Positron emission tomography in infections associated with immune dysfunction
Ankrah, Alfred
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10.33612/diss.144628960
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2020
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Ankrah, A. (2020). Positron emission tomography in infections associated with immune dysfunction.
University of Groningen. https://doi.org/10.33612/diss.144628960
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Chapter 15
Discussion, Future perspectives and Conclusion
Discussion, Future
perspectives and
Conclusion
Ankrah AO
CHAPTER 15
This thesis examined the role of positron emission tomography (PET) in infections associated with immune dysfunction (IAID). There are many infections that can either cause or be associated with immune dysfunction.1 This thesis focussed on three of these infections: human immunodeficiency virus (HIV), invasive fungal infections (IFIs) and tuberculosis (TB). The final chapter of this thesis discusses five topics on the use of PET in IAID that have been highlighted in the previous chapters, considers the limitations of PET in IAID, and explores future perspectives. The five topics considered are: disease activity in IAID lesions metabolic indices used in IAID evaluation metabolic map of the disease burden and pattern of metabolic uptake in IAID predictive or prognostic value of PET and earlier changes in IAID pathology investigation of pathophysiology or therapeutic intervention of IAID
Disease activity of IAID lesions
The disease activity of lesions due to IAID, specifically IFIs and TB2‐4, correlates with the metabolic uptake of FDG on PET imaging. Both IFIs and TB give granulomatous reaction and have an intense uptake on FDG scan. The FDG uptake of lesions in both IFIs and TB is intense in active disease and decreases as the lesions respond to therapy.3, 5 The FDG uptake in IFI and TB serves as a measurable quantity that can be used to monitor the status of a disease. In HIV, FDG uptake measures the disease activity of the HIV‐associated infections which include IFIs and TB, HIV associated malignancy and some other associated conditions such as arterial inflammation or subcutaneous uptake that is associated with patients that develop lipodystrophy due to highly active antiretroviral therapy.6, 7The FDG uptake directly due to HIV binds to resting lymphocytes in the circulation causing the lymphocytes to home into the lymph nodes. The activation of the resting lymph nodes results in FDG uptake in the lymph nodes. The uptake is these nodes is not a measure of the disease activity; the pattern of nodal uptake helps determine the stage of HIV.6 The FDG uptake in TB and IFI lesions is a reflection of the immune response to the infection which is more intense in active disease and decreases with treatment of the infection. A lesion due to TB or IFI may have FDG uptake on completion of antimicrobial treatment reflecting the attempt by the immune system to get rid of residual fibrosis in a healed lesion containing no microorganisms anymore.8, 9 On the other hand, the immune system often tries to limit an infection by forming a wall around an infectious foci which may result in an abscess or cavity. After treatment of the infection the body may succeed in clearing all viable microorganism outside these structures with viable microorganism present in these structures that are well contained and incapable of spreading to the rest of the tissues or causing damage. This may result in a residual anatomic lesion with persistent FDG activity in a patient that will have clinical and microbiologic evidence of a cured infection. This explains why in this thesis and in the literature, persistent FDG uptake was observed in some TB and IFI patients that had completed antimicrobial treatment with evidence of a clinical and microbiologic cure. In patients with either immune system clearing fibrosis or containing an infection the FDG uptake would not completely normalize to the surrounding tissue. This also explains why, as reported in a recent study10, patients who have a complete metabolic response after antimicrobial therapy are unlikely to develop a relapsed infection. In the case of patients with persistent FDG lesions after completion of antimicrobial therapy, the outcome is unclear. The patient who have no microorganism in the residual lesions have no risk of relapse similar to the patients with a complete metabolic response. In patients in whom the microorganism is in check by the immune system and where the microorganism is
sequested in residual lesions, the infection is likely to relapse in the future when there is any disruption to the function of the immune system .
