Association between chronic osteomyelitis
and deep-vein thrombosis
Analysis of a nationwide population-based registry
Te-Yu Lin1; Yu-Guang Chen2; Wen-Yen Huang3; Cheng-Li Lin4; Chiao-Ling
Peng5; Fung-Chang Sung6; Chia-Hung Kao6,7
Introduction
Osteomyelitis is an infection of bone and bone marrow caused by haematogenous or contiguous spread of the organism from a local infection and or an open traumatic fracture (1). Progressive destruction of the bone and the formation of sequestra are characteristics
of this disease, which can be classified into acute or chronic based on clinical symptoms and time duration. Despite major
medical and surgical advances in the management of patients, osteomyelitis remains extremely difficult to treat because of biofilm
formation. The structure of a biofilm consists of three basic elements: bacteria, an extra cellular matrix, and other interstitial
metabolic components. Hence, the term “cure” is not used because the bone infection can relapse after many years of successful remission. From this viewpoint, osteomyelitis behaves similarly to a
benign tumour, because it rarely kills, but tends to return without complete ablation (2).
Venous thromboembolism (VTE) is a severe condition and is associated with high morbidity and mortality, and impaired health-related quality of life (3-5). The traditional risk factors of VTE are malignancy, a history of VTE, autoimmune disease, heart disease, respiratory disease, obesity, nephrotic syndrome, and myocardial infarction (6). Infections are also considered a classical risk factor requiring thromboprophylaxis (7). Rogers et al. revealed that 52% of hospitalised VTE cases were preceded by an infection (8). Schmidt et al. observed a three- to 12-fold risk of VTE within
the first two weeks after various acute infections, gradually decreasing
thereafter (9). The associations between chronic infec- tions and VTE are less clear. Chronic osteomyelitis is a common
between chronic osteomyelitis and VTE is limited. Therefore, we conducted a nationwide population-based cohort study to investigate whether chronic osteomyelitis increases the risk of DVT and
PE.
Methods
Data source
We established a longitudinal cohort study from Taiwan National Health Institute Research Database (NHIRD) with hospital admissions of the whole population insured in Taiwan, and this cohort
study contains healthcare claims between 1996 and 2010. The National Health Institute (NHI) provides coverage to over 99% of the population of Taiwan (10). The NHIRD consists of registration data, the details of which have been reported in previous studies (11, 12). The Taiwan National Health Research Institutes (NHRI) maintains the NHIRD, and before releasing electronic files, personal identification information is encrypted to protect patient
privacy. This study was exempted from informed consent by the Institutional Review Board of China Medical University (CMUREC-101-012).
Study population
Cases analysed were those diagnosed with chronic osteomyelitis (the first hospitalisation for chronic osteomyelitis) between 1998 and 2010. The date of the first hospitalisation for chronic osteomyelitis was identified as the index date. Chronic osteomyelitis
was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 730.1. Patients with a history of PE (ICD-9-CM code 415.1, excluding ICD-9-CM code 415.11) or DVT (ICD-9-CM code 453.8) before the index date and those with incomplete age or sex information were excluded. All remaining patients without a history of DVT or PE from the entire NHIRD were included. The patients with
chronic osteomyelitis and comparison controls were selected by 1: 1 matching on a propensity score. The propensity score was calculated by a logistic regression to estimate the probability of the
treatment assignment given the baseline variables including age, sex, and Charlson comorbidity index score. Outcome variables included the development of DVT or PE during the follow-up
peri-5.53, 95% CI=3.46-8.84 for DVT and HR = 3.50, 95% CI=1.86-6.60 for PE).
Discussion
This is the first nationwide population-based cohort study to investigate the associations between chronic osteomyelitis and VTE.
Our study adjusted for many classical VTE risk factors, suggested that chronic osteomyelitis is an independent risk factor for VTE. We observed that adults with chronic osteomyelitis have 2.49-fold risks of developing DVT compared with matched controls.
Many risk factors are known for VTE. Smeeth et al. found that
acute infections are associated with increased risk of VTE in community settings (15). Osteomyelitis is a heterogeneous disease in
its pathophysiology, clinical presentations, and management.
