Glaudemans Et Al-2015-Diabetic Medicine

Invited Review

Challenges in diagnosing infection in the diabetic foot

A. W. J. M. Glaudemans1, I. Uckay2,3 and B. A. Lipsky2,41Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands, 2Service

of Infectious Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland, 3Orthopaedic Surgery Service, Geneva University Hospitals and

Faculty of Medicine, Geneva, Switzerland and 4Division of Medical Sciences, University of Oxford, Oxford, UK

Accepted 10 March 2015

Abstract

Diagnosing the presence of infection in the foot of a patient with diabetes can sometimes be a difficult task. Because open

wounds are always colonized with microorganisms, most agree that infection should be diagnosed by the presence of

systemic or local signs of inflammation. Determining whether or not infection is present in bone can be especially

difficult. Diagnosis begins with a history and physical examination in which both classic and secondary findings

suggesting invasion of microorganisms or a host response are sought. Serological tests may be helpful, especially

measurement of the erythrocyte sedimentation rate in osteomyelitis, but all (including bone biomarkers and

procalcitonin) are relatively non-specific. Cultures of properly obtained soft tissue and bone specimens can diagnose

and define the causative pathogens in diabetic foot infections. Newer molecular microbial techniques, which may not

only identify more organisms but also virulence factors and antibiotic resistance, look very promising. Imaging tests

generally begin with plain X-rays; when these are inconclusive or when more detail of bone or soft tissue abnormalities is

required, more advanced studies are needed. Among these, magnetic resonance imaging is generally superior to standard

radionuclide studies, but newer hybrid imaging techniques (single-photon emission computed tomography/computed

tomography, positron emission tomography/computed tomography and positron emission tomography/magnetic

resonance imaging) look to be useful techniques, and new radiopharmaceuticals are on the horizon. In some cases,

ultrasonography, photographic and thermographic methods may also be diagnostically useful. Improved methods

developed and tested over the past decade have clearly increased our accuracy in diagnosing diabetic foot infections.

Diabet. Med. 32, 748759 (2015)

Introduction

As the incidence of diabetes mellitus increases worldwide and

people with this disease live longer, the number of patients

developing a diabetic foot complication is growing dramat-

ically. The most common foot problem is an ulceration,

which is most often related to the consequences of prolonged

peripheral neuropathy, often in association with peripheral

arterial disease. While all foot wounds require treatment,

those that are infected are at the highest and most urgent risk

of dire consequences, including lower extremity amputation

and occasionally infection-related death [1]. They are also

the only foot wounds that require antimicrobial therapy.

Thus, diagnosing infection is key to proper treatment of

diabetic foot wounds.

How, then, should we define infection of the diabetic foot?

Many clinicians might respond, I know it when I see it, but

infection appears to be mostly in the eye of the beholder.

Infections are generally defined in one of two ways: 1) the

laboratory isolation of pathogenic microorganisms from a

normally sterile site (e.g. blood, cerebral spinal fluid, sterilely

collected deep tissue) or 2) a constellation of clinical signs

and symptoms compatible with an infectious syndrome. The

classic clinical manifestations of infection, dating from

antiquity, are: erythema (rubor), warmth (calor), swelling

(tumor), pain or tenderness (dolor). There are two major

problems with diagnosing diabetic foot infections. First, all

open wounds are colonized with microorganisms, making

culture results diagnostically non-definitive. Second, the

presence of peripheral neuropathy and vascular disease can

either diminish or mimic inflammatory findings, both in the

soft tissue and underlying bones, reducing their usefulness.

At presentation for medical care, about half of these wounds

are clinically infected [2,3].

Clinical presentation and probe-to-bonetesting

Clinical evaluation (see Table 1) begins with the patients

history. Patients with diabetic foot infections will typicallyCorrespondence to: Benjamin A. Lipsky. E-mail: [email protected]

748 2015 The Authors.

Diabetic Medicine 2015 Diabetes UK

DIABETICMedicine

DOI: 10.1111/dme.12750

have a history of a current or recent (although occasionally

forgotten) wound that caused a break in the protective skin

envelope. These may be caused by mechanical, chemical or

thermal trauma, but are most often attributable to pressure

on a neuropathic (deformed and insensate) foot. On physical

examination, infections are more likely to be present in

wounds that are chronic (present for > 2 weeks), large

( > 2 cm2) or deep ( > 3 mm). Other than cases of erysip-

elas/cellulitis or surgical site infections, infection in the

diabetic foot is an epiphenomenon of underlying problems

related to various concomitant comorbidities. Most impor-

tant among these are peripheral neuropathy (affecting

sensory, motor and autonomic nerves) and peripheral arterial

disease. These disorders can either lead to a diminution of the

expected inflammatory response or be the cause of these signs

and symptoms [4]. The great majority of patients with a

diabetic foot infection have peripheral neuropathy affecting

the feet. In a sizeable percentage of them, Charcot neuro-

osteoarthropathy may be present. In the acute stages this can

manifest as a red, warm, painful foot, mimicking soft tissue

infection, while in the chronic phase it can lead to bony

abnormalities that may suggest osteomyelitis [5]. Similarly,

peripheral arterial disease, which is present in the majority of

patients with diabetic foot infections, may impair manifes-

tations of erythema, warmth or induration, or cause pain

(claudication) or dependent rubor [6]; thus, seeking cardinal

or textbook signs of inflammation, such as warmth,

redness, pain/tenderness, swelling, or loss of function alone

may not be sufficient to diagnose infection. Clinicians must

often seek other potential manifestations of infection, such as

fever, shivering, or purulent secretions, and ask about any

spreading inflammation over the preceding hours or days

[7,8]. Because these findings are often lacking in diabetic foot

infection, some advocate defining infection of a wound by

the presence of secondary findings, such as foul odour,

serous exudate, undermining of the wound rim, discoloured

or friable granulation tissue [9].