Metabolic indices used in the evaluation of IAID
IAID frequently present with multiple lesions at different sites in the body. In the evaluation of response to therapy by PET the standardized uptake value (SUV) is used. The maximum standardized uptake value (SUVmax), which provides the highest SUV in a voxel, or peak standardized uptake value (SUVpeak), which provides the highest average SUV in a predefined volume (1cm3), are often used in assessing response to therapy11‐13. The metabolic indices have their limitations and may be affected by noise in the image or the way the volume of interest is defined in the lesion. In the case of IAID where there are multiple lesions, these measurements do not accurately depict the total disease burden. In the evaluation of disease, the SUV of the most intense lesion is often used and the change in SUV calculated. This is not representative of the overall disease burden and is particularly problematic in IAID where there can be differential responses to treatment of different lesions in the same host. In an attempt to overcome this limitation, researchers and clinicians used the total lesion glycolysis (TLG) and metabolic volume (MV) in the evaluation of some cancer with good results.14, 15 The total lesion glycolysis measures the total FDG uptake in a lesion or a region of interest.16 This thesis presented the use of the global TLG from all the IFI lesions in patients and compared it to the use of SUVmax and SUVpeak. This thesis (Chapter 9) demonstrated that global TLG better correlated with the visual assessment of FDG PET when monitoring infection compared to the other metabolic indices.9 Recently, a paper has been published on the need to use the TLG in the evaluation of TB.17 Using artificial intelligence, measuring the global TLG in a patient with widespread disease is a matter of minutes in a reproducible manner.18 The use of the global TLG in IAID (TB and IFIs) and HIV associated malignancies which are often widespread represents a true reflection of the overall disease burden and more accurately reflects the disease. The use of TLG may have its challenges especially in IAID where two or more pathology may coexist and all have FDG avid lesions. In this case the overall TLG may underestimate the response to antimicrobial therapy. In most cases though, the IAID is the predominant lesion. When most lesions respond to antimicrobial treatment leaving a few lesions, a histologic assessment of residual lesions is necessary to determine whether this is due to different pathology or differential response to the antimicrobial.
Metabolic map of the overall burden of disease and pattern of metabolic uptake
FDG PET provides a metabolic map of the overall disease burden for IFIs and TB.19, 20 FDG PET is a whole‐ body imaging procedure and provides functional information from almost the whole body. IFIs and TB are granulomatous infections and give a high FDG signal with high contrast resolution from most parts of the body. The whole‐body imaging allows the assessment of most sites of the body in one study. PET allows the diagnosis of previously undiagnosed sites that may alter the management of IAID. In TB for example, any extrapulmonary TB lesions with the exception of TB lymphadenitis is usually treated for more than the standard 6‐month regimen for drug‐susceptible TB.21 Again, the diagnosis of some pathology such as TB pericarditis may lead to the addition of some anti‐inflammatory drugs to the TB treatment. In both TB and IFIs the diagnosis of spondylodiscitis may lead to prolongation of therapy. The whole body map also allows on to follow‐up the response of different lesions to therapy, bearing in mind that IAID often shows heterogeneous response. FDG is a nonspecific PET tracer but the pattern of the uptake may help in understanding underlying disease. In HIV, the pattern of lymph node uptake determines the stage of HIV infection. This pattern was described in this thesis (Chapter 4). In the early stage FDG uptake is visible in the peripheral cervical and axillary nodes, with a generalized lymphadenopathy present in the midstage and in the late stage more central lymphadenopathy or involving mesenteric and ileocecal nodes with most of the previous uptake absent. Patient with high viral load also show splenic uptake.6, 715
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In TB, the immune status of the patient may determine the pattern of uptake. In patients with a relatively intact immune system the uptake of FDG is predominantly a pulmonary pattern with mediastinal lymph nodes, while in immunosuppressed patients the uptake is more generalized in the lymph nodes with more extrapulmonary involvement.19, 22, 23 IFIs are caused by different species which can be classified as molds or yeasts. The most common type of mold is Aspergillosis and the most common yeast is Candida. Aspergillosis normally presents with relatively larger lesions whilst candida normally presents with smaller lesions that are multiple and may present as disseminated infection.20 Knowing the different patterns of FDG uptake in the various IAID may be useful in the interpretation of a report. The finding of relatively small and multiple lesions in IFI may prompt the nuclear physician to look out for infective endocarditis or spondylodiscitis which may be easily missed in a disseminated candida infection.
