Diagnosis of Acute Osteomyelitis


Indication Overview

Osteomyelitis is an infection localized to the bone, most commonly due to the bacterium Staphylococcus aureus (S. aureus),1,2 occurring when infection spreads from soft tissues of joints to bone tissue (i.e., contiguous spread), as a result of direct implantation of an infectious agent to bone during surgery or penetrating trauma or due to direct deposits from the blood stream (hematogenous seeding).3 Osteomyelitis is a progressive infection and can be divided into an acute or subacute stage, progressing to a chronic stage if left untreated (i.e., inflammatory destruction, necrosis, and bone deformation).4 Differentiation between acute and chronic osteomyelitis is associated with the timing of disease onset (i.e., injury or presence of infection). A diagnosis of acute osteomyelitis is made when the disease has been discovered within two weeks after initial onset, while chronic osteomyelitis refers to disease that has existed for several months at the time of diagnosis.5 Management primarily includes early treatment with antimicrobial therapy.5 Orthopedic surgery (e.g., debridement) may be required in some cases (e.g., complicated penetrating trauma or chronic non-resolving or unresponsive to antibiotic therapy osteomyelitis).

Osteomyelitis occurs in both children and adults and in various subpopulations, including in people with prostheses, diabetes, HIV and AIDS, and sickle-cell disease (SCD), and in athletes.2,6-15 Common sites of infection include the skull, hip (pelvis, sacroiliac joints, hip joints, and proximal femur), spine, and lower extremities (e.g., knee).5,16,17 Foot osteomyelitis, often referred to as "pedal osteomyelitis" or "diabetic foot," is most common in diabetic patients.18

The most common method of diagnosing osteomyelitis involves sampling the infected tissue either through bone biopsy or surgery and having laboratory procedures to confirm the existence of bacterial involvement. This is a relatively invasive and costly procedure and there has been an effort to explore alternate non-invasive techniques, including diagnostic imaging, for identifying the presence of infection.19 Nuclear bone scintigraphy is a frequently performed nuclear medicine procedure for the detection of bone disorders.20,21

Population: Adults and children presenting with symptoms consistent with acute osteomyelitis, which include bone pain, tenderness, lower extremity warmth, and swelling.22

Intervention: Bone scintigraphy (bone scan).

Bone scintigraphy is a common method used to diagnose acute osteomyelitis.20,21 Most bone scintigraphs are conducted with the administration of methylene diphosphonate labelled with technetium-99m (99mTc-MDP).13 After the radioisotope has been injected into the blood, it accumulates in the bone.13 Imaging usually occurs in three phases — the first phase (called the angiographic phase) is obtained at the time of administration of 99mTc-MDP; the second phase, or blood pool phase, is obtained in the first few minutes after injection to assess alterations in vasculature due to inflammation; and the third phase is obtained three to six hours after injection, to look at bone uptake. Images are acquired with a nuclear medicine gamma camera. Early images are usually static (e.g., planar images) but the delayed bone or skeletal images can be taken as planar or multi-planar cross-sectional single-photon emission computed tomography (SPECT) or SPECT/CT (computed tomography) images (i.e., images like a conventional CT with the bone scan findings incorporated into the CT images — referred to as hybrid imaging), and the diagnosis is determined by the accumulation of the radioactive tracer.5 Radiotracer accumulates in relatively greater amounts in areas of bone turnover and where there is osteoblast activity, indicative of new bone formation.23 Ischemia, which is common in osteomyelitis, can prevent the isotopes from collecting and can lead to false-negative results.

Comparators: For this report, the following diagnostic tests are considered as alternatives to bone scintigraphy with 99mTc:

  • Computed Tomography (CT)
  • Leukocyte Indium-111 White Blood Cell Scan (111In-WBC)
  • Magnetic Resonance Imaging (MRI)
  • 18F-fluorodeoxyglucose Positron Emission Tomography (18FDG-PET)
  • Ultrasound (U/S)

Outcomes: Eleven outcomes (referred to as criteria) are considered in this report:

  • Criterion 1: Size of the affected population
  • Criterion 2: Timeliness and urgency of test results in planning patient management
  • Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition
  • Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition
  • Criterion 5: Relative impact on health disparities
  • Criterion 6: Relative acceptability of the test to patients
  • Criterion 7: Relative diagnostic accuracy of the test
  • Criterion 8: Relative risks associated with the test
  • Criterion 9: Relative availability of personnel with expertise and experience required for the test
  • Criterion 10: Accessibility of alternative tests (equipment and wait times)
  • Criterion 11: Relative cost of the test.

Definitions of the criteria are in Appendix 1.

Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE with In-Process records via Ovid; The Cochrane Library (2011, Issue 1) via Wiley; PubMed; and University of York Centre for Reviews and Dissemination (CRD) databases. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concepts were radionuclide imaging and osteomyelitis.

Methodological filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses (HTA/SR/MA), randomized controlled trials, and non-randomized studies, including diagnostic accuracy studies. No date or human limits were applied to the HTA/SR/MA search. For primary studies, the retrieval was limited to documents published between January 1, 2006, and February 18, 2011, and the human population. Both searches were also limited to English language documents. Regular alerts were established to update the search until October 2011. Detailed search strategies are located in Appendix 2.

Grey literature (literature that is not commercially published) was identified by searching relevant sections of the CADTH Grey Matters checklist. Google was used to search for additional web-based materials. The searches were supplemented by reviewing the bibliographies of key papers. See Appendix 2 for more information on the grey literature search strategy.

Targeted searches were done as required for the criteria, using the aforementioned databases and Internet search engines. When no literature was identified that addressed specific criteria, experts were consulted.

Search Results

Twenty potential clinical articles were identified through the HTA/SR/MA filtered search and 18 were subjected to full text review. One hundred and seventy-four potential primary studies were identified with a search of primary studies. Additional studies were identified in searches for grey literature, targeted searches, and alerts.

This review focused on acute osteomyelitis; however, studies that did not explicitly state that the osteomyelitis was acute were included in this report. Studies that were solely based on chronic osteomyelitis were excluded.

Information from two meta-analyses,24,25 one systematic review,26 and one primary study27 was used to inform criterion 7 on diagnostic accuracy. For the other criteria, included studies were not limited by study design or date, and were obtained from the HTA/SR/MA search, the primary studies search, grey literature searching, targeted searching, and handsearching.

Summary table

Table 1: Summary of Criterion Evidence

Domain 1: Criteria Related to the Underlying Health Condition
Criterion Synthesized Information
1 Size of the affected population Adult acute osteomyelitis

Osteomyelitis affects 1 in every 10,000 people worldwide.1 Assuming this incidence rate applies to Canada, the estimated size of the population is 0.01%.

Pediatric acute osteomyelitis

13 in 10,000 children experience acute osteomyelitis in the US.2 Assuming the incidence rate in Canada is similar to that in the US, this corresponds to more than 1 in 1,000 (0.1%) and less than or equal 1 in 100 (1%) children.

The estimated size of the affected adult population is more than 1 in 10,000 (0.01%) and less than or equal to 1 in 1,000 (0.1%). The estimated size of the affected pediatric population is more than 1 in 1,000 (0.1%) and less than 1 in 100 (1%).
2 Timeliness and urgency of test results in planning patient management Adult and pediatric acute osteomyelitis

The priority for bone scintigraphy in suspected osteomyelitis is 2 to 7 days from the time and date on which the request for an examination is received by the imaging department to the date on which the examination is performed (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). In children, imaging results have a significant impact on the management of the condition or the effective use of health care resources and in adults, the impact is moderate.
3 Impact of not performing a diagnostic imaging test on mortality related to the underlying condition Adult acute osteomyelitis

Undiagnosed osteomyelitis can lead to septicemia28 and, in rare cases, death.29 Statistics Canada reports that in 2007, 83 patients died from osteomyelitis.