Based on the available evidence, the 2012 guidelines on

diabetic foot infections produced by both the Infectious

Diseases Society of America and the International Working

Group on the Diabetic Foot advocate defining infection as

the presence of at least two of the classic findings of

inflammation or purulence [10]. Because of the problems

discussed above, in situations where clinicians are uncertain

about whether or not infection is present, some advocate

empirical treatment with antibiotic agents for 2 or 3 days to

see if clinical signs or symptoms improve. We do not

condone this approach, as it is likely to lead to overtreatment

of uninfected wounds based on a misperceived belief that the

response is to antibiotic therapy. Because diabetic foot

wounds respond to standard wound care, such as cleansing,

debridement, appropriate dressings, pressure offloading and

improved glycaemic control, improvement may not actually

be related to antibiotic-induced killing of infecting patho-

gens. Our recommended approach in such a situation is to

optimize wound care and carefully observe the patient;

should more clear evidence of infection appear, cultures and

antibiotic treatment are then appropriate.

Diagnosing osteomyelitis of the diabetic foot is particularly

problematic. Patients with a history of foot wounds, or with

deep wounds (especially over bony prominences) are more

likely to develop infection of the underlying bone [2]. In

almost all cases, diabetic foot osteomyelitis occurs in a

patient who has a current or recent soft tissue wound

through which contiguous infection leads to bone involve-

ment. Notably, bone infection can sometimes occur under

what appears to be a clinically uninfected ulcer [11]. The

presence of a sausage toe, a red, swollen, warm digit, is

typical of diabetic foot osteomyelitis. The only virtually

pathognomonic clinical sign of osteomyelitis, however, is the

presence of fragments of bone in the wound or dressing, or

fragments found during debridement. In contrast to long

bones, osteomyelitis of the diabetic toe often lacks a

sequestrum or sinus tract that can been easily distinguished

from an overlying ulcer [12].

The probe-to-bone test can be helpful in diagnosing

diabetic foot osteomyelitis, but only if it is performed and

interpreted correctly. The clinician should probe after deb-

riding the wound, using a blunt metal (not wood or plastic)

probe; a characteristic feel of a hard, gritty surface consti-

tutes a positive test [1]. The test is, however, not pathogno-

monic for bone infection. Indeed, based on several reports,

the sensitivity ranges from ~ 60 to 87%, the specificity from

85 to 91%, and the positive predictive value from 87 to

90%. The negative predictive value is only 5662% [1315].

Thus, a key issue in interpreting the test is the pretest

probability of osteomyelitis in the patient population being

studied. Where the clinical or imaging features make the

likelihood of osteomyelitis high, a positive test may be

sufficient for diagnosing probable osteomyelitis. By contrast,

where the suspicion of bone infection is low, a negative test is

helpful in ruling out the diagnosis. The test requires some

Table 1 Summary of potentially useful clinical findings in diagnosingdiabetic foot infection

A. History1. Long duration ( > 4 weeks) of foot wound2. Previous infection at the same or a nearby site3. Presence of new pain in the wound (especially in a

previously insensate foot)4. Presence of immunosuppressive condition (beyond that

related to diabetes)B. Physical examination

1. Large wound ( > 2 cm2)

2. Deep wound ( > 3 mm)3. Classic signs of inflammation (tenderness, pain, redness,

warmth, induration)4. Secondary signs of infection (foul odour, friable or

discoloured granulation tissue, rim undermining,purulent or non-purulent secretions)

2015 The Authors.Diabetic Medicine 2015 Diabetes UK 749

Invited Review DIABETICMedicine

experience to gain mastery and the interobserver concor-

dance is relatively low, with a j index of ~ 50% [16]. On itsown, the performance characteristics of the probe-to-bone

test are similar to those of other less regarded variables, such

as an ulcer area > 2 cm2 or an erythrocyte sedimentation

rate of > 70 mm/h [17].

Serum inflammatory markers

As with other local infections, serum inflammatory markers

are frequently not elevated in diabetic foot infections, espe-

cially in chronic cases. As the available literature reports

conflicting performance characteristic results, recommenda-

tions on the relative usefulness of the several available tests

vary. Some have found higher baseline levels of C-reactive

protein, erythrocyte sedimentation rate and white blood cell

levels in osteomyelitis cases than in those of soft-tissue

infections [18]. While serological tests cannot be used alone,

and the recommended thresholds for differentiating these two

vary, most consider an erythrocyte sedimentation rate

of > 6070 to be perhaps the most suggestive of osteomyelitis

[19]. The serum procalcitonin level is one of the newer tests

promulgated for diagnosing infections. Only a few studies

have reported results in patients with skin and soft tissue

infections; these have found that procalcitonin correlates with

disease classification (being more often elevated in compli-

cated than uncomplicated infections), clinical course of

infection, and other laboratory markers of inflammation

[20]. Results in patients with diabetic foot infections, espe-

cially osteomyelitis, have generally been disappointing [21

23]. Levels are higher in infected than in uninfected diabetic

foot ulcers, but the performance characteristics are not as good

as the erythrocyte sedimentation rate or C-reactive protein

levels [24]. Our review of the available studies suggests that, in

the absence of systemic manifestations of localized infection,

procalcitonin does not help to distinguish acute infection from

acute ischaemia or other non-infectious conditions, or to

differentiate soft-tissue infection from osteomyelitis.