Predictive and prognostic value of PET in IAID
The prognostic value of PET in many cancers has been documented in literature. The prognostic value in infections has been evaluated less clear. In recent years however, the ability of PET to predict clinical outcomes is gaining prominence. In HIV, FDG PET has been used to identify patient with subclinical TB.24 Subclinical TB can cause a serious immune reconstitution TB, that may even be fatal if highly active antiretroviral therapy is initiated without recognising the subclinical TB. Again, the metabolic uptake of the thymus in HIV patients receiving HAART may serve as a prognostic indicator of the recovery or regeneration of the depleted T cells. Patients that would regenerate the T cell function show thymic uptake and those with poor thymic uptake show poor regeneration of the T cells.25In patients with IFI, this thesis presented (in Chapter 9) how the global total lesion glycolysis due to IFIs and the metabolic volume at the onset of therapy can discriminate patients who are likely to achieve a complete metabolic response with antifungals and patients who would not achieve a complete metabolic response by antifungal treatment alone. Furthermore, the change of the metabolic uptake early in antifungal therapy can predict whether the patient was likely to respond to the antifungal agent or not.9, 26 In TB the predictive role of FDG PET has been explored on many situations, including: prediction of latent TB infection (LTBI) in patients likely to progress to active disease27, 28 prediction of patients on standard 6‐month drug susceptible TB treatment that are likely to respond using either a baseline and follow‐up scan at 2 months or a single scan at 4 months29, 30 prediction of patients with drug‐resistant TB who are likely to respond as early as 2 months in a regimen that lasts about 2 years31 prediction of patients that are not likely to relapse after completion of TB treatment10 The ability to predict LTBI patient who are likely to progress to active disease is important to identify patients who must urgently be offered TB preventative treatment. This may be particularly important in TB endemic areas that have a high population with LTBI and where preventive treatment may not be practical in every patient with LTBI. Again, the ability to predict the response to treatment early in disease avoids unnecessary exposure of patients to ineffective therapies that may be toxic and may lead to drug resistant species. In this thesis (Chapters 10 and 14), the persistence of metabolic activity in TB lesions in patient with a clinical and microbiologic cure was discussed. A recent study has demonstrated that a complete metabolic response or a negative FDG PET scan at the end of treatment was predictive for the absence of TB relapse for at least two years after completion of treatment.10
The treatment of IAID is generally prolonged, associated with adverse effects and the tendency to develop drug resistance. The predictive or prognostic value of PET enables the clinician to identify patients that may not respond to treatment early and respond appropriately without patient enduring unnecessary and potentially toxic treatment. Metabolic changes precede anatomical change which may lead to detection of IAID at a time when anatomical changes have not occurred. In TB, abnormal metabolic uptake has been detected in morphologically normal sized lymph nodes. In IFIs, lesions can be detected on PET without being detected on anatomical based imaging due to metabolic changes preceding anatomic changes as presented in Chapter 8. This can lead to early initiation of treatment to improve the outcome of the treatment of these IAID. Similarly, during treatment changes noted on PET occur much earlier than anatomic based imaging in both fungal infections. This allows earlier and better prediction of outcomes of IAID with PET than most anatomic based imaging modalities that are used in IAID. In HIV, early changes in pathology such as increased subcortical FDG uptake in HIV associated neurocognitive disorder occur long before the anatomical change of cortical atrophy and dilatation of the ventricles.6,7
Investigation of pathophysiology or therapeutic interventions associated with IAID
PET is a noninvasive imaging modality that enables in vivo assessment of IAID at the histological level in human or experimental animals. Animal models of IAID have been developed and are used to study disease or therapeutic interventions. In HIV, PET studies on the simian immunodeficiency virus, a retrovirus similar to HIV enabled us to understand the pattern of lymphoid activation during the course of HIV.6,7 There are animal models for different type of TB lesions and fungal infections. PET allows the study of infections in these animals over time without having to either sacrifice or conduct invasive procedures to get samples for histopathological analysis. Using PET, an animal is able to serve as its own control and several lesions within one animal and the response of these different lesions to the same plasma concertation of antimicrobial can be studied.32 This reduces the number of animals, and the time and resources needed in evaluation of IAIDs in animals. Similarly, in humans the use of PET can considerably reduce the time resources and number of subjects needed to investigate IAIDs. One of the major challenges in the treatment of TB has been the long duration of treatment which leads to nonadherence by patients and l treatment failures, thereby promoting resistant species. Different strategies have been tried to reduce the regimen but have been unsuccessful till date. In a recent study33 reported in Nature Medicine, researchers used 11C‐rifampicin in 12 patients on the standard 6‐month TB treatment to show that the amount of rifampicin reaching TB cavities is inadequate despite plasma and normal tissue concentrations being adequate. The use of therapeutic drug monitoring would be unsuccessful in addressing the problem of lengthy duration and prevention of development of resistant species. PET allowed researchers to propose that doubling the dose of rifampicin in the current TB regimen may shorten the duration of TB treatment. Some IFIs, such as aspergillosis, are associated with large lesions that normally have cavities. It is likely there may be insufficient amount of antifungal drugs getting to these lesions and PET imaging is well placed to evaluate this. The pathophysiology underlying IAID can be quite complex and in vitro experiments and even animal models may only experiment on one aspect of disease on its own but not the whole spectrum of disease. In TB for example, some mice models may lack TB cavities but have TB granulomas. PET allows the in vivo investigation of underlying pathophysiology as it occurs in the human body in the complex environment of the human disease where an interplay of other biological systems that may not be simulated by any experimental condition or animal model may be present. In IAID due to immune dysfunction the presentation of infection may be different from infections in the immunocompetent person and PET allows in vivo study of the pathophysiology.
