Published online May 1, 2006
PEDIATRICS Vol. 117 No. 5 May 2006, pp. 1673-1679 (doi:10.1542/peds.2005-2009)
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Venous Thrombosis Associated With Staphylococcal Osteomyelitis in Children

Blanca E. Gonzalez, MDa,c, Jun Teruya, MD, DSca,b,c, Donald H. Mahoney, Jr, MDa,c, Kristina G. Hulten, PhDa,c, Rachael Edwards, BSb,c, Linda B. Lambertha,c, Wendy A. Hammerman, RNa,c, Edward O. Mason, Jr, PhDa,c and Sheldon L. Kaplan, MDa,c

a Departments of Pediatrics
b Pathology, Baylor College of Medicine, Houston, Texas
c Texas Children's Hospital, Houston, Texas


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND. Venous thrombosis (VT) in children with Staphylococcus aureus osteomyelitis occurs rarely. We describe clinical features of infections and molecular characterization of isolates of children at Texas Children's Hospital with S aureus osteomyelitis and VT.

METHODS. We reviewed records and imaging studies (chest radiographs, ultrasound, computed tomography, and MRI) of 9 patients at Texas Children's Hospital with acute S aureus osteomyelitis and new onset VT between August 1999 and December 2004. Isolates were fingerprinted by pulsed-field gel electrophoresis and tested for the presence of genes encoding selective virulence factors.

RESULTS. The mean age of the patients was 10.6 years. All 9 of the patients had osteomyelitis with sites of infection adjacent to the VT. The femoral and popliteal veins were most commonly affected. Two patients had VTs develop on the same side in which a central line had been in place. Four patients had chest radiographs consistent with septic emboli; inferior vena cava filters were placed in 3. Evaluation for hypercoagulable state revealed 3 patients with lupus anticoagulant, 1 with anticardiolipin IgG antibody, and 5 with no defect. Most laboratory abnormalities had resolved at follow-up. Seven patients had infections caused by methicillin-resistant S aureus belonging to the same clonal group (USA300); all were community acquired. Seven isolates carried the Panton-Valentine leukocidin (luk-S-PV and luk-F-PV) genes.

CONCLUSIONS. The predominant community-acquired, methicillin-resistant S aureus clone in Houston, Texas, (USA300) may have a unique propensity to cause VT in association with osteomyelitis. Management of the venous thrombosis in this setting may be complicated by the rapid evolution of septic emboli.

Key Words: venous thrombosis • Staphylococcus aureus • osteomyelitis

Abbreviations: VT—venous thrombosis • CA—community acquired • MRSA—methicillin-resistant Staphylococcus aureus • TCH—Texas Children's Hospital • PFGE—pulsed-field gel electrophoresis • MSSA—methicillin-susceptible Staphylococcus aureus • LMWH—low molecular weight heparin • IVC—inferior cava filter • PVL—Panton-Valentine leukocidin

Venous thrombosis (VT) is an uncommon event in children and is typically associated with the presence of central venous catheters, trauma, sepsis, malignancies, and preexisting coagulation disorders.1–3 To our knowledge, since 1971 <15 children have been reported with osteomyelitis caused by Staphylococcus aureus complicated by VT.4–13

Since the emergence of community-acquired (CA) methicillin-resistant S aureus (MRSA), severe manifestations of staphylococcal infections, including sepsis syndrome, purpura fulminans, necrotizing fasciitis, and severe necrotizing pneumonia have been encountered more frequently.14–18 At Texas Children's Hospital (TCH), >75% of CA S aureus infections are caused by CA MRSA.19, 20 We describe the clinical and hematologic features of 9 patients admitted to TCH between 1999 and 2004 with the diagnosis of S aureus osteomyelitis complicated by VT, as well as the molecular characteristics of their isolates.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Prospective surveillance of patients with CA S aureus infections and collection of isolates at TCH in Houston, Texas, have been performed since August 1, 2001.19 Patients admitted to TCH between August 1, 2001, and December 31, 2004, with invasive staphylococcal infections (ie, osteomyelitis, septic arthritis, pneumonia, sepsis, etc) who developed a VT were identified. The infectious disease service consult records at TCH also were reviewed for the 3 years before August 2001 for patients with similar diagnoses. Medical charts were assessed for demographic, clinical, and laboratory information (approved by the institutional review board at Baylor College of Medicine). Relevant radiographs were also reviewed. Our definitions of "community acquired" and "health care associated" have been outlined.19 The available hypercoagulability evaluations were performed and interpreted by experienced professionals in the pathology coagulation laboratory.

