Abstract
Aim
To conduct a systematic review and meta-analysis comparing the incidence of fracture-related infections (FRI) following surgical management of closed and open fractures in HIV-positive and HIV-negative patients.
Methods
A systematic literature search was conducted using MEDLINE, ProQuest, Web of Science, The Cochrane Library and Scopus. Our own files and reference lists of identified key articles were also searched. We included studies where the primary outcome was the development of FRI in patients with open and closed fractures.
Results
Eleven studies were included for data synthesis. HIV-positive patients had a non-significant increase in FRI when compared to HIV-negative patients (in open and closed fractures combined). Open fractures treated in the pre-antiretroviral era had a 5.6 times greater risk for developing a FRI. In the post-antiretroviral era (1997 onwards) HIV-positive patients did not have a greater risk of FRI than HIV-negative patients for both open and closed fractures. The small retrospective natures of these studies, together with the heterogeneous outcome definitions used, are limitations to this study.
Conclusion
While there are few large prospective studies, the available data suggests that before the introduction antiretroviral therapy HIV infection was associated with a greater risk of FRI. In the post-antiretroviral era HIV infected patients did not show an increased risk of FRI.
Keywords: HIV, AIDS, Infection, Post-operative, Fracture-related infection, Post-traumatic infection, Chronic osteomyelitis, Sepsis, Surgical site infection
Highlights
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Meta-analysis comparing the incidence of fracture-related infections (FRI) in closed and open fractures in HIV+ and HIV- patients.
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HIV-positive patients had a non-significant increase in FRI when compared to HIV-negative patients.
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Open fractures treated in the pre-antiretroviral era had a 5.6 times greater risk for developing a FRI.
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In the post-antiretroviral era (1997 onwards) HIV-positive patients did not have a greater risk of developing a FRI.
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In the post-antiretroviral era HIV infected patients did not show an increased risk for the development of FRI.
1. Introduction
Fracture-related-infection (FRI) is the new working definition to describe the dreaded complication of local fracture site sepsis following trauma.1 This definition was reached in 2017 by expert consensus. FRI is frequently encountered in the immune-competent and immunosuppressed patient alike, but the possible association between human immunodeficiency virus (HIV) and FRI is not yet clearly established.
HIV infection is characterized by both immune suppression and chronic inflammation. This results in immune exhaustion with effector T-cell dysfunction and immune senescence.2, 3, 4 Immune activation occurs through a series of complex mechanisms involving increased pro inflammatory cytokine production and the activation of dendritic cells via the Toll-like receptor pathway. Dendritic cells are known to play an important role in osteoimmunology and infection defense. HIV infection is associated with numerous deleterious effects on the functioning of neutrophils, monocytes and B-lymphocytes that collectively result in decreased bacterial phagocytosis. As a result, there is an increased risk of bacterial infection in patients living with HIV. Methicillin-resistant Staphylococcus Aureus infections occur 6–18 times more commonly than in the general population.5 Sogaard et al. recorded 275 bacterial non-AIDS related infections over a period of 3.9 years in a study involving 10 851 HIV infected patients.6 The authors found that patients not on antiretroviral (ARV) therapy, with CD4 cell counts < 350 cells/mm3 or estimated glomerular filtration rate < 60 ml/h, were at increased risk of bacterial infection. As a result, orthopaedic surgeons have been concerned that HIV-positive patients may be at risk for post-operative infections. This association between HIV infection and FRI in both open and closed fractures has not been clearly elucidated and several conflicting studies have been published.
This study aimed to perform a systematic review and meta-analysis comparing the incidence of FRI's following surgical management of closed and open fractures in HIV-positive and HIV-negative patients.
2. Materials and methods
The review was conducted according to the Cochrane Handbook and reported according to the Preferred Reporting Items for Systematic reviews and Meta- Analysis (PRISMA) guidelines.7,8 A PRISMA checklist was completed and can be viewed as Appendix A.
2.1. Eligibility criteria
Studies involving HIV-positive patients who underwent operative fixation (internal or external) of open or closed fractures were considered eligible. All experimental and epidemiological study designs including randomized controlled trials, non-randomized controlled trials, quasi-experimental, prospective and retrospective cohort studies, case control studies and analytical cross-sectional studies were included. Only studies involving human subjects and published in English were considered. In order to improve the quality of data analysed we only included studies with a control group of HIV negative patients. Review articles, case reports, congress proceedings, abstract-only and conference reports were also excluded. Further grounds for exclusion included studies on haemophiliacs, series involving only arthroplasty procedures, pin-tract sepsis and non-trauma related implant surgery.