Pediatric acute osteomyelitis

Although infections are one of the main causes of death in children, the amount attributed to osteomyelitis is unknown.6

Diagnostic imaging tests for osteomyelitis would have no impact on mortality in both the adult and pediatric populations
4 Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition Adult and pediatric acute osteomyelitis

If left untreated, osteomyelitis infection can become chronic and cause a loss of blood supply to the affected bone, leading to the eventual death of the bone tissue, which results in significant morbidity and reduced quality of life.

Diagnostic imaging tests would have moderate impact on morbidity and quality of life in the adult population and significant impact in the pediatric population.

 

Domain 2: Criteria Comparing 99mTc with an Alternative or Comparing Between Clinical Uses
Criterion Synthesized Information
5 Impact on health disparities To be scored locally.
6 Relative acceptability of the test to patients Adult osteomyelitis

No specific information was found regarding the relative impact on acceptability to adults of 18FDG-PET, or leukocyte scan. All of these alternatives are likely to be well tolerated, although patients may have some concern over the radiation exposure associated with each alternative.

Bone scintigraphy: Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

CT: Patients may have concerns about radiation exposure and potential side effects of contrast agents. Patients may also feel claustrophobic while in the scanner.

MRI: Patients undergoing MRI are susceptible to anxiety, panic, or claustrophobia during and after the test.30,31 Patients also have problems accepting the injection of the contrast dye (e.g., nausea, vertigo, metallic taste), holding their breath, and remaining still on the MRI table, and may not be confident in the diagnostic procedure itself.31-34

18FDG-PET
Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent. Patients undergoing 18FDG-PET are required to fast prior to the scan.

Pediatric osteomyelitis

In addition to the concerns listed above, children undergoing CT or MRI may require sedation to ensure they remain still for the duration of the examination.35-37

U/S: In children, U/S is often preferred to other imaging tests, as there is no radiation and the test does not require sedation of children.13

Overall, bone scanning with 99mTc-radiolabelled isotopes is:
  • minimally more acceptable than CT scanning in both adult and pediatric patients
  • minimally less acceptable than 18FDG-PET in adult patients
  • minimally less acceptable than MRI in adult patients
  • moderately more acceptable than MRI in pediatric patients
  • similarly acceptable to leukocyte scanning in adult patients
  • minimally less acceptable than U/S in pediatric patients.
7 Relative diagnostic accuracy of the test

Adult acute osteomyelitis

The review of the current literature yielded two meta-analyses (MAs), one systematic review (SR), and two primary studies that evaluated various comparators in the diagnosis of osteomyelitis, including bone scintigraphy.24-27,38 The results of studies that evaluated various comparators in the diagnosis of osteomyelitis including bone scintigraphy are summarized in the table:

Test Sensitivity (%) Specificity (%)
MAs (Pooled Data Results)24,25
Bone scan 81 to 90.3 28.0 to 84.5
Bone biopsy Reference Standard Reference Standard
MRI* 88.2 to 90.1 73.9 to 98
18FDG-PET 94.1 87.3
Leukocyte scan 74 to 89 68 to 83.8
SRs26
Bone scan 78 to 84 33 to 50
18FDG-PET 28.6 to 100 70 to 90
Primary Study27
Bone scan 86 100
CT 50 85
18FDG-PET 43 67

CT = computed tomography; 18FDG-PET = 18F-fluorodeoxyglucose positron emission tomography; MA = meta-analysis; MRI = magnetic resonance imaging; SR = systematic review.

*NB: Kapoor et al.25 reported a range of 77.3% to 100% and 44% to 100% for the sensitivity and specificity of MRI, respectively, However, only pooled sensitivities and specificities were included in this table.

Pediatric acute osteomyelitis

Bone scintigraphy has been demonstrated to be the best predictor of osteomyelitis and MRI results are secondary to it.19 CT would be the next preferred test, with U/S yielding the lowest diagnostic odds ratio (DOR).

Test Sensitivity (%) Specificity (%)
Bone scan 81 84
U/S 55 47
MRI 81 67
CT 67 50

CT = computed tomography; MRI = magnetic resonance imaging; U/S = ultrasound.

Overall, the diagnostic accuracy of bone scanning using 99mTc-radiolabelled isotopes is:

  • moderately better than that of CT in both adult and pediatric patients
  • minimally better than that of 18FDG-PET in adult patients
  • minimally lower than that of leukocyte scanning in adult patients
  • similar to that of MRI in adult patients
  • minimally better than that of MRI in pediatric patients
  • significantly better than that of U/S in pediatric patients.
8 Relative risks associated with the test Non–radiation-related Risks Bone scanning has been reported to be safe to use and few allergic reactions have been described.39,40 The overall rate of adverse reactions to radiopharmaceuticals is reported to be between 1 and 2 per 100,000 doses.40 With CT and MRI, some patients may experience an allergic reaction or side effect from the contrast agent. The frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%) and the frequency of moderate reactions ranges from 0.004% to 0.7%.41 Radiation-related Risks Among the modalities used to detect osteomyelitis, with the exception of MRI and U/S, all tests expose the patient to ionizing radiation. In general, gallium scan, 18FDG-PET, and leukocyte scan confer larger doses of radiation than bone scanning. Overall, bone scanning using 99mTc-radiolabelled isotopes:
  • has a similar safety profile to that of CT in both adult and pediatric patients
  • is minimally safer than 18FDG-PET in adult patients
  • is minimally safer than leukocyte scanning in adult patients
  • is minimally less safe than MRI in adult patients
  • is minimally safer than MRI in pediatric patients
  • is minimally less safe than U/S in pediatric patients.
9 Relative availability of personnel with expertise and experience required for the test As of 2006 in Canada, there were 2,034 diagnostic radiologists, 221 nuclear medicine physicians, 12,255 radiological technologists, 1,781 nuclear medicine technologists, and 2,900 sonographers available across Canada. The Territories do not have the available personnel to perform and interpret tests for osteomyelitis. Other jurisdictions (e.g., Prince Edward Island) may offer limited nuclear medicine services.

Assuming the equipment is available, if bone scanning using 99mTc-radiolabelled isotopes is not available, it is estimated that:
  • more than 95% of procedures could be performed in a timely manner using CT in both adult and pediatric patients
  • fewer than 25% of the procedures can be performed in a timely manner using 18FDG-PET in adult patients
  • 75% to 94% of the procedures can be performed in a timely manner using leukocyte scanning in adult patients
  • 75% to 94% of the procedures can be performed in a timely manner using MRI in both adult and pediatric patients
  • 25% to 74% of the procedures can be performed in a timely manner using U/S in pediatric patients.
10 Accessibility of alternative tests (equipment and wait times) No nuclear medicine cameras are available in the Yukon, Northwest Territories, or Nunavut.42 The average wait time for urgent bone scan in 2010 ranged from 1 to 6 days, and for non-urgent scans, ranged from 7 to 73 days.43

No CT scanners are available in Nunavut,42 and no MRI scanners are available in the Yukon, Northwest Territories, or Nunavut.42

The median CT and MRI wait times ranged from 8 to 22 days and 30 to 75 days, respectively.43 Another report stated that the mean wait time for CT was 4.6 weeks and MRI was 8.9 weeks.44

As of November 2010, there were approximately 31 Canadian centres performing publicly funded PET scans.45 These centres are all located in British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.45

U/S machines are considered to be widely available.