Isolates were recovered from storage at –80°C and were grown on tryptic soy agar plates containing 5% sheep blood (BBL; Beckton Dickinson, Cockeysville, MD). DNA was isolated using the UltraClean Microbial DNA kit as recommended by the manufacturer (MO Bio Laboratories, Inc, Solana Beach, CA). Detection of PVL (luk-S-PV and luk-F-PV) cna, fnbA, fnbB and clf genes by polymerase chain reaction and determination of the accessory gene regulator was performed as described elsewhere.19, 21

Determination of SCCmec Type
The SCCmec type was determined using the methods by Okuma et al.22 Positive controls were NCTC 10492 (SCCmec type I), N315 (SCCmec type II), 85/2082 (SCCmec type III), and CA 05 (SCCmec type IVa).

Fingerprinting
Nine strains were grown on tryptic soy agar plates containing 5% sheep blood (BBL). Genomic DNA for pulsed-field gel electrophoresis (PFGE) was prepared using a modified procedure based on the method by Murray et al.23 Plugs were equilibrated in 1 mL of 1x NEB 4 buffer (New England Biolabs Inc, Beverly, MA) for 5 minutes before restriction enzyme digestion. The solution was removed, and 300 µL of 1x NEB 4 buffer and 1.5 µL (30 U) Sma I (New England Biolabs) were added per sample. One half of a digested plug was inserted into the well of a 1% pulsed-field certified agarose-0.35 x TBE gel (Bio-Rad; 1 x TBE is 89 mM Tris, 89 mM boric acid, and 2 mM ethylenediaminetetraacetic acid [pH 8.4]), and PFGE was performed using the CHEF DR III system in 0.35 x TBE using the Harmony protocol (block 1: 5–15 seconds for 10 hours; block 2: 15–60 seconds for 13 hours, 120° angle, 6 V/cm).24 Band separation and reproducibility were achieved by running gels at 100 to 135 mA. PFGE profiles were compared visually and digitally by Pearson correlations/unweighted pair group method with arithmetic mean using the GelComparII computer software (Applied Maths, Kortrijk, Belgium). The relationships between strains were based on criteria published previously.25


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Nine patients with invasive S aureus infection and VT were identified. Eight patients were admitted between August 1, 2001, and December 31, 2004, and 1 patient was identified in the 3 prior years. All of the patients were male with a mean age of 10.6 years (7 were ≥10 years; Table 1). Seven patients had infections caused by MRSA, all of which were considered CA. Two patients had infections caused by CA methicillin-susceptible S aureus (MSSA). Overall, from August 2001 to December 31, 2004, 116 patients at TCH had acute hematogenous osteomyelitis caused by CA MRSA; 7 (6%) developed VT.


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  		TABLE 1 Clinical Characteristics of Children With S aureus Osteomyelitis and VT

 
VT
The femoral veins were the most commonly thrombosed (50% of the patients) with clots extending frequently into the popliteal veins (Table 1; Fig 1). Only 1 patient had a superficial venous system thrombosis (left saphenous vein). All 9 of the patients had osteomyelitis and pyomyositis located adjacent to the site of the thrombosis. The mean time to diagnosis was 6 days after admission (range: 1–19 days). The majority of the VTs were detected when imaging was performed to evaluate the osteomyelitis/pyomyositis. Six VTs were detected by MRI; 3 were demonstrated by either computed tomography or venous ultrasound with Doppler flow.


Figure 1
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  		FIGURE 1 Magnetic resonance venography and computed tomography of the chest in a patient with S aureus osteomyelitis and VT. Image shows interruption of flow in the right femoral vein. This patient had a femoral-popliteal thrombosis and multiple septic emboli shown on the computed tomography scan. He required the insertion of an inferior vena cava filter.

 
Four patients had evidence of septic emboli in pulmonary imaging. In 3, the initial chest radiographs showed multiple nodular lesions. The fourth patient had bilateral interstitial lung disease that progressed to nodular densities 8 days later (2 days before the diagnosis of the VT).

