th><th>Specificity (%)</th><th>Accuracy (%)</th><th>PPV (%)</th><th>NPV (%)</th></tr></thead><tbody><tr><td>Initial <sup>18</sup>F-FDG PET SUV<sub>max</sub> lesion</td><td>4.73</td><td>69</td><td>100</td><td>76</td><td>50</td><td>100</td></tr><tr><td>Final <sup>18</sup>F-FDG PET SUV<sub>max</sub> lesion</td><td>4.10</td><td>100</td><td>100</td><td>100</td><td>100</td><td>100</td></tr><tr><td>Final <sup>18</sup>F-FDG PET SUV<sub>mean</sub> lesion</td><td>2.10</td><td>85</td><td>100</td><td>88</td><td>67</td><td>100</td></tr><tr><td>Tomographic LS 4h</td><td>1.19</td><td>85</td><td>100</td><td>88</td><td>67</td><td>100</td></tr></tbody></table>

Abbreviations: <sup>18</sup>F-FDG PET, 18-Fluoro-deoxyglucose positron emission tomography; AUC, area under the curve; LS, Leukocyte scintigraphy; NPV, negative predictive value; PPV, positive predictive value; SUV<sub>max</sub>, maximum standardized uptake value; SUV<sub>mean</sub>, mean standardized uptake value.

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Box plots of the SUV<sub>max</sub>-lesion-to-background of the final <sup>18</sup>F-FDG PET scan and the 4-hour tomographic LS lesion-to-background ratios for predicting no recovery (left panel) or recovery (right panel) in patients with NOE according to the clinical follow-up. <sup>18</sup>F-FDG PET, 18-Fluoro-deoxyglucose positron emission tomography; LS, leukocyte scintigraphy; NOE, necrotizing otitis externa; SUV<sub>max</sub>, maximum standardized uptake value.</figcaption></figure>

threshold value presumably guards against obtaining false-positive results, particularly due to inflammation.<sup>18-20</sup> Inflammatory processes, which are frequently associated with NOE, indeed lead to high glycolytic avidity.<sup>18-20</sup> Importantly, <sup>18</sup>F-FDG PET was the only predictive factor of recovery when combined with all clinical factors, such as age, sex, comorbidities, the type/duration of symptoms, and the type of microorganism involved. It is therefore an invaluable prognostic biomarker for monitoring NOE during treatment. Our results are consistent with the potential role of <sup>18</sup>F-FDG PET-CT in a series of 8 patients who underwent <sup>18</sup>F-FDG PET for monitoring antibiotic treatment of NOE.<sup>12</sup> Compared with LS, <sup>18</sup>F-FDG PET offers better spatial resolution, lower costs, and greater availability. Moreover, <sup>18</sup>F-FDG PET is well accepted by patients with NOE, who are often frail and elderly, with only 1 intravenous injection and a total examination time of less than 2 hours. Interestingly, an <sup>18</sup>F-FDG PET scan performed at the initial NOE diagnosis provides 100% specificity

by using a threshold of 4.73, which is of informative value (Table 2). Even if the observed PET uptake was highly variable between patients and did not correlate with clinical factors such as age, sex, comorbidities, treatment, type/duration of symptoms, and type of microorganism involved, this high specificity could identify poor responders to antibiotic treatment early. This predictive value needs to be further explored but is in line with the recommendations proposed for other infections, such as peripheral bone,<sup>21</sup> prosthetic joint,<sup>22</sup> and vascular graft<sup>13</sup> infections.

LS showed lower prognostic performances when compared to <sup>18</sup>F-FDG PET, with an accuracy of 88%, based on a 4 hours lesion-to-background ratio threshold of 1.19 (Table 2, Supplemental Table 1, Figure 1). Our results are consistent with a study that reported an 89% accuracy for the visual analysis based on planar and SPECT LS absorption kinetics between acquisitions at 4 and 24 hours after injection in a population of 27 patients with a relatively low
<figure><img src="image_7.png" /><figcaption>**Figure 2.** Axial PET/CT (a, c) and LS SPECT/CT 4-hour image (b, d) slices. (a, b) High uptake (red arrows) in the right ear 6 weeks after treatment in a 64-year-old female patient: persistent infection. (c, d) No significant uptake (blue arrows) in the left ear 6 weeks after treatment in a 68-year-old male patient: nonpersistent infection. CT, computed tomography; PET, positron emission tomography; LS, leukocyte scintigraphy; SPECT, single photon emission computed tomography.</figcaption></figure>

rate of nonrecovery (only 15%).¹⁴ Interestingly, we found better performances in predicting patient recovery with acquisitions performed at 4 hours postinjection than at 24 hours postinjection in planar and SPECT acquisitions.

This likely reflects the rapid uptake kinetics of leukocytes in NOE, as has been previously reported in vascular graft infections.¹³ Restricting acquisitions to only 4 hours postinjection would facilitate the LS procedure for frail and
elderly patients with NOE. It is important to note that 3 patients underwent LS less than 8 days after stopping anti-briotic treatment, which is not in accordance with the recommendations.¹³⁻¹⁵ However, excluding these 3 patients had no impact on the diagnostic performances of LS, as shown in Supplemental Table 2.

To the best of our knowledge, our study is the first to directly compare the diagnostic performances of ¹⁸F-FDG PET and LS to monitor NOE treatments. The current study provides early prognostic biomarkers of antibiotic therapy responses in patients with NOE, which fills a gap in the current assessment of such patients.

Moreover, our study is the first to evaluate the prognostic role of ¹⁸F-FDG PET in a series of 17 patients compared with a previous study that examined 8 patients with NOE by 18F-FDG PET.¹² Our outcome for the recovery from NOE was only based on clinical and otoscopic symptoms and by definition excluded any recourse to imaging techniques. All patients were nevertheless followed clinically with a mean delay of 19 months after completing the initial antibiotic therapy to ascertain that they were cured. All analyses were based on semiquantitative approaches to provide objective results. Our study was, however, limited by the small number of patients included, reflecting the rarity of this disease.

## Conclusion

¹⁸F-FDG PET is the first-line imaging modality for evaluating NOE treatment responses, with excellent diagnostic performances. LS with only 4 hour acquisitions appeared to suffice to evaluate NOE treatment responses. Both biomarkers constitute early prognostic biomarkers for predicting antibiotic treatment response in patients with NOE. Large multicenter trials using ¹⁸F-FDG PET are needed to validate these preliminary results.

## Acknowledgments

The authors thank all nuclear physicians, ENT physicians, and radio-pharmacists who contributed to this study.

## Author Contributions

The authors contributed significantly to the analysis and interpretation of the data (M.H., A.Va., S.M., N.V., L.I., D.T.C., C.R., A.Ve.), to the writing of the manuscript (M.H., A.Va., S.M., C.R., A.Ve.) and to the revision of the manuscript (C.R., A.Ve.). All the authors have read and approved the final manuscript.

## Availability of Data and Materials

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

## Consent to Participate

All the patients included in the study gave their consent to participate.

## Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

## Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

## Ethics Approval

The institutional ethics committee (Comité d'Ethique du CHRU de Nancy) approved the evaluation of retrospective patient data, and the trial was registered at [ClinicalTrials.gov (n°2023PI003-404).](https://ClinicalTrials.gov)

## Sponsorships

None.

## ORCID iDs

Alice Vasseur https://orcid.org/0009-0009-5911-8293

Saifeddine Melki https://orcid.org/0000-0002-1100-6753

## Supplemental Material

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