key: cord-018461-lq1m9h41 authors: Elgazzar, Abdelhamid H.; Elmonayeri, Magda title: Inflammation date: 2014-06-27 journal: The Pathophysiologic Basis of Nuclear Medicine DOI: 10.1007/978-3-319-06112-2_4 sha: doc_id: 18461 cord_uid: lq1m9h41 Inflammation was described as early as 3000 BC in an Egyptian papyrus [1] and is still a common problem despite continuous advancements in prevention and treatment methods. The delineation of the site and extent of inflammation are crucial to the clinical management of infection and for monitoring the response to therapy [2]. Infl ammation was described as early as 3000 BC in an Egyptian papyrus [ 1 ] and is still a common problem despite continuous advancements in prevention and treatment methods. The delineation of the site and extent of infl ammation are crucial to the clinical management of infection and for monitoring the response to therapy [ 2 ] . This issue is relevant to nuclear medicine, since physiological along with morphological imaging has an important role in achieving this goal. Infl ammation is a complex tissue reaction to injury. Injury may be caused not only by living microbes, i.e., bacteria, viruses, or fungi, leading to infection, but also by injurious chemical, physical, immunological, or radiation agents: • Physical agents -Trauma -Heat • Chemical agents -Chemotherapy -Industrial accidents • Immunological agents -Antigen-antibody reactions • Radiation -Radiation therapy -Nontherapeutic radiation exposure Infl ammation is fundamentally a protective reaction against the cause of cell injury as well as the consequence of such injury. However, infl ammation is potentially harmful and may even be life threatening. Since most of the essential components of the infl ammatory process are found in the circulation, infl ammation occurs only in vascularized tissue. Infl ammation is generally considered a nonspecifi c response, because it happens in the same way regardless of the stimulus and the number of exposures to the stimulus [ 2 ] . This is different from the immune system, which has memory, and the antigens are specifi c and induce a specifi c response. Infl ammation may be classifi ed as acute or chronic. Acute infl ammation is the immediate or early response to injury and is of relatively short duration. It lasts for minutes, hours, or at most a few days. Chronic infl ammation, on the other hand, is of longer duration and may last from weeks to years [ 3 ] . The distinction between acute and chronic infl ammation, however, depends not only on the duration of the process but also on other pathological and clinical features. Acute infl ammation continues only until the threat to the host has been eliminated, which usually takes 8-10 days, although this is variable. Infl ammation is generally considered to be chronic when it persists for longer than 2 weeks [ 2 ] . Many regional and systemic changes accompany acute infl ammation and are mediated by certain chemicals produced endogenously called chemical mediators and are behind the spread of the acute infl ammatory response following injury to a small area of tissue into uninjured sites. These chemical mediators include mediators released from cells such as histamine and prostaglandins and others in plasma which are released by some systems contained in the plasma which are the four enzymatic cascade systems: the complement, the kinins, the coagulation factors, and the fi brinolytic system which produce several infl ammatory mediators [ 4 -6 ] . Table 4 .1 summarizes the main chemical mediators of infl ammation. Acute infl ammation is characterized by the following major regional components: Local Vascular Changes 1. Vasodilation following transient vasoconstriction is one of the most important changes that accompany acute infl ammation, and it persists until the end of the process. It involves fi rst the arterioles and then results in the opening of new capillary beds in the area. 2. Increased vascular permeability due to: • Contraction of endothelial cells with widening of intercellular gaps • Direct endothelial injury, resulting in endothelial cell necrosis and detachment • Leukocyte-mediated endothelial injury: Leukocytes adhere to the endothelium, which becomes activated, thereby releasing toxic oxygen species and proteolytic enzymes and causing endothelial injury. Increased permeability of the microvasculature, along with the other changes described, leads to leakage with formation of "exudate," an infl ammatory extravascular fl uid with a high protein content, much cellular debris, and a specifi c gravity above 1.020. This is the hallmark of acute infl ammation, which may also be called exudative infl ammation. It indicates signifi cant alteration in the normal permeability of the small blood vessels in the region of injury. The two components of exudate, fl uid and protein, serve good purposes. Fluid increase helps to dilute the toxins. Protein increase includes globulins that provide protective antibodies, while fi brin helps to limit the spread of bacteria and promotes healing. Exudate varies in composition. In early or mild infl ammation, it may be watery (serous exudate) with low plasma protein content and few leukocytes. In more advanced infl ammation, the exudate becomes thick and clotted (fi brinous exudate). When large numbers of leukocytes accumulate (Fig. 4.3 ) , the exudate consists of pus and is called suppurative, while if it contains erythrocytes due to bleeding, it is referred to as hemorrhagic. Pus, accordingly, is a variant of exudate that is particularly rich in leukocytes, mostly neutrophils and parenchymal cell debris. Exudate should be differentiated from "transudate," which is a fl uid with low protein Facilitates phagocytosis of bacteria by macrophages (opsonization of bacteria) Kinin system Bradykinin included in the system is the most important vascular permeability factor, also a mediator for pain which is a major feature of acute infl ammation Coagulation factors Responsible for the conversion of soluble fi brinogen into fi brin, a major component of the acute infl ammatory exudate Fibrinolytic system Plasmin included in the fi brinolytic system is responsible for the lysis of fi brin into fi brin degradation products, which have a local effect on vascular permeability concentration and a specifi c gravity of less than 1.012. Transudation is associated with normal endothelial permeability [ 3 , 5 ] . Local Cellular Events 1. Margination After stasis develops, leukocytes will be peripherally oriented along the vascular endothelium, a process called leukocytic margination ( Fig. 4.1 ). Leukocytes emigrate from the microcirculation and accumulate at the site of injury. Once outside the blood vessel, the cells migrate at varying rates of speed in interstitial tissue toward a chemotactic stimulus in the infl ammatory focus. Through chemoreceptors at multiple locations on their plasma membranes, the cells are able to detect where the highest concentrations of chemotactic factors are and to migrate in their direction. Granulocytes, including the eosinophils, basophils, and some lymphocytes, respond to such stimuli and aggregate at the site of infl ammation. The primary chemotactic factors include bacterial products, complement