Investigators have sought other serum markers that may

help diagnose infection, especially osteomyelitis. One such

marker is bone sialoprotein because Staphylococcus aureus

isolates from patients with osteomyelitis express bone

sialoprotein-binding protein that binds the corresponding

bone matrix protein. In one pilot study of patients with a

diabetic foot ulcer, serological assays for bone sialoprotein-

binding protein discriminated cases of osteomyelitis from

those with just soft tissue infections [25]. Another innovative

approach could be the measurement of bone turnover

markers, which might indirectly help with the diagnosis

and monitoring of patients with osteomyelitis. Bone alkaline

phosphatase and serum amino-terminal telopeptides are two

such markers; however, in a recent study analysing their

performance in 54 patients with diabetes, neither marker was

useful in detecting osteomyelitis, either at baseline or follow-

up, nor did they help predict outcome [26]. One new idea is

to investigate the value of measuring local cytokine titres in

patients with osteomyelitis. A preliminary retrospective study

of immunohistochemical staining of bone biopsy specimens

of patients with diabetic foot osteomyeltis showed that stains

for interleukin-6 were intensively positive in cases with acute

infection while stains for tumour necrosis factor-a werepositive in chronic or reparative states [27]. Further studies

are needed to see if these markers may prove useful as, for

example, interleukin-6 expression is also high in the acute

Charcot foot [28].

Histopathology

In some cases osteomyelitis can only be diagnosed by

examining a specimen of bone, obtained either at the time

of surgery or by percutaneous biopsy. Most believe the

criterion standard for diagnosing bone infection is obtaining

positive results on both culture and histopathological exam-

ination of bone. This is because bone cultures can be falsely

negative if a patient is taking antibiotics and falsely positive

because of contamination of the specimen, while histopa-

thology can be falsely negative if the infected area is missed

or inaccurate when read by an inexperienced pathologist.

Unfortunately, cultures of soft tissue, even deep aspiration

near the infected bone, do not provide sufficiently accurate

results compared with bone specimens. Even needle bone

puncture appears to provide significantly fewer positive

results (58%) compared with transcutaneous bone biopsy

(97%) [29]. A recent study has shown that when bone

cultures are negative, subsequent occurrence of osteomyelitis

within 2 years follow-up is infrequent [30].

Bone specimens from patients with long-standing diabetes

may be found to have myelofibrosis, osteonecrosis and

osteoporosis at affected sites, but are usually normal or

unremarkable when the bone is not infected [31]. Thus, the

presence in bone of inflammatory cells (particularly poly-

morphonuclear leukocytes, but also mononuclear cells) and

the presence of necrosis indicate bone infection, especially if

microorganisms are visible microscopically and there is no

other reason for chronic inflammation. The criteria for

histopathological diagnosis of osteomyelitis, however, have

not been validated or standardized. The findings of a recent

study showed a remarkable lack of agreement among

pathologists who independently reviewed 39 consecutive

diabetic foot bone biopsy specimens blinded to the patients

clinical characteristics [32]. In only one-third of cases was

there complete agreement on the presence or absence of

osteomyelitis and in 41% of cases there was a clinically

important disagreement between at least two of the pathol-

ogists. This distressing result may have been at least partly

related to the absence of an agreed-upon classification

scheme for diabetic foot osteomyelitis. In light of this finding

and based on extensive experience, Cecilia-Matilla et al. [33]

proposed a well defined scheme of four histopathological

types of diabetic foot osteomyelitis according to the cell



DIABETICMedicine Challenges in diagnosing infection in the diabetic foot Glaudemans et al.

groups present and the histopathological changes in the bone

samples: acute osteomyelitis; chronic osteomyelitis; acute

chronic osteomyelitis; and fibrosis stage (an unresolved final

process of bone infection with fibrotic, avascular tissue).

Using this scheme they showed much less intra-observer

variability between two pathologists [34]. One member of

this group developed a clinical classification scheme for types

of osteomyelitis: without ischaemia or soft tissue involve-

ment (class 1); with ischaemia but without soft tissue

involvement (class 2); with soft tissue involvement (class 3);

and with ischaemia and soft tissue involvement (class 4).

Applying these criteria in a study of 48 patients showed that

the classes were associated with a statistically significant

trend among the four types toward increased severity,

amputation rates and mortality [35]. Other groups will need

to test these classification schemes and it remains to be seen if

they gain wider acceptance.

Culture

Although detecting microorganisms within a diabetic foot

wound (see Table 2) does not currently define the presence of

infection, it is a necessary step for selecting the optimum

therapeutic approach. For over 150 years, we have used

methods developed by Pasteur and others to detect and

classify pathogens. These methods have been useful, but are

limited by several problems. Firstly, we only grow the

organisms we know how to look for, and these easy-to-grow

species may actually be laboratory weeds and we may be

missing true pathogens that standard techniques fail to

identify. Secondly, cultivating microorganisms and deter-

mining their sensitivity patterns usually takes at least 2

3 days, even with the newer more rapid techniques. During

this waiting period we are forced to treat the patient with an

empiric antibiotic regimen, which has been shown to be

inappropriate in almost a quarter of cases [36]. With the

growing pandemic of antibiotic resistance pathogens this

problem is likely to worsen, and it has major clinical and

financial consequences [37]. Thirdly, with over a third of

diabetic foot infections being polymicrobial, we cannot

currently determine which of the microorganisms are truly

playing a pathogenic role and which are merely colonizers.

Fourthly, standard culture methods lead to false-negative

results in patients who are already being treated with

antimicrobial agents, a common clinical situation. Finally,

we have learned that bacteria in wounds are commonly

found in biofilms, making them more difficult to culture (as

well as to treat) [38]. So, how do we address these problems?

To start, while we still depend on the microbiology

laboratory, clinicians need to properly collect and quickly

send them optimum specimens. Although taking a swab of a

wound is easy and inexpensive, it clearly provides a

suboptimum specimen, giving culture results that are both

less sensitive and less specific than with a tissue specimen

[39]. This is clearly a situation where garbage in (a poorly

obtained wound specimen, especially when it takes hours to

get to the laboratory) leads to garbage out (an unhelpful

laboratory report such as mixed cutaneous flora or no S.

aureus found). Quantitative microbiology, championed by

some over the past 50 years, is not the answer, both because

it has not been shown to prove a wound is infected and

because non-research clinical laboratories do not provide this

complex and expensive service.

