We presented the case of a 14-year-old female with a secondary systemic vasculitis few months after posterior spinal fusion due to idiopathic scoliosis aiming to highlight the difficulties during the diagnostic process. Differentiating possible etiologies for secondary systemic vasculitis is sometimes confounding. Symptoms and laboratory findings may be misleading and decision-making could be controversial and problematic [1–5]. Herein, we faced a significant problem in distinguishing the possible causative factor that triggered the immunologic over-reaction and caused the systematic vasculitis. Due to lack of precedence, we had entertained 2 possibilities for the present clinical dilemma: a low-grade chronic infection; and delayed immune reaction to the metal of implant. Although initial clinical and laboratory findings were in favor of an allergenic etiology, we finally identified the presence of periprosthetic spinal infection. However, the question if the infection triggered the systemic immune reaction or the immune hyper-reactivity and possible formation of seroma resulted in contamination and periprosthetic infection remained unanswered.
Systemic vasculitis is a disease with broad spectrum of clinical symptoms. The severity ranges widely from life threatening fulminant conditions to relatively minor skin disease [1–5]. The etiology is clearly multifactorial; among the potential influences on disease expression are genetic factors (HLA and others), ultraviolet light, infections, toxins, drugs, and allergies [1–5]. In our case, we could identify two potential contributing factors for the development of a secondary systematic reaction: late infection which is not unusual and metal allergy to titanium or titanium alloy components, that is relatively rare . However, it is likely that cases involving implant-related metal sensitivity have been underreported because of the difficulty of diagnosis [1, 11]
Metal hypersensitivity has been associated mainly with hip joint replacement recipients with metal on metal bearing surfaces. This could be attributed to exposure to degradation products (i.e wear particles of metal on metal bearing surfaces) that mediate t immunologic effects and/or cell toxicity [6–8]. Spinal implants are static load-bearing devices subjected to micromotion at least until fusion is achieved. The long instrumentations for spinal deformity involve many couplings of screws, rods and interconnecting devices, all with a potential to fretting corrosion. Therefore, spinal instrumentation can cause metal ion release from fretting corrosion with elevated levels in body fluids . This has been demonstrated by several studies on metal ion levels in spinal instrumentation [12, 13]. Moreover, titanium particulate debris at the level of a spinal arthrodesis could elicit a cytokine-mediated particulate-induced response favoring pro-inflammatory infiltrates, increased expression of intracellular tumor necrosis factor-alpha, increased osteoclastic activity, and cellular apoptosis, as shown in an animal model by Cunningham et al.  In the clinical setting, the presence of titanium particulate debris, secondary to motion between spinal implants could serve as the impetus for late-onset inflammatory-infectious complications and long-term osteolysis of an established posterolateral fusion mass .
Patients presenting with signs of a systemic reaction should be evaluated for sensitivity. Assessment of hypersensitivity has historically been conducted in vivo by skin testing (i.e. patch testing or intradermal testing) [15–17] and in vitro by leukocyte migration inhibition testing (termed LIF or MIF testing) [18, 19] and MELISA (memory lymphocyte immunostimulation assay) [20–22]. MELISA reactivity is directly dependent on lymphocyte concentration; the higher the lymphocyte concentration per test, the stronger the reactivity [20–22]. While in vivo testing protocols and commercial kits do exist, there is continuing concern about the applicability of skin testing to the study of immune responses to implants, particularly since there is a lack of knowledge about and availability of appropriate challenge agents [15–17]. Basketter et al.  and Okamura et al. , suggested specific titanium salts for testing in case of suspected titanium allergy. Although the utility of migration inhibition assays in various clinical settings has been demonstrated [18, 19], only Merritt et al.  have applied leukocyte migration testing to assess biocompatibility of implanted devices. In our case, there was no availability of in vitro leukocyte migration inhibition testing.
Except for the clinical scenario of immune hypersensitivity due to metal allergy, other potential diagnoses or etiologies should always be considered. Delayed immune response due to sub-acute, low virulence infection is one possible cause [1, 26]. A complete diagnostic work up should be performed, including cultures of urine and blood samples, chest x-rays, blood count, and evaluation of erythrocyte sedimentation rate and C-reactive protein levels . Surgical wound should always be assessed both clinically for signs of inflammation, fistulas or fluid collections and with imaging studies (MRI, CT, ultrasonography) which usually indicate the presence periprosthetic infection . However, even in cases with loud clinical symptomatology and increased suspicion for the presence of infection, there should be a great level of awareness. Aseptic fistulas might become the gate of infection appeared in the body of the patients, whose implants worked improperly. The patients who suffered the complication were allergic to the metals included in the implant [1, 26]. This could be the case in our patient. Increased immune reaction due to metal allergy could induce a secondary formation of seroma, dehiscence of surgical wound and eventually contamination and establishment of a periprosthetic infection; and vice versa, a primary periprosthetic infection could cause an over-reaction of the immune system in the form of systemic vasculitis.
Other possible etiologic factors of systemic immunologic response should probably be excluded using the appropriate laboratory exams. Antinuclear antibodies, rheumatoid factor, anti-neutrophil cytoplasmic antibodies, antibodies to glomerular basement membrane and complement levels should be assessed in order to exclude immunologic pathologies [4, 5] Hepatitis B surface antigen, hepatitis C antibody, and HIV antibodies should be evaluated in order to excluded immune-hyper-reactivity due to viral infection . In our case all above mentioned laboratory exams were within normal values.
Removal of a device that has served its function should be considered, since removal may alleviate the symptoms. However, in the case of instrumented posterior spinal fusion there should always be taken into account the great possibility of loss of reduction if the implants are removed too early . The severity of systemic symptoms should be weighed over the potential loss of reduction. In a retrospective analysis of 45 cases with late developing infection after instrumented posterior spinal fusion for scoliosis, Muschic et al  suggested re-instrumentation after implant removal in order to reduce the loss of correction.
In conclusion, the development of a secondary systemic vasculitis after orthopaedic surgeries and especially spinal instrumented procedures is a generally rare. Metal hypersensitivity and periprosthetic infection are well-recognized etiologic factors. Significant difficulties in evaluating suspected titanium hypersensitivity still exists, as there are no standardized valid patch tests and leukocyte migration testing is not broadly available. The case reports and studies published so far reflect the diagnostic uncertainties in evaluating suspected titanium hyper-reactivity and show that this condition is uncommon. Investigation for the presence of late infections should always be performed as they could be directly or indirectly related to triggering of immune hypersensitivity and systemic reaction.