University of Groningen
Positron emission tomography in infections associated with immune dysfunction Ankrah, Alfred
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10.33612/diss.144628960
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Positron Emission Tomography in infections associated with immune dysfunction
AAllffrreedd O O.. AAnnkkrraahh
The printing of this thesis was financially supported by the University Medical Center Groningen.
Cover: Johnson Kofi Oppong
Cover image: 3D volume rendered PET/CT of the lung of a patient with TB/HIV coinfection Printing: Ridderprint , www.ridderprint.nl
ISBN: 978‐94‐6416‐252‐3.
© A.O. Ankrah, 2020
Copyright of the published articles is with the corresponding journal or otherwise with the author. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the permission in writing from the author or the copyright‐owning journal.
Positron emission
tomography in infections associated with immune
dysfunction
PhD thesis
to obtain the degree of PhD at the University of Groningen
on the authority of the Rector Magnificus Prof. C. Wijmenga
and in accordance with the decision by the College of Deans.
This thesis will be defended in public on Monday 30 November 2020 at 16:15 hours
by
Alfred Otoe Ankrah
born on 8 September 1974in Kumasi, Ghana
Supervisors
Prof. A.W.J.M. Glaudemans Prof. M.M. Sathekge Prof. R.A.J.O Dierckx
Co-supervisor Dr. H.C. Klein
Assessment committee Prof. A.W. Friedrich Prof. L.F. de Geus-Oei Prof. A. Signore
Contents
Chapter 1 General introduction 7
Part 1 17
Chapter 2 PET/CT in immunodeficiency disorders 19
Chapter 3 Radiopharmaceuticals for PET imaging of infection 33
Chapter 4 The role of nuclear medicine in the staging and management of Human immune deficiency virus and associated diseases 51
Chapter 5 Arterial inflammation in young patients with human immunodeficiency virus infection: a cross‐sectional study using FDG‐PET/CT 71
Part 2 83
Chapter 6 Imaging fungal infection in children 85
Chapter 7 The role of PET in monitoring therapy in fungal infections 109
Chapter 8 Added value of FDG PET/CT in the management of invasive fungal infections 131
Chapter 9 Role of FDG PET/CT in monitoring treatment response in patients with invasive fungal infections 145
Part 3 161
Chapter 10 Tuberculosis 163
Chapter 11 PET/CT imaging of Mycobacterium tuberculosis infection 195
Chapter 12 Imaging latent tuberculosis infection with radiolabeled nitroimidazoles 215
Chapter 13 Monitoring response to therapy 221
Chapter 14 Comparison of Fluorine(18)‐fluorodeoxyglucose and Gallium(68)‐citrate PET in patients with tuberculosis 245
Chapter 15 Discussion, future perspectives and conclusion 261
Chapter 16 273
Chapter 16.1 English summary 275
Chapter 16.2 Dutch summary 277
Chapter 16.3 Acknowledgements 281
Chapter 16.4 Curriculum vitae 282
Chapter 1
General Introduction
General Introduction
Ankrah AO
CHAPTER 1
Introduction
Human beings are surrounded by millions of microorganisms. Some of these microorganisms are useful, others cause harm and others just coexist with no beneficial or deleterious effects on humans [1]. The harmful microorganisms usually invade the human body and cause infections. An infection arises when the microorganisms outside the body or living on mucosal surfaces of the body invade the tissues, multiply and damage the tissues of the host. Infections are a significant cause of morbidity and mortality, and disproportionately affect developing countries [2]. Infections are usually due to viruses, bacteria, fungi, or parasites [3]. The immune system is responsible for defending the body against infections and foreign antigens.
The immune system
The immune system is an intricate system that prevents infectious pathogens from entering the body and also eliminates these infectious agents or their products if they succeed in gaining access to the host. Apart from microorganisms, the immune system recognizes and eliminates any foreign antigen such as toxins, allergens, and molecular sequences that are not part of the host, such as the molecular sequences found in malignant or transplanted tissue [4, 5].
The immune system is functionally divided into the innate and adaptive components. The innate component includes physical barriers, soluble proteins, bioactive molecules, and membrane and cytoplasmic receptors [6,7]. The adaptive immune system depends on specific receptors present on T and B lymphocyte to produce their function. These specific receptors are produced in response to invading antigens and are not constitutionally present like the receptors of the innate immune system.
The adaptive immune system mounts a more specific immune response to invading microorganisms.
The adaptive immune system requires a complex rearrangement of genes to express the receptors on B cells and T cells that are crucial to the adaptive immune response [8].
Immune dysfunction
An individual with a compromised immune system is susceptible to a wide range of infections. The immunocompromised host is at a higher risk of infections. The patient with immune dysfunction is at risk of getting both pathogenic and opportunistic infections. Opportunistic infections do not usually cause disease in people with a functional immune system. The type of infection the immunocompromised individual develops usually depends on the component of the immune system that is disrupted, and the degree to which that component is affected.