15
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Limitation of PET in IAID
IAID are a heterogeneous group of infections and PET may play a specific role in a particular infection that may not be applicable in another. It is important that we evaluate the role especially in these infections of medical and global importance to derive the full benefit of PET. FDG is the most commonly used tracer but has the notable limitation of nonspecificity. The search for the ideal PET tracer for infection is still on going. This ideal tracer should be able to distinguish infection from sterile inflammation and cancer. Again, FDG has some notable limitations in the evaluation of lesions in areas with high physiologic uptake of tracer like the brain and urinary system. In this thesis, Gallium 68 citrate (68Ga citrate), also a nonspecific tracer, demonstrated the ability to better evaluate brain lesions because of the lack of accumulation of citrate in the brain. Again, in this thesis and confirming other reported studies in literature, 68Ga citrate was less likely to accumulate in sterile inflammation and may be useful in assessing residual infection after completion of antimicrobial therapy.PET in coronavirus disease (COVID‐19)
The year 2020 has witnessed the disruption of healthcare systems, social life and economies of most nations in world by the COVID‐19 pandemic.34‐36 COVID‐19 is caused by the virus Severe Acute Respiratory Syndrome Cororona Virus‐2 (SARS‐COV‐2) and is a highly infectious disease. The virus is a relatively new infectious agent in humans and is believed to have originated from Wuhum China in December 2019.37 SARS‐COV‐2 on it own does not cause immunosuppression. Patients with underlying diseases, however, including some immunosuppressive conditions are more likely to get severe infection and possibly die of the infection when infected by SARS‐COV‐2.38 Imaging, especially with CT of the chest has been found to be useful in the diagnosis of the infection especially very early in the infection where the gold standard for diagnosis of the infection, real‐time reverse‐transcriptase polymerase chain reaction may yeild false negative results.39 Thoracic CT is also useful in assessing the severity of COVID‐19 and monitoring the clinical course of the disease. The most commonly seen feature on CT scan seen early in the infection are bilateral ground glass opacities with or without consolidation in the peripheral lung. In the latter stages of disease consolidation, linear opacities, ‘crazy‐paving’ patterns of the lung become more prominent features.37 A number of papers have discussed PET in COVID‐19.40‐46 In these publications all the lesions identified on CT showed meatabolic uptake when imaged with FDG PET. The potential of FDG PET to pick up inflammation that occur in extrathoric site where virus may be replicating in COVID‐19 was highlighted in some publication.42,44 However, the waiting time after injection and imaging would mean patients diagnosed with COVID‐19 will have to stay longer in imaging units which would expose staff to risk of infection. PET is therefore not recommended in the routine work‐up of known COVID‐19 patients. In the interpretation of PET/CT studies on must be aware of the pattern of COVID‐19 on the CT and maintain a high index of suspicion especially in areas with high transmission rates. This will help identify previously undiagnosed COVID‐19. The role of PET/CT in COVID‐19 is currently limited to the incidental finding and reporting of features of COVID‐19 infection in patients coming for imaging for PET/CT imaging for some other indication to limit the spread of the disease.44‐46
Future Perspectives
Hybrid imaging
PET is integrated with a tomographic based imaging technique, often computed tomography (CT) but more recently with magnetic resonance imaging (MRI). In IAID, MRI is particularly useful for special sites like the central nervous system or spondylodiscitis. The use of PET/MRI will combine all the advantages of PET with MRI which will improve the diagnosis of these specific conditions. Again, MRI
does not use ionising radiation and therefore the overall radiation burden of PET integrated with MRI will be reduced compared to PET/CT and this will be beneficial in children.20
PET imaging can also be combined with optical imaging to assess superficial and deep infections. TB and fungal infections may give rise to superficial infection that do not usually require imaging to determine the extent. In other conditions with immune dysfunction such as the diabetic foot it may be necessary to determine the extent of the superficial infection before treatment especially when surgical intervention such as debridement is anticipated. The combination of PET with optical imaging will allow the assessment of the deep tissue (bone) by PET and superficial tissue (soft tissue) by optical imaging that can potentially help the management of these infections.47
Therapeutic interventions related to PET