Assuming the personnel is available, if bone scanning using 99mTc-radiolabelled isotopes is not available, it is estimated that:
  • more than 95% of procedures could be performed in a timely manner using CT in both adult and pediatric patients
  • fewer than 25% of the procedures can be performed in a timely manner using 18FDG-PET in adult patients
  • 75% to 94% of the procedures can be performed in a timely manner using leukocyte scanning in adult patients
  • 25% to 74% of the procedures can be performed in a timely manner using MRI in both adult and pediatric patients
  • more than 95% of the procedures can be performed in a timely manner using U/S in pediatric patients.
11 Relative cost of the test

According to our estimates, the cost of bone and gallium scan with 99mTc-based radioisotopes is $471.50. 18FDG-PET is significantly more costly than bone scintigraphy. Leukocyte scintigraphy and MRI are minimally more costly than bone scintigraphy. CT is minimally less costly. U/S is moderately less costly.

Relative costs
Test Total costs ($) Cost of test relative to 99mTc-based test ($)
Bone and gallium scan 471.50 Reference
CT 262.56 –208.94
Leukocyte scan 586.01 +114.51
MRI 577.00 +105.50
18FDG-PET 1050.00 +578.50
U/S 49.15 –422.35

 

CT = computed tomography; DOR = diagnostic odds ratio; 18FDG-PET = 18F-fluorodeoxyglucose positron emission tomography; Gd = gadolinium; MRI = magnetic resonance imaging; SCD = sickle-cell disease; 99mTc-MDP = technetium-99 methylene diphosphonate; U/S = ultrasound.

Criterion 1: Size of affected population (link to definition)

Adult acute osteomyelitis

In 1972, Lidgren and Lindberg estimated that acute osteomyelitis affects 10 in 100,000 people in the developed world each year.1 Common sites of infection include the pelvis, sacroiliac joints, hip joints, and femur. Osteomyelitis is more common in males than in females (approximately two-thirds of all cases are male);1 however, the reasons for this are unknown.1,5 Joint replacement surgery is recognized as a primary cause of adult acute osteomyelitis.2 Tsakonas and colleagues reported that of the 58,351 patients who underwent hip and knee surgery in Canada in 2005-2006, 780 (1.3%) had a joint infection within one year of surgery.14

Pediatric osteomyelitis

Osteomyelitis occurs in infants and in children between eight and 14 years of age.1 The Alberta's Children's Hospital reported that 16 cases per 10,000 admissions were diagnosed with osteomyelitis in 2005.2 The male to female ratio was 1.9 to 1, demonstrating again that boys were almost twice as likely to have the disease. The majority of cases (83%) were diagnosed as acute osteomyelitis.12 In neonates, osteomyelitis is more frequent, occurring in one in 1,000 neonates.2

Subpopulations of osteomyelitis

SCD
A Cochrane Review on the use of antibiotics to treat osteomyelitis in people with SCD noted that osteomyelitis is one of the most common infectious complications in people with SCD.46 The prevalence of osteomyelitis among people with SCD is estimated to be in the range of 12% to 17.8%.46 Currently, it is estimated that 8,605 Canadians have SCD,47 roughly equating to 1,033 to 1,500 cases of osteomyelitis.

Diabetes
According to the Canadian Diabetes Association, more than 9 million Canadians are living with diabetes or prediabetes.48 According to a previous CADTH report, the annual rate of diabetic foot infection is estimated at 36.5 per 1,000 patients with diabetes in settings with good access to health care, and approximately 15% of patients with diabetes will develop foot osteomyelitis during the course of their disease.12

HIV/AIDS
Osteomyelitis is the second most common cause of infection in patients with HIV or AIDS and is most commonly found in the hip. As of 2009, there were more than 69,000 adult Canadians with HIV or AIDS.49 HIV patients are also susceptible to a unique form of osteomyelitis called "bacillary angiomatoid osteomyelitis," caused by rickettsia-like bacteria.1

Athletes
The presence of groin pain in athletes ranges from 5% to 13%.9 Groin pain can be a symptom of osteomyelitis of the pubis. Although the exact etiology of this disease in this subpopulation is unknown, it is thought that trauma experienced to the symphysis pubis during sports-related activity may make it susceptible to bacterial infection. Osteomyelitis of the pubis appears to be a male-dominated disease.9

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Criterion 2: Timeliness and urgency of test results in planning patient management (link to definition)

Timeliness

Timing of diagnosis in acute osteomyelitis is crucial, as osteomyelitis is a progressive disease. Failure to diagnose and treat promptly can lead to progressive infection, resulting in inflammatory destruction, necrosis, and bone deformation, which can progress to a chronic and persistent stage.4 Early intervention (within 10 to 20 days of infection)2 can lead to accurate treatment with an antibiotic regimen,8,14,26 prevention of chronic osteomyelitis,7,14 and long-term morbidity in 60% of cases.7 In osteomyelitis of the diabetic foot, for example, the infection can be restricted to a certain area in the bone and allow for wound healing if the infection is detected early in the disease development.7

Urgency

According to the urgency classifications developed by the Saskatchewan Ministry of Health, the urgency of bone, white blood cell (WBC or leukocyte), or gallium scan for the evaluation of suspected osteomyelitis is two to seven days (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). MRI for chronic osteomyelitis is also recommended within two to seven days from the time and date on which the request for an examination is received by the imaging department to the date on which the examination is performed.50 X-rays of early-phase acute osteomyelitis often appear normal.2 According to Pineda et al., osteomyelitis must compromise 30% to 50% of bone mineral content and be a minimum of 1 cm in order to be noticeable in plain radiographs.13

Pediatric acute osteomyelitis

In children, early findings and subtle changes are not visible on x-ray images until five to seven days after onset of disease,13 or until two weeks after onset of infection.17 Bone scans can identify these features within 24 to 49 hours of the onset of infection.17 Pediatric osteomyelitis is often found in the long bones, and a delay in diagnosis can lead to damage of the growing cartilage and arrest of bone lengthening.17

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Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition (link to definition)

Osteomyelitis can lead to septicemia28 and, in rare cases, death.29 Statistics Canada data demonstrate that in 2007, 83 patients died from osteomyelitis (ICD-10 code M86).51 None of the deaths were coded as acute cases.51 It is not known whether any of these deaths could have been avoided with more timely diagnostic imaging.

Mortality rates among diabetics52,53 and HIV patients1 have been reported.

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Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition (link to definition)

A prompt diagnosis of acute osteomyelitis can prevent further complications, including sepsis, fractures of the infected bone, deforming bone damage, and soft tissue damage.13,14,17,54,55 Failure to perform a diagnostic imaging test can therefore have a negative impact on patient morbidity and quality of life.