Causes of immune dysfunction
The cause of immunodeficiency may be primary or secondary. The primary causes are relatively rare and directly affect the components of the immune system [9]. The secondary causes are due to an underlying disease or an invasive event such as medical interventions or trauma. The secondary immunodeficiency may be due to intensive chemotherapy, immunosuppressive therapy, posttransplant states, hematologic malignancies, and patients who have received total body radiation to prepare for stem cell transplantation. It may also be due to human immunodeficiency virus infection (HIV), malnutrition, diabetes mellitus, and chronic kidney disease [10]. The population with immunodeficiency has dramatically expanded over the last few decades. The expansion has resulted in a distinct population who are predisposed to infections and may not present with typical clinical symptoms and signs. The diagnosis of infection in these patients can be quite challenging.
8 9
1
Chapter One
General management of infections
The introduction of potent antimicrobial drugs marked a major breakthrough in the fight against infections; however, the development of resistance to antimicrobial agents has made the treatment of infections more complex [11]. The management of infections includes preventive methods like vaccine administration, personal and public healthcare interventions and in some special cases prophylactic antimicrobial treatment [12‐14]. Infection management also includes early diagnosis, correct staging, treating and monitoring therapy [15]. Early diagnosis and the institution of appropriate treatment reduces the morbidity and mortality associated with infections. The correct staging of an infection is essential to identify previously undiagnosed sites of infection that might alter the strategy for treating the infection [16].
Monitoring of infection during antimicrobial therapy is crucial to determine whether the treatment is effective or not. Antimicrobial may not be effective for several reasons: the microorganism may not be susceptible for the antimicrobial, or the antimicrobial may not reach the site of infection in adequate amounts. The concentration of antimicrobial at the site of infection may be suboptimal because the plasma concentration of the antimicrobial is inadequate or drug concentration at the infected site is not appropriate because the antimicrobial is unable to penetrate the infected tissue effectively in the necessary concentration despite adequate plasma and healthy tissue concentrations achieved by the antimicrobial. An in vivo method of monitoring infection that evaluates the whole body is useful for infections in patients with immune dysfunction where infections have the tendency to disseminate or may be present at unusual sites [17]. It is also prudent to have a tool capable of determining whether the appropriate amount of antimicrobial reaches the infection site [18].
Challenges in the diagnosis of infection in patients with immune dysfunction
Clinical symptoms and signs lead to the suspicion of an infection. A thorough physical examination may direct the clinician to the site of an infection. The clinical signs that may help to localize the site of an infection are often blunted or completely absent in the immunocompromised patient [19]. Serological studies may also be helpful in the evaluation of some infections. The usefulness of serology, however, may be diminished under certain types of immunosuppression [20]. The gold‐standard for the diagnosis of an infection is the microbiological recovery of the microorganism by culture. The recovery of the organism by culture allows the confirmation of the viability of the microorganisms and enables drug susceptibility testing to be conducted. The results of culture are only available after at least 24 hours, more frequently after 48 hours; but for some pathogens it may take several weeks before the results are available. Culture analysis may delay the diagnosis of the infection and the subsequent initiation of antimicrobial treatment which could be detrimental to the patient. Furthermore, in some cases, culture is not able to isolate the microorganism. Microscopy may provide quicker results, but microscopy does not determine if the microorganisms are viable and drug susceptibility testing cannot be done. More recently, molecular testing for some microorganisms offers more rapid diagnosis and, in some cases, also allows the identification of specific drug resistance patterns [21]. The molecular tests are not 100% accurate, and many different tests need to be combined to diagnose some infections. The methods currently used in the diagnosis of infections allow physicians to diagnose the type of infection and determine the drug susceptibility, but are unable to determine the overall burden of the disease or detect occult sites of infections.
Imaging in infections
Medical imaging is an important part of the management of infections. It can help to diagnose an infection by identifying pathology in different parts of the body. Imaging is often used to monitor the treatment by acquiring serial longitudinal studies. The changes observed on imaging at different time‐
1
Introduction to the thesis
points during antimicrobial treatment may provide information about the response of the infection to antimicrobial treatment. The use of mathematical algorithms and computer processing in imaging has allowed tomographic (three‐dimension) images of the body to be reconstructed and the site(s) of pathophysiological process(es) accurately localized. Modern imaging techniques make it possible to acquire anatomical images with high spatial resolution that can localize very small structures. Similarly, nuclear medicine imaging including positron emission tomography (PET), allows the acquisition of functional images of pathophysiology with high contrast resolution but with relatively poor spatial resolution. Hybrid imaging with PET integrated with an anatomic‐based tomographic imaging modality, either computed tomography (CT) or magnetic resonance imaging (MRI), enables functional data to be combined with high resolution anatomic imaging to assess pathology from almost the whole human body [22]. This allows both pathophysiology and anatomy of pathology to be accurately assessed and improve the overall diagnosis of the infection.