Risk Factors
Six patients had no family history of VT or of conditions predisposing to thrombus formation. One patient had second-degree relatives with multiple episodes of VTs requiring lifelong anticoagulation. Another patient had a first-degree relative who died of an acute myocardial infarction at <50 years of age. One patient's family history was unknown.

Hypercoagulablility workup was performed in 8 patients. Three patients had positive lupus anticoagulant, and 1 patient had high positive IgG anticardiolipin antibody. Lupus anticoagulant became negative in 2 patients after the acute phase of the infection resolved (1 patient was lost to follow-up, and the fourth patient did not have repeated levels). Factor V Leiden mutation was not detected in the 8 patients tested. Functional antithrombin levels and homocysteine levels were within reference ranges when tested. Functional proteins C and S were measured in 8 patients, none of whom were receiving warfarin at the time the measurements were performed. Five of these measurements were performed within 14 days of the diagnosis of the thrombosis. Functional proteins C and S levels were low in 3 patients (mean 31% activity and 30% activity of normal, respectively; reference range: protein C, 80–175%; protein S, 50–130%). These levels returned to normal after the acute event had resolved. Fibrinogen levels were available in 7 patients at the time the thrombosis was diagnosed and were elevated (mean: 611 mg/dL [6.11 g/L]; range: 484–749 mg/dL [4.84–7.49 g/L]; reference range: 280–440 mg/dL [2.80–4.40 g/L]).

A central venous catheter had been in place or was still present in 5 of the 9 patients when the VT was diagnosed. Three patients had osteomyelitis of a bone in the proximity of the VT and a central venous catheter located at a distant or contralateral site. Two patients had VTs develop on the same side in which a femoral central line had been in place (patients 4 and 5 in Table 1). These patients also had osteomyelitis of a bone in the proximity of the VT (ipsilateral). They were diagnosed on hospital days 19 and 10 (16 and 8 days after the central line was placed), respectively. Both of these patients had pulmonary abnormalities: patient 4 had bilateral airspace disease and patient 5 had radiographic features of septic emboli present by day 5 of admission.

Laboratory
Five patients had platelet counts <100000/mm3 (100 x 109/L) on admission (mean: 79000/mm3 [62 x 109/L]; range: 65000–96000/mm3 [65–96 x 109/L]). The mean platelet count for all of the patients was 343000/mm3 (343 x 109/L) at the time of diagnosis of the thrombosis. All of the patients had an elevated erythrocyte sedimentation rate and C-reactive protein. D-dimer measured in 7 of the 9 patients on admission to the hospital was elevated (>4000 ng/mL; normal: <4000 ng/mL). Two of these patients presented with a VT on admission. The other 5 were diagnosed with a VT an average of 10 days after admission (range: 5–19 days).

The mean duration of positive blood cultures was 5 days (range: 1–11 days). Five patients were no longer bacteremic at the time of VT diagnosis.

Therapy
The 7 patients with infection caused by an MRSA were treated with vancomycin for a minimum of 42 days. The 2 patients with MSSA infection received nafcillin initially for 2 weeks and then were switched to intravenous cefazolin to complete a total of 42 days of therapy.

Five of the 9 patients had low molecular weight heparin (LMWH) initiated when the VT was identified. For these patients, anticoagulation was continued with either LMWH or warfarin for a mean of 4.9 months (range: 2.5–10 months). Three patients were started on intravenous unfractionated heparin (the target activated partial thromboplastin time was >65 seconds) and continued their therapy with warfarin. Antifactor Xa was followed in patients on LMWH with a target level of 0.5 to 1.0 U/mL. The international normalized ratio target for warfarin therapy was between 2.0 and 3.0. One patient with a deep pelvic vein thrombus and a left atrial mass received aspirin alone.

Three patients had chest radiographs on admission showing multiple septic pulmonary emboli and experienced rapid deterioration of their respiratory status. Two of these patients were intubated within 12 hours of presentation, and the third was placed on bilevel positive airway pressure. These 3 patients had intravascular filters (Greenfield [Boston Scientific, Natick, MA], Günter Tulip [Cook Inc, Bloomington, IN], and Recovery Nitinol [BARD Peripheral Vascular, Tempe, AZ]) placed in an attempt to diminish the showering of emboli to the lungs, because anticoagulation had been started with no improvement in their respiratory status. The filters were placed within 48 hours of admission in each case. One patient had improvement in oxygenation within 2 days and never required mechanical ventilation. The other patients, who had had filters placed while already on mechanical ventilation, continued to have clinical and radiographic deterioration of pulmonary status requiring high-frequency oscillator ventilation.