PET imaging is able to determine that an antibody is delivered to the site of infection. Applying the principle of theragnostics, the PET radioisotope can be replaced with a therapeutic agent and allow radioimmunotherapy of IAID. This may help in the treatment of resistant infection such as totally resistant drug TB when there is no other therapeutic option and may help reduce the duration of treatment that is given for long periods such as in IFIs and TB.47, 48 Nanoparticles have been labeled with antimicrobial peptides to deliver increased concerntration of antimicrobial drugs to the infection site. PET can be used to determine the distribution of the microbial attached to this nanoparticle to ensure that it is delivered to the site of infection47, 49 In HIV associated neurodegenerative disorder (HAND), radioimmunotherapy may be explored to kill HIV infected cell in the central nervous system. This may slow down the progression or even reverse the progress of HAND.49New tracer development
PET and SPECT tracers PET imaging has advantages over SPECT imaging such as the better spatial resolution and better ability to quantify tracer uptake. The use of PET tracers where SPECT tracers have been useful may be an advantage. White blood cell labeling is the imaging method of choice for infection. White blood cells have been labeled with FDG and copper 64 (64Cu). The 64Cu labeled white blood cells had favourable results in the imaging of infections. The longer half‐life of 64Cu of 12.7 hours compared to the 110 minutes of fluorine enables delayed imaging which is crucial for infection imaging.50, 51There are a number of useful infection tracers that have been labeled to Tc‐99m (99mTc) using the indirect method resulting in mixed complexes. 18F‐labeling options are now available for most compounds using conjugation techniques such as click chemistry, succinides and 18F‐AlF‐methodology. The 99mTc infection tracers can be replaced with 18F to develop the equivalent PET tracers.52‐54
Longer lived PET radioisotopes The use of longer lived PET radioisotopes such as 64Cu with a half‐life of 12.7 hours and zirconium 89 (89Zr) with a half‐life of 78.4 hours is very useful for the labelling of peptides and proteins which require longer imaging times. The radioimmununotherapies discussed above involve the use of proteins and labelling with these relatively long‐lived radioisotopes will be important to fully harness the potential of PET. Increase in availability of nonFDG PET radiopharmaceutical The production of Germanium 68/ Gallium 68 generators (68Ga generators) provides a readily available source of a PET radioisotope in a generator for at least 6 months of the year.55 A generator produced radioisotope removes the need for a cyclotron with all the expertise needed to run it and the complex machinery needs to produce it. 68Ga based PET tracers such as 68Ga citrate or labeled peptides in IAIDs
15
may have a more prominent role. This is a particularly attractive option for developing countries that bear the largest burden of some IAID as TB and HIV where the cost and expertise for running an expensive cyclotron is a major limitation to the use of PET imaging. The production of 64Cu has recently become more feasible. A simpler method of production using liquid targets will make 64Cu more readily available to be used in IAID.56 The search for the ideal tracer that will distinguish infection from inflammation is still ongoing. Tracers that are specific for IAID, like IFI tracers such as 68Ga siderophores have already been tested in animal models with good results57,58. Infection‐specific tracers for IAID that affect a lot of people like TB should be developed. The use of artificial intelligence in interpretation The use of artificial intelligence in determining the overall disease burden and determining the changes would make the results more reproducible and more likely to be applied across different imaging systems from different centers which will improve multicenter trials for PET in IAIDs. The use of the global disease score with help of artificial intelligence would enhance the use of global total lesion glycolysis in IAID.18
Improvement in PET imaging technology
The use of total body scanners or digital PET scanners would allow patients to be imaged with lower activities of PET radiopharmaceutical in much shorter acquisition times. This would decrease the radiation burden to the patient and also reduce the motion error due to the shorter time.17 Incoperation of PET/CT in IAID into major international guidelines Despite the mounting evidence of the use of PET/CT in IAID, the modality is not yet part of major international guidelines for the IAID. PET/CT is likely to be added to international guidelines as the evidence builds up with more more studies especially large radomized multicentered clinical trials become available.
Conclusion
PET is a useful biomarker for IAID. An ideal biomarker for infection must possess characteristics for diagnosis, prognosis and therapy follow‐up. Furthermore, biomarkers should be both sensitive and specific, measurable with good precision, reproducible, readily available, affordable, responsive to minor changes, and provide timely results. It is clear that current FDG PET has almost all the characteristics of an ideal tracer for infection with the exception of lack of specificity and it is likely that the development of new PET tracers will address this problem.268 269
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