Gallium-68 citrate PET/CT for diagnosis and treatment response assessment of infections - Prospective study.

doi:10.21203/rs.3.rs-4905201/v1

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Gallium-68 citrate PET/CT for diagnosis and treatment response assessment of infections - Prospective study.

https://doi.org/10.21203/rs.3.rs-4905201/v1

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The objective of this study was to evaluate the utility of Ga-68 citrate PET/CT imaging for diagnosing infection and for the assessment of treatment response. The scan interpretation was based on visual comparison of uptake of Ga-68 citrate in the region of interest which was compared to the normal side / adjacent soft tissue / blood pool. Semi-quantitative parameter maximum standardized uptake value (SUVmax) was retrospectively analysed as well. The PET/CT findings were correlated with tissue diagnosis, clinical symptoms, biochemical parameters like C- reactive protein (CRP), Erythrocyte sedimentation rate (ESR), and Total leucocyte count (TLC) and other imaging modalities with a statistically significant association with inflammatory markers CRP (p = 0.001) and ESR (p = 0.07). Tissue diagnosis was considered the gold standard and out of the 43 patients included in the study, 28 had a tissue diagnosis. Sensitivity, specificity, positive, and negative predictive values were calculated at 100%, 66.6%, 85%, and 100%. Ga-68 citrate is a promising tool for assessing the presence of skeletal/soft tissue infections for diagnosis and treatment response assessment, significantly impacting clinical decision-making in accurately treating patients and surgical planning.

Health sciences/Diseases

Health sciences/Medical research

Ga-68 citrate PET / CT

Skull base osteomyelitis

Infection

For decades, Nuclear Medicine has been at the forefront of infection imaging and has explored the utility of Ga-67 citrate for diagnosing various infections. However, due to its various drawbacks, it has slowly become unpopular. Ga-68 citrate is a radiopharmaceutical explored recently and has shown promising results. Ga-68 citrate follows a similar mechanism of uptake as Ga-67 citrate. Areas of infection have an abundance of leukocytes. Gallium in plasma is bound tightly to iron transport protein transferrin and enters the cell through the transferrin (TF) receptor, thus accumulating in infectious foci. Macrophages also have high expression of TF receptors. There is increased capillary permeability at sites of infections, and Gallium leaks from the vascular epithelium at these sites. (20) It is also taken up directly by the pathogen itself. It then binds to lactoferrin (LF), which is present in the leukocytes. The gallium-bound LF then binds to the activated macrophages present at the site of inflammation.

Pathogens causing infection produce siderophores due to little free iron present in tissues. These siderophores have a high affinity for iron and gallium due to their similarity in their structure and properties. The gallium-siderophore complex retains itself within the cell after direct entry. It has found recent interest amongst Nuclear Medicine professionals due to the ease of production, the lower cost, lower radiation exposure to the patient, and better patient compliance due to shorter scan time. Conventional imaging (1), like computed tomography, X-rays, and ultrasonography, may miss the early stages of infection when apparent structural abnormalities are lacking. MRI is very sensitive and has the advantage of detailed anatomy but is of limited value in patients with metallic implants and the presence of postoperative edema or aseptic inflammation (1). F-18 FDG can be used for infection imaging but lacks specificity due to its mechanism of uptake in both inflammation and infections; it also has the disadvantage of cyclotron production. FDG is taken up by any metabolically active cell as it is a glucose analog and accumulates in the cell after phosphorylation. WBC imaging is sensitive but the procedure is long and cumbersome with a higher radiation exposure to radiation personnel involved in radiopharmaceutical preparation. WBC imaging has limited value in the setting of neutropenia, a limitation which can be overcome using Ga-68 citrate. Ga-68 citrate is a generator produced radiopharmaceutical and helps differentiate infection from aseptic inflammation (2).

In our study, we looked at the incremental value of Ga-68 citrate in the diagnosis of infection. Our study comprised the following patient groups: 1) Skull base osteomyelitis, 2) long bone infections, 3) prosthesis-related infections, 4) end-of-treatment assessment for spinal tuberculosis, and 5) soft tissue infections.

