Elsevier

The Lancet

Volume 354, Issue 9180, 28 August 1999, Pages 765-770
The Lancet

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Nuclear medicine's role in infection and inflammation

https://doi.org/10.1016/S0140-6736(99)06070-5Get rights and content

Summary

Nuclear medicine imaging techniques can help in patient evaluation where infectious and non-infectious inflammatory disorders are suspected. When selected and tailored to the clinical situation, most techniques already in use or available soon provide information with high sensitivity. However, almost all currently available techniques lack the specificity to discriminate between infectious and non-infectious inflammation. In undiagnosed fever, this non-specificity may be an advantage since fever of unknown origin is caused by infection in only about 25% of cases, but in the postoperative patient the reliable differentiation between infection and sterile inflammation is highly relevant to clinical management. The range of radiopharmceuticals to investigate infectious and non-microbial inflammatory disorders is expanding and developments in protein/peptide chemistry and in labelling technology should lead to agents with very high specific activities. Nuclear medicine has to add specificity to its already high sensitivity if it is to distinguish both categories of inflammatory disorder.

Section snippets

Inflammation

Infectious diseases remain prominent in clinical medicine. Dealing with patients with presumed or established infective disorders, clinicians often struggle with questions (panel 1) that nuclear medicine is attempting to answer. Before dealing with these questions in detail we will briefly discuss inflammation and review how radiopharmaceuticals act with the inflammatory process.

All inflammatory processes, infectious and non-infectious, develop along a known sequence: leakage of fluid, small

Well-established radiopharmaceuticals

Panel 2 summarises the six techniques which have been most intensly investigated and which are in clinical use.

67Ga-citrate

Gallium-67 binds to transferrin in the blood, extravasates at the site of inflammation, and is then bound to lactoferrin. In a low-iron environment it has a high binding affinity for siderophores. There is physiological uptake in liver, spleen, bone marrow and kidney and, later, in the colon, which may hamper visualisation of infection/inflammation in or in the vicinity of these organs.2

111In-leucocytes

Autologous leucocytes labelled with indium-111 are considered the “gold standard” nuclear medicine technique in infection and inflammation, (figure 1). After intravenous administration, the radionuclide is rapidly cleared from the normal lungs and the blood pool and there is high influx in predominantly neutrophilic infiltrates. There is high physiological uptake in spleen and liver, but the absence of uptake in kidneys, bladder, gallbladder, and bowel makes this preparation appropriate for

99mTc-HMPAO-leucocytes

The above comments on 111In-leucocytes apply to radiolabelled leucocytes generally, but with two major exceptions. Leucocytes labelled with technetium-99m (the linker being hexamethylpropylene-amine-oxime, HMPAO) has the advantages of continuous availability, low radiation burden, and ideal γ-ray energy. However, this agent is less stable than 111In-leucocytes; every hour 5–7% of the radiolabel elutes from white blood cells, leading to significant activity in kidneys, bladder, gallbladder, and

99mTc-antigranulocyte MoAb

MoAbs directed against granulocyte surface antigens such as non-specific cross-reacting antigen NCA-95 localise in infectious foci along two specific pathways via specific binding to epitopes expressed on activated granulocytes, followed by diapedesis of these white blood cells at infectious foci, and through non-specific leakage due to enhanced vascular permeability at the site of inflammation. Formatted as the small Fab' antibody fragment, this agent is rapidly cleared from the circulation

99mTc-HIG

HIG labelled with 99mTc-iminothiolane is an “innovative drug” in many European countries. It has been successfully used to measure inflammation.4 Because of physiological uptake in the colon another 99mTc-HIG preparation was developed, with hydrazinonicotinylamide as chelator. The first clinical study showed good performance in various infections and inflammatory conditions.5

18F-deoxyglucose (FDG)

Positron emission tomography (PET) with 18FDG is now widely used. FDG is taken up by inflammatory cells with increased metabolic requirements. In contrast to glucose, deoxyglucose cannot leave the cell once it is taken up, so it can be used to image scintigraphically cells with high glucose uptake such as tumour cells and inflammatory cells.6, 7, 8

Selection of nuclear medicine procedure

As the number of radiopharmaceuticals increases, so the choice of agent becomes more difficult. The nuclear medicine specialist has to select the radiopharmaceutical most likely to answer the questions posed by the referring physician. Those questions (panel 1) now need further elaboration. The lesions may have already been detected by other techniques but it is unclear whether it is inflammatory or has another cause (degenerative, neoplastic, or ischaemic). The choice of nuclear medicine

Suspected bone infection

When an acute bone lesion is suspected, most often after plain radiography, scintigraphy with 99mTc-methylenediphosphonate (MDP) is the first step. Although the technique is very sensitive, it is not specific,9 because trauma, degenerative arthritis, and other bone disorders will yield positive images and remain positive for years. 99mTc-MDP cannot exclude infection in chronic osteomyelitis. Greater specificity, with equal sensitivity for inflammation, is obtained with any of the six

Suspected soft-tissue infection

Again, the utility of the various techniques is related to the site in the body and to the acuteness of the inflammation. 99mTc-leucocytes give good results in acute sepsis but chronic lesions are not well imaged because of low influx of leucocytes.