Positron emission tomography
PET is an imaging technique that uses radioactive isotopes (positrons) to image pathophysiology in the body. A positron is a positive electron that is produced by radioactive decay. A positron travels a short distance in the medium where it is produced and then it combines with an electron. The positron is annihilated, and the mass of the positron and electron it combines with is converted to energy. The energy is produced as gamma rays consisting of two photons with a 511 Kev energy travelling in the opposite direction to each other. The two photons can be detected by a PET camera, and the origin of the positron can be determined by coincident detection. A positron is used as a PET tracer in its elemental form (as an ion or molecule) or more frequently, bound to, or incorporated within a molecule. A PET tracer mimics a biochemical process that occurs in the body. The biochemical processes underlying disease can therefore be imaged by PET tracers when these are administered to humans or experimental animals. PET imaging has the advantage of being able to quantify the amount of radioactivity in a given lesion allowing quantification of disease activity which is useful in the monitoring of disease activity over time.
18F‐fluorodeoxyglucose
There are a number of PET tracers currently available. 18F‐fluorodeoxyglucose (FDG) is the most common PET tracer used in clinical practice. FDG is a glucose analogue that has the positron fluorine‐
18 incoperated in a deoxyglucose molecule. FDG images glucose uptake by cells within the body. If the cells involved in a pathophysiologic process use more glucose than usual, the abnormal glucose uptake can be imaged by a PET camera after administration of FDG. FDG enters a cell via a glucose transporter on the cell membrane. FDG is then phosphorylated like glucose but is unable to continue down in the biochemical pathway for glucose metabolism. FDG‐phosphate remains trapped in the cell and the increased glucose utilization can be imaged by PET. The PET tracers are usually administered by the intravenous route. The PET tracer is administered in very minute amounts and therefore do not usually exert any biologic or pharmacologic effect on the body.
PET in infection
PET imaging of infection has been accomplished with several tracers both at the clinical and preclinical stage. FDG is the most common PET tracer used for the imaging of infections. The immune cells involved in defending the body against infection increase their glucose uptake during infection. This generates a PET signal that can be imaged with FDG. Infections have been known to have FDG uptake for more than a quarter of a century [23]. The FDG signal generated by infections was previously regarded as a nuisance when interpreting PET scan in the assessment of oncology patients. In recent years, however, the FDG PET signal from infection is being utilized in the management of various infections [24]. Apart from FDG, other PET tracers like Gallium‐68 citrate have been used in infections
10 11
1
Chapter Onewith varying success in clinical practice. There are many PET tracers in the preclinical stage for infection imaging.
Infections and the patient with immune dysfunction
Infections may be associated with immune dysfunction in different ways. The infection may directly cause immunosuppression, they may be opportunistic in nature or they may have immune dysfunction as part of their pathogenesis.
Several infections are known to cause immune suppression. In humans, human immunodeficiency virus (HIV) and human T‐cell lymphotrophic virus are known to directly depress the immune system.
Other viruses like cytomegalovirus, Eptstein Barr virus and human herpes virus 8 are opportunistic viral infections, but act to further depress the immune system. Some intracellular bacteria including Mycobacteria tuberculosis, Ehrlichia chaffeensis, Brucella melitensis, Coxiella burnetti, Bartonella sp.
and Norcadia farcinia have indirect effects on the immune system and may cause immunosuppression.
The mechanism of causing immunosuppression by the bacteria varies, but tuberculosis (TB) and chronic brucellosis involve the induction of cytokine production by the host [25]. Invasive fungal infections (IFIs) are frequently opportunistic infections. Some IFIs like aspergillosis also disrupt some components of the immune system during their pathogenesis [26].
HIV and TB are global pandemics and are treated for long periods with multiple different antimicrobials simultaneously. HIV is associated with numerous infections, malignancies and other disorders that require monitoring. IFIs are relatively rare but are ubiquitous and have large medical importance because of the increasing population of immunocompromised individuals. Monitoring the treatment of TB and IFI is crucial to the management of these infections. In HIV, monitoring the side‐effect of drugs or the HIV‐associated malignancies or infections is vital. In this thesis, the role of PET in HIV, IFIs and TB, three widespread infections associated with immune dysfunction and with high morbidity, mortality, and public health significance (TB and HIV), is examined.
Outline of thesis
This thesis is divided into three parts. The first part covers a general overview of use of PET/CT in immunodeficiency disorders and the PET tracers used and then focusses on PET in HIV, with HIV as an example of an infection directly causing immunosuppression (Chapters 2‐5).
The second part of the thesis covers PET in IFIs. IFIs provides an example of an infection associated with immunosuppression due to the microorganism being an opportunistic infection (Chapters 6‐9).