Study Subjects

A prospective study was conducted for 43 patients, and patients with suspicion of infection or treatment failure underwent a Ga-68 citrate PET/CT between January 2020 and November 2021. Among these, eight patients underwent a follow-up scan post-treatment to assess their treatment response. The Institutional Review Board (IRB No.12511) of Christian Medical College, Vellore, India, approved the study. All scans were performed in accordance with relevant guidelines and regulations.

The inclusion criteria: Those patients clinically suspected of infections who underwent a Ga-68 citrate PET/CT. Exclusion criteria: Pregnancy and lactation.

[68Ga] Citrate PET/CT imaging

Ga-68 was eluted from the Ge-68/Ga-68 generator with HCL after labeling with Buffer citrate solution for 10 minutes and passing through the Waters cartridge. Each patient received an intravenous (IV) dose of 3-5mCi /111-185MBq of Ga-68 citrate. Ga-68 citrate was administered intravenously with an uptake time of 60 minutes. A CT scan with contrast (Omnipaque-80ml-adults and for pediatric age group-body weight x 2) was performed first with the following parameters: tube current of 110mAs, tube voltage of 130 kV, and slice thickness of 3-5mm. Subsequently, PET images were obtained through the same region, with each bed position lasting 2 minutes and a total of 3 beds. Processing of the images was performed using iterative reconstruction followed by a PET scan for the area of interest one-hour post-IV administration of Ga-68 citrate, following which PET imaging for the area of interest was performed. The interpretation was based on a visual assessment of Ga-68 citrate tracer uptake in the region that is suspected of infection, and the tracer uptake in the scan was correlated with clinical, biochemical, microbiological, and other radiological parameters.

Imaging interpretation:

Visual interpretation of images was performed based on uptake of the tracer in the area of suspicion. The visual comparison was made with the normal side / adjacent soft tissue / blood pool. Image interpretation was performed by at least two experienced Nuclear Medicine physicians.

Computed tomography (CT) images were viewed and interpreted in detail by an experienced radiologist for anatomical correlation. Almost all patients with diagnosis of skull base osteomyelitis (SBO) additionally underwent Magnetic Resonance Imaging (MRI) as well.

Semi-quantitative analysis using maximum standardized uptake value (SUVmax) was performed retrospectively. The SUVmax was compared to the opposite normal side soft tissue/bone or the blood pool uptake.

Histopathological examination

Among the 43 patients, 28 patients underwent tissue diagnosis in the form of biopsy or pus culture.

Statistical analysis

Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 21.0.

Statistical analysis was used for continuous data; the descriptive statistics of the total number of the population, i.e., n, mean, and standard deviation (SD), was calculated, and for non-normally distributed data, the median and interquartile range (IQR) were calculated. All categorical variables were represented as numbers and percentages. The chi-square and Fisher's exact test were used to find the association between categorical variables. All tests were two-sided at alpha () = 0.05 level of significance. All analyses were done using Statistical Package for Social Sciences (SPSS) software Version 21.0 (Armonk, NY: IBM Corp).

Tissue diagnosis was considered the gold standard; out of the 43 patients included in the study, 28 had a tissue diagnosis. Sensitivity, specificity, positive, and negative predictive values were calculated at 100%, 66.6%, 85%, and 100%. Out of the 15 patients who did not have a tissue diagnosis, Ga-68 citrate PET /CT scan interpretation was based on visual assessment, clin ical symptoms, correlation with biochemical markers like C- reactive protein (CRP), Erythrocyte sedimentation rate (ESR), and Total leucocyte count (TLC) and other imaging modalities.

Ethics statement

The study involved human participants and was reviewed by the Ethics Committee of the Institutional Review Board of Christian Medical College, Vellore, India. A written informed consent was obtained from the patient or their relative.

A total of 43 patients with suspicion of infection or treatment failure who met the inclusion criteria and underwent a Ga-68 citrate PET/CT between January 2020 – November 2021 were included in the study. Among these, eight patients had a follow-up scan post-treatment to look for treatment response. The mean age of males (72%) was 54.8 years, and females (28%) was 51 years.