The future of microbiology certainly appears to be the

newer molecular technologies that are currently making their

way into many diagnostic laboratories. These techniques will

allow rapid identification (probably in less than an hour) of

all of the microorganisms in a wound. Furthermore, they will

rapidly report on the presence of genes that code for

pathogenicity and for resistance to commonly used antibiotic

agents. If this sounds like a distant dream, or an episode of

Crime Scene Investigation, it is not [40]. Newer molecular

tools allow detection of the > 500 species of microorganisms

that constitute the microbiota on various colonized surfaces,

including the skin. Remarkable progress in sequencing

bacterial genomes and the development of new molecular

approaches has facilitated an understanding of the steps in

the evolution of the complex flora of skin microbiota as well

as the development of wound infection.

We now recognize that bacteria within a diabetic foot

wound are often in biofilms, i.e. composites of aggregated

cells encased in an extracellular matrix of hydrated polymers

Table 2 Comparison of methods for identifying causative pathogens in diabetic foot infections

Type of processing Major advantages Major disadvantages When to order Other comments

Standard culture Widely availableRelatively inexpensive

Only identifies knownpathogensResults depend on type ofspecimen collected and rulesregarding reporting

If only method availableUnusual organisms unlikely

Can be supplemented byGram-stained smear

Moleculardiagnosticmethods

More sensitiveIdentifies wider rangeof organismsMore rapid

Not widely available yetMore expensiveUncertainty about how tointerpret results

Unusual organisms more likelySevere infectionPatient on antibiotic therapyRapid identification important

May also provideinformation on thepresence of genescoding for virulencefactors and antibioticresistance



and debris, which impair wound healing and protect the

enmeshed bacteria from host immune responses and anti-

microbials. This has led to the concept of microorganisms in

a wound behaving as functionally equivalent pathogroups,

in which species that usually behave in a non-pathogenic

manner on their own may co-aggregate to act synergistically

to cause a chronic infection. Molecular methods have

uniformly shown that most diabetic foot ulcers host many

more bacterial species in greater numbers than previously

appreciated. Available data suggest that diabetic foot

infections more often arise from the presence of specific

combinations of pathogens than a simple increase in the

microbial load of any one opportunistic microbe. Further-

more, compared with the superficial flora, those from the

deep tissue are more complex and diverse, and especially

rich in anaerobic species. Investigations in the diabetic foot

have shown that the enrichment of the number of S. aureus

organisms may be a precursor to developing clinically

apparent infection in a diabetic foot ulcer. Microbiota

studies have also shown that certain wound flora are

associated with several specific clinical characteristics of

the diabetic foot, including ulcer depth (a surrogate for

wound severity) and duration (which may be a surrogate for

delayed wound healing) [41].

Studies examining the role of S. aureus, the predominant

pathogen in diabetic foot infection, have highlighted the co-

existence of several populations, and that a combination of

five specific genes may help distinguish colonized from

infected wounds and predict ulcer outcome, which contrib-

utes to more appropriate use of antibiotics [42]. Studies have

also shown that using oligonucleotide arrays to determine the

type of clonal complex of S. aureus isolates by DNA arrays is

a promising technique for distinguishing uninfected from

infected wounds, predicting ulcer outcome and thereby

contributing to more appropriate use of antibiotics [43].

Metagenomic approaches have vastly increased our knowl-

edge on the genomes, activity and functionality of the

complex ecosystem residing within the diabetic foot ulcer.

Imaging techniques

The role of imaging in managing the infected diabetic foot

(see Table 3) is expanding and now often plays a key role in

both diagnosis and successful treatment. The aims of all

existing imaging techniques include helping to either exclude

an infection or to confirm the diagnosis, to evaluate the

extent of an existing infection, and to differentiate among

bone infection (osteomyelitis), soft tissue infection and

neuro-osteoarthropathy (Charcot foot). Unfortunately, there

is no single imaging technique that can routinely and

accurately provide all of this information. Key concerns are

that some imaging tests are insensitive when used for an early

diagnosis of the disease, while others are non-specific, as they

cannot easily differentiate between bony changes related to

neuro-osteoarthropathy vs. infection.

Radiological imaging techniques

Plain X-ray

Plain radiography of the foot, taken in at least two different

projections, should virtually always be the initial imaging test

[44,45]. It is inexpensive, widely available, and can detect

major bone structural changes as well as tissue gas and foreign

bodies. Characteristic changes in the early phase of osteomy-

elitis are focal lucency, loss of trabecular pattern and cortical

destruction; later abnormalities include periosteal reaction,

sclerosis and new bone formation [45]. Overall, the sensitivity

( ~ 60%) and the specificity ( ~ 80%) of plain radiography in

diagnosing osteomyelitis in the infected diabetic foot are

relatively low [5]. This relates to three major limitations: 1)

bony changes are only visible when there is demineralization

of > 3050% of the bone, which usually takes at least 2

4 weeks; 2) radiography is suboptimal for detecting soft tissue

infection, although some non-specific signs (induration,

obliteration of peri-articular fat planes) may be seen; and, 3)

differentiating infection from neuro-osteoarthropathy, which

may sometimes co-exist, is difficult. It is possible to overcome

some of these limitations by performing serial radiographs

(e.g. every 2 weeks), whichmay be useful in detecting changes

that are characteristic of osteomyelitis over time [10]. For

many patients in whom the likelihood of osteomyelitis is

either very high or low, the results of plain radiographs may

be sufficient to confirm the clinical suspicion.