components C5a and C3a, kallikrein and plasminogen activators, products of fi brin degradation, prostaglandins, and fi brinopeptides. Histamine is not a chemotactic factor but facilitates the process. Some bacterial toxins, This defense mechanism is particularly important in bacterial infections. The polymorphonuclear leukocytes and macrophages ingest debris and foreign particles. Acute infl ammation has several possible local sequelae. These include resolution, suppuration (formation of pus), organization, and progression to chronic infl ammation. Resolution means complete restoration of tissues to normal. Organization of tissues refers to their replacement by granula-tion tissue with formation of large amounts of fi brin, growth of new capillaries into fi brin, migration of macrophages into the zone, and proliferation of fi broblasts resulting in fi brosis and consequently exudate becoming organized. Acute infl ammation may progress to a chronic form characterized by reduction of the number of polymorphonuclear leukocytes but proliferation of fi broblasts with collagen production. Commonly, chronic infl ammation may be primary with no preceding acute infl ammatory reaction. Chronic infl ammation, whether following acute infl ammation or not, is characterized by a proliferative (fi broblastic) rather than an exudative response with predominantly mononuclear a b cell infi ltration (macrophages, lymphocytes, and plasma cells) (Fig. 4.3b ) . Vascular permeability is also abnormal, but to a lesser extent than in acute infl ammation with formation of new capillaries. Abscess is defi ned as a collection of pus in tissues, organs, or confi ned spaces, usually caused by bacterial infection. The fi rst phase of abscess formation is cellulitis, characterized by hyperemia, leukocytosis, and edema, without cellular necrosis or suppuration. This stage is also called phlegmon. It may be followed in some organisms by necrosis and liquefaction and walling off of the pus, which results in abscess formation that can be present with both acute and chronic infl ammation. Three major systemic changes are associated with infl ammation: leukocytosis, fever, and an increase in plasma proteins. Leukocytosis is an increased production of leukocytes due to stimulation by several products of infl ammation such as complement component C3a and colony-stimulating factors. A febrile response is due to the pyrogens. The increase in plasma proteins is due to the stimulation of the liver by some products of infl ammation, leading to increased synthesis of certain proteins referred to as acute-phase reactants which include C-reactive protein, fi brinogen, and haptoglobin and are anti-infl ammatory [ 2 ] . Healing of tissue after injury is closely linked to infl ammation since it starts by acute infl ammation. Healing may lead to restoration of normal structure and function of the injured tissue (resolution) or to the formation of a scar consisting of collagen (repair) when resolution cannot be achieved because the tissue is severely injured or cannot regenerate. In either case, acute infl ammation occurs fi rst and for this reason is considered the defensive phase of healing. Healing (resolution and repair) occurs in two overlapping phases, reconstruction and maturation, and may take as long as 2 years. The reconstructive phase starts 3-4 days after injury, continues for approximately 2 weeks, and is characterized by fi broblasts followed by collagen synthesis. The maturation phase is characterized by cell differentiation, scar formation, and remodeling of the scar; it begins several weeks after injury and may take up to 2 years to complete. Pathophysiology of Major Soft Tissue Infl ammation An abdominal abscess may be formed in an abdominal organ or within the abdomen outside the organs. There are several types of abdominal infection: abscess; cellulitis (phlegmon), i.e., early infl ammation of the soft tissue prior to or without formation of an abscess; and peritonitis. Abscesses fall into three categories: The organisms causing abscesses may reach the tissue by direct implantation such as penetrating trauma, may spread from contiguous infection, through hematogenous or lymphatic routes from a distant site, or through migration of resistant fl ora into an adjacent, normally sterile area such as in perforation of an abdominal viscus. Factors predisposing to abscess formation include impaired host defense mechanisms; trauma/surgery; obstruction of urinary, biliary, or respiratory passages; foreign bodies; chemical or immunological irritation; and ischemia. Abdominal surgery (particularly of the colon, appendix, and biliary tree) and trauma are the most common; less common are appendicitis, diverticulitis, and pelvic infl ammatory disease. The formation of fi brin in the abdominal cavity is a common pathophysiological pathway for abdominal abscess formation due to diminished fi brin degradation. Hyaluronan-based agents were found to reduce adhesion formation after surgery and reduce abscess formation in experimental peritonitis. Possible mechanisms of action of hyaluronan include modulation of the infl ammatory response and enhanced fi brinolysis [ 7 ] . Low pH, large bacterial inocula, poor perfusion, the presence of hemoglobin, and large amounts of fi brin (which impedes antibiotic penetration) make the abscess a cloistered environment that is penetrated poorly by many antimicrobial therapies [ 8 , 9 ] . Therefore, management of these infections requires prompt recognition, early localization, and effective drainage, as well as appropriate antimicrobial use. Once the diagnosis is made and the abscess is localized, treatment should begin promptly. Percutaneous or open surgical drainage should be used. Broad-spectrum antibiotics should be given until culture and sensitivity data are obtained. Localization is crucial since, for example, percutaneous drainage is inappropriate for abscesses in certain locations such as the posterior subphrenic space or in the porta hepatis. In the liver, abscesses occur in the right lobe in approximately 95 % of the cases, and in 70 % of cases, the liver abscesses are solitary [ 10 ] . Accumulation of leukocytes in the abscess is the pathophysiological basis for using labeled white blood cells for abscess imaging. In the acute phase, migration of leukocytes is vigorous. Later, the migration rate slows, and the cell type changes from predominantly neutrophils to mononuclear cells (lymphocytes, plasma cells, and macrophages). This pathophysiological change associated with the chronic state explains the better diagnostic accuracy of labeled leukocyte scans in acute as opposed to chronic abscesses. Infl ammatory bowel disease (IBD) is an idiopathic disease, probably involving an immune reaction of the body to its own intestinal tract. The two major types of IBD are ulcerative colitis (UC) and Crohn's disease (CD). Crohn's disease is also referred to as regional enteritis, terminal ileitis, or granulomatous ileocolitis. IBD is a dis-ease of industrialized nations and observed most commonly in Northern Europe and North America. Incidence among whites is approximately four times that of other races, slightly greater in females and higher in Ashkenazi Jews (those