Patient Profile

Among the 43 patient patients, the provisional/proven diagnosis included 18 patients with SBO, seven patients with long bone osteomyelitis, 12 patients with an infected prosthesis, one patient with a post-treatment assessment of spinal tuberculosis, and five patients with soft tissue infection that included: Right pyelonephritis with prostatic abscess, to evaluate surgical bypass graft site infection of the left femoral-posterior tibial artery, to evaluate infective etiology for an abdominal aortic aneurysm, to evaluate infective etiology for saccular aneurysm of abdominal aorta below the superior mesenteric artery, and to differentiate between an infective versus hemorrhagic cysts in a patient with autosomal dominant polycystic kidney disease with persistent fever.

Ga-68 citrate PET- CT and other infective parameter assessment

Results were concluded based on an association between the Ga-68 citrate PET-CT scan findings and other parameters such as biopsy, pus culture, biochemical infective markers, MRI findings, and clinical outcome. Inflammatory markers such as CRP, ESR, and TLC were also evaluated, and a statistically significant (p = 0.001) association was found between CRP and Ga-68 citrate PET-CT scan findings that were suggestive of infection.

Positive Ga-68 citrate scan findings for infection had a statistically significant association with inflammatory markers CRP (p = 0.001) and ESR (p = 0.07), which were high in 75% (n = 25/33) and 93% (n = 31/33) patients, respectively. Tissue diagnosis with biopsy and pus culture in 85% (n = 17/20) and 56% (n = 14/25) patients, respectively, were suggestive of infection and showed statistically significant association with Ga-68 citrate scan findings with a p-value of 0.016 for biopsy and p-value of 0.009 for pus culture. Only 16 (predominantly consisting of SBO patients) out of 43 patients underwent an MRI scan, 15 of whom had findings positive for infection on both MRI and Ga-68 citrate PET/CT. But statistically significant association (p = 0.06) could not be evaluated due to the small number that underwent an MRI scan.

Semi-quantitative assessment

Semi-quantitative assessment with SUVmax from the region of interest was retrospectively assessed. The SUVmax was compared to the opposite normal side soft tissue/bone or the blood pool uptake. The positive Ga-68 citrate PET/CT scans presented with a mean SUVmax of 7.79 ± 3.58 for a confidence level of 95%.

Follow-up patient results

Eight patients with SBO had a follow-up scan to assess their treatment response. Complete metabolic response was defined by the absence of residual Ga-68 citrate activity in the region of prior infection as compared to the pre-therapy Ga-68 citrate scan. Incomplete treatment response was defined as residual activity in the region of prior infection but with a decrease in the area involved. Failure of treatment was defined as an increase in Ga-68 citrate activity with new areas of activity / involvement.

Table 1

Clinical details of patients with complete treatment metabolic response on follow up imaging
Treatment response
S.No.	Clinical detail	First Ga-68 citrate Scan finding	Other parameters s/o infection	Treatment detail	Second Ga-68 citrate scan finding	Other parameters in agreement with scan findings
1.	SBO	Positive for SBO with extensions	Positive pus culture and biopsy, High ESR, and CRP, MRI s/o infection	Surgical debridement	Negative	CRP, TLC normalised
2.	Chronic Osteomyelitis – right ankle	Positive for right ankle osteomyelitis, with associated soft tissue thickening and edema	Positive pus culture and biopsy, High ESR, CRP and TLC	Medical management with antibiotics	Negative	ESR, CRP showed declining trend with normal TLC
3.	Chronic Osteomyelitis – left femur	Positive for left femur osteomyelitis with diffuse cortical thickening and remodelling	Positive pus culture and biopsy, High ESR, CRP, and TLC	Surgical debridement with washout	Negative	ESR, CRP showed declining trend
4.	Chronic Osteomyelitis – right distal femur (Fig. 3)	Positive for osteomyelitis in the right distal femur with fracture involving the distal meta diaphyseal region	Positive pus culture and biopsy, High ESR, CRP, and TLC	Surgical debridement with washout	Negative	ESR normalised

