The SCIentinel study--prospective multicenter study to define the spinal cord injury-induced immune depression syndrome (SCI-IDS)--study protocol and interim feasibility data

Abstract

Background: Infections are the leading cause of death in the acute phase following spinal cord injury and qualify as independent risk factor for poor neurological outcome ("disease modifying factor"). The enhanced susceptibility for infections is not stringently explained by the increased risk of aspiration in tetraplegic patients, neurogenic bladder dysfunction, or by high-dose methylprednisolone treatment. Experimental and clinical pilot data suggest that spinal cord injury disrupts the balanced interplay between the central nervous system and the immune system. The primary hypothesis is that the Spinal Cord Injury-induced Immune Depression Syndrome (SCI-IDS) is 'neurogenic' including deactivation of adaptive and innate immunity with decreased HLA-DR expression on monocytes as a key surrogate parameter. Secondary hypotheses are that the Immune Depression Syndrome is i) injury level- and ii) severity-dependent, iii) triggers transient lymphopenia, and iv) causes qualitative functional leukocyte deficits, which may endure the post-acute phase after spinal cord injury.

Methods/design: SCIentinel is a prospective, international, multicenter study aiming to recruit about 118 patients with acute spinal cord injury or control patients with acute vertebral fracture without neurological deficits scheduled for spinal surgery. The assessment points are: i) <31 hours, ii) 31-55 hours, iii) 7 days, iv) 14 days, and v) 10 weeks post-trauma. Assessment includes infections, concomitant injury, medication and neurological classification using American Spinal Injury Association impairment scale (AIS) and neurological level. Laboratory analyses comprise haematological profiling, immunophenotyping, including HLA-DR expression on monocytes, cytokines and gene expression of immune modulators. We provide an administrative interim analysis of the recruitment schedule of the trial.

Discussion: The objectives are to characterize the dysfunction of the innate and adaptive immune system after spinal cord injury and to explore its proposed 'neurogenic' origin by analyzing its correlation with lesion height and severity. The trial protocol considers difficulties of enrolment in an acute setting, and loss to follow up. The administrative interim analysis confirmed the feasibility of the protocol. Better understanding of the SCI-IDS is crucial to reduce co-morbidities and thereby to attenuate the impact of disease modifying factors to protect neurological "outcome at risk". This putatively results in improved spinal cord injury medical care.

Trial registration drks-id: DRKS00000122 (German Clinical Trials Registry).

Figure 1

Multicenter structure and trial management. Legend: Scheme of the trial workflow. BL-C = Berlin-Charité, BL-T = Berlin-Trauma-Hospital; TU = Biometry Tübingen; ZH-U = Zurich-University Hospital; ZH-B = Zurich-Balgrist; TO = University Hospital Toronto.

Figure 2

Relay-interaction of the immune system and the central nervous system. Legend: Groups for primary comparison in relation to the major sympathetic outflow (vegetative innervation). In Group I (SCI of the neurological level T4 or above) the lesion is localized within the spinal segments C2-T5, resulting in a disturbance of the sympathetic innervation of immunologically relevant organs through the coeliac ganglion and further ganglia connected through lower segments of the spinal cord. Of note, the neurological level is defined by the ISNCSCI as the most cranial segment with normal sensory function and a muscle grade of at least 3/5 with normal function in the segments above on both sides of the body, i.e. in case of a neurological level T4, the lesion begins in the segment T5. In Group II (SCI of the neurological level T5 or below) the lesion is located in the spinal segment T6 or below. Thus, the sympathetic outflow to the coeliac ganglion is expected being only partially disrupted or completely preserved. Group III consists of patients with vertebral fracture alone without injury to the spinal cord (control). Here, the sympathetic innervation is intact.

Figure 3

Longitudinal trial design. Legend: Assessment points and time frames. The starting point of the time line is the time of injury not the time of surgery. In the case of difficulties in scheduling the visits 2 to 5 may be conducted within the indicated time windows (italic). The circadian rhythmics are respected.

Figure 4

SCI-IDS Immunephenotyping – qualitative and quantitative measures. Legend: Scheme of blood collection, sample preparation and analysis procedures. ConA = Concanavalin A, ELISA = Enzyme Linked Immunosorbent Assay, ELISPOT = Enzyme Linked Immunosorbent Spot, FACS = Fluorescence-activated cell sorting, IFN-g = Interferon-gamma, TNF-g = Tumor necrosis factor – gamma.