Disorders in the chest such as sarcoidosis and Pneumocystis carinii infection may be well imaged using 67Ga13, 14 but this agent is not useful in the abdomen because of excretion in the gut.

Abdominal abscesses are imaged adequately with radiolabelled

Fever of unknown origin

Fever (pyrexia) of unknown origin (FUO) is defined as a rise in body temperature above 38·8°C, on at least three occasions, present for at least 3 weeks or more that is unexplained after a week of thorough clinical investigation.19 The yield of scintigraphy-ie, being helpful to diagnose infections—seems to be much greater in patients who have potentially diagnostic clues than in those without.20 The contribution of nuclear medicine to the diagnosis of FUO is difficult to judge because there are

Septicaemia

In patients with microbiologically proven bloodstream infection, the clinician often needs to know if there are focal lesions, primary or metastatic. The urge to do such investigations is stronger when the microorganisms detected are ones that readily produce metastatic foci such as staphylococci, streptococci, salmonellae, and Candida spp. Detection of such foci dictate the need for surgery and/or prolonged antimicrobial treatment. Although this is a common indication for nuclear medicine

Remaining questions

We have concentrated on question 1 in panel 1 because that is the one for which answers are beginning to emerge. Question 2 asks about the size and extent of an infectious focus, an assessment that may be important for treatment. Systematic investigations in this area are lacking. Question 3 may be even more important. The duration of antimicrobial treatment for deep-seated and difficult infections is arbitrary. Serial scintigraphy may help but this issue too needs further study. Finally, the

Expectations for the future (1–5 years)

The aims in the development of new radiopharmaceuticals for infection-inflammation are: (1) to avoid the use of possible infected blood, autologous or allogenic; (2) to take advantage of smaller molecules with rapid clearance so that the referring clinician can have an answer the same day; (3) to develop agents with receptor interaction; (4) to distinguish between infection and non-infectious inflammation; and (5) to make even wider use of 99mTc-labelled agents.

Agents under clinical development

111In-HIG

HIG labelled with 111In leaks out of vessels at sites of increased vascular permeability (figure 2). Unlike radiolabelled leucocytes and antigranulocyte MoAbs, it is hardly taken up in the normal bone marrow. Very good results were obtained in over 100 patients with hip and knee protheses suspected of having joint infection.23 In contrast to the other experimental agents 111In-HIG has been studied in a variety of clinical conditions. It seems most helpful to detect bone, joint and joint

Radiolabelled sterically stabilised liposomes

Liposomes were proposed as vehicles to image infection and inflammation some 20 years ago, but they are too rapidly cleared from the circulation by the mononuclear/phagocyte system. However, if a hydropholic polymer such as polyethyleneglycol is introduced into the lipid bilayer, the liposomes seem to be protected from recognition by the monocyte/phagocyte, leading to prolonged residence time in the circulation and enhanced uptake in pathological sites (figure 3). Such stabilised liposomes can

Radiolabelled anti-E-selectin MoAb

E-selectin is an endothelial adhesion molecule exclusively expressed on the luminal surface of activated (“inflamed”) cells and capable of binding to leucocytes.30 F(ab)2 fragments of a MoAb against E-selectin radiolabelled with 111In or 99mTc have been used successfully to image arthritis.31 To overcome the possible induction of human anti-mouse antibodies, a bio-engineered single-chain antibody construct is being tested.

99mTc-anti-CD-15 MoAb

This IgM antibody interacts with antigens specifically expressed on neutrophils. It seems not to induce anti-mouse antibodies and after labelling with 99mTc it provided good imaging results in less than 60 min post-injection in patients with equivocal appendicitis. There was a temporary drop in circulating leucocyte count, with full recovery less than 1 h post-injection.32

Radiolabelled receptor-binding proteins and peptides

The search for agents close to the profile of the ideal radiopharmaceutical to image infection and inflammation includes several small proteins and peptides exhibiting high affinity for receptors, present on inflammatory cells. These include chemotactic peptides, tuftsin antagonist, interleukin-1 (IL-1), IL-1 receptor antagonists, IL-2, IL-8, platelet factor 4, octreotide, and substance P.33 Almost all of these agents provide good imaging of infectious and non-infectious inflammation within a

99mTc-ciprofloxacin derivative

Ciprofloxacin, a fluoroquinolone antimicrobial agent, binds to the DNA gyrase enzyme present in all dividing bacteria, even to those resistant to ciprofloxacin. Fluoroquinolones do not bind to dead bacteria nor do they accumulate in the normal bowel, or in non-microbial inflammatory processes such as in Crohn's disease. It is claimed that with these 99mTc-labelled agents it is possible to discriminate between infection and sterile inflammation.36 First clinical studies in several centres so far

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