2.2. Information sources and search strategy
The following electronic databases were searched for articles published up to 18 April 2019: MEDLINE through the OVID interface, ProQuest, Web of Science, The Cochrane Library and Scopus. We also searched our own files, consulted with experts, reviewed reference lists from identified articles and searched for cited references of key publications. The following combination of keywords and Medical Subject Headings (MeSH) terms were used: “HIV” AND “Fractures” OR “HIV” AND “Orthopaedics” AND “Infection”.
2.3. Eligibility assessment
Two authors (LN and LM) independently screened the titles and abstract of each citation identified in the search, and those possibly meeting the eligibility criteria were extracted to undergo full review in duplicate. Disagreements were resolved by consensus and where this could not be achieved a third adjudicator (RR) acted as arbitrator. Inter-observer chance-corrected agreement was measured using a kappa statistic.
2.4. Outcomes of interest
The main outcome of interest was the development of a FRI at the site of surgery. We planned a sub-analysis of studies according to whether they were conducted in the pre- or post-ARV era. Pre-ARV era studies were defined as those conducted before 1996 or studies who had no patients on ARV therapy. Post ARV-era studies were defined as those conducted after 1996 or included patients on ARV therapy.
2.5. Quality and risk of bias analysis
Two reviewers independently assessed eligible studies for risk of bias using the Newcastle-Ottawa Quality Assessment Scale.9 Each study was judged from three broad perspectives: study group selection, group comparability, and the outcome of interest. Funnel plots were constructed to identify possible publication bias.
2.6. Statistical analysis
The meta-analysis was conducted using Review Manager version 5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).10 Heterogeneity between studies was assessed using univariate chi-square analysis and I2. Results are reported as odds ratio (OR), with 95% confidence intervals (CI), and presented as forest plots. Random effects models were used where the I2 statistic was found to be >25% (representing significant heterogeneity), otherwise a fixed effects model was used.
3. Results
3.1. Study selection
The electronic database search strategy identified 3841 publications. Fourteen additional records were identified, bringing the total to 3855 initial studies. From these, 56 publications were extracted for full-text review, of which 11 were included in the final data synthesis (Fig. 1).
Fig. 1.
Flow diagram showing selection of included studies.
3.2. Study characteristics
Table 1 details the study designs of the included studies, while Table 2 denotes the patient HIV-characteristics and reported infection rates. The 11 included studies spanned 25 years with nine from Africa11, 12, 13, 14, 15, 16, 17, 18, 19 and two from the United States.20,21 All studies were cohort studies of which eight were prospective and three retrospective. Sample sizes ranged from 14 to 647 with a total of 2634 patients. Two studies examined closed fractures only12,16; three evaluated both closed and open fractures,13,14,21 and six studies focused exclusively on open fractures.11,15,17, 18, 19, 20 Fractures were generally classified according to the Gustilo-Anderson classification for open fractures (seven studies)11,15,17, 18, 19, 20, 21 and two according to an infection Risk Category (RC) group,13,14 with one study grouping patients according to individual CD4 counts.12 Fixation methods varied substantially from IM nails (28%), plates (28%), pins/wires/screws (10%), external fixation (8%) and prostheses (5%). Four studies used an ASEPSIS (Additional treatment, presence of Serous discharge, Erythema, Purulent exudate, Separation of the deep tissues, Isolation of bacteria, duration of inpatient Stay) score >10 to construe fracture-related infection,11,13,14,17 while five studies used the presence of a purulent discharge,12,15,16,19,20 one study used the Centre for Disease Control time period definition,21 while the last used the presence of an infection deep to skin and soft tissues.18 Follow-up ranged from one to 39 months with an average of 11,3 months. Three studies were conducted before the introduction of ARV therapy in 1996 16, 20, 21, and two did not involve any patients on ARV's.14,15 We classified these five studies as pre-ARV. The remaining studies were defined as post-ARV era studies.
Table 1.