Magnetic resonance imaging

When plain radiography fails to provide a clear answer about

the involvement of bone in a diabetic foot, advanced imaging is

usually needed. Magnetic resonance imaging (MRI) is widely

considered the best available radiological imaging technique

currently available to detect the presence and extent of bone

and soft tissue involvement. It is useful, when available and not

contraindicated, to identify the extent of the involved soft

tissue andbone, provide information on vascular perfusion (by

different MRI perfusion sequences, such as arterial spin

labelling and dynamic susceptibility contrast imaging) and

may help guide surgical options [46,47].When osteomyelitis is

presentMRI of affected bone shows a decreased bonemarrow

signal on T1-weighted sequences, and increased signal inten-

sity on T2-weighted images. A finding of increased T2 signal

and normal T1 signal represents oedema suggestive of soft

tissue infection [47]. Administering i.v. gadolinium aids

evaluation of soft tissue involvement and may help demon-

strate abscesses, synovitis, deep tissue necrosis and sinus tracts

[47,48] and to differentiate cellulitis (which enhances with

gadolinium) from non-infectious oedema (with no enhance-

ment) [49]; however, as gadolinium is relatively contraindi-

cated in patients with renal impairment, which is found in

many patients with diabetic foot infection, its use to enhance

MRI is limited in these patients. For the diagnosis of diabetic

foot osteomyelitis MRI has an overall sensitivity of ~ 90%

and a specificity ~ 80% [45].




Table

3Types

ofim

agingtestsfordiabeticfootinfections

Imagingtest

Majoradvantages

Majordisadvantages

Relative

costs()

Sensitivity/

specificity

When

toorder

Other

comments

Plain

X-rays

Relativelyinexpensive

Widelyavailable

Candetectmajorbone

structuralchanges,tissuegas

andforeignbodies

Bonechanges

only

visiblewhen

dem

ineralization

>3050%;

Suboptimalfordetectingsoft

tissueinfection,differentiating

infectionfrom

osteoarthropathy

100200

Sensitivity

~60%

Specificity

~80%

Should

usuallybethefirst

imagingtestordered

Serialrepeatradiographs

could

overcomeseveral

limitationsbydetecting

changes

over

time

MRI

Ableto

identify

extentof

involved

softtissueandbone

Provides

inform

ationon

vascularperfusion

Mayhelpguidesurgicaloptions

Noradiationexposure

Cannotalwaysdifferentiate

infectionfrom

osteoarthropathy

Often

limited

availability

Requires

skilledradiologist

Cannotim

agepatientswho

havevarioustypes

ofim

planted

devices

orwhohave

claustrophobia

500800

Sensitivity

~90%

Specificity

~80%

Inpatientswhorequire

additionalim

agingwhen

softtissueinvolvem

entis

suspectedordiagnosis

remainsuncertain

after

preliminary

evaluations

Extensivelystudiedand

widelyconsidered

thebest

availableim

agingtechnique

CT

Goodim

agingofsofttissuefluid

col-lection,jointeffusion,

foreignbodies,bonecortex

Toguideaspirationsorbiopsies

Softtissuecontrastlower

than

withMRI

Difficultto

dem

arcate

healthy

from

infected

tissue

300400

Sensitivity

~80%

Specificity

~70%

Only

when

other

better

advancedim

aging

techniques

are

notavailable

Notrecommended

by

diabeticfootinfection

guidelines

Bonescan

+SPECT/CT

Widelyavailable

Longexperience

SPECT/CTincreasesdiagnostic

accuracy

Low

specificity

because

of

increaseduptakein

anycause

of

increasedboneform

ation

300400

Sensitivity

~90%

Specificity

~50%

Toruleoutinfectionwhen

suspicionislow;otherwise

only

asecondary

technique

Althoughapositivebone

scanisaslikelyto

beafalse-

asatrue-positive,anegative

scanlargelyrulesoutan

infection

WBCscan+

SPECT/CT

Specificforleukocyticinfiltration

Resultsnotaffectedby

antibiotictreatm

ent

Accurately

detectsboth

acute

andchronicinfections

Requires

laboriouspreparation

under

sterileconditions

Associatedwithrisk

topatient

andtechniciansfrom

handling

potentiallyinfectiousblood

600800

Sensitivity72100%

Specificity

67100%

Consider

when

degreeof

clinicalsuspicionandMRI/

radiographicfindingsare

incongruentorwhen

MRIis

contraindicatedornot

available*

Flow-chartforcorrect

acquisitionand

interpretationresultsin

higher

diagnosticaccuracy

Leadsto

betterlocalization

ofsite

andextentof

infection

FDG-PET/CT

Shortacquisitiontime

Highim

ageresolution

Avoidsneedforblood

manipulation

Low

physiologicalbackground

uptake

Increaseduptakein

inflammation

andmalignancy,aswellas

infection

Noconsensuscriteria

for

interpretation

8001200

Sensitivity29100%

Specificity

6793%

Consider

when

degreeof

clinicalsuspicionandMRI/

radiographicfindingsare

incongruentorwhen

MRIis

contraindicatedornot

available*

Needconsensuscriteria

on

when

todeclare

ascan

positiveornegativeandhow

todifferentiate

between

infection,inflammationand

osteoarthropathy

PET/M

RI

Absolute

simultaneousmatch

betweentissueinform

ationof

both

techniques

BetterlocalizationofPETsignal

Noradiationexposure

withMRI

Expensive

Lim

ited

availability

Longacquisitiontime

Lim

ited

published

experience

10001500

Notavailable

Unknown

Hasthepotentialto

become

thepremieradvanced

imagingtechnique

ideal

one-stopshoppingapproach

MRI,magneticresonance

imaging;CT,computedtomography;SPECT,single-photonem

issioncomputedtomography;FDG-PET,18F-fluorodeoxyglucose-positronem

issiontomography.WBC:

whitebloodcells

*Noconsensuswithin

thenuclearmedicinecommunityonwhichnucleartechniqueistheprocedure

ofchoice.



