Positron emission tomography in infections associated with immune dysfunction
Ankrah, Alfred
DOI:
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 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.
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
8 9points 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.18
F‐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
with 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
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
ability 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.
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