Infections and spinal cord injury: Covid-19 and beyond

List of abbreviations

ARDS

acute respiratory distress syndrome

bDMARDs

biological disease-modifying anti-rheumatic drugs

CT

computerized tomography

Covid-19

coronavirus disease 2019

GCs

glucocorticoids

HPA

hypothalamic-pituitary-adrenal

IUC

indwelling urethral catheter

ICU

intensive care unit

ISNCSCI

International Standards for Neurological Classification of the Spinal Cord Injury

JAKi

Janus kinase inhibitors

MRI

magnetic resonance imaging

NICE

National Institute for Clinical Excellence

NE

norepinephrine

PI

pulmonary infections

PEP

positive expiratory pressure

PPE

personal protective equipment

ISC

self-catheterization

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

SPC

suprapubic catheter

SCI

spinal cord injury

SCIP

spinal cord-injured patients

SNS

sympathetic nervous system

SPNs

sympathetic preganglionic neurons

UTI

urinary tract infections

WHO

World Health Organization

Introduction

An epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in Wuhan in December 2019 and quickly spread across the world. The 2019 coronavirus disease (Covid-19) was declared a pandemic on March 11, 2020, by the World Health Organization (WHO). On February 7th, 2021, 105,962,538 cases were confirmed worldwide with 2,313,136 deaths ( ). This new SARS-CoV-2 has brought higher levels of illness, deaths, and fear to our planet than any other virus in current history. In this context, it is mandatory to determine the effect in people with spinal cord injury (SCI).

SCI induces numerous chronic disorders that put these individuals at a high risk of severe Covid-19 prognosis. Specifically, the SCI population presents higher rates of hypertension, SCI-induced immunosuppression, and, if the metameric level is T8 or above, respiratory failure with continuous or episodic hypoxemia due to respiratory muscle weakness. Sympathetic denervation following SCI compromises body temperature regulation, as a result of dysautonomia, which not only complicates the early diagnosis of Covid-19 which places them at risk of a poor prognosis, but also makes it difficult to control infection transmission to other patients and/or healthcare staff.

In general population, clinical symptoms appear after an incubation period of around 5 days ( ), presented in order of frequency as: fever (87.9%), dry cough (67.7%), asthenia (38.1%), dyspnea (18.6%), pharyngeal pain and odynophagia (13.9%), headache (13.6%), arthromyalgia (14.8%), chills (11.4%), nausea or vomiting (5%), nasal congestion (4.8%), and anosmia and diarrhea (3.7%). Approximately 80% of patients present as asymptomatic or with few symptoms including dry cough and fever or low-grade fever ( ), but the remaining 20% of cases develop around the 7th day after the onset, severe hypoxemic respiratory failure that progresses to Acute Respiratory Distress Syndrome (ARDS) (15% of the total) and even to multi-organ failure (5% of the total), requiring mechanical ventilation and admission to an Intensive Care