The major limitation of MRI is that it cannot always

reliably differentiate between infection and neuro-osteoar-

thropathy. Findings supporting neuro-osteoarthropathy are

the presence of intra-articular bodies or subchondral cysts and

involvement of multiple joints, while findings suggesting

osteomyelitis are diffuse signal enhancement in an entire bone,

replacement of fat adjacent to abnormal bone and the

presence of a concurrent skin ulcer or a sinus tract [50].

Differentiating these two conditions is especially problematic

when an infectious process is superimposed on a Charcot foot,

when a patient has had a recent surgical intervention in the

foot, or when osteosynthesis material is present at the site of

interest. Other potential limitations of MRI are its limited

availability inmany locations, high costs, the need for a skilled

specialist radiologist and its inability to image patients with

various types of implanted devices (e.g. orthopaedic metal-

work, pacemaker, surgical clips) or who have claustrophobia.

Ultrasonography/computed tomography

Diagnostic ultrasonography and computed tomography (CT)

each play a limited role in the evaluation of diabetic foot

disorders and are not recommended in most published

diabetic foot guidelines [46,49,51,52]. If other and better

techniques are not available, ultrasonography may be used to

detect the presence of soft tissue fluid collections, joint

effusion and foreign bodies [49] and to guide peri-articular

aspirations or soft tissue biopsies [53]. CT is more accurate

than plain radiography for evaluation of cortical erosions,

focal areas of lucency, bone sequestra [45] and soft tissue

gas. Compared with MRI, however, the soft tissue contrast is

lower and it is more difficult to demarcate between healthy

and infected tissue.

Nuclear medicine imaging techniques

Nuclear medicine techniques detect in vivo pathophysiolog-

ical changes, sometimes even before anatomical changes are

observable. The role of nuclear medicine techniques for

imaging infectious diseases has been enhanced by new

insights into methods to acquire and interpret standard

imaging techniques, recent developments in integrated cam-

era systems that combine physiological and anatomical data

and the availability of more specific tracers.

Bone scintigraphy

Three-phase bone scintigraphy was among the first, and

remains the most widely used, nuclear imaging procedure for

the diagnosis of musculoskeletal infections. This technique

has a high sensitivity (i.e. when all three phases are negative

infection is highly unlikely) but unfortunately a low speci-

ficity (i.e. many false-positive results). Any cause of increased

bone formation (e.g. recent surgery, fractures, malignancy,

metabolic bone disease, prosthetic loosening) may cause

increased uptake of diphosphonates in the late (third) phase.

Furthermore, in several of these conditions there may also be

increased blood flow (first phase) or blood pool (second

phase). Meta-analyses of the use of three-phase bone

scintigraphy for detection of diabetic foot infection using

only planar imaging, or combined with single-photon emis-

sion computed tomography (SPECT), estimate a sensitivity

of ~ 90% but a specificity of ~ 50% [45,48,54]. Although

recent development in camera systems (SPECT/CT) may lead

to better diagnostic accuracy, the many causes of high

diphosphonate uptake make this technique a secondary

imaging technique for diagnosing diabetic foot infection. Its

main usefulness is that a negative scan largely rules out an

infection, although scintigraphy may be falsely negative in

patients with lower extremity ischaemia.

Labelled white blood cells

The use of radiolabelled white blood cells (WBC) is still

considered the best nuclear imaging technique for musculo-

skeletal infections. Labelling with 99mTechnetium is preferred

to 111Indium as it has better radiation characteristics, requires

a lower radiation dose, has higher image resolution and lower

costs. This technique is quite specific for detecting leukocytic

infiltration, its results are not affected by recent or current

antibiotic treatment [55,56] and it can accurately detect both

acute and chronic (even low grade) infections. The disadvan-

tages ofWBC scintigraphy include the fact that its preparation

is laborious, it must be performed under sterile conditions, it

takes a trained technician ~ 3 h to do the labelling and it

exposes the patient to a relatively high dose of radiation. In

addition, the tests requirement for handling potentially

infectious blood puts both technicians and patients at risk.

The role of radiolabelled WBCs in diabetic foot infections

has been extensively investigated, with reported sensitivities of

72100% and specificities of 67100% [48,54,57,58]. The

poorer results are generally reported from studies using only

planar imaging with poor spatial resolution and no bony

landmarks to help differentiate soft tissue infection from

osteomyelitis. The reasons for the variability in reported

diagnostic accuracies include variations in labelling proce-

dures, acquisitionprotocols and interpretationcriteria [59,60].

Recently, data from two studies led to a proposal for a new

flow chart for the correct acquisition and interpretation of

WBC scintigraphy including dual-time point imaging (34 h

and 2024 h after administration) with time decay-corrected

acquisition [55,61]. Over time, an increase in WBC uptake

strongly supports an infection, whereas a decrease in uptake

makes infection highly unlikely. In doubtful or equivocal

cases, performing a semi-quantitative analysis using the

contralateral side as reference may be useful. Following this

flowchart results in high diagnostic accuracy; its implemen-

tation in new guidelines developed by the Infection and

Inflammation Committee of the European Association of

Nuclear Medicine should lead to better and more compara-

ble study results at different centres.

In the past decades, some suggested that the combining of

bone scans with WBC scintigraphy, or bone scan/WBC




scintigraphy and bone marrow imaging, might improve

diagnostic accuracy. Unfortunately, studies found that using

these techniques together did not substantially improve the

results [59,62]. We believe that when nuclear medicine

specialists use the correct protocol for WBC imaging and

interpretation there is no need for additional bone and/or

bone marrow imaging.