Finally, the thesis considers PET in TB. TB is an infection that has immune dysfunction as part of the pathogenesis of the infection. TB infection may occur in patients who initially are not immune suppressed. For the infection to progress, some immune dysfunction occurs as a result of host pathogen interaction or another cause of immunosuppression, such as HIV infection or treatment with immunosuppressive drugs, is required (Chapters 10‐14).
In Chapter 2, the thesis outlines the role of PET/CT in immunodeficiency disorders in general. This discusses the role of PET/CT in immunedeficiency associated malignancies, infections and other disorders. The situation in which PET/CT may have advantage over currently existing diagnostic platforms is highlighted and the special role in malignancy such as radiotherapy planning and prognostic value is documented. The role of PET/CT in diabetes mellitus which is also associated with immune dysfuntion is also considered.
1
Introduction to the thesis
In Chapter 3, the thesis considers the PET tracers that are currently used for imaging of infections.
Patients with immunosuppression are at risk of both pathogenic and opportunistic infections.
Infections occur more commonly in the immunosuppressed. This chapter highlights the clinical utility of FDG PET/CT in certain specific infections. It also discusses several experimental tracers that are in developmental or preclinical stage that could potentially be used in infections.
In Chapter 4, the thesis focuses on the role of nuclear medicine in HIV with emphasis on PET/CT. HIV directly depresses the immune system and may cause profound immunosuppression unless the progress of HIV is interrupted by highly active antiretroviral therapy (HAART). In this chapter the clinicopathologic correlation of FDG PET uptake and the immunovirologic status of patients is discussed. The role of PET in HIV‐associated malignancy, infections and disorders such as HIV‐related liopodystrophy, HIV neurocognitive disease and arterial inflammation in HIV is also considered.
In Chapter 5, the thesis compares arterial inflammation as measured by FDG PET in young patients with HIV to age‐ and sex‐matched controls without HIV infection. The chapter shows that in young patients with low or no risk factors for cardiovascular disease, there is a marginally higher arterial inflammation in patients with HIV.
In Chapter 6, the thesis examines the available literature on the role of FDG PET in IFIs with emphasis on its role in children. The literature of FDG in IFI is very limited but the information for children is even more scarce. This chapter discusses the epidermiology, diagnostic challenges and the differences of these between adults and children. The use of FDG PET/CT in pulmonary and extrapulmonary sites is enumerated. The role of other tracers, both SPECT and PET, in IFIs is also considered.
In Chapter 7, the thesis presents the literature on the role of PET in monitoring treatment of IFIs. The delay in initiating treatment in IFI is associated with high morbidity and mortality. However, the diagnosis of IFIs can be challenging. Patients are frequently treated with antifungal agents without micobiological isolation of the organism but based on clinical, serological and radiological findings. It is important to monitor the antifungal therapy to ensure the patient is responding and to prevent resistance. The role of PET in monitoring antifungal drugs is considered in this chapter.
In Chapter 8, the thesis assesses the added value of FDG PET/CT to the anatomical‐based studies commonly used in the management of IFIs. The metabolic changes from PET are known to precede the anatomical changes. The added value of the metabolic data to the anatomic data provided by other imaging methods was assessed and FDG PET/CT was found to help determine the activity anatomic lesion, stage infection and pretherapy assessment for patients to undergo stem cell transplantation.
In Chapter 9, the thesis examines on the role of FDG PET/CT in monitoring therapy in IFIs. The chapter describes the use of FDG PET/CT in monitoring antitherapy. FDG PET/CT determines when therapy should be discontinued, prolonged or changed. The chapter also describes the use of metabolic parameters such as total leson glycolysis and metabolic volume fom the whole body to follow up IFIs.
In Chapter 10, the thesis presents the literature on the role of PET/CT in TB. This chapter looks at the role of FDG PET in pulmonary and extrapulmonary situations. The chapter discusses the ability of FDG PET/CT to predict which patients with latent TB will progress and also the ability of FDG PET/CT to identify subclinical TB. The chapter emphasizes the complementary role of the CT component in adding specificity to the FDG PET in some cases of extrapulmonary TB. The chapter also describes the role of PET/CT in imaging and tracking events in TB granuloma and the potential of PET/CT to unravel the role of neutrophils in TB progression.
Chapter 11 of the thesis presents the correlation of the pathophysiology of TB and the findings of PET/CT from literature and their clinical applications. The pathophysiology of the lipid membrane, the
12 13
1
Chapter Oneability to image with PET/CT, and the role of other tracers were explored. The challenges of current diagnostic platforms used in TB and impact of HIV on the radiological diagnosis was also emphasized.
The ability of PET to monitor treatment TB was also briefly discussed.