who have immigrated from Northern Europe) than in other groups. The risk of developing UC is higher in nonsmokers and former smokers than in current smokers. Incidence peaks in the second and third decades of life. A second smaller peak occurs in patients aged 55-65 years. CD and UC can occur in childhood, although the incidence is much lower in children younger than 15 years with some differences in presentation and more negative effect on quality of life in younger age group [ 11 ] . The etiology of IBD is unsettled. Suspected factors include environmental, infectious, genetic, autoimmune, and host factors. A great deal of research has been performed to discover potential genes linked to IBD. One of the early linkages discovered was on chromosome 16 ( IBD1 gene), which led to the identifi cation of the NOD2 gene (now called CARD15 ) as the fi rst gene clearly associated with IBD (as a susceptibility gene for Crohn's disease). Studies have also provided strong support for IBD susceptibility genes on chromosomes 5 (5q31) and 6 (6p21 and 19p). None of these mechanisms have been implicated as the primary cause, but they are postulated as potential causes. The lymphocyte population in persons with IBD is polyclonal, making the search for a single precipitating cause diffi cult. The trigger for the activation of the immune response has not been defi ned. However, possible triggers include a pathogenic organism (unidentifi ed yet), an immune response to an intraluminal antigen (e.g., cow's milk protein), or an autoimmune process with immune response to an intraluminal antigen and a similar antigen present on intestinal epithelial cells. In any case, activation of the immune system leads to infl ammation of the intestinal tract, both acute and chronic [ 12 -19 ] . The pathophysiology of IBD is still incompletely understood and is under active investigation, but the common end pathway is infl ammation of the mucosal lining of the intestinal tract, causing ulceration, edema, bleeding, and fl uid and electrolyte loss. The infl ammation of the intestinal mucosa includes both acute infl ammation with neutrophilic infi ltration and chronic with mononuclear cell infi ltration (lymphocytic and histiocytic) [ 20 ] . In UC, infl ammation always begins in the rectum, extends proximally a certain distance, and then abruptly stops. A clear demarcation exists between involved and uninvolved mucosa. The rectum is always involved in UC, and no "skip areas" are present. UC primarily involves the mucosa and the submucosa, with formation of crypt abscesses and mucosal ulceration. The mucosa typically appears granular and friable. In more severe cases, pseudopolyps form, consisting of areas of hyperplastic growth with swollen mucosa surrounded by infl amed mucosa with shallow ulcers. In severe UC, infl ammation and necrosis can in rare cases extend below the lamina propria to involve the submucosa and the circular and longitudinal muscles. UC remains confi ned to the rectum in approximately 25 % of cases. In the remainder of cases, UC spreads proximally and contiguously. Pancolitis occurs in 10 % of patients. The small intestine is essentially not involved, except when the distal terminal ileum is infl amed in a superfi cial manner, referred to as backwash ileitis. Even with less than total colonic involvement, the disease is strikingly and uniformly continuous. As the disease becomes chronic, the colon becomes a rigid foreshortened tube that lacks its usual haustral markings, leading to the lead pipe appearance observed on barium enema. The skip areas (normal areas of the bowel interspersed with diseased areas) observed in CD of the colon do not occur in UC. CD, on the other hand, consists of segmental involvement by a nonspecifi c granulomatous infl ammatory process. The most important pathological feature is the involvement of all layers of the bowel, not just the mucosa and the submucosa, as is characteristic of UC. Furthermore, CD is discontinuous, with skip areas interspersed between one or more involved areas. Late in the disease, the mucosa develops a cobblestone appearance, which results from deep longitudinal ulcerations interlaced with intervening normal mucosa. The three major patterns of involvement in CD are (1) disease in the ileum and cecum, occurring in 40 % of patients; (2) disease confi ned to the small intestine, occurring in 30 % of patients; and (3) disease confi ned to the colon, occurring in 25 % of patients. Rectal spar-ing is a typical but not constant feature of CD. However, anorectal complications (e.g., fi stulas, abscesses) are common. Much less commonly, CD involves the more proximal parts of the GI tract, including the mouth, tongue, esophagus, stomach, and duodenum. CD causes three patterns of involvement: (1) infl ammatory disease, (2) strictures, and (3) fi stulas. The incidence of gallstones and kidney stones is increased in CD because of malabsorption of fat and bile salts. Gallstones are formed because of increased cholesterol concentration in the bile, caused by a reduced bile salt pool. Patients who have CD with ileal disease or resection also are likely to form calcium oxalate kidney stones. With the fat malabsorption, unabsorbed long-chain fatty acids bind calcium in the lumen. Oxalate in the lumen normally is bound to calcium. Calcium oxalate is poorly soluble and poorly absorbed; however, if calcium is bound to malabsorbed fatty acids, oxalate combines with sodium to form sodium oxalate, which is soluble and is absorbed in the colon (enteric hyperoxaluria). The development of calcium oxalate stones in CD requires an intact colon to absorb oxalate. Patients with ileostomies do not develop calcium oxalate stones. Extraintestinal manifestations of IBD include iritis, episcleritis, arthritis, and skin involvement, as well as pericholangitis and sclerosing cholangitis. The most common causes of death in IBD are peritonitis with sepsis, malignancy, thromboembolic disease, and complications of surgery. Malnutrition and chronic anemia are observed in long-standing CD. Children with CD or UC can exhibit growth retardation. Patients with UC most commonly present with bloody diarrhea, whereas patients with CD usually present with non-bloody diarrhea. Abdominal pain and cramping, fever, and weight loss occur in more severe cases. The presentation of CD is generally more insidious than that of UC. UC and CD are generally diagnosed using clinical, endoscopic, and histologic criteria. However, no single fi nding is absolutely diagnostic for one disease or the other. Furthermore, approximately 20 % of patients have a clinical picture that falls between CD and UC; they are said to have indeterminate colitis. Accordingly, imaging may be needed for the detection and for evaluation of the disease activity during its course. The chest is a common site of various types of infection, acute and chronic. Such infections are frequent in the elderly and in immunosuppressed patients, including cancer patients. Common infl ammatory conditions relevant to nuclear medicine include pneumonia, sarcoidosis, diffuse interstitial fi brosis, and Pneumocystis ( jiroveci ) carinii pneumonia (See also Chap. 12 ). Sarcoidosis is an infl ammatory condition of uncertain etiology