Single-photon emission computed tomography/computed

tomography

Using new integrated camera systems that combine physio-

logical and anatomical data has now become standard

procedure. SPECT/CT has several advantages over standard

or dual isotope scans: it can provide excellent cortical spatial

resolution, is less expensive than dual scintigraphy, delivers a

lower radiation dose, and can be used with several different

isotope agents. In WBC scintigraphy adding SPECT/CT to

the early images (34 h) leads to better localization of the site

and the extent of the infection, and better differentiation

between soft tissue infection and osteomyelitis [61], thereby

achieving better diagnostic accuracy [63]. Using a composite

severity index (a standardized hybrid image-based scoring

system) appears to add prognostic value for diagnosing

diabetic foot osteomyelitis to 99mTc-SPECT/CT [64].

Another additional potential use of SPECT/CT is helping to

determine when diabetic foot osteomyelitis has resolved.

This is a key issue for knowing when to discontinue

antibiotic therapy and whether or not surgical treatment

may be needed, yet it is probably even more difficult than

diagnosing infection. One study with 29 patients with

diabetic foot osteomyelitis found that a negative WBC

SPECT/CT at the end of antibiotic therapy had a 100%

negative predictive value (and 71.5% positive predictive

value) for detecting relapse of infection [65].

18F-fluorodeoxyglucose positron emission tomography

The newer technology of positron emission tomography

(PET) with 18F-fluorodeoxyglucose (FDG) has several theo-

retical advantages over standard scintigraphy: it avoids the

need for blood manipulation (like WBC scintigraphy); acqui-

sition time is shorter; image resolution is higher; and

physiological FDG background uptake is low. The major

limitation of this technique is that, in addition to infection,

FDG accumulates in malignancies and inflammation, because

cells involved in all three of these processes metabolize glucose

as a source of energy [66]. Increased glucose metabolism of

leucocytes, macrophages, monocytes, lymphocytes and giant

cells occurs in infectious and inflammatory diseases, but

uptake is also seen in regenerating and traumatic processes.

The FDG-PET method may be helpful in the diagnosis of

diabetic foot infection, but its role in the evaluation of

diabetic foot infection has yet to be clarified [67]. Diagnostic

accuracies have varied from 54 to 94% [6871]. A recent

systematic review and meta-analysis found nine studies

comprising 299 patients evaluated for diabetic foot prob-

lems. The quantitative analysis of four selected studies

provided the following results on a per patient-based

analysis: sensitivity 74%; specificity 91%; positive likelihood

ratio 5.56; negative likelihood ratio 0.37; and diagnostic

odds ratio 17 [72]. What is now needed is a consensus about

which criteria should be used to declare the results of a scan

as positive or negative and how best to differentiate between

infectious and non-infectious entities. For now, when FDG-

PET imaging shows no increased uptake infection is unlikely,

but when FDG uptake is increased, it is challenging to

differentiate between the various causes: infection, inflam-

mation, neuro-osteoarthropathy, recent surgery, fractures,

osteophytes, enthesopathy and degenerative changes. Cur-

rently, PET camera systems are combined with CT to allow

precise anatomical localization of the FDG uptake (Fig. 1).

This facilitates differentiation between osteomyelitis and soft

tissue infection, but does not solve the problem of differen-

tiating among infection, inflammation and osteoarthropathy.

Notably, elevated blood glucose levels negatively influence

the accuracy of FDG-PET scans; obviously, this is a common

finding in patients with suspicion of an infected diabetic foot.

Other nuclear tracers

67 Gallium (67 Ga)-citrate. 67 Ga-citrate was previously used

extensively for imaging infections but its suboptimum

intrinsic characteristics (poor spatial resolution, non-specific

binding) and the development of better tracers have resulted

in it rarely being used currently. In a recent study of 67Ga-

SPECT/CT with 55 patients with suspected diabetic foot

osteomyelitis it had a negative predictive value of 100%, but

a positive predictive value of only 50% [73].

Antigranulocyte antibodies. Considerable efforts have been

devoted to developing in vivo methods for WBC labelling

that could overcome the limitations of in vitro-labelled

WBCs. Although production of antigranulocyte monoclonal

antibodies (e.g. Scintimun, LeukoScan) has been promis-

ing, the results have not been found to be better than in vitro99mTc-labelled WBCs.

Labelled WBCs for PET imaging. WBCs have also been

labelled in vitro with FDG in an attempt to develop a more

specific PET tracer. Only a few published studies are

available on this tracer (none of which included patients

with an infected diabetic foot) and results have varied

[59,74]. Unfortunately, this technique delivers high amounts

of radioactivity and, because of the short half-life of 18F

(110 min), it is technically not feasible to perform imag-

ing > 45 h after injection.

Which imaging technique is the first choice?

Both the Infectious Disease Society of America and the

International Working Group on the Diabetic Foot have



included recommendations in their guidelines for imaging

diabetic foot infections. Recently, a promising combined

diagnostic flow chart was proposed by a committee of

expert clinicians, radiologists and nuclear medicine spe-

cialists [56]. Plain radiography is recommended in all

patients who present with a potential diabetic foot

infection, to look for bony as well as soft tissue abnor-

malities [1]. If both the clinical presentation and X-rays

are most compatible with osteomyelitis, no further diag-

nostic evaluation is needed. For patients in whom either

the diagnosis or the optimum surgical approach is unclear,

additional imaging with MRI is recommended [1]. Nuclear

medicine imaging techniques should be considered in cases

in which clinical suspicion and MRI/radiographic findings

are incongruent or inconclusive, or when MRI is contra-

indicated or not available. There is no general consensus

within the nuclear medicine community on which nuclear

technique should be the procedure of choice, but most

would recommend either labelled WBCs with SPECT/

CT or FDG-PET/CT. Large-scale studies, preferably

comparing these techniques with MRI, are needed to

determine the most appropriate imaging tool and to

analyse the cost-effectiveness of all available imaging

techniques.