Outcome
Patients were followed up closely by their primary care physician, hematology, and the infectious disease services for the entire duration of their illness and until anticoagulation was discontinued. On average, the thromboses completely resolved (as evidenced by reimaging) in 7 patients by 10 weeks (range: 2.5–32 weeks). One of the 3 patients with filters had complete radiologic resolution of the VT by 12 weeks with subsequent retrieval of the Recovery Nitinol filter. Retrieval of a Guenther Tulip filter was unsuccessful in another patient and remains in place; however, anticoagulation was stopped after 10 months. The third patient remains on anticoagulation with the filter in place.

Molecular Analysis
Eight isolates were available for molecular analysis (Table 2). Seven were methicillin resistant and carried the SCCmec type IV associated with CA organisms. PFGE revealed that the 7 CA MRSA isolates shared a common pulsed-field type (USA300). The PVL genes were present in all but the available MSSA isolate. All of the isolates tested positive for genes encoding FnbA, FnbB, and ClfA and were accessory gene regulator group I (Table 2).


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  		TABLE 2 Molecular Characteristics of S aureus Strains Isolated From Children With Osteomyelitis and VT

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Venous thromboses are serious events that may carry devastating consequences. The estimated incidence in children is 0.07 per 10000 with neonates and adolescents being the most susceptible groups.1 Inherited thrombotic risk factors, underlying conditions associated with thrombosis, and the use of intravenous catheters account for the majority of such events.2, 3, 26 Although infrequently reported, S aureus infections, especially osteomyelitis, have been associated with VT and pulmonary emboli in children (Table 3). 4 At TCH, the number of venous thromboses in patients with S aureus osteomyelitis and pyomyositis has increased dramatically since 2001. Reviewing the data from the 3 years before August 1, 2001, we found only 1 patient (64 patients with S aureus osteomyelitis of large bones or vertebrae in the TCH Infectious Disease Service consultation database over this period) who developed a VT with an S aureus (MSSA)-invasive infection. The increased number of VTs has coincided with the establishment of USA300 ST8 as the predominant clone of CA S aureus in Houston.19 Between August 2001 and December 31, 2004, 116 patients at TCH had acute hematogenous osteomyelitis caused by CA MRSA, and 7 (6%) developed VT. In the 13 other reported cases of VT associated with S aureus osteomyelitis in children, all of the isolates were methicillin susceptible (Table 3). In contrast, the majority of our patients had disease associated with CA MRSA isolates. This is the first documentation of an increased frequency of VT in acute osteomyelitis caused by the USA300 S aureus clone.


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  		TABLE 3 Summary of Published Cases of VT in Patients With S aureus Osteomyelitis

 
The genes that encode for the exotoxin PVL (lukS-PV and lukF-PV) are common in the community strains of MRSA circulating in the United States.18, 19, 27 Although predominantly associated with skin and soft tissue infections,19, 20 PVL genes have also been present in strains isolated from patients with severe necrotizing pneumonia, purpura fulminans, and severe sepsis.14, 16–18 Also, more complications occurred in patients with musculoskeletal infections caused by CA S aureus strains carrying the PVL genes compared with those with isolates lacking these genes.28 Only 1 of the available isolates in our study lacked the PVL genes.

Genetic prothrombotic defects did not seem responsible for the VTs in our patients. Functional proteins C and S were decreased in 3 patients as a consequence of the infectious process, but, subsequently, these levels returned to baseline. Two patients had transient presence of lupus anticoagulant that disappeared after the acute event. Fibrinogen levels were also elevated in the tested patients. Seven children had elevation of D-dimer measured at the time of the diagnosis of the VT. Whether following this parameter in children with VTs associated with invasive S aureus infection is useful requires additional study.29

The incidence of pulmonary embolisms in children is low, but mortality rates may be as high as 30%.30, 31 We reported that of 57 patients with invasive CA S aureus infections and abnormal pulmonary findings, 11 (19%) had septic emboli, the majority in patients with bone and joint infections.32 In the present study, none of our patients died, but many of their complications and the prolonged hospitalizations were related to their pulmonary insult. Aggressive therapy should be instituted once pulmonary emboli are recognized.