*s/o - suggestive of

Table 2

Clinical details of follow up patients with incomplete treatment response
Incomplete treatment response (S.No.1–3) and disease progression (S.No. 4)
S.No.	Clinical detail	Ga-68 citrate Scan finding	Other parameters s/o infection	Treatment detail	Second Ga-68 citrate scan finding	Other associated parameters s/o residual infection	Further management
1.	SBO	Positive for SBO with involvement of retropharyngeal space	Positive pus culture and biopsy, High ESR, CRP MRI with features s/o infection	Surgical debridement	Positive	MRI with persistent features, raised ESR, declining CRP and TLC	Antibiotics for residual disease
2.	SBO	Positive for right sided SBO with involvement of right nasopharyngeal wall, right parapharyngeal space, right carotid space	Positive pus culture and biopsy, High ESR, High CRP, MRI with features of infection	Surgical debridement	Positive	MRI with persistent features, raised CRP, normal TLC	Antibiotics for residual disease
3.	SBO	Positive for left SBO involving the left para pharyngeal space	Positive Biopsy, High CRP, MRI with features of infection	Surgical debridement	Positive	ESR, CRP showed declining trend with normal TLC	Antibiotics for residual disease
4.	SBO	Positive for left SBO involving left lateral wall of the nasopharynx	Positive pus culture & biopsy, High ESR & CRP, MRI with features of infection	Surgical debridement	Positive	CRP and TLC increased, MRI with persistent features	Antibiotics for disease progression

Ga-67 citrate has been well-known for decades as the imaging agent for detecting infections (3). It has been used for the diagnosis of various clinical conditions such as pyrexia of unknown origin, autoimmune-related inflammations, sarcoidosis, pancreatitis, idiopathic pulmonary fibrosis, osteomyelitis, pulmonary Wegener’s granulomatosis and chronic bronchial asthma. (4)

Compared to Ga-68, Ga-67 has a much longer half-life of 78 hours and emits high-energy gamma radiations ranging from 92 to 300 KeV (3, 5, 6). Due to slow uptake, delayed imaging of up to 72 hours is required (5). The high energy of the radiation gives it unfavourable imaging characteristics and high radiation exposure to the patients. Ga-67 imaging uses a gamma camera, and planar imaging often misses deep-seated lesions and requires supplementation by acquisition with single photon emission tomography. The effective dose of Ga-68 per unit of administered activity is 2.6x10-2 mSv/MBq, while Ga-67 is 1.1x10-1 mSv/MBq (7). Ga-67 requires a cyclotron for production, making the tracer much more expensive than Ga-68, produced via an on-site Ge-68/Ga-68 generator. Ga-68 is a positron emitter, and images are acquired via PET/CT acquisition (5), which gives the advantage of anatomical imaging (8). A shorter half-life, lower radiation dose, better imaging characteristics, and lower cost make Ga-68 citrate a better choice for an imaging agent (9, 10). Several studies have looked into the ability of Ga-68 citrate to differentiate between infection and aseptic inflammation and assess treatment response (11, 12).

Among the limited studies on the utility of Ga-68 citrate in the diagnosis of infection, it has been best documented in the diagnosis of osteomyelitis. Some of the advantages of this tracer over other tracers include, improved specificity (76% vs 60%) as compared to MRI and the inability of MRI to pick multifocal osteomyelitis due to lack of whole body survey, unlike PET/CT imaging as documented in the study by Nanni et al (13). Skull base osteomyelitis (SBO) is a disease with significant morbidity and mortality risks, occurs mostly in patients with Diabetes Mellitus or with immunosuppression status. The two variants of SBO are Lateral SBO (LSBO) & Central SBO (CSBO).

Patients present with unrelenting otalgia that is disproportionate to the clinical signs, persistent purulent otorrhea, granulation tissue at the bony cartilaginous junction of the external auditory canal and facial nerve paralysis. Central SBO patients present with persistent headache, with nocturnal increase in intensity. Both varieties of SBO lead to eventual development of lower cranial nerve paralysis and vascular thrombosis. It is crucial for the surgeon to identify suitable sites for biopsy and debridement, as identification of the pathogen guides the clinician to initiate appropriate antimicrobial therapy. In addition, the decision on its continuation / cessation in order to prevent relapse is equally important and challenging. MRI studies may be useful, but may be limited in identifying the active disease, as it solely relies on anatomical changes.