Future perspectives in imaging

Positron emission tomography/magnetic resonance imaging

Simultaneous imaging with the recently developed combined

PET/MRI camera system has the potential to become the

premier technique for assessing the infected diabetic foot. It

combines acquisition and quantification of functional data at

the molecular level with superior soft tissue resolution and

anatomical detail. Advantages include providing an absolute

match between the tissue information of both techniques

under the same physiological conditions (PET/CT is per-

formed sequentially, not simultaneously), better localization

of the PET signal within soft tissues, no radiation exposure

withMRI, and a one-stop-shopping approach for the patient

by allowing the acquisition of diagnostic quality imaging

results of nuclear medicine and radiological techniques in one

visit. This hybrid PET/MRI imaging could optimally differ-

entiate among soft tissue infection, osteomyelitis, inflamma-

tion and neuropathic osteoarthropathy [75].

Possible new positron emission tomography

radiopharmaceuticals

In most clinical situations, and particularly in the low grade

infected diabetic foot, imaging at late time points (e.g. 24 h

(a) (b)

(c) (d)

FIGURE 1 Example of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/ computed tomography (CT) imaging in a patient with

diabetes with suspicion of an infected foot. (a) sagittal PET view. (b) Sagittal PET/CT fusion. (c) Transversal PET view. (d) Transversal PET/CT

fusion. Note increased FDG uptake most compatible with osteomyelitis involving the plantar aspect of the fifth metatarsus and infection in the

adjacent soft tissues (Figure provided courtesy of Dr Zohar Keidar, Ramban Health Care Campus, Haifa, Israel).




after injection) is necessary because of the slow leukocyte

accumulation in infected sites as compared with bone

marrow. Regrettably, this delay between injection and

imaging is not possible using 18F as radiolabel, but fortu-

nately, 64Copper, with a half-life of 12.7 h, appears to be a

more suitable radionuclide for labelling of white blood cells;

the first attempts to in vitro labelling of WBCs with 64Copper

have been successful [76], and we are anxiously waiting for

the first clinical results.68Ga-citrate PET/CT imaging is another emerging tech-

nology. The imaging characteristics of the PET tracer 68Ga

are superior to those of 67Ga because it provides higher

spatial resolution and because of the quantification potential

of PET. 68Ga-citrate has other advantages, including rapid

blood clearance, quick diffusion and the fact that it can be

produced in any hospital by generator without the need of a

cyclotron on site; however, to date there has been only one

study in 31 patients with suspected osteomyelitis (showing a

diagnostic accuracy of 90%) and there is no experience in

patients with infected diabetic foot [77].

Tailored radiopharmaceuticals

Advances in molecular techniques and translational medicine

have taken nuclear medicine to the threshold of a new

diagnostic era. Personalized medicine, based on individual

characteristics of the patient and the pathogen, is now under

investigation in large oncological trials and has the potential

to provide optimum treatment in infectious diseases. Nuclear

medicine techniques provide the opportunity to characterize

pathophysiological processes histologically, highlight the cell

type(s) involved, detect the presence of a potential target,

quantify the pathogenic bacteria and biologically active

molecules (e.g. cytokines and chemokines) and detect the

presence of apoptopic and autoreactive cells [78]. It may also

allow evidence-based biological therapy by assessing which

molecule will localize in an infected area, then using the same

unlabelled molecule therapeutically [78].

Photographic foot imaging and infrared thermography

Patients at risk of foot ulcers should be screened regularly by

an appropriately trained healthcare professional. In some

situations, however, this rather time-consuming, relatively

intrusive and costly procedure may not be logistically

possible. In those situations, using telemedicine diagnostic

support in the home environment may allow the required

foot assessment. Recently, investigators developed a photo-

graphic foot imaging device to use for home monitoring for

the early diagnosis of foot ulcers and pre-ulcerative lesions in

patients with diabetes [79]. The device provided high-quality

digital photographs of the plantar foot surface that could be

remotely assessed by a foot specialist.

As infections tend to cause inflammation and increased

blood flow, increased skin temperature is another important

sign of possible foot infection. Home monitoring of foot

temperatures by infrared thermometry has been shown to be

effective in patients with diabetes [80]. In fact, infrared

thermal cameras may be useful to either detect infections or

to predict which patients are at risk of future foot compli-

cations [81], including infections [82]. In a recent study of 38

patients with a diabetic foot complication assessed with

photographic and temperature sensing devices, diagnosis of

infection from photographs was specific ( > 85%) but not

very sensitive ( < 60%), while thermography was sensitive

( > 90%) but not very specific ( < 25%). Diagnosis based on

the combination of both techniques was both sensitive

( > 60%) and specific ( > 79%) with good intra-observer

agreement [83]. These techniques are promising for the home

monitoring of high-risk patients with diabetes to facilitate

early diagnosis of signs of infection [83].

Conclusions

In the past decade we have made great strides in diagnosing

infection in the diabetic foot. Clinical examination (history,

physical, probe-to-bone) remains the first and most important

diagnostic approach. Laboratory tests, especially the erythro-

cyte sedimentation rate, but disappointingly not procalcitonin,

provide some help, especially with diagnosing and following

osteomyelitis, butwe need better tests. The coming availability

of molecular microbiology in clinical laboratories will almost

certainly help to not only more rapidly identify causative

pathogens, but also to provide information on their potential

virulence. Advanced imaging techniques, particularly hybrid

imaging possibilities (SPECT/CT and PET/MRI) have made

these tests more useful in both diagnosing infection and

helping to direct therapy. Our clinical forbears would be

jealous of our diagnostic armamentarium, but our students

seem poised to benefit from the next generation of the new

techniques that are now emerging.

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