In Chapter 12, the thesis postulates the potential role of nitroimidazole‐based PET tracers in the management of latent TB infection (LTBI). The non‐replicative persistent stage of Mycobactrium tuberculosis bacilli in latent TB infection is associated with hypoxia. This chapter proposes imaging the hypoxia in the bacilli in non‐replicating persistant state to understand and possibly identify patients with latent TB that may benefit most from preventive TB treatment.
In Chapter 13, the thesis explores the use of PET/CT as an imaging biomarker for infection with emphasis on TB. There is no ideal biomarker to follow up infections. Serum biomarkers in clinical use and in experimental stages are frought with challenges leading to false positives and negatives.
Infection itself may manifest as different enties in the same patient. It is clear that a combination of biomarkers is needed to monitor infections. The ability of PET to quantify uptake sets it apart as an imaging biomarker to monitor disease. The pros and cons of using FDG PET/CT as a biomarker for infection is discussed in this chapter.
In Chapter 14, the thesis presents the head‐to‐head comparison of FDG and Gallium 68 citrate (68Ga‐
citrate) PET in the treatment of TB. The chapter shows that FDG PET detects more lesions than 68Ga‐
citrate PET. 68Ga‐citrate PET was better in detection of intracerebral pathology and was less likely to accumulate in post‐infective inflammation. The chapter discusses the potential pros and cons of using
68Ga based PET tracers and its potential in the developing world which bear the brunt of TB.
In Chapter 15, the conclusions and future perspectives of the thesis is presented. This chapter considers five topics from the previous chapters, highlights the limitations and discusses future perspectives of PET in infections associated with immue dysfunction.
1
Introduction to the thesis
REFERENCES
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2. Pinheiro P, Mathers CD, Krämer A. The Global Burden of Infectious Diseases. In: Krämer A., Kretzschmar M., Krickeberg K. (eds) Modern Infectious Disease Epidemiology. Statistics for Biology and Health. Springer, New York, NY
3. Ankrah AO, Elsinga PH. (2020) Radiopharmaceuticals for PET Imaging of Infection. In: Signore A., Glaudemans A.
(eds) Nuclear Medicine in Infectious Diseases. Springer, Cham.
4. Lindsay BN. The immune system Essays Biochem 2016; 60:275‐301.
5. Chaplin DD. Overview of the immune response. J Allergy Clin Immunol 2010; 125:S3‐23.
6. Hiemstra PS. The role of epithelial beta‐defensins and cathelicidins in host defense of the lung. Exp. Lung Res 2007;
33:537‐42
7. Holmskov U, Thiel S, Jensenius JC. Collectins and ficolins: humoral lectins of the innate immune defense. Annu Rev Immunol 2003; 21:547‐78
8. Gary W. Litman, Jonathan P. Rast, Sebastian D. Fugmann. The origins of vertebrate adaptive immunity. Nat Rev Immunol 2010; 10:543‐53.
9. McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol 2018; 14:61.
10. Chinen J, Shearer WT. Secondary immunodeficiencies, including HIV infection. J Allergy Clin Immunol 2010;
125:S195‐203.
11. Aminov RI. A brief history of the antibiotic era: lessons learned and challenges for the future. Front Microbiol 2010;
1:134.
12. Anger J, Lee U, Ackerman AL, et al. Recurrent Uncomplicated Urinary Tract Infections in Women: AUA/CUA/SUFU Guideline. J Urol 2019; 202:282‐9.
13. Hakim J, Musiime V, Szubert AJ, Mallewa J, Siika A, Agutu C, et al. Enhanced Prophylaxis plus Antiretroviral Therapy for Advanced HIV Infection in Africa. N Engl J Med 2017; 377:233‐45.
14. Storr J, Twyman A, Zingg W, et al. Core components for effective infection prevention and control programmes:
new WHO evidence‐based recommendations. Antimicrob Resist Infect Contro. 2017; 6:6.
15. Vincent JL. The Clinical Challenge of Sepsis Identification and Monitoring. PLoS Med 2016; 13:e1002022.
16. del Rosal T, Goycochea WA, Méndez‐Echevarría A, García‐Fernández de Villalta M, Baquero‐Artigao F, Coronado M, et al. ¹⁸F‐FDG PET/CT in the diagnosis of occult bacterial infections in children. Eur J Pediatr 2013; 172:1111‐5.
17. Sathekge MM, Ankrah AO, Lawal I, Vorster M. Monitoring Response to Therapy. Semin Nucl Med 2018 ;48:166‐
81.
18. Ordonez AA, Wang H, Magombedze G, et al. Dynamic imaging in patients with tuberculosis reveals heterogeneous drug exposures in pulmonary lesions. Nat Med 2020. https://doi.org/10.1038/s41591‐020‐0770‐2
19. Ankrah AO, Glaudemans AWJM, Klein HC, Dierckx RAJO, Sathekge M. The Role of Nuclear Medicine in the Staging and Management of Human Immune Deficiency Virus Infection and Associated Diseases. Nucl Med Mol Imaging 2017; 51:127‐39.
20. Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006; 8:128‐39.
21. Oommen S, Banaji N. Laboratory diagnosis of tuberculosis: Advances in technology and drug susceptibility testing.
Indian J Med Microbiol 2017; 35:323‐31.
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Chapter One22. Glaudemans AW, de Vries EF, Galli F, Dierckx RA, Slart RH, Signore A. The use of (18)F‐FDG‐PET/CT for diagnosis and treatment monitoring of inflammatory and infectious diseases. Clin Dev Immunol 2013; 2013:623036.
23. Larson SM. Cancer or inflammation? A Holy Grail for nuclear medicine. J Nucl Med 1994; 35:1653‐5.
24. Glaudemans AW, Signore A. FDG‐PET/CT in infections: the imaging method of choice? Eur J Nucl Med Mol Imaging 2010; 37:1986‐91.
25. Elfaki MG, Al‐Hokail AA, Kambal AM. (2012) Microbial Immunosuppression. In: Kupar S, Portela MB. (eds) Immunosuppression‐ role in health and disease. IntechOpen, DOI: 10.5772/28841.
https://www.intechopen.com/books/immunosuppression‐role‐in‐health‐and‐diseases/microbial‐
immunosuppression.
26. Schneider A, Blatzer M, Posch W et al. Aspergillus fumigatus responds to natural killer (NK) cells with upregulation of stress related genes and inhibits the immunoregulatory function of NK cells. Oncotarget. 2016;7:71062‐71.
1
Introduction to the thesis
Part 1
PET in immunodeficiency disorders, tracers used in infection and PET in HIV
PART 1
Chapter 2
PET/CT in Immunodeficiency Disorders
Ankrah AO and Sathekge MM
Book chapter in: PET/CT in Infection and Inflammation. Clinicians’ Guides to Radionuclide Hybrid Imaging. Wagner T., Basu S. (eds) Springer, Cham 2018
PET/CT in
Immunodeficiency Disorders
Ankrah AO, Sathekge MM
Book chapter in: PET/CT in Infection and Inflammation. Clinicians’ Guides to Radionuclide Hybrid
Imaging. Wagner T., Basu S. (eds) Springer, Cham 2018
CHAPTER 2
Abstract
Immunodeficiency disorders cover a wide range of disorders that produce various degrees of immunosuppression with different expressions of disease. These disorders may be a primary defect in the immune system, but are more frequently secondary to some other disease. PET/CT has been utilized in the management some of the conditions causing immunosuppression. In malignancies associated with immunosuppression, PET may help in the diagnosis, staging, assessing recurrence and help in planning radiotherapy. In infections associated with immunodeficiency, PET may help diagnose the infection by directing biopsy, detect previously unknown sites of infection and monitor the treatment of the infection. In chronic conditions like diabetes PET may play a role in the management of conditions where the diagnosis can be daunting to clinicians like diabetic foot infections. The role of PET/CT in some of these disorders is briefly discussed.
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2
Chapter TwoIntroduction
Immunodeficiency disorders encompass a wide array of clinical conditions in which there is an aberration of one or more of the components of the immune system. These disorders may be primary or secondary to some other medical condition or intervention. Primary disorders usually become apparent in childhood but may present later in life. Secondary immunodeficiency disorders are more common [1, 2]. The last few decades have witnessed a steady increase in the population with immunodeficiency disorders. This is as a result of a number of factors. The high prevalence of human immunodeficiency virus infection (HIV) with 36.7 million infections worldwide is an important contributing factor [3]. In addition, advances in medical intervention have increased the immunocompromised population considerably. There are more patients in the posttransplant state who are on immunosuppressive therapy, more people using potent anti‐cancer chemotherapy, and an increased survival of patients with hematologic disorders and malignancies [1]. Also, chronic disease such as diabetes mellitus and the use of drugs such as corticosteroids or immunosuppressant in inflammatory disease have added to the numbers. Finally, our increased understanding of underlying mechanism of immunosuppression with the discovery of new primary immunodeficiency has also contributed to this increase [1, 4].
Opportunistic infections occur in immunocompromised host over and above infections encountered by other people [5]. The clinical and radiological features of infections in the immunodeficiency state are usually diminished as a result of the blunted inflammatory response. This may delay the diagnosis.
Malignancies on the other hand tend be more aggressive and occur in a younger age in certain immunodeficiency states [6, 7], see Fig. 1.
PET/CT combines functional imaging with anatomical imaging, and hence it is an important tool in the early diagnosis and management of conditions associated with immunodeficiency where anatomically changes may be diminished.
PET/CT in HIV
The clinical manifestation of patients with HIV is highly variable. Patients with HIV present with a wide range of infections, malignancies, and other disorders.