Characteristics of the included studies investigating HIV and fracture-related infection incidence for dichotomous variable analysis.
| Author | Year | Location | Design | Open/Closed Fractures (total) | Intervention Type (n) | Fracture location (n) | Follow-up period |
|---|---|---|---|---|---|---|---|
| Aird et al. | 2011 | South Africa | Cohort series Prospective |
Open (133) | Nails (55), Plates (32), Pins/Wires/Screws (4), Ex-Fix (32) | Tibia (43), Femur (38), Forearm (37), humerus (14), Other (3) | 1 month |
| Bahebeck et al. | 2009 | Cameroon | Cohort series Prospective |
Closed (544) | Nails (351), Plates (165), Pins/Wires/Screws (31), Ex-Fix (0), Prosthesis (99) | Not specified | 3 months |
| Bates et al. | 2012 | Malawi | Cohort series Prospective |
Open (102) Closed (536) |
Nails (±180)b, Plates (±300)b, Pins/Wires/Screws (±160)b | Mixed (not specified, mostly femurs) | 6 weeks |
| Harrison et al. | 2002 | Malawi | Cohort series Prospective |
RC0 and RC1 categories useda | Nails (±18)b, Plates (±88)b, Pins/Wires/Screws (±160)b, Prosthesis (±7)b | Not specified | 3 months |
| Harrison et al. | 2004 | Malawi | Cohort series Prospective |
Open (27) | Ex-Fix (27) | Tibiae | 3 months |
| Hoekman et al. | 1991 | Rwanda | Cohort series Prospective |
Closed (217) | Nails (73), Plates (124), Prosthesis (20) | Tibia (19), Femur (167), Forearm (14), Humerus (13), acetabulum (1), Ankle (2), Mandible (1) | 30 months (12–45 months) |
| Howard et al. | 2013 | South Africa | Cohort series Prospective |
Open (85) | Nails (21), Plates (7), Ex-Fix (57) | Tibiae | ≥1 month |
| Nieuwoudt et al. | 2016 | South Africa | Cohort series Retrospective |
Open (94) | Ex-Fix (94) | Tibiae | 12 months |
| O'Brien et al. | 1994 | New York | Cohort series Retrospective |
Open (15) | Nails (10), Pins-Wires/Screws (1), Ex-Fix (1) | Tibiae | 6–24 months |
| Paiement et al. | 1994 | San Francisco | Cohort series Retrospective |
Open (89) Closed (347) |
Unknown | Not specified | 26 weeks (4–89 weeks) |
| Phaff et al. | 2015 | South Africa | Cohort series Prospective |
Open (51) | Nails (21), Plates (10), Pins/Wires/Screws (6) | Tibia (9), Femur (13), Forearm (5), Humerus (5), Olecranon (1), Fibula (1) | 39 months (34–48 months) |
Infection Risk Category 0 (RC0) and Infection Risk Category 1 (RC1) classification system used.
Only graphs were used to indicate the number of different types of surgery used in original study, hence our estimation ±
Table 2.
Number of HIV infected patients, nature of fracture and overall infection rates in selected studies included in dichotomous variable meta-analysis.
| Author, year | HIV + n (%) | HIV – n (%) | HIV Unknown n (%) | Total (n) | Patients on ARV (n) | Antibiotics (duration in days) | HIV + open fractures, n (%) | HIV + closed fractures n (%) | HIV + Infection rate (%) | HIV – Infection rate (%) |
|---|---|---|---|---|---|---|---|---|---|---|
| Aird, 2011 | 33 (25%) | 86 (65%) | 14 (11%) | 133 | Not reported | Flucloxacillin 1g q6hrs PO +/− Gentamycin 240 mg IV (3) |
33 (25%) | N/A | 15,15% | 22,1% |
| Bahebeck, 2009 | 74 (11%) | 572 (89%) | 0 | 646 | 44 | Group A: Cefuroxime 750 mg IV (10) Group B: Cefuroxime 1,5g IV (stat) |
N/A | 74 (11%) | 5,4% | 6,8% |
| Bates, 2012 |
132 (22%) | 477 (78%) | 0 | 609 | 7 | Closed #’s: Cefuroxime 750 mg IV (stat) Open #’s: Cefuroxime 750 mg q8hrs IV (3) |
Unknown | Unknown | 9,1% | 7,8% |
| Harrison, 2002 | 38 (21%) | 141 (79%) | 0 | 179 | 0 | Cephazolin 1g IV (stat) | 12 (7%) | 5 (3%) | 15,8% | 6,8% |