characterized by the presence of noncaseating granulomas involving multiple organs. The disease is now recognized as a member of a large family of granulomatous disorders and has been reported from all parts of the world. Current evidence points to genetic predisposition and exposure to yet unknown transmissible agent(s) and/or environmental factors as etiological agents [ 21 ] . The lung is most commonly and usually the fi rst site of involvement, and the infl ammatory processes extend through the lymphatics to the hilar and mediastinal nodes [ 22 ] . The lung is involved in more than 90 % of cases. Pulmonary sarcoidosis starts as diffuse interstitial alveolitis, followed by the characteristic granulomas. Granulomas are present in the alveolar septa as well as in the walls of the bronchi and pulmonary arteries and veins. The center of the granuloma contains epithelioid cells derived from mononuclear phagocytes, multinucleated giant cells, and macrophages. Lymphocytes, macrophages, monocytes, and fi broblasts are present at the periphery of the granuloma [ 23 ] . Sarcoidosis represents a challenge to clinical investigation because of its unpredictable course, uncertain response to therapy, and diversity of potential organ involvement and clinical presentations [ 24 ] . The diagnosis is based on a compatible clinical and/or radiological picture, histopathological evidence of noncaseating granulomas in tissue biopsy specimens, and exclusion of other diseases capable of producing similar clinical or histopathological appearances. Even microscopically, the noncaseating granulomas are not specifi c [ 21 ] . Infection by mycobacterial species other than Mycobacterium tuberculosis frequently leads to the production of noncaseating granulomas [ 25 ] . The condition is underdiagnosed in some areas. However, owing to the increasing awareness, it is being diagnosed more frequently than a few decades ago [ 26 ] . The disease runs a benign course with spontaneous remission of the activity though some degree of residual pulmonary function abnormality persists. Only a minority of patients develop complicated disease that may lead to blindness, renal failure, liver failure, and heart involvement. Corticosteroids remain the mainstay of treatment. Treatment under close clinical monitoring should be tailored to suit the needs of the individual patient hence the need to evaluate disease activity [ 26 ] . Advanced age, the presence of pulmonary symptoms, the presence of parenchymal lesions on chest radiograph, a previous history of treatment with corticosteroids, and the presence of extrathoracic involvements at the time of detection are possible prognostic factors in patients with sarcoidosis [ 27 ] . The mode of onset and the extent of the disease are also related to prognosis. An acute onset with erythema nodosum or asymptomatic bilateral hilar lymphadenopathy usually heralds a self-limiting course, whereas an insidious onset, especially with multiple extrathoracic lesions, may be followed by relentless, progressive fi brosis of the lungs and other organs Pneumocystis carinii ( jiroveci ) pneumonia (PCP) is a condition that may be endemic or epidemic. It is caused by Pneumocystis carinii , which was considered as a protozoon and recently as a fungus. The condition is common in premature infants, debilitated children, and in other immunocompromised conditions, particularly the acquired immune defi ciency syndrome (AIDS), but it is also seen in congenital immunodeficiency and in patients who are receiving chemotherapy and corticosteroids. It remains a signifi cant cause of morbidity and mortality in human immunodefi ciency virus and nonhuman immunodefi ciency virus-associated immunosuppressed patients [ 28 ] . It is the most common infection in AIDS patients, and it remains an important cause of morbidity and mortality [ 29 ] . The introduction of highly active antiretroviral therapy in industrialized nations however has led to dramatic declines in the incidence of AIDSassociated complications, including PCP. In the developing countries, no decline has occurred [ 30 ] . Transmission is usually airborne. The pathological changes are predominantly in the lungs with an infl ammatory reaction consisting of plasma cells of variable amount, monocytes, and histiocytes. This disease has also been reported in immunocompetent patients, and in this case the presentation is more closely resembling the disease of immunocompromised patients other than AIDS patients [ 31 , 32 ] . The diagnosis is currently established through identifi cation of the organisms in bronchial secretions obtained by bronchoalveolar lavage or bronchial washings [ 33 ] . Gallium-67 is an important imaging modality that helps in the diagnosis and evaluation of the activity of the disease. Interstitial pulmonary fi brosis, a sometimes fatal condition, is characterized by parenchymal infl ammation and interstitial fi brosis. The pathological changes start with alveolitis; this is followed by derangement of the alveolar-capillary units, leading to the end stage of fi brosis. There is a correlation between the infl ammatory activity and the amount of gallium-67 activity in the lungs [ 34 ] . Urinary tract infection (UTI) is common particularly in children. There are two main varieties of acute renal infection: pyelitis, which is confi ned to the renal pelvis, and pyelonephritis, where the renal parenchyma is also involved. It is not always possible to differentiate between the two conditions on clinical grounds. The pathology of acute pyelitis is not very well understood. The importance of the condition, however, lies in the fact that recurrent subclinical attacks are believed to be signifi cant in the pathogenesis of chronic pyelonephritis [ 35 ] . The number of patients with chronic kidney disease and consequent end-stage renal disease is rising worldwide [ 36 ] . End-stage kidney disease , defi ned as that requiring dialysis or receipt of a transplant or that which may lead to death from chronic kidney failure, generally affects less than 1 % of the population [ 37 ] . Among today's challenges is to identify those at greatest risk for endstage renal disease and intervene effectively to prevent progression of early chronic kidney disease and conditions leading to chronic disease [ 37 ] . Rarely, uncomplicated acute pyelonephritis causes suppuration and renal scarring. However, urinary infections in patients with renal calculi, obstructed urinary tract, neurogenic bladder, or diabetes are frequently much more destructive and have ongoing sequelae [ 38 ] . Acute pyelonephritis is a common medical problem. The diagnosis and management of this condition is complex. Patients initially diagnosed with pyelonephritis typically exhibit symptoms and laboratory evidence suggesting infected urine, with signs referable to upper urinary tract infection. However, no consistent set of signs and symptoms are sensitive and specifi c for this diagnosis. Symptoms of acute pyelonephritis generally develop rapidly over a few hours or a day. Symptoms of lower UTI may or may not be present. These include dysuria; urinary frequency, hesitancy, and urgency; gross hematuria; and suprapubic discomfort, heaviness, pain, or pressure. Additionally, fl