HIV‐Associated Malignancy
HIV‐associated malignancies are classified as AIDS‐defining cancers (ADCs) and non‐AIDS‐defining cancers (NADCs). The ADCs include invasive cervical cancer, non‐Hodgkin’s lymphoma, and Kaposi’s sarcoma. The rates of ADCs have declined considerably after the introduction of Highly active antiretroviral therapy (HAART); however, they are still elevated compared to the rates in patients without HIV. The NADCs include Hodgkin’s lymphoma, lung cancer, hepatic and anal cancers; these cancers appear to have increased in the era of HAART [8–10]. The role of PET/CT in these cancers is similar to patients without immunosuppression and is outlined in Table1 [11–13]. In cancers such as cervical cancer and aggressive lymphoma, FDG PET/CT is used in the initial evaluation before therapy, defining the extent of disease, predicting early treatment response, and assessing response at the end of therapy [15–18], see Figure 2.
FDG PET/CT may be used to distinguish primary CNS lymphoma and infectious space occupying lesions in the brain [19, 20]. In HIV‐associated Kaposi sarcoma, FDG PET/CT is able to detect occult lesions which are difficult to detect on other imaging modalities [21, 22], see Figure 3.
2
Overview of PET in immunodeficiency disorders
HIV‐Associated Infections
TB usually manifests as a cavitatory lung disease frequently affecting the upper lobes. In the presence of immunosuppression such as HIV, the lesions tend to involve middle and lower lobes more often and cavitation occurs less frequently [22–24], see Figure 4. Extrapulmonary TB is also more likely to be diagnosed in HIV [23, 24]. TB disease activity correlates with FDG uptake on PET/CT. FDG PET/CT can be used to detect TB, stage infection and assess response to therapy to TB [22–24]. In Pneumocystis jiroveci pneumonitis where there are differences in manifestation in different immunodeficiency disorders such as HIV and renal transplant recipients, FDG PET/CT has demonstrated its usefulness in early diagnosis [25, 26].
Figure 1
A 36-year-old male with HIV infection with an undifferentiated sarcoma involving the right neck and a concurrent squamous cell carcinoma of the left eyelid. A metastatic lesion to the left lung is seen on the MIP image.
Figure 2
Assessment of Hodgkin’s lymphoma on completion of therapy.
Upper images show FDG PET/CT on completion of therapy.
Lower images are the baseline FDG PET/CT scan with splenic, hepatic skeletal and nodes above and below the diaphragm.
There is complete metabolic and morphologic response. Illustrates the use of FDG PET/CT at the end of therapy.
TTaabbllee 11:: FDG PET/CT in malignancies associated with immunodeficiency [12–14]
Diagnosis
• Determine site of biopsy
• Differentiation of benign from malignant lesions
• Carcinoma of unknown primary evaluation
• Detect sites of suspicious malignant lesions Staging
Response evaluation Restaging
Suspected recurrence Follow‐up
Radiotherapy planning Prognosis—SUVmax, TLG, MTV
SUVmax maximum standard uptake value, TLG total lesion glycolysis, MTV metabolic tumor volume
22 23
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Chapter TwoFigure 3
Patient with HIV CD4 count 94 cells/mm3 and viral load 1,158,944 copies per mL. Biopsy of the inguinal region revealed nodular Kaposi sarcoma.
The axillary or mediastinal lymph nodes also noted may be related to HIV lymphadenopathy.
Other causes of lymphadenopathy such as lymphoma or TB may only be excluded by histological assessment.
Fgiure 4
HIV and TB coinfection demonstrating miliary TB of the lung and TB adenitis of the mediastinal and abdominal nodes. The spleen is much more intense than the liver.
This demonstrates both atypical pulmonary and extrapulmonary TB encountered in the HIV patient
Fever of Unknown Origin (FUO)
PET/CT has been shown to be useful in evaluation of FUO [27, 28]. In HIV, viremia did not impede the performance of FDG PET/CT [29]. FDG PET/CT is indicated in HIV and other immunodeficiency states when initial clinical assessment and primary investigation do not reveal the cause of the fever [11].
Other Conditions in HIV
PET/CT has been shown to be useful in the management of conditions such as lipodystrophy associated with the use of HAART in HIV. These patients demonstrate marked increase of FDG in subcutaneous tissue which resolves when offending drug is withdrawn [30, 31]. Another condition where PET/CT potentially makes a difference is HIV‐associated neurocognitive disorder (HAND). When dementia occurs in HIV, an increased subcortical uptake on FDG PET/CT scan after the exclusion of other causes of dementia is an early indicator of HAND [32, 33]. FDG PET/CT can detect carotid artery inflammation which may serve as an early marker to detect proartherosclerotic process in HIV patients who are at a higher risk of developing a stroke or myocardial infarction compared to the general population [34, 35]. FDG PET/CT has demonstrated that in well‐controlled HIV patients with well‐suppressed viral loads there is no increased arterial inflammation compared to people without HIV [36].