In a population with diabetic foot, the risk of amputation is 5% to 42%.7,8,52 A study by Eckman et al. conducted a quality of life survey in patients with non–insulin-dependent diabetes mellitus (NIDDM) who experienced an amputation.10 The 36-item Short Form health status questionnaire (SF-36) is a self-administered survey that allows patients to rate their general health status on different health attributes, yielding a score of 0 (poorest health) to 100 (best health).56 Diabetic patients who underwent amputation rated their overall health a score of 49.1, compared with 69.1 for diabetic patients who had not undergone amputation.10

In the pediatric population, failure to treat osteomyelitis can have serious long-term consequences, including chronic bone damage, limb deformity, and sepsis.57 Brodie abscess — a type of subacute osteomyelitis — is common in children, especially boys, and is usually found in the distal and proximal portions of the tibia.13

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Criterion 5: Relative impact on health disparities (link to definition)

Osteomyelitis affects people with underlying health problems, such as SCD, diabetes, or AIDS, more frequently than it does healthy individuals. Osteomyelitis is more common in males than in females (approximately two-thirds of all cases are male).1 For example, a recent systematic review found that only nine (5.3%) of 171 athletes with osteomyelitis or osteitis pubis were female.9

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Criterion 6: Relative acceptability of the test to patients (link to definition)

The following are applicable to adults or children with suspected osteomyelitis:

Bone scanning
Limited information was identified on the acceptability of bone scanning to patients. A retrospective study on the use of bone scanning in children with osteosarcoma or Ewing sarcoma suggested that any test, including a bone scan, causes psychological strain on the children and the parents.58 Patients, or parents of patients, may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

CT
Patients undergoing CT scan may have concerns about radiation exposure and may also feel claustrophobic while in the scanner. This may be less of a problem with new CT scanners, if available (MIIMAC expert opinion). Patients may also be required to hold their breath for a substantial period of time, which is seen as "uncomfortable" and "difficult."59 Children undergoing CT may require sedation. Sedation may be avoided by depriving the child of sleep and feeding him or her prior to the test.60

18FDG-PET
Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

Leukocyte scan 111In-WBC
Patients may have concerns about radiation exposure and the intravenous injection of radiopharmaceutical agent.

MRI
Because of the closed space of an MRI, patients may experience feelings of claustrophobia as well as be bothered by the noise; however, this may be less of a problem with new MRI machines, if available (MIIMAC expert opinion). It has been reported that up to 30% of patients experience apprehension and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.30,31 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some. The entire MRI exam takes 30 to 60 minutes and children and infants are often sedated to ensure that they remain still for the duration of the examination.60 Sedation may be avoided by depriving the child of sleep and feeding him or her prior to the test.60

U/S
Some discomforts associated with U/S include cold, unspecified pain, and tenderness. In a study comparing U/S with MRI in undiagnosed shoulder pain, 100% of the patients participating said that they would be willing to undergo the U/S exam again.33 This test may be preferred in pediatric patients as there is no exposure to ionizing radiation or radiation, and the test does not require sedation of children.

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Criterion 7: Relative diagnostic accuracy of the test (link to definition)

Four studies24-27 were identified pertaining to the diagnostic accuracy of imaging in cases of suspected osteomyelitis: two MAs,24,25 one SR,26 and two primary studies.27,38 Review papers that were systematic in their methods were not included. Three studies evaluated the diagnostic accuracy of radiographs (x-ray),24,25,27 two evaluated leukocyte scan,24,26 three evaluated MRI,24,25,27 three 18FDG-PET,24,26,38 and two CT.24,27 No studies assessed the diagnostic accuracy of U/S for osteomyelitis. A high-level summary of the included studies is included below and further detail is provided in Appendix 3.

Meta-analyses

Dinh et al.24

This MA evaluated the diagnostic accuracy of imaging tests for diagnosis of osteomyelitis in diabetic patients with foot ulcers.24 A histopathological examination or microbial culture of bone specimens was the gold standard required for study inclusion.24 A total of 917 articles were found in the literature search (1966 to February 27, 2007), nine of which were included in the analysis.24 An additional 59 studies were identified by searching reference lists of potentially relevant articles.24 Although the search strategy included six imaging comparators (MRI, CT, bone scan, PET, leukocyte scan, and x-ray), the authors were unable to find a study evaluating either CT or PET that met their inclusion criteria.24 Pooled sensitivity and specificity, the summary measure of accuracy (Q*), and diagnostic odds ratio (DOR) were calculated.24

Six of the nine studies included bone scintigraphy as a comparator. The final pooled sensitivity and specificity were 0.81 (95% CI, 0.73 to 0.87; P < 0.001) and 0.28 (95% CI, 0.17 to 0.42; P = 0.01), respectively. The DOR was 2.10, indicating poor discriminating ability compared with biopsy. The Q* value was 0.62, suggesting moderate accuracy for diagnosis of osteomyelitis.24

Four studies of plain radiography (x-rays) met the inclusion criteria. Pooled sensitivity and specificity for diagnosis of osteomyelitis was 0.54 (95% CI, 0.44 to 0.63; P = 0.006) and 0.68 (95% CI, 0.53 to 0.80; P = 0.01), respectively. The DOR was 2.84 and the Q* score 0.60, indicating low-to-moderate accuracy.24

Six of the nine studies evaluated 111In-leukocyte scan as a comparator and the final pooled sensitivity and specificity were 74.0 and 68.0, respectively, while the DOR was 2.84. The Q* value was 0.60, indicating low-to-moderate accuracy.24

Four studies evaluated the use of MRI. Pooled sensitivity and specificity was 0.90 (95% CI, 0.82 to 0.95) and 0.79 (95%CI, 0.62 to 0.91). The DOR was 24.36, indicating excellent discriminatory power of MRI. The Q* score was 0.74, highest amongst included diagnostic tests.24

Kapoor et al.25

This MA evaluated the diagnostic accuracy of MRI for osteomyelitis of the foot and compared this with bone scanning, plain radiography, and WBC studies.25 A total of 2,070 articles were found from the literature search (1966 to June 2006), 16 of which were included in the analysis.25 Eleven of the 16 studies included almost exclusively diabetic patients.25 Seven studies compared MRI with 99mTc bone scanning, nine with plain radiography, and three with WBC scanning.25 Results demonstrated that the DOR for MRI was consistently better than for bone scanning (seven studies — 149.9 [95% CI, 54.6 to 411.3] for MRI versus 3.6 [95% CI, 1.0 to 13.3]) for bone scan, x-ray (nine studies — 81.5 [95% CI, 14.2 to 466.1] for MRI versus 3.3 [95% CI, 2.2 to 5.0) for x-ray), and WBC studies (three studies — 120.3 [95% CI, 61.8 to 234.3] versus 3.4 [95% CI, 0.2 to 62.2]). Hence, MRI was a stronger predictor of osteomyelitis in the foot and ankle than either 99mTc bone scan or x-ray.25

Systematic review

Van der Bruggen et al.26

A recent SR by Van der Bruggen and colleagues assessed the diagnostic accuracy of different imaging tests including scintigraphy and 18FDG-PET, for imaging of osteomyelitis and prosthetic bone and joint infections.26 The authors conclude that because of considerable heterogeneity between studies, pooled sensitivity and specificity calculations are not possible.26 Of the 29 articles (N = 1,054 patients) of 18FDG-PET identified, the authors conclude that this imaging technique is adequate for chronic (note: not acute) osteomyelitis.26

Primary studies

Larson et al.27

Larson and colleagues recently performed a retrospective chart review of patients with pressure ulcer in the United States to access the diagnostic accuracy of preoperative x-ray or CT scan (obtained up to one year preoperatively) compared with results of bone biopsy taken during surgical debridement.27 Charts of 44 patients indicated that 50% of patients with biopsy-proven osteomyelitis were identified by preoperative CT scans, compared with 88% using x-ray. Interestingly, 85% of patients without biopsy-proven osteomyelitis were detected by preoperative CT scan and 32% with x-ray. The overall sensitivity of either radiologic study was 61% and the overall specificity of both studies was 69%.27

Familiari et al.38

Familiari and colleagues recently conducted a prospective observational study in Europe to compare the diagnostic accuracy of 99mTc exametazime WBC scintigraphy and sequential 18F-FDG-PET/CT for diagnosis of osteomyelitis in the diabetic foot. Thirteen diabetic patients (12 male and one female; mean age 62.2 ± 10.9 years) with suspected osteomyelitis were enrolled. After bone biopsy (gold standard), osteomyelitis was confirmed in seven patients, two patients had soft-tissue infection without bone involvement, and four patients had no infection. 99mTc exametazime WBC scintigraphy was found to have a sensitivity of 86% and specificity of 100%; the positive and negative predictive values were 100% and 86%, respectively. Conversely, 18FDG-PET/CT had a sensitivity of 43% and specificity of 67%; the positive and negative predictive values were 60% and 50%, respectively. The authors conclude that 18FDG PET/CT has a low diagnostic accuracy for osteomyelitis and cannot replace 99mTc exametazime WBC scintigraphy in patients with diabetic foot.38

Pediatric acute osteomyelitis

No MAs, SRs, or review papers with information regarding the diagnostic accuracy, specific to a pediatric population, were found. One primary study19 was found that specifically evaluated the accuracy of imaging modalities in the diagnosis of acute osteomyelitis in a pediatric population.