ank pain and tenderness, unilateral or sometimes bilateral, are present. Fever is not always present. When present, it is not unusual for the temperature to exceed 103 °F (39.4 °C). Rigor, chills, malaise, and weakness may be present. Anorexia, nausea, vomiting, and diarrhea may also be present. Most patients have signifi cant leukocytosis, pyuria with leukocyte casts in the urine, and bacteria on a gram stain of unspun urine. Many conditions and clinical situations are associated with an increased risk of pyelonephritis. Table 4 Pyelonephritis is signifi cantly more common in females (higher in white than in black) compared to males. Approximately 10-30 % of women develop a symptomatic UTI at some point in their lives. Acute pyelonephritis is a bacterial infection of the kidney with acute infl ammation of the pyelocaliceal lining and renal parenchyma centrifugally along medullary rays. This can occur by more than one way. Most often it occurs because of ascending infection from the lower urinary tract (Fig. 4.4 ) . The initial colonization of the walls of the ureter is in areas of turbulent fl ow which leads to paralysis of peristalsis. Dilation and functional obstruction result in subsequent pyelonephritis. Another way is by direct refl ux of bacteria. Hematogenous spread to the kidney by gram-positive and less likely by gram-negative organisms is the third way that can occur. This has become less prevalent since the advent of rapid use of antibiotics. Little or no evidence supports lymphatic spread. Grossly, the kidney is enlarged and edematous. The cut surface may show small abscesses in the cortex, and more often there are wedgeshaped purulent areas streaking upward from the medulla, with normal areas of the kidney tissue intervening in between infected zones (Fig. 4.5 ) . Frequently, the pelvis and calyces are infl amed and dilated. In severe infection, renal papillary necrosis may be present. Microscopically, there is intense infl ammation, with infi ltration of polymorphonuclear leukocytes throughout the interstitial tissue and abscess formation. There is destruction of the tubules, but the glomeruli and blood vessels are often unaffected. The disease remains essentially focal in character, with areas of normal tissue. Following treatment and Chronic pyelonephritis is a chronic condition affecting the pelvis and parenchyma and resulting from recurrent or persistent renal infection. It occurs almost exclusively in patients with major anatomic anomalies, including urinary tract obstruction, struvite calculi, renal dysplasia, or, most commonly, vesicoureteral reflux (VUR) in young children. Grossly, the kidney shows normal areas alternating with zones of scarring. Wedgeshaped scars can be seen on the subcapsular surface of the kidney. The appearance differs, depending on the presence or absence of obstruction. Chronic pyelonephritis in the presence of intra-or extrarenal obstruction shows dilation of the pelvocalyceal system and sometimes peripelvic fibrosis. If no obstruction is present, the pelvic change is in the form of peripelvic fibrosis rather than dilation ( Fig. 4.6 ) . Microscopically, the scarred areas show changes in the interstitium and tubules. The interstitial tissue shows infiltration by predominantly lymphocytes and plasma cells. The tubules become atrophic and may collapse (Fig. 4.7 ) . The glomeruli may be normal in some cases, while in others periglomerular fibrosis is present. Osteomyelitis indicates an infection involving the cortical bone as well as the marrow (see Chap. 6 ). It is classified into many types based on several pathological and clinical factors [ 42 -49 ] including route of infection, patient age, etiology, and onset. Hematogenous osteomyelitis most commonly affects children, and the metaphyses of long bones are the most common sites. Nonhematogenous osteomyelitis, on the other hand, occurs as a result of penetrating trauma, spread of a contiguous soft tissue infection, or inoculation, as in drug addicts [ 48 -54 ] . Many organisms have been encountered in the pathogenesis of osteomyelitis, particularly gram-positive organisms, the most common being Staphylococcus aureus [ 44 -46 ] . Like many other pathological conditions of bone, infections cause reactive new bone formation which -among other factors, particularly increased blood flow -is the principle reason for the accumulation of It is diffi cult to draw the line between acute and chronic osteomyelitis. Chronic osteomyelitis has been defi ned as a skeletal infection with a duration as short as 5 days or as long as 6 weeks. It is characterized by less marked infl ammatory cell infi ltrates than acute infection and may exhibit a variable amount of necrotic tissue. Acute septic arthritis is a medical emergency, since it may result in destruction of the articular cartilage and permanent disability if treatment is delayed [ 55 ] . See Chap. 6 for more details on skeletal infl ammations. FUO describes an illness of several episodes of fever exceeding 38.3 ºC or at least 3-week duration, with no diagnosis after an appropriate inpatient or outpatient evaluation. There are many causes of fever of unknown origin. Infection accounts for only about 25 % of these causes. Many radioisotopes have been used to detect and localize infection (see Table 4 .3 ). Several mechanisms explain the uptake of these radiotracers at the site of infection: 1. Increased vascular permeability - 111 In and 99m Tc human polyclonal IgG - 111 In monoclonal IgM antibody - 111 In and 99m Tc liposomes - 111 In biotin and streptavidin -99m Tc nanocolloids56 - 111 In chloride -67 Ga citrate 2. Migration of WBCs to the site of infection - 111 In-and 99m Tc-labeled leukocytes -99m Tc anti-WBC antibodies 3. Binding to proteins at the site of infection, i.e., 67 Ga citrate (lactoferrin and other ironcontaining proteins) 4. Binding to WBCs at the site of infection -Chemotactic peptides -Interleukins 5. Binding to bacteria -99m Tc-labeled ciprofl oxacin antibiotic -67 Ga citrate 6. Metabolic trapping, i.e., F-18 fl uorodeoxyglucose Since there are limitations to the radiopharmaceuticals available for imaging infection, the search continues for better agents with ideal properties [ 56 -59 ] . They should: 1. Be easy to prepare 2. Have low cost and wide availability 3. Ensure rapid detection and localization of infections (< 3 h) 4. Have low toxicity and produce no immune response 5. Clear rapidly from the blood with no significant uptake in the liver, spleen, GI tract, bone, kidneys, bone marrow, or muscle 6. Clear rapidly from the background 7. Have high specifi city and sensitivity and be able to differentiate infection from other causes of infl ammation and tumors 8. Be able to differentiate acute from chronic infection Gallium-67 has been used for many years to detect infl ammation. The multiple mechanisms of uptake of gallium by infl ammatory tissue include the following: 1. Increased vascular permeability 2. Gallium-67-binding substances at the site of infl ammation • Transferrin (due to leakage of plasma proteins) • Lactoferrin (secreted with lysosomal contents of stimulated or dead neutrophils) • Siderophores produced by bacteria 3. Leukocytes: direct uptake 4. Bacteria: direct uptake Sfakianakis et al. [ 60 ] found that 111 In leukocyte imaging accuracy was best for relatively acute infections (less than 2 weeks) but yielded a 27 % false-negative rate among patients with prolonged infections. On the other hand, 67 Ga imaging had its highest sensitivity in long-standing processes, with false-negative results of 19 % in relatively acute infections of less than 1-week duration. In a comparative study of rabbits with experimental abscesses, Bitar et al. [ 61 ] found that 111 In leukocytes were clearly superior to gallium for imaging early abscesses. Furthermore, they found that the accumulation of 111 In leukocytes in experimental subcutaneous abscesses was inversely proportional to the age of the abscess. In abscesses 1-2 h, 6-8 h, 24 h, and 7 days old, 10.4, 5.2, 3, and 0.73 % of the injected dose, respectively, was accumulated. 