Our study evaluated 18 (41%) patients with suspected skull base osteomyelitis (Fig. 1) and 7 (16%) patients with long bone osteomyelitis (Fig. 3). Out of the 18 patients with SBO, 16 had a Ga-68 citrate PET/CT scan that was positive for infection. Of these 16, 13 patients had tissue diagnosis suggestive of infection; of which, nine patients had both biopsy and pus cultures positive for infection, four patients had biopsy suggestive of osteomyelitis, two patients had an MRI with findings suggestive of osteomyelitis, and one patient who clinically presented with left ear pain and mucopurulent blood-stained discharge and had a positive Ga-68 citrate scan. Among SBO patients, 81% (13/16) had tissue diagnosis and cultures suggestive of infection. Our study found good utility of Ga-68 citrate PET/CT in diagnosing skull base osteomyelitis and in treatment response evaluation which is often a challenge for the surgeon as a repeat biopsy is an invasive procedure and treatment is most often surgical and gives confidence to the treating Physician on whether to continue or discontinue long term antibiotics based on imaging findings. Six patients underwent Ga-68 citrate PET/CT scan for diagnosis of suspected long bone osteomyelitis, and one patient with chronic hip arthritis to look for any focus of infection. Four patients had a positive scan, of which 3 had a positive biopsy and pus culture, confirming the scan findings, and 1 had high inflammatory markers. Three patients had a negative Ga-68 citrate PET/CT scan, of which one patient had a negative pus culture and biopsy, and the other two patients had a normal CRP, which, as per our study, showed significant association with scan findings.

In our study, 12 patients were evaluated for suspected prosthesis-related infections, of which 7 (58%) were joint prostheses, and 5 (42%) were long bone prostheses. Of the 12 patients, 7 had a Ga-68 citrate scan findings suggestive of infection, five patients had tissue diagnosis suggestive of infection (two patients had a positive biopsy, and three had a positive pus culture) and good association was found with raised inflammatory markers (6/7 patients had raised ESR and CRP levels). Criteria for interpreting prosthesis-related infection were similar to those used in the study by Tseng et al. (2) in which specific uptake of the radiotracer in the bone prosthesis interface and radiotracer uptake around the prosthetic soft tissue, rather than the uptake intensity was considered positive. Five patients had a negative Ga-68 citrate PET/CT scan, of which two patients had no growth in pus cultures, and the rest had normal CRP and TLC levels. Tseng et al. (2) compared the utility of Ga-68 citrate PET/CT and F-18 FDG PET/CT in the diagnosis of lower limb prosthesis related infections and found Ga-68 citrate PET/CT had a higher specificity (88% vs 38%) and promising results in being able to differentiate between aseptic inflammation from an infective focus. A study done by E. Aro et al. (14) explained that adverse reactions from metallic debris would take up F-18 FDG and would be indistinguishable from an infective focus.

Our study evaluated five patients for soft tissue-related infections. Three patients had a negative scan, and the findings were confirmed with a pus culture. Two patients had a positive scan; one patient had a positive pus culture, and the other had a negative one, which was a false positive scan finding. A small cohort study done by Salomaki et al. (15) compared the utility of Ga-68 citrate PET/CT with F-18 FDG PET/CT for diagnosing soft tissue infection and found that F-18 FDG was superior in diagnosing soft tissue infections. This can also be attributed to the high blood pool activity of Ga-68 citrate and its limited utility in delayed imaging due to the short half-life of the tracer. Another case study by Vorster and Sathekge (16) reported a patient with tuberculous granuloma of the central nervous system. It explained the utility of the tracer in diagnosing brain infection due to the lack of physiological biodistribution in the brain, unlike F-18 FDG. This possibility needs to be further explored.