Acute osteomyelitis frequently evolves into a chronic disease. Several studies have shown that DVT is associated with acute osteomyelitis in children (16, 17). However, studies on the association
between chronic osteomyelitis and DVT/PE are scarce. Our result provide epidemiological evidence of the relationship between these two diseases.
The patients with chronic osteomyelitis and comparison controls
were selected by 1: 1 matching on a propensity score. The propensity score was calculated by a logistic regression to estimate
the probability of the treatment assignment given the baseline variables including age, sex, and Charlson comorbidity index score. Chronic osteomyelitis remains an independent risk factor for developing DVT and PE after adjusting for these covariates. The pathogenesis of VTE includes alteration in blood flow (stasis), vascular endothelial injury, and changes in the blood (hypercoagulable status). Chronic osteomyelitis is a systemic inflammatory disorder which could cause decreased mobility and affect venous stasis.
Inflammation cascade triggered by chronic infection plays a major role in the pathogenesis of venous thrombosis (18). Several
reports document the proinflammatory properties of cytokines and cellular adhesion molecules and the natural anti-inflammatory properties of interleukin-10 (IL-10) in animal models (19-21). Modulation of proinflammatory selectins in these animal models indicates that both thrombosis and vein wall inflammation can be decreased during early and later stages of venous thrombosis
(22-27). These findings of basic experimental studies are compatible with epidemiological results.
Most chronic osteomyelitis patients in the present study were
male, and DVT risks increased in both sexes with chronic osteomyelitis. The incidence rate of DVT and PE increased with age in
the patients with chronic osteomyelitis and comparison cohorts, which is compatible with previous studies (28). As people age, they become less active, and the function of the cardiopulmonary system deteriorates. This phenomenon contributes to DVT caused by
blood stasis. Recent studies have shown that frailty, which is commonly associated with aging, can activate coagulation and inflammatory pathways (29, 30).
Because osteomyelitis involves the bone and bone marrow region and subsequently destroys surrounding endothelial cells, this local factor can cause an abnormal coagulant cascade that affects endothelial cell alteration and adhesion molecule expression, as observed in Lemierre’s syndrome (31). Our study indicated that the HR of DVT is relatively higher than that of PE (
_
Table 2 and_
Table 3), indicating that the predominant effect of the local factor is stronger than that of the systemic hypercoagulable state. The risk of PE was not significant between the control and osteomyelitis group even without any VTE comobidity (CCI score=0).This study showed that the incidence rates of DVT increased in patients with any comorbidity in both cohorts. These results were statistically significant for the subsets with CCI score 0 and _3 (
_
Table 2). We observed that the increased classical risk factor for DVT (CCI score increased) may have reduced the effect of increasing risk of DVT by chronic osteomyelitis. These results wererobust according to Cox proportional-hazards regression analysis for the increased risks of DVT and PE in chronic osteomyelitis with interaction of CCI score (
_
Table 3). Thus, a multidisciplinary team should guide the assessment, treatment and holistic care of patients with chronic osteomyelitis.This study had potential limitations. The NHIRD does not contain detailed information regarding smoking habits, body mass
index, and family history of VTE, all of which might be confounding factors in this study. Additionally, information on the osteomyelitis severity scale, such as disease activity, functional impairment,
and physical damage was not available in our data. The paucity of drug data, such as hormone replacement therapy, contraceptive medications, and glucocorticosteroids might have affected
the outcome measurement. The evidence derived from a retrospective cohort study is also generally lower in statistical quality
than that from randomised trials because of potential biases related to adjustments for confounding variables. Despite our meticulous study design and control measures for confounding factors, bias resulting from unknown confounders might have affected our results.
The major strength of our study is its use of a nationwide population-based database that included a relatively large number of
chronic osteomyelitis cases, showing that patients with chronic osteomyelitis have 2.49-fold risks of developing DVT, compared with
matched controls. We recommend that physicians should consider chronic osteomyelitis in their evaluation of risk factors for DVT.