67 Ga uptake, on the other hand, was not signifi cantly affected by abscess age (Table 4.4 ) . In abscesses 7 days old, 67 Ga accumulated to a greater extent than did 111 In-labeled leukocytes. Thus, Bitar et al., based on animal studies, and Stakianakis et al. came independently to the conclusion that 111 In-labeled WBCs are more suitable for acute infections of short duration, while 67 Ga labeling is better for infections of longer duration. In rats, McAfee et al. [ 62 ] showed that as many as 10 % of circulating neutrophils accumulate daily at focal sites of infl ammation. This high propensity of white blood cells to migrate to an abscess makes positive identifi cation of the abscess likely on an 111 In WBC image. The authors also showed abscess-to-muscle ratios of 3,000 to 1 with 111 In WBCs at 24 h compared with 72 to 1 with 67 Ga and 7 to 1 with 111 In chloride. Accordingly, a small dose of only 500 μCi of 111 In leukocytes is suffi cient for positive identifi cation and localization of abscesses on an image. In 67 Ga imaging, a higher dose of approximately 5 mCi is needed. There is a higher radiation dose to the spleen from 500 μCi of 111 In WBC but radiation doses to gonads, marrow, and the whole body are higher with 5 mCi of 67 Ga. 99m Tc HMPAO-labeled WBCs could provide fast diagnosis and localization of the abdomen (within 2-4 h). Physiological bowel activity, however, is found in 7 % at 2 h and in 28 % of patients imaged with this agent at 4 h. Leukocytes labeled with 111 In or 99m Tc HMPAO are superior to those labeled with 67 Ga for acute infections in terms of sensitivity and specifi city [ 63 , 64 ] . In a recent systematic review of the published studies in humans cited in PubMed written in English, French, German, Italian, and Spanish, it was again found that labeled leukocyte is a sensitive method to localize abdominal abscesses and can guide dedicated US and CT investigations to improve their diagnostic potential [ 65 ] . Table 4 .5 lists the main advantages and disadvantages of the major radiopharmaceuticals used for infl ammation imaging. Several monoclonal antibodies are used to detect infections. These antibodies are mainly directed against receptors on infl ammatory cells. Labeled antigranulocyte agents most commonly used are intact murine immunoglobulin G (IgG) antibodies against normal cross-reactive antigen-95 (anti-NCA-95, 99m Tc-BW250/183, 99m Tc-besilesomab [Scintimun®]) and the murine Tc anti-NCA-90 Fab fragments can recognize a specifi c cross-reacting antigen (NCA-90) (the surface antigenic glycoprotein) on granulocytes, promyelocytes, and myelocytes [ 66 -68 ] . LeukoScan uptake at the site of infection is explained partly by the migration of circulating antibody-labeled granulocytes to the site of infection. Uptake is also explained by the fact that the greater proportion of the labeled antibody fragment is in a free soluble form which can easily cross capillary membranes, binding to the leukocyte once in situ. This mechanism is favored by the increased capillary permeability at the site of infection. An important advantage of LeukoScan is the 5 min preparation time compared with the 2 h 30 min required by a specialized team for labeling leukocytes. Despite the fact that LeukoScan involves the i.v. injection of mouse proteins, no anaphylactic or other hypersensitivity reactions were observed. 99m Tc ciprofl oxacin ( Infecton ) is also being used to image infection. Ciprofl oxacin is a broad-spectrum fl uoroquinolone antibiotic that inhibits DNA gyrase and/or topoisomerase IV of bacteria. Patients receive 99m Tc ciprofl oxacin 10 mCi, and images are obtained at 1, at 3-4, and, occasionally, at 24 h postinjection. 99m Tc ciprofl oxacin may be useful in distinguishing infection from infl ammation. Early images of noninfectious rheumatologic infl ammatory conditions were positive, but activity decreased with time [ 69 ] . 111 In-and 99m Tc-labeled chemotactic peptide analogs have been used for detecting and localizing infections. Imaging can be performed at less than 3 h postinjection, which compares favorably with the 18-24 h or more for most other agents [ 54 ] . Labeled liposomes have been used for scintigraphic imaging of infection and infl ammation [ 70 ] . Boerman et al. [ 71 ] used 111 In-labeled sterically stabilized liposomes (long circulating) in rats and showed that the clearance of this agent is similar to that of 111 In IgG. The uptake in abscess was twice as high as that of IgG and the abscess was visualized as early as 1 h post injection. 99m Tc nanocolloid has also been tried but has not gained wide acceptance. F-18 fl uorodeoxyglucose (FDG-PET) has emerged as an important diagnostic agent for infectious and noninfectious soft tissue and skeletal infl ammations including infl ammatory bowel disease, fevers of unknown origin, rheumatologic disorders, tuberculosis infection, fungal infection, pneumonia, abscess, postarthroplasy infections, chronic and vertebral osteomyelitis, sarcoidosis, and chemotherapy-induced pneumonitis [ 72 -74 ] . Infl ammatory conditions show high FDG uptake which is related to increased glucose metabolism that is produced by stimulated infl ammatory cells, macrophage proliferation, and healing [ 75 ] . While uptake of FDG continues to increase at malignant sites for several hours, as can be shown by an incremental increase of the standardized uptake values (SUV), infl ammatory lesions peak at approximately 60 min, and their SUV either stabilize or decline thereafter. This difference in the behavior of FDG in malignant versus infl ammatory cells can be explained best by the varying levels of enzymes that degrade deoxyglucose-6-phosphate in the respective cells. Glucose-6-phosphatase dephosphorylates intracellular FDG-6-phosphate, allowing it to leave the cell. It has been shown that most tumor cells have low levels of this enzyme, while its expression is high in the mononuclear cells [ 76 -85 ] . For this reason, imaging at 2 time points after administration of FDG may prove to be important in differentiating between these two common disorders. Diagnosis and localization of infection by clinical and laboratory methods is often diffi cult. The results frequently are nonspecifi c and imaging may be needed. Imaging of infection may be achieved by either nuclear medicine or other strictly morphological methods. Several nuclear medicine modalities are used