The indications for filter placements in children during sepsis are unknown. Greenfield and Proctor33 retrospectively studied 175 patients with sepsis who had intravascular filters placed for prophylaxis, contraindication to anticoagulation, or VT, among others. The youngest patient was 14 years old. Subsequent septic episodes or filter removal because of complications had not occurred after 1 year in survivors. One conclusion was that, for septic patients who are hemodynamically unstable and cannot tolerate additional respiratory compromise associated with pulmonary emboli, placement of an endovascular filter was warranted. Three of our patients had intravascular filters placed because of multiple septic emboli and deterioration of respiratory status despite the use of unfractionated heparin. Only 1 patient had the filter placed before intubation was required. He responded favorably to this intervention, as his respiratory status improved dramatically thereafter. The other 2 patients also had the filters placed while still bacteremic. Cahn et al34 have followed 15 children with inferior cava filters (IVCs), none placed in the setting of infection, for a mean of 9 years. Complications, such as filter migration, pulmonary emboli, or IVC thrombosis, did not develop. To date, no complications have arisen in our patients, who continue to have close follow-up.

Could the increase in the diagnosis of VT be related to the introduction of more sensitive imaging modalities? MRI has been available at TCH since the late 1980s, and yet it was not until 2001 that VTs were recognized more frequently, making this explanation unlikely, although an increase in the recognition of VT on MRI by radiologists is possible. The presence of PVL genes is associated with greater systemic and local inflammation in children with S aureus osteomyelitis and also may be associated with VT.35 If VT is suspected in the child with S aureus osteomyelitis, the preferred imaging modality is ultrasound with Doppler flow.

Thrombosis is a complication of intravenous catheters.26, 36 In the 2 patients whose lines and osteomyelitis were at the same site, the presence of pulmonary emboli in the course of the disease is more suggestive of the VT being related to infection rather than being catheter related. A prospective study in 20 children with femoral vein catheters showed an incidence of catheter-related femoral vein thrombosis of 35% without associated morbidity.37 Younger and smaller children were at greater risk for thrombosis in this study.

The predominant pvl-positive CA MRSA clone in Houston (USA300), which is also present in many areas of the United States, may have a unique propensity to cause deep VT in association with acute osteomyelitis. The importance of other hypercoagulation risk factors in the evolution of VT in this setting is unclear. Physicians caring for children with osteomyelitis in areas where CA MRSA isolates are now common, or will be in the future, should be aware and appropriately screen for this complication, especially when septic pulmonary emboli are present. Aggressive anticoagulant therapy should be considered in these patients. The role of IVC filters is uncertain. Early collaboration with hematology colleagues with expertise in thrombosis management may be advantageous.


   ACKNOWLEDGMENTS
 
This study was supported in part by a grant from Pfizer, Inc.


   FOOTNOTES
 
Accepted Oct 19, 2005.

Address correspondence to Sheldon L. Kaplan, MD, Texas Children's Hospital, Mail Code 3-2371, 6621 Fannin St, Houston, TX 77030. E-mail: skaplan{at}bcm.tmc.edu

Financial Disclosure: Dr Kaplan is the recipient of a grant from Pfizer for an S Aureus surveillance study.


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 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics



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Panton-Valentine leukocidin-secreting Staphylococcus aureus causing severe musculoskeletal sepsis in children: A NEW THREAT
J Bone Joint Surg Br, September 1, 2007; 89-B(9): 1239 - 1242.
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 The Annals of PharmacotherapyHome page
P. N Johnson, R. P Rapp, C. T Nelson, J. Butler, S. Overman, and R. J Kuhn
Characterization of Community-Acquired Staphylococcus aureus Infections in Children
Ann. Pharmacother., September 1, 2007; 41(9): 1361 - 1367.
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 NEJMHome page
R. S. Daum
Skin and Soft-Tissue Infections Caused by Methicillin-Resistant Staphylococcus aureus
N. Engl. J. Med., July 26, 2007; 357(4): 380 - 390.
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 JBJSHome page
S. T. Hollmig, L. A.B. Copley, R. H. Browne, L. M. Grande, and P. L. Wilson
Deep Venous Thrombosis Associated with Osteomyelitis in Children
J. Bone Joint Surg. Am., July 1, 2007; 89(7): 1517 - 1523.
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