Transplantation
Patients undergoing solid organ transplant or hematopoietic stem cell transplant are at risk of developing secondary malignancies and infections due to the immunosuppressed state to prevent rejection [37, 38]. FDG PET/CT was found to diagnose these malignancies and infections with high
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Overview of PET in immunodeficiency disorders
sensitivity and specificity in solid organ transplants and hematopoietic stem cell transplant [39]. It is particularly specific for the detection of posttransplant lymphoproliferative disease [40]. FDG PET/CT may also play a role in the evaluation of gastrointestinal graft versus host disease [41, 42]. FDG PET/CT has been found to be a useful predictor of outcome of transplant in some lymphomas. There are however conflicting outcomes regarding the predictive value in pretransplant studies in non‐Hodgkin’s lymphoma [43–47].
Hematologic Malignancies
The role of FDG PET/CT in the various hematologic malignancies is considered in Table.2 [48–65].
Table 2: FDG PET/CT in hematologic malignancies Malignancy Role of FDG PET/CT
Lymphoma Staging and response assessment for aggressive lymphoma (Lugano classification) [48]
Detects disease in normal sized nodes and more likely to determine splenic and diffuse bone marrow disease than other imaging modalities [49, 50]
In early Hodgkin’s and DLBC lymphoma may obviate the need for bone marrow assessment [51, 52]
Detect and directs biopsy for transformation of indolent to aggressive lymphoma [53, 54]
Multiple
Myeloma Characterizes osseous and extra osseous disease involvement [55–57]
May replace routine bone marrow biopsy assessment during follow‐up [58–60]
Plasmacytoma Detects additional disease in patients suspected to have solitary plasmacytoma upstaging disease and changing management [61]
Leukemia Not routinely used in management. In CLL may detect and direct biopsy when Richter’s transformation is suspected [62–65]
Fungal Infections
Invasive aspergillosis and candidiasis and other invasive fungal infections (IFIs) are usually diagnosed in immunocompromised patient [66]. These usually occur in patients with hematological disorders, hematologic stem cell and solid organ transplant, intensive chemotherapy or primary immunodeficiency like chronic granulomatous disease [66, 67]. FDG PET/CT detects activity in different fungi and the FDG uptake corresponds to disease activity [67–69]. It was found to detect IFIs earlier compared to conventional imaging and to monitor disease activity and direct antifungal therapy [70–
72].
Febrile Neutropenia
Febrile neutropenia (FN), a complication of patients undergoing myelosuppressive therapy is considered to be a sign of life‐threatening infections. In FN however, infections usually lack localizing clinical signs. FDG PET/CT was found to be useful in detecting infectious foci including IFIs, septic emboli from central venous catheters. The high negative predictive value of FDG PET/CT facilitated the management of such patients [73, 74].
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Chapter TwoInflammatory Conditions
Many inflammatory disorders use corticosteroid or other drugs to depress the immune system in order to control symptoms of inflammatory disease. FDG PET/CT is able to monitor the activity of many of these inflammatory diseases and help determine whether the immunosuppressive therapy must be discontinued, increased, or maintained [75].
Diabetes Mellitus
Chronic conditions like diabetes are an important cause of immunosuppression. Conditions which frequently occur in diabetes where PET/CT can play a role are considered in Table 3 [76–84].
Table 3: FDG PET/CT conditions frequently occurring in diabetes mellitus Disorder Usefulness of FDG PET/CT
Tuberculosis Useful—Has been considered under HIV infections [11, 22–24]
Osteomyelitis Particularly useful in vertebral osteomyelitis [76]
Diabetic foot Varying results have been reported [77–81]
Spondylodiscitis Very useful [82]
Infective endocarditis
Patient preparation important and must be considered complimentary to other imaging modalities [83, 84]
Limitations of PET/CT
FDG is a nonspecific tracer and the distinction between benign and malignant process becomes even more challenging in immunosuppression where granulomatous conditions coexist.
Future Perspectives and Conclusion
Several other PET tracers are being used or are at various stages of development for management of immunodeficiency disorders. F18 Fluorothymidine (FLT) a marker of tumor proliferation whose uptake correlates with Ki67 and has been used in lymphomas. It is particularly useful for monitoring therapies containing cytostatic drugs [85–87]. Ga 68 CXCR4 targets the chemokine receptor expressed in many solid and malignant cancers. It is a potential therapy target for many cancers, especially hematologic malignancy [88–90]. Other PET tracers could potentially have an impact on the management of immunodeficiency disorders [91]. PET/CT plays a major role in many immunodeficiency disorders. This role is likely to expand, as new tracers are developed to deal with challenges faced in immunosuppressive disorders.
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Overview of PET in immunodeficiency disorders
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