Malcius et al.19

A study conducted in Lithuania by Malcius and colleagues examined the accuracy of several radiological tests in the diagnosis of osteomyelitis, specifically in a pediatric population.19 Children aged one to 18 years were eligible for participation and a total of 183 patients (mean age of 10.3 years) were enrolled.19 The following tests were performed: bone scan (99mTc), x-ray, MRI, CT, and U/S.19 For a complete summary of diagnostic accuracy of tests, refer to Appendix 3.19 The authors concluded that late x-ray (taken a median of 15 days after hospitalization) is the most accurate imaging method, followed by bone scan and MRI (at the onset of disease).19

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Criterion 8: Relative risks associated with the test (link to definition)

Non–radiation-related Risks

Bone scanning
Several studies61-64 reported mild adverse events with 99mTc-labelled tracers (e.g., skin reactions), and one case report published in 1985 reported a patient who experienced a rash following two bone scans with 99mTc-MDP, one in 1983 and one the following year.65 The authors concluded this patient had an allergic reaction to MDP on both occasions. This case report references an older study that reported 22 adverse reactions to 99mTc-MDP, in which 20 of the reactions were either "probably" or "possibly" caused by MDP.

CT
Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.66 In addition, patients may experience mild side effects from the contrast agent, such as nausea, vomiting, or hives. A 2009 retrospective review of all intravascular doses of low-osmolar iodinated and gadolinium (Gd) contrast materials administered at the Mayo Clinic between 2002 and 2006 (456,930 doses) found 0.15% of patients given CT contrast material experienced side effects, most of which were mild. A serious side effect was experienced by 0.005% of patients.67 CT is contraindicated in patients with elevated heart rate, hypercalcemia, and impaired renal function. According to the American College of Radiology Manual on Contrast Media,41 the frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%). Moderate reactions resembling an allergic response (i.e., rash, hives, urticaria) are also very unusual and range in frequency from 0.004% to 0.7%.41

18FDG-PET
The Pharmacopeia Committee of the Society of Nuclear Medicine (SNM) conducted a four-year prospective evaluation of adverse reactions to PET and reported no adverse reactions among the 33,925 scans conducted in 22 participating PET centres in the United States.68

Leukocyte scan
Several studies61,64,69 reported mild adverse events with 99mTc-labelled tracers, including those used to label WBC (e.g., skin reactions). No reaction rates were provided.

MRI
MRI is contraindicated in patients with metallic implants, including pacemakers.70 MRI is often used in conjunction with the contrast agent Gd. Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.66 Side effects of Gd include headaches, nausea, and metallic taste. Gd is contraindicated in patients with renal failure or end-stage renal disease, as they are at risk of nephrogenic systemic fibrosis. According to the American College of Radiology Manual on Contrast Media,41 the frequency of severe, life-threatening reactions with Gd is extremely rare (0.001% to 0.01%). Moderate reactions resembling an allergic response (i.e., rash, hives, urticaria) are also very unusual and range in frequency from 0.004% to 0.7%.41

U/S
There are no reported risks associated with U/S in the literature that was reviewed.

Radiation-related Risks

Among the modalities available to diagnose acute osteomyelitis, bone scan, leukocyte scan, gallium scan, PET, and CT expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures can be found in Table 2. Radiation exposure can be a concern for testing pediatric patients, as the risk of radiation-induced cancer is two to three times greater in children and adolescents than in adult patients.71

Table 2 : Effective Doses of Radiation

Procedure Average Effective Dose (mSv) Pediatric Effective Dose (mSv)
99mTc-labelled tracers bone scan28,72 1 to 10 0.03 to 3
CT28,72,73 Less than 0.1 to 7.3 Less than 0.03
18FDG-PET72 10 to 30 3 to 10
Leukocyte scan28 10.0 NA
MRI72 0 0
U/S72 0 0
Average background dose of radiation per year 1 to 3.074-76 1 to 3.074-76

CT = computed tomography; 18FDG-PET = 18F-fluorodeoxyglucose Positron Emission Tomography; MRI = magnetic resonance imaging; mSv = millisievert; NA = not available; 99mTc = technetium-99m; U/S = ultrasound.

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Criterion 9: Relative availability of personnel with expertise and experience required for the test (link to definition)

The personnel required to perform imaging tests to diagnose osteomyelitis are presented by imaging modality. A summary of the availability of personnel required for the conduct of methods to diagnose osteomyelitis by bone scintigraphy or any of the alternative imaging modalities is provided in Table 3.

Bone scintigraphy
In Canada, physicians involved in the performance, supervision, and interpretation of bone scans should be nuclear medicine physicians or diagnostic radiologists with training or expertise in nuclear imaging.77 Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Nuclear medicine technologists are required to conduct bone scans. Technologists must be certified by the Canadian Association of Medical Radiation Technologists (CAMRT) or an equivalent licensing body. Expertise in pediatric imaging may be required.

All alternative imaging modalities
In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic CT scans, MRI, and U/S should be diagnostic radiologists78 and must have a Fellowship or Certification in Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Foreign-trained radiologists also are qualified if they are certified by a recognized certifying body and hold a valid provincial license.77 Expertise in pediatric imaging may be required.

Medical radiation technologists (MRTs) must be certified by CAMRT or an equivalent licensing body.

Service engineers are needed for system installation, calibration, and preventive maintenance of the imaging equipment at regularly scheduled intervals. The service engineer's qualification will be ensured by the corporation responsible for service and the manufacturer of the equipment used at the site.

Qualified medical physicists (on-site or contracted part-time) should be available for the installation, testing, and ongoing quality control of CT scanners, magnetic resonance (MR) scanners, and nuclear medicine equipment.77

CT
For the performance of CT scan, MRTs who are certified by CAMRT or an equivalent licensing body recognized by CAMRT are required. The training of technologists specifically engaged in CT should meet with the applicable and valid national and provincial specialty qualifications.

18FDG-PET
In Canada, physicians involved in the performance, supervision, and interpretation of PET scans should be nuclear medicine physicians or diagnostic radiologists with training/expertise in nuclear imaging. Physicians should have a Fellowship of Certification in Nuclear Medicine or Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Technologists must be certified by CAMRT or an equivalent licensing body.

Leukocyte scan
Leukocyte scanning requires the same personnel as bone scanning with 99mTc-based radioisotopes. No literature was identified regarding the expertise required for handling and processing WBCs.

MRI
For the performance of MRI, medical technologists must have CAMRT certification in magnetic resonance or be certified by an equivalent licensing body recognized by CAMRT.