| Harrison, 2004 | 7 (26%) | 20 (74%) | 0 | 27 | 0 | Cephazolin 1g IV (stat) then ‘oral antibiotics for 48 h’ (2) | 7 (26%) | N/A | 71,4% | 20% |
| Hoekman, 1991 | 43 (20%) | 171 (80%) | 0 | 214 | N/A | No parenteral antibiotics used Topical Penicillin/Streptomycin (stat) |
N/A | 43 (20%) | 9,3% | 4,7% |
| Howard, 2013 | 28 (33%) | 56 (66%) | 0 | 84 | 3 | Cloxacillin 1g q6hrs IV (2) | 28 (33%) | N/A | 10,7% | 19,6% |
| Nieuwoudt, 2016 | 31 (33%) | 63 (66%) | 0 | 94 | 17 | Cephazolin 2g IV stat then Cephazolin 1g q8hrs, Gentamycin 240 mg daily IV, Metronidazole 500 mg IV q8hrs (3) | 31 (33%) | N/A | 6,5% | 3,2% |
| O'Brien, 1994 | 3 (21%) | 11 (79%) | 0 | 14 | N/A | Not specified: ‘Standard treatment protocol including intravenous antibiotics’ | 3 (21%) | N/A | 100% | 9,1% |
| Paiement, 1994 | 30 (6%) | 446 (94%) | 0 | 476 | N/A | Not specified if antibiotics were used | 9 (2%) | 21 (4%) | 16,7% | 5,4% |
| Phaff, 2015 |
13 (29%) | 23 (51%) | 9 (20%) | 45 | 1 | Flucloxacillin 1g q6hrs PO +/− Gentamycin 240 mg IV (3) |
13 (29%) | N/A | 7,7% | 8,7% |
3.3. Combined infection risk in HIV patients
The point estimate of the risk associated with FRI was greater in HIV-positive patients as compared to HIV-negative patients when combining both open and closed fractures (OR 1.67). However, the 95% CI included one (95% CI 0.92–3.02, p = 0.02, I2 = 51%; Fig. 2).
Fig. 2.
Forest plot with risk of bias summary for combined infection risk in open- and closed fractures (pre-and post ARV era combined).
3.4. Open fractures infection risk in HIV patients
For isolated open fractures point estimate of the risk associated with a FRI was higher for open fractures in HIV-positive patients compared to their HIV-negative counterparts (OR 2.01) with the 95% CI including one (95% CI 0.93–4.34, p = 0.009, I2 = 61%; Fig. 2).
3.5. Closed fractures infection risk in HIV patients
Closed fractures in HIV-positive patients had a greater risk of developing FRI as compared to HIV-negative patients (OR 1.11, 95% CI 0.51–2.41, p = 0.43, I2 = 0%; Fig. 2).
3.6. Subgroup analysis 1: open fractures pre-and post-ARV's
Open fractures in the pre-ARV era were associated with a 5.6 times higher risk of FRI in HIV-positive patients when compared to HIV-negative patients (OR 5.57, 95% CI 2.66–11.66, p = 0.23; I2 = 31%). In the post-ARV era open fractures were not associated with an increased FRI risk in the HIV-positive patient (OR 0.92, 95% CI 0.56–1.51, p = 0.65, I2 = 0%; Fig. 3).
Fig. 3.
Subgroup analysis 1: Forest plot with risk of bias summary for open fractures in the pre- and post ARV eras.
3.7. Subgroup analysis 2: closed fractures pre- and post-ARV's
Closed fractures, in both the pre- and post-ARV era, were not associated with an increased risk of FRI in HIV-positive patients compared to HIV-negative patients (OR 1.04, 95% CI 0.49–2.21, p = 0.43, I2 = 0%; Fig. 4).
Fig. 4.
Subgroup analysis 2: Forest plot with risk of bias summary for closed fractures in the pre- and post ARV eras.
3.8. Risk of bias and study limitations
Heterogeneity ranged from 51% for all studied combined to 61% for open fractures and 0% for closed fractures. The funnel plot (Fig. 5) suggested possible publication bias.
Fig. 5.
Funnel plot for publication bias.
4. Discussion
As a result of its deleterious effect on the immune system and the known increased prevalence of infections in general, HIV infection is generally considered as a risk factor for infection following orthopaedic surgery. However, this intuitive assumption has not been validated in the literature and the impact of HIV infection remains uncertain.