to diagnose and localize soft tissue and skeletal infections. These include 111 In-labeled white blood cells, 67 Ga citrate, IgG polyclonal antibodies labeled with 111 In or 99m Tc, monoclonal antibodies such as antigranulocyte antibodies, 99m Tc HMPAOlabeled white blood cells, 99m Tc nanocolloid, 99m Tc-DMSA, 99m Tc-glucoheptonate, 99m Tc-MDP multiphase bone scan, 111 In-labeled chemotactic peptide analogs, and F-18-FDG. X-ray, CT, MRI, and ultrasonography are other modalities useful in the diagnosis and localization of both soft tissue and skeletal infl ammations. These studies are complementary to the physiological modalities of nuclear medicine. The strategy for imaging soft tissue infections depends on the pathophysiological and clinical features, including whether localizing signs and symptoms are present and the location and duration of the suspected infection. Abdominal abscess: Rapid and accurate diagnosis of an abdominal abscess is crucial. The mortality from untreated abscesses approaches 40 % and may reach 100 % in some series. The mortality among patients treated reaches 11 % [ 86 -93 ] . Delayed diagnosis is associated with higher mortality in spite of treatment. If localizing signs suggest abdominal infection, morphological modalities, predominantly ultrasound ( Fig. 4.8 ) and CT (Fig. 4.9 ) , may be used fi rst, depending on the location of suspected infection in the abdomen. Standard radiographs have low sensitivity, although when seen, fi ndings are specifi c. The advantages of these modalities are numerous, but most importantly, they provide quick results and adequate anatomic details. These studies can be used to guide needle aspiration and abscess drainage. Ultrasound can be used portably for critically ill patients. One of the major limitations of these modalities is the inability to differentiate infected from noninfected tissue abnormalities, particularly in early stages of infection (phlegmon) before formation of abscesses. The diagnostic accuracy of these morphological modalities may be compromised in cancer patients, and the evaluation of studies that use these techniques may be diffi cult. This is because the interpretation of these modalities depends on the presence of normal anatomical markers, which may be altered or obliterated by either the cancer treatment or the cancer itself [ 94 ] . For example, both CT and MRI are often of little value in distinguishing posttreatment scarring from recurrent tumor. When the results of the morphological modalities are inconclusive, nuclear medicine techniques may be used to detect abdominal infections. The ability to image the entire body is the major advantage of nuclear medicine modalities ( Fig. 4.10 ) . Hence, radionuclide techniques are often used in cases with no localizing signs. In one study, 16 % of patients suspected of having abdominal infection in fact had extraabdominal infections as seen on 111 In leukocyte scans [ 95 ] . Accordingly, negative morphological modalities, when used fi rst, may be followed by whole-body nuclear imaging. Labeled WBC studies are the most specifi c for acute infections (Figs. 4.11 and 4.12 ) . Ga-67 is more suitable for infection of longer duration (Fig. 4.13 ). 99m Tc HMPAO-labeled WBCs frequently are used in critically ill patients [ 39 ] after US and/or CT have yielded inconclusive results. It is worthy of note that 99m Tc HMPAO-labeled WBCs provide quicker results than 67 Ga-or 111 In-labeled WBCs. Minoja et al. [ 96 ] reported a sensitivity of 95 %, a specifi city of 91 %, and an accuracy of 94 % for 99m Tc-labeled WBC scanning in intensive care unit patients with occult infections. Gallium-67 scan has been reported to have better diagnostic specifi city than the C-reactive protein test for abdominal infections [ 97 ] . Infl ammatory Bowel Disease: Upright chest radiography and abdominal series, barium enema, and upper GI CT scanning, MRI, and ultrasonography are the main imaging modalities used for the diagnosis. CT scanning and ultrasonography are best for demonstrating complications such as intra-abdominal abscesses and fi stulas. Evaluation of the extent of the disease and disease activity is often diffi cult. A wide variety of approaches depicting the different stages of the infl ammatory response have been developed. Nonspecifi c radiolabeled compounds, such as 67Ga citrate and radiolabeled polyclonal a b Fig. 4.9 Representative images of CT scans of the abdomen illustrating ( a ) periappendicular abscess ( arrow ) and ( b ) hepatic abscess ( arrow ) human immunoglobulin, accumulate in infl ammatory foci due to enhanced vascular permeability. Specifi c accumulation of radiolabeled compounds in infl ammatory lesions results from binding to activated endothelium (e.g., radiolabeled anti-E-selectin), the enhanced infl ux of leukocytes (e.g., radiolabeled autologous leukocytes, antigranulocyte antibodies, or cytokines), the enhanced glucose uptake by activated leukocytes (18F-fl uorodeoxyglucose), or direct binding to microorganisms (e.g., radiolabeled ciprofl oxacin or antimicrobial peptides). Scintigraphy using autologous leukocytes, labeled with 111 In or 99mTc, is still considered the "gold standard" nuclear medicine technique for the imaging of infection and infl ammation, but the range of radiolabeled compounds available for this indica-tion is still expanding. Recently, positron emission tomography with 18F-fl uorodeoxyglucose has been shown to delineate various infectious and infl ammatory disorders with high sensitivity . In a study [ 98 ] , gallium, magnetic resonance imaging (MRI), and PET-FDG were compared for their ability to detect disease activity. PET-FDG showed more than twice as many lesions in the abdomen of patients with Crohn's disease as did gallium. Not all lesions on MRI were FDG positive, suggesting they might represent areas of prior infl ammation. The role of the chest X-ray cannot be overemphasized. The chest X-ray should be used as the initial imaging modality for most chest pathologies. In-111 WBC In-labeled leukocyte scan obtained in a patient with a 10-day history of fever and no localizing signs. Anterior and posterior images reveal physiological uptake in the bone marrow, liver, and spleen with no abnormal accumulation of labeled cells In many instances, however, an additional modality is needed to evaluate certain chest conditions including infections. Although CT often clearly depicts chest pathology including infections, 67 Ga still is commonly used in such cases. 111 In leukocytes have limited utility for chest infections. Siemon et al. [ 99 ] studied 67 Ga imaging in a variety of pulmonary disorders and found excellent sensitivity and specifi city (Table 4 .6 ). Gallium-67 has also been widely used in AIDS patients to detect PCP (Fig. 4.14 ) . It is highly sensitive and correlates with the response to therapy. In a study comparing 67 Ga, bronchial washing, and transbronchial biopsy in 19 patients with PCP and AIDS, 67 Ga and bronchial washing were 100 % sensitive compared with 81 % for transbronchial biopsy [ 101 ] . 67 Ga is also valuable in idiopathic pulmonary fi brosis, sarcoidosis, and amiodarone toxicity [ 102 , 103 ] . It is also useful in monitoring response to therapy of other infections including tuberculosis (Fig. 4.15 ). 