U/S
Sonographers (or ultrasonographers) should be graduates of an accredited school of sonography or have obtained certification from the Canadian Association of Registered Diagnostic Ultrasound Professionals. They should be members of their national or provincial professional organization. Sonography specialties include general sonography, vascular sonography, and cardiac sonography.78 In Quebec, sonographers and MRTs are grouped together; in the rest of Canada, sonographers are considered a distinct professional group.78

Table 3: Medical Imaging Professionals in Canada78

Jurisdiction Diagnostic Radiology Physicians Nuclear Medicine Physicians Medical Radiation Technologists Nuclear Medicine Technologists Sonographers Medical Physicists
NL 46 3 263 15 NR NR
NS 71 5 403 71 NR NR
NB 47 3 387 55 NR NR
PEI 7 0 57 3 NR 0
QC 522 90 3,342 460 NR NR
ON 754 69 4,336 693 NR NR
MB 58 8 501 42 NR NR
SK 61 4 359 36 NR NR
AB 227 18 1,229 193 NR NR
BC 241 21 1,352 212 NR NR
YT 0 0 0 0 NR 0
NT 0 0 26 1 NR 0
NU 0 0 0 0 NR 0
Total 2,034 221 12,255 1,781 2,900* 322*

AB = Alberta; BC = British Columbia; MB = Manitoba; NB = New Brunswick; NL = Newfoundland and Labrador; NR = not reported by jurisdiction; NS = Nova Scotia; NT= Northwest Territories; NU = Nunavut; ON = Ontario; PEI = Prince Edward Island; QC = Quebec; YT = Yukon.

*This represents a total for all of the jurisdictions.

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Criterion 10: Accessibility of alternative tests (equipment and wait times) (link to definition)

There are notable variations in the availability of medical imaging technologies across Canada. Table 4 provides an overview of the availability of equipment required to diagnose osteomyelitis. Data for nuclear medicine cameras (including SPECT) are current to January 1, 2007. The number of CT, MRI, and SPECT/CT scanners is current to January 1, 2010. Information on the availability of PET and PET/CT scanners is current to November 30, 2010. Data were not available for U/S.

Table 4: Diagnostic Imaging Equipment in Canada42,45,78

  Nuclear Medicine Cameras CT Scanners MRI Scanners SPECT/CT Scanners PET or PET/CT
Number of devices 60378 46042 21842 9642 3645
Average number of hours of operation per week (2006-2007)78 40 60 71 NR NR
Provinces and Territories with no devices available YT, NT, NU NU YT, NT, NU PEI, YT, NT, NU NL, PEI, SK, YT, NT, NU

CT = computed tomography; MRI = magnetic resonance imaging; NL = Newfoundland and Labrador; NR = not reported; NT = Northwest Territories; NU = Nunavut; PEI = Prince Edward Island; PET = positron emission tomography; PET/CT = positron emission tomography/computed tomography; SK = Saskatchewan; SPECT/CT = single-photon emission computed tomography/computed tomography; YT = Yukon.

Bone scanning
For bone scintigraphy, nuclear medicine facilities with gamma cameras (including SPECT) are required. As of January 1, 2007, there was an average of 18.4 nuclear medicine cameras per million people, with none available in the Yukon, Northwest Territories, or Nunavut.78

CT
No CT scanners are available in Nunavut.78 The average weekly use of CT scanners ranged from 40 hours in Prince Edward Island to 69 hours in Ontario, with a national average of 60 hours.78 In 2010, the average wait time for a CT scan in Canada is 4.2 weeks.44

18FDG-PET
A 2010 Environmental Scan published by CADTH reported that there are approximately 31 Canadian centres equipped to perform PET scans.45 These centres are located in the provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.45 There are 36 PET or PET/CT scanners, four of which are used for research purposes only.45

Leukocyte scan
It was assumed that leukocyte scan was considered a nuclear imaging test and therefore the wait for bone tests was, on average at one Montreal hospital, eight days.79 Data from 2007 state that nuclear imaging cameras are available at a rate of 18.4 per million people. However, there are no cameras available in the Yukon Territories, Northwest Territories, or Nunavut.44

MRI
No MRI scanners are available in the Yukon, Northwest Territories, or Nunavut.78 According to the Canadian Institute for Health Information's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006-2007 ranged from 40 hours in Prince Edward Island to 99 hours in Ontario, with a national average of 71 hours.78 In 2010, the average wait time for MR imaging in Canada was 9.8 weeks.44

U/S
U/S machines are widely available across the country. According to the Fraser Institute, the average wait time for U/S in 2010 was 4.5 weeks.44

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Criterion 11: Relative cost of the test (link to definition)

Fee codes from the Ontario Schedule of Benefits were used to estimate the relative costs of bone scanning and its alternatives. Technical fees are intended to cover costs incurred by the hospital (i.e., radiopharmaceutical costs, medical or surgical supplies, and non-physician salaries). Maintenance fees are not billed to OHIP — estimates here were provided by St. Michael's Hospital in Toronto. Certain procedures (i.e., PET scan, CT scan, MRI scan) are paid for, in part, out of the hospital's global budget; these estimates were provided by The Ottawa Hospital. It is understood that the relative costs of imaging will vary from one institution to the next.

According to our estimates (Table 5), the cost of bone and gallium scan with 99mTc-based radioisotopes is $471.50. CT is a minimally less costly alternative and 18FDG-PET is significantly more costly than bone scintigraphy, and leukocyte scintigraphy and MRI are both minimally more costly than bone scintigraphy. U/S is moderately less costly.

Table 5: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)80

Fee Code Description Tech. Fees ($) Prof. Fees ($) Total Costs ($)
Bone and Gallium Scintigraphy
J867 Blood flow and pool imaging 58.75 29.30 88.05
J851 Bone scintigraphy — single site 87.00 50.95 137.95
J853 Gallium scintigraphy — single site 126.85 50.95 177.80
Maintenance fees — global budget 67.70   67.70
TOTAL 340.30 131.20 471.50
CT
X231 CT — pelvis — without IV contrast   91.15 91.15
Technical cost — from global budget 150.00   150.00
Maintenance fees — from global budget 21.41   21.41
TOTAL 171.41 91.15 262.56
Leukocyte Scintigraphy
J884B and J884C 111In leukocyte scintigraphy — single site 329.00 50.95 379.95
J866B and J866C Application of tomography (SPECT), maximum 1 per nuclear medicine examination 44.60 31.10 75.70
J867B and J867C First transit — with blood pool images 58.75 29.30 88.05
Maintenance fees — from global budget 42.31   42.31
TOTAL 474.66 111.35 586.01
MRI
X471 Multislice sequence, 1 extremity and/or 1 joint   66.10 66.10
X475C x3 Repeat (another plane, different pulse sequence; to a maximum of 3 repeats)   99.30 99.30
X487 When Gd is used   38.60 38.60
Technical cost — from global budget 300.00   300.00
Maintenance fees — from global budget 73.00   73.00
TOTAL 373.00 204.00 577.00
18FDG-PET
Proxy code Professional fee for PET   250.00 250.00
Technical cost — from global budget 800.00   800.00
TOTAL 800.00 250.00 1050.00
U/S
J182 Extremities — per limb 26.15 19.70 45.83
Maintenance fees — global budget 3.30   3.30
TOTAL 29.45 19.70 49.15

CT = computed tomography; 18FDG-PET = 18F-fluorodeoxyglucose positron emission tomography; Gd = gadolinium; 111In = Indium 111; IV = intravenous; MRI = magnetic resonance imaging; PET = positron emission tomography; prof. = professional; SPECT = single-photon emission computed tomography; tech. = technical; U/S = ultrasound.