In our study, treatment response was assessed in 8 patients (Fig. 2). Four patients (Clinical details mentioned in Table 1) had good treatment responses, one with SBO and three with long bone chronic osteomyelitis. A good correlation was noted with inflammatory markers of infection, such as CRP and ESR, which had normalized during follow-up imaging. Three patients (Clinical details mentioned in Table 2: S.No.1–3) with SBO who had undergone surgical debridement and antibiotic treatment had incomplete treatment responses. Two of them had an MRI, which showed evidence of residual infection. Inflammatory markers showed a declining trend but had not normalized during the time of follow-up imaging. One patient (Clinical detail mentioned in Table 2: S.No.4) with left SBO had treatment failure, which was picked up on the follow-up scan and correlated with MRI findings and rising inflammatory markers. New areas of involvement were noted, and he was found to have bilateral SBO, indicating treatment failure with disease progression. Among the inflammatory markers, CRP was found to have a statistically significant (p = 0.001) association with Ga-68 citrate scan findings. End-of-treatment response after two years of anti-tubercular therapy (ATT) for spinal tuberculosis was assessed in one patient. The patient was symptom-free, and a Ga-68 citrate scan was performed to decide whether to stop ATT. Ga-68 citrate findings showed no tracer uptake in the previously involved region, which enhanced the clinician’s confidence in decision-making. A study done by Vorster et al. (17) studied 13 patients who were previously diagnosed with tuberculosis and underwent a Ga-68 citrate PET/CT to look at the utility of Ga-68 citrate PET/CT in the detection of extrapulmonary sites, the bone being one of the sites. Other sites included lymph nodes, pleura, spleen, and gastrointestinal tract. Eighty percent more lesions were detected on Ga-68 citrate PET than on CT.

Our study noted that Ga-68 citrate could localize in a broad spectrum of bacteria, including both gram-positive and gram-negative. Two species of fungi, i.e., Aspergillus fumigatus and Candida Albicans, were also noted in tissue diagnosis of patients with a positive Ga-68 citrate PET/CT scan. This makes Ga-68 citrate a versatile tool for diagnosing a variety of pathogens and can contribute significantly to the need for specific diagnosis in this era of antimicrobial resistance.

We initially performed a 30-minute imaging protocol for the first 15 patients, sufficient to visualize the disease process, but there was high blood pool activity. Delayed imaging of 90 minutes was additionally done for one patient, which showed minimal degradation of image quality. Following this, a 60-minute protocol was performed and was sufficient to visualize the pathological process, giving enough time to improve the background-to-target ratio due to blood pool clearance. A study by Kumar et al. (18) mentions that Ga-68 citrate can detect lesions within 30 minutes and, after that, an increase in the intensity of uptake in the lesions by 60 minutes due to blood pool clearance. Another study by Xu et al. (19) also noted that the quality of images significantly deteriorated by 120 minutes.

Limitations of the study

We could not acquire delayed images with Ga-68 citrate due to the short half-life of the tracer. The radionuclide has less sensitivity for soft tissue infection due to the high blood pool activity of the tracer. The other limitations were small sample size, single-center experience, and inter-observer variability in the scan interpretation. A comparison with F-18 FDG PET/CT was not performed; hence, we cannot comment on the additional advantages of one over the other.

In conclusion, Ga-68 citrate is a promising tool for assessing the presence of skeletal/soft tissue infections for diagnosis and treatment response assessment, significantly impacting clinical decision-making in accurately treating patients. The tracer was especially useful in the diagnosis and treatment response assessment of skull base osteomyelitis patients, planning the extent of surgery, and planning antibiotic management, especially when the clinical signs often persist despite adequate treatment response.

Author Contribution

H.E.J wrote the main manuscript text and prepared the figures 1-3S.S.S, J.H, D.M, R.O, N.S, P.R, R.T, R.S, S.S, A.O, and V.K reviewed the manuscriptR.K contributed for the statistical analysis of the study

Acknowledgement:

The author declares no conflict of interest. The study involved human participants and was reviewed by the Ethics Committee of Institutional Review Board. A written informed consent was obtained from the patient or their relative.

Data Availability

The data collected in the raw format has been attached in the for of an excel sheet under supplementary files for reviewers for assessment

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No competing interests reported.

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Gallium-68 citrate PET/CT for diagnosis and treatment response assessment of infections - Prospective study.

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Abstract

Figures

Introduction

Methods

Statistical analysis

Results

Patient Profile

Ga-68 citrate PET- CT and other infective parameter assessment

Semi-quantitative assessment

Follow-up patient results

*s/o - suggestive of

Discussion

Limitations of the study

Conclusion

Declarations

Author Contribution

Acknowledgement:

Data Availability

References

Additional Declarations

Supplementary Files

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