111 In WBC imaging is less helpful, as the specifi city of abnormal pulmonary uptake (either focal or diffuse) is very low. Noninfectious problems that cause abnormal uptake include congestive heart failure, atelectasis, pulmonary embolism, ARDS, and idiopathic conditions [ 104 ] . The CT scan has good sensitivity and specifi city in the diagnosis of renal infections. Ultrasound has been used frequently to evaluate the kidneys with suspected infections, even though it is not sensitive. It is used primarily to screen for obstruction or abscess when resolution of UTI is slower than expected with treatment. The sensitivity of US has been shown to be less than 60 % [ 105 ] and is signifi cantly inferior to that of cortical scintigraphy (sensitivity of 86 % and specifi city of 81 % using 99mTc-glucoheptonate). Positive ultrasonography can obviate the need for DMSA; however, because of a large number of false-negative results with reported sensitivities of 42-58 % and underestimation of the pyelonephritis lesions, ultrasonography cannot replace 99mTc-DMSA [ 106 ] . To date 99mTc-DMSA is considered the most sensitive method for the detection of acute pyelonephritis in children ( Fig. 4.16 ). It also permits the photopenic area to be calculated as the infl ammatory volume which correlates with the severity of infection and the possibility of scar formation even though some of the defects detected might be too small to be clinically signifi cant. Currently US is recommended as the initial imaging modalities by the American Academy of Pediatrics and the National Institute for Health and Clinical Excellence (NICE) in atypical and recurrent UTI in pediatric age group [ 107 , 108 ] . The pathophysiological basis of the ability of Doppler sonography in detecting acute pyelonephritis is the fact that in the acute phase of pyelonephritis the, focal decrease of renal perfusion due to edema causes vascular compression, intravascular granulocyte Anterior Posterior From [ 100 ] aggregation, or both, leading to capillary and arteriolar occlusion facilitating the detection of these hypovascular areas [ 109 ] . Several imaging techniques are being utilized for the detection of osteomyelitis including the standard radiograph, computerized tomography, magnetic resonance imaging, and several nuclear medicine modalities. The choice of modality depends on the clinical presentation, particularly its duration, the site of suspected infection, and whether the site of suspected infection has been affected by previous pathology. The pathophysiology of skeletal infl ammations and relevant scintigraphic considerations are discussed in detail in Chap. 5 , on the musculoskeletal system. When no localizing clinical signs are present, which is common in cancer and immunosup-pressed patients, nuclear medicine procedures are often the imaging modalities chosen. The ability to screen the entire body is particularly important for many such cases. The optimal choice of radiotracer again depends on the duration of infection (Fig. 4.17 ) . 111 In-labeled white blood cells are the most specifi c for acute infections, but false-positive results have been reported with some tumors, swallowed infected sputum, GI bleeding, and sterile infl ammation. False-negative results have been reported in infections present for more than 2 weeks. More rarely, such false-negative results occur for infections present for only 1 week. Gallium-67 is less specifi c than labeled WBCs, as it is taken up by many tumors and by sterile infl ammation. Several radiolabeled antibody preparations and a radiolabeled antibacterial agent have been introduced and evaluated, but none of these have been used widely. Labeled antibody scintigraphy uses antigranulocyte agents, most commonly intact murine immunoglobulin G (IgG) antibodies against normal Fig. 4 .14 Gallium-67 images of an AIDS patient with a 5-week history of fever. Images show diffuse uptake in both lungs illustrating the typical pattern of gallium-67 in PCP cross-reactive antigen-95 (anti-NCA-95, 99m Tc-BW250/183, 99m Tc-besilesomab [Scintimun ® ]) and the murine Fab fragment of the IgG antibody directed against the glycoprotein cross-reactive antigen-90 (anti-NCA-90, 99m Tc-sulesomab, LeukoScan ® ). 99m Tc-IgG scintigraphy is a highly sensitive technique for the recognition of infec-tion but has a low specifi city PET-FDG has now taken the place occupied by citrate of Gallium-67. Visualization of infl ammatory lesions does not just rely on the presence of immune cells, but uptake requires the activation of these immune cells. FDG-PET reveals infectious and noninfectious infl ammatory diseases as well as malignant a Fig. 4.15 ( a , b ) Gallium-67 studies of a patient with tuberculosis. Initial study ( a ) showing abnormal uptake of the right lung ( arrows ) which disappeared on follow-up study ( b ) 3 months after starting therapy, indicating excellent response to treatment diseases; all are causes of fever of unknown origin. Recent studies support the use of FDG-PET in the patient with FUO [ 72 , 73 , 110 ] . FDG is sensitive and its short half-life does not delay the performance of any additional radionuclide studies that might be needed. Various chronic infectious diseases that are frequent clinical challenges are better diagnosed with the use of PET, particularly when this imaging is combined with CT. For noninfectious infl ammatory diseases, FDG-PET has proved particularly helpful for the diagnosis and management of large vessels arteritis and infl ammatory bowel disease [ 74 , 111 , 112 ] . Correlation with morphological modalities after successful radionuclide localization of infection can be of great help. For example, this correlation provides anatomical information prior to surgical interventions. Morphological modalities are useful in the management of infl ammatory diseases particularly if localizing signs are present. They have the very important advantages of better spatial resolution than nuclear medicine modalities. X-rays, CT, MRI, and US usually yield fast results but unfortunately may not distinguish infected from noninfected tissue. Many morphological and functional imaging modalities are available to help diagnose and localize infl ammation of the soft tissue and bone. It is clear that no single technique is ideal in all situations. The choice depends on several factors, including whether localizing signs are present, the site of possible infection, whether anatomy is normal or altered by surgery or trauma, the duration of symptoms and signs, and the presence of other underlying diseases such as cancer. For physicians, understanding the pathophysiological changes is crucial for deciding on an appropriate diagnostic strategy. Understanding pathophysiological changes also helps the nuclear physician to recognize and explain the scintigraphic patterns of infl ammatory conditions (Table 4 .7 summarizes common examples). Further evaluation of PET in diagnosis, localizing, and follow-up of infl ammations is a current interest. The discovery of new radiopharmaceuticals that will be ideal for more specifi c imaging of infl ammation is an important topic for future research. 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