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Appendix 1: Multi-Criteria Decision Analysis Definitions

Domain 1: Criteria Related to the Underlying Health Condition
Criterion Definition
1. Size of the affected population The estimated size of the patient population that is affected by the underlying health condition and that may potentially undergo the test. The ideal measure is point prevalence, or information on how rare or common the health condition is.
2. Timeliness and urgency of test results in planning patient management The timeliness and urgency of obtaining the test results in terms of their impact on the management of the condition and the effective use of health care resources.
3. Impact of not performing a diagnostic imaging test on mortality related to the underlying condition Impact of not performing the test, in whatever way, on the expected mortality of the underlying condition. Measures could include survival curves showing survival over time, and/or survival at specific time intervals with and without the test.
4. Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition Impact of not performing the test, in whatever way, on the expected morbidity or on the quality of life reduction of the underlying condition. Measures of impact may include natural morbidity outcome measures such as events or disease severity, or might be expressed using generic or disease-specific quality of life rating scales with and without the test.
Domain 2: Criteria Comparing 99mTc with an Alternative, or Comparing between Clinical Uses
Criterion Definition
5. Relative impact on health disparities Health disparities are defined as situations where there is a disproportionate burden (e.g., incidence, prevalence, morbidity, or mortality) amongst particular population groups (e.g., gender, age, ethnicity, geography, disability, sexual orientation, socioeconomic status, and special health care needs).

Impact on health disparities is assessed by estimating the proportion of current clients of the 99mTc-based test who are in population groups with disproportionate burdens.

(Explanatory note: The implication of this definition is that, everything else being the same, it is preferable to prioritize those clinical uses that have the greatest proportion of clients in groups with disproportionate burdens.)
6. Relative acceptability of the test to patients Acceptability of the 99mTc-based test from the patient's perspective compared with alternatives. Patient acceptability considerations include discomfort associated with the administration of the test, out-of-pocket expenses or travel costs, factors that may cause great inconvenience to patients, as well as other burdens. This criterion does not include risks of adverse events but is about everything related to the experience of undergoing the test.
7. Relative diagnostic accuracy of the test Ability of the test to correctly diagnose the patients who have the condition (sensitivity) and patients who do not have the condition (specificity) compared with alternatives.
8. Relative risks associated with the test Risks associated with the test (e.g., radiation exposure, side effects, adverse events) compared with alternatives. Risks could include immediate safety concerns from a specific test or long-term cumulative safety concerns from repeat testing or exposure.
9. Relative availability of personnel with expertise and experience required for the test Availability of personnel with the appropriate expertise and experience required to proficiently conduct the test and/or interpret the test findings compared with alternatives.
10. Accessibility of alternatives (equipment and wait times) Availability (supply) of equipment and wait times for alternative tests within the geographic area. Includes consideration of the capacity of the system to accommodate increased demand for the alternatives. Excludes any limitation on accessibility related to human resources considerations.
11. Relative cost of the test Operating cost of test (e.g., consumables, health care professional reimbursement) compared with alternatives.

99mTc = technetium-99m.

Appendix 2: Literature Search Strategy

OVERVIEW

Interface:

Ovid

Databases:

Ovid MEDLINE In-Process & Other Non-Indexed Citations and Ovid MEDLINE <1948 to February 18, 2011>

Date of Search:

February 22, 2011

Alerts:

Monthly search updates began February 22, 2011 and ran until October 2011.

Study Types:

Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies, and diagnostic accuracy studies.

Limits:

No date limit for systematic reviews; publication years 2006 – February 2011 for primary studies

English language

Human limit for primary studies

SYNTAX GUIDE
/ At the end of a phrase, searches the phrase as a subject heading
MeSH Medical subject heading
.fs Floating subheading
exp Explode a subject heading
* Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings
? Truncation symbol for one or no characters only
ADJ Requires words are adjacent to each other (in any order)
ADJ# Adjacency within # number of words (in any order)
.ti Title
.ab Abstract
.hw Heading word: usually includes subject headings and controlled vocabulary
.tw Text word: searches title, abstract, captions, and full text
.mp Keyword search: includes title, abstract, name of substance word, subject heading word and other text fields
.pt Publication type
.nm Name of substance word: used to search portions of chemical names and includes words from the CAS Registry/EC Number/Name (RN) fields
.jw Journal words: searches words from journal names
/du Diagnostic use
/ri Radionuclide imaging

 

Ovid MEDLINE Strategy
Line # Search Strategy
1 Technetium/
2 exp Technetium Compounds/
3 exp Organotechnetium Compounds/
4 exp Radiopharmaceuticals/
5 radioisotope*.mp.
6 (technetium* or Tc-99* or Tc99* or Tc-99m* or Tc99m* or 99mTc* or 99m-Tc* or 99mtechnetium* or 99m-technetium*).tw,nm.
7 Radionuclide Imaging/
8 Bone Diseases, Infectious/ri
9 Osteomyelitis/ri
10 (((radionucl* or nuclear or radiotracer*) adj2 (imag* or scan* or test* or diagnos*)) or scintigraph* or scintigram* or scintiphotograph*).tw.
11 (bone* adj5 (imaging or scan*)).tw.
12 (WBC adj5 (imaging or scan*)).tw.
13 (white blood cell* adj5 (imaging or scan*)).tw.
14 (leukocyte* adj5 (imaging or scan*)).tw.
15 or/1-14
16 Osteomyelitis/
17 Bone Diseases, Infectious/
18 (osteomyelitis or osteomyelitides).tw.
19 (bone* adj inflammation*).tw.
20 (bone* adj3 infection*).tw.
21 or/16-20
22 Meta-Analysis.pt.
23 Meta-Analysis/ or Systematic Review/ or Meta-Analysis as Topic/ or exp Technology Assessment, Biomedical/
24 ((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).tw.
25 ((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).tw.
26 ((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).tw.
27 (data synthes* or data extraction* or data abstraction*).tw.
28 (handsearch* or hand search*).tw.
29 (mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).tw.
30 (met analy* or metanaly* or health technology assessment* or HTA or HTAs).tw.
31 (meta regression* or metaregression* or mega regression*).tw.
32 (meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.
33 (medline or Cochrane or pubmed or medlars).tw,hw.
34 (cochrane or health technology assessment or evidence report).jw.
35 or/22-34
36 exp "Sensitivity and Specificity"/
37 False Positive Reactions/
38 False Negative Reactions/
39 du.fs.
40 sensitivit*.tw.
41 (predictive adj4 value*).tw.
42 distinguish*.tw.
43 differentiat*.tw.
44 enhancement.tw.
45 identif*.tw.
46 detect*.tw.
47 diagnos*.tw.
48 accura*.tw.
49 comparison*.tw.
50 Comparative Study.pt.
51 (Validation Studies or Evaluation Studies).pt.
52 Randomized Controlled Trial.pt.
53 Controlled Clinical Trial.pt.
54 (Clinical Trial or Clinical Trial, Phase II or Clinical Trial, Phase III or Clinical Trial, Phase IV).pt.
55 Multicenter Study.pt.
56 (random* or sham or placebo*).ti.
57 ((singl* or doubl*) adj (blind* or dumm* or mask*)).ti.
58 ((tripl* or trebl*) adj (blind* or dumm* or mask*)).ti.
59 (control* adj3 (study or studies or trial*)).ti.
60 (non-random* or nonrandom* or quasi-random* or quasirandom*).ti.
61 (allocated adj "to").ti.
62 Cohort Studies/
63 Longitudinal Studies/
64 Prospective Studies/
65 Follow-Up Studies/
66 Retrospective Studies/
67 Case-Control Studies/
68 Cross-Sectional Study/
69 (observational adj3 (study or studies or design or analysis or analyses)).ti.
70 cohort.ti.
71 (prospective adj7 (study or studies or design or analysis or analyses or cohort)).ti.
72 ((follow up or followup) adj7 (study or studies or design or analysis or analyses)).ti.
73 ((longitudinal or longterm or (long adj term)) adj7 (study or studies or design or analysis or analyses or data or cohort)).ti.
74 (retrospective adj7 (study or studies or design or analysis or analyses or cohort or data or review)).ti.
75 ((case adj control) or (case adj comparison) or (case adj controlled)).ti.
76 (case-referent adj3 (study or studies or design or analysis or analyses)).ti.
77 (population adj3 (study or studies or analysis or analyses)).ti.
78 (cross adj sectional adj7 (study or studies or design or research or analysis or analyses or survey or findings)).ti.
79 or/36-78
80 Case Reports.pt.
81 79 not 80
82 15 and 21 and 35
83 limit 82 to english language
84 15 and 21 and 81
85 limit 84 to (english language and humans and yr="2006 -Current")

 

OTHER DATABASES
PubMed Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used.