In 1991 Hoekman et al. reported an increase in the risk of post-operative infection following surgical fracture fixation in symptomatic HIV infected individuals.16 Jellis subsequently reported a 33% infection rate following internal fixation of closed fractures and a 72% infection rate in open fractures.22 Noteworthy, is that Jellis et al. reported an increase in adult haematogenous osteomyelitis and late implant-related infections as patient immune competency decreased. In 2002 Harrison et al. found a significant increase in early wound infection following open, but not closed fractures, in HIV positive patients.14 Harrison et al. investigated the prevalence of late infection and found no implant related infection in 26 HIV positive patients at one year follow-up.15 A subsequent study from the same center in Malawi again failed to show an increased risk of early wound infection following clean surgery, but found that the infection rate doubled in contaminated wounds.13 Contrary to the findings of Jellis, this study did not show an increase in chronic infections in HIV positive patients. Two further studies from South Africa added to the controversy. The first noted an increased risk of infection in open fractures in patients with advanced HIV disease (CD4 < 350 cells/mm3).11 The second failed to show an increase in early wound infection in HIV positive patients with open tibia fractures.17 These conflicting reports prompted us to perform a systematic review and meta-analysis to determine whether HIV infection increases the risk of developing FRI.
This study's point estimate suggests a possible higher infection rate in HIV-positive patients for combined closed and open fractures but due to low patient numbers this is associated with wide confidence intervals. Previous systematic reviews on the topic have also found insufficient evidence to confirm an association between HIV infection and infection. Kigera et al. primarily looked at post-operative surgical site infection after clean orthopaedic implant surgery, thus excluding open fractures.23 Twelve out of a total of 16 studies included in their meta-analysis focused on haemophiliac patients. The authors found an overall pooled risk ratio for infection of 1,8 (95% CI 1.3–2.4). Following sensitivity analysis with removal of the poor-quality studies this ratio was reduced to 1.4 (95% CI 0.5–3.8) and they concluded that the results were inconclusive and that more robust studies were required. This study included a large proportion of haemophilia studies as well as a large study by Jellis which contributed 33% of the study weight. This report was excluded from our analysis as it was a narrative review with no description of methodology and did not meet our inclusion criteria. Wijesekera et al. published a detailed systematic review in 2016 looking at early and late infection in open and closed fractures, as well as pin-site infection rates.24 They found no apparent increased risk of early or late infection in closed fractures, but stated that most studies involving open fractures treated with internal fixation did show higher infection rates. They cautioned against drawing any firm conclusions in this regard due to variations in study quality.
While the lack of high-quality studies prohibits a definitive answer in terms of the risk imparted by HIV, this meta-analysis again suggests the possibility of an increased infection risk. However, high quality evidence in this regard remains absent. The heterogeneous results reported in the included studies are noteworthy and care must be taken when interpreting these results. We observed a risk of publication bias and there are concerns with regards the quality of individual studies. The nature of retrospective reviews included in our study lends itself to selection bias.
It appears that the widespread introduction of ARV therapy in 1997 may have further confounded the issue. Earlier studies favored an increased infection risk in HIV-positive patients in open and closed fractures combined,16,20,21 while after 1996, this association has weakened.11, 12, 13, 14, 15,17, 18, 19 Despite lower study heterogeneity in the post-ARV studies sub-analysis our results remained statistically insignificant.
HIV-positive patients with open fractures treated in the pre-ARV era had a greater risk of FRI – 5.6 times higher than HIV-positive patients. Unfortunately these studies had very small sample sizes. In the post-ARV era this risk dramatically reduced to match that of HIV-negative patients. The effect of ARV's on the immune defense against bone infection may therefore be meaningful and presents itself as a field for future research. The current evidence does not suggest that closed factures in HIV-positive patients are associated with a greater infection risk.
4.1. Limitations
It is notable that the studies included in this review were conducted at a limited number of centres (n = 6; Table 1). Furthermore, there was no clear indication of participant selection or description of inclusion or exclusion criteria in a number of studies. In terms of the outcome measures there was considerable diversity with regards to the definition of the presence of infection. The lack of blinding with regards to HIV status was either not noted or not present in the majority of studies. When looking at the statistical methods employed, only a handful of studies provided an estimate of the random variability of the data in the form of confidence intervals.
The great diversity of study subjects, study objectives and methodology, various classification systems and the inclusion of gunshot wounds does lessen the overall generalizability of our meta-analysis. Many of the studies had a low event rate and larger studies are needed. Larger prospective studies with homogenous definitions and methods would greatly add to the quality of forthcoming analyses on this subject matter.
5. Conclusion
The assumption that HIV infection increases the risk for fracture-related infection remains unsubstantiated. While there are few large prospective studies, this study suggests that before antiretroviral therapy HIV infection was associated with a greater risk of FRI. In the post-antiretroviral era HIV-infected patients did not show an increased risk of FRI. More data is required from well-designed larger studies to inform future analysis.
Funding
No specific funding was received in relation to this study.
Declaration of competing interest
The authors have no conflicts of interest to disclose.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jor.2020.01.023.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
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