Cochrane Library
Issue 1, 2011

Same MeSH, keywords, and date limits used as per MEDLINE search, excluding study types and Human restrictions. Syntax adjusted for Cochrane Library databases.

 

GREY LITERATURE SEARCHING
Dates for Search: March 2011
Keywords: Included terms for radionuclide imaging and osteomyelitis.
Limits: No limits

The following sections of the CADTH grey literature checklist, "Grey matters: a practical tool for evidence-based medicine" were searched:

  • Health Technology Assessment Agencies (selected)
  • Clinical Practice Guidelines
  • Databases (free)
  • Internet Search.

 

Appendix 3: Diagnostic Accuracy

Table 6: Diagnostic Accuracy of Bone Scan and the Alternative Tests Based on the Information Presented in the Included Studies

Test Author Reference Standard Outcome
Sens % Spec % Acc % DOR PPV % NPV % Localization Rate
Bone scan Dinh et al. 2008 Bone Biopsy/Surgery 81.0 28.0 NR 2.10 NR NR NR
Kapoor et al. 2007 Bone Biopsy/Surgery (head-to-head studies) 90 28.5 - 3.6 NR NR NR
Eckman et al. 1996 Bone Biopsy/Surgery 86 45 NR NR NR NR NR
Van der Bruggen et al. 2010* Bone Biopsy/Surgery 78 to 84 33 to 50 NR NR NR NR NR
Familiari et al. 2011 Bone Biopsy (diabetic population) 86 100 92 NR 100 86 NR
X-ray Dinh et al. 2008 Bone Biopsy/Surgery 54.0 68.0 NR 2.84 NR NR NR
Eckman et al. 1996 Bone Biopsy/Surgery 62.0 64.0 NR NR NR NR NR
Larson et al. 2010 Bone Biopsy/Surgery 88.0 32.0 NR NR NR NR NR
MRI Kapoor et al. 2007 Bone Biopsy/Surgery (head-to-head studies) 90 98 NR 149.9 NR NR NR
Bone Biopsy/Surgery 77.3 to 100 44 to 100 NR 42.1 NR NR NR
Dinh et al. 2008 Bone Biopsy/Surgery 90.0 79.0 NR 24.36 NR NR NR
18FDG-PET/PET-CT Van der Bruggen et al. 2010* Bone Scan 78 70 74 NR NR NR NR
Bone Biopsy/Surgery 94 to 100 87 to 100 NR NR NR NR NR
Bone Biopsy/Surgery (diabetic population) 28.6 to 100 NR NR NR NR NR NR
Bone Biopsy/Surgery (orthopediatric implant infection) < 30 90 NR NR NR NR NR
Familiari et al. 2011 Bone Biopsy (diabetic population) 43 67 54 NR 60 50 NR
CT Larson et al. 2010 Bone Biopsy/Surgery 50 85 NR NR NR NR NR
Leukocyte scan Dinh et al. 2008 Bone Biopsy/Surgery 74 68 NR 10.07 NR NR NR
Eckman et al. 1996 Bone Biopsy/Surgery 89.0 79.0 NR NR NR NR NR
Van der Bruggen et al. 2010* Bone Biopsy/Surgery NR NR NR NR NR NR 47%

Acc = accuracy; bone scan = bone scintigraphy; CT = computed tomography; DOR = diagnostic odds ratio; MRI = magnetic resonance imaging; NLR = negative likelihood ratio; NPV = negative predictive value; NR = not reported; PLR = positive likelihood ratio; PPV = positive predictive value, sens= sensitivity; spec= specificity.
*Systematic Review
Primary Study data

Table 7: Summary of Diagnostic Accuracy Measures of the Tests in Pediatric Acute Osteomyelitis19

Test Sens % Spec % Acc % PPV % NPV % PLR NLR DOR
Bone scan 81 84 82 94 59 5.11 0.23 22.3
Bone biopsy/labs 1.0 1.0 NA NA NA NA NA NA
CT 67 50 65 91 17 1.33 0.67 2.0
18FDG-PET or PET/CT NA NA NA NA NA NA NA NA
U/S 55 47 54 082 19 1.04 0.96 1.08
MRI 81 67 79 93 40 2.44 0.28 8.67
X-ray — early (late) 16
(82)
96
(92)

27
(83)

96
(99)
16
(32)
3.81
(9.88)
0.88
(0.19)

4.34
(51.17)

Leukocyte scan NA NA NA NA NA NA NA NA

Acc = accuracy; bone scan = bone scintigraphy, CT = computed tomography; DOR = diagnostic odds ratio; 18FDG-PET = 18-fluorodeoxyglucose positron emission tomography; MRI = magnetic resonance imaging; NA = not available; NLR= negative likelihood ratio; NPV = negative predictive value; PLR = positive likelihood ratio; PPV = positive predictive value; sens = sensitivity; spec = specificity.

 

Appendix 4: Definitions

Brodie abscess: A necrotic cavity surrounded by dense granulation tissue.81 A sequela of chronic bone infection.

Cephalhematomas: A blood cyst, or swelling of the scalp in a newborn due to an effusion of blood beneath the skull, often resulting from birth trauma.82

Dead space: A cavity that remains after the incomplete closure of a surgical or traumatic wound, leaving an area in which blood can collect and delay healing.81

Dermographism: Inflammation of skin and muscles; generalized itch is frequent with this condition.83

Fistulae: An abnormal passage from an internal organ to the body surface or between two internal organs.81

ICD-10: International Classification of Diseases (ICD) version 10. The ICD is the international standard diagnostic classification for all general epidemiological, many health management purposes, and clinical use. It is used to classify diseases and other health problems recorded on many types of health and vital records, including death certificates and health records. In addition to enabling the storage and retrieval of diagnostic information for clinical, epidemiological, and quality purposes, these records also provide the basis for the compilation of national mortality and morbidity statistics by World Health Organisation Member States.84

Necrosis: Death of areas of tissue or bone surrounded by healthy parts of tissue or bone.85

Relative risk (RR): The ratio of the chance of a disease developing among members of a population exposed to a factor, compared with a similar population not exposed to the factor. In many cases, the RR is modified by the duration or intensity of exposure to the causative factors.86

Sacroiliac joints: The joint formed by the sacrum and ilium where they meet on either side of the lower back.81

Sickle-cell disease (SCD): Or sickle cell anemia (SCA); a severe, chronic, incurable condition that occurs in people homozygous for hemoglobin. The abnormal hemoglobin results in distortion and fragility of the erythrocytes. SCD is characterized by crisis joint pain, thrombosis, and fever, and by chronic anemia with splenomegaly, lethargy, and weakness.81

Surgical debridement: The removal of foreign material and devitalized tissue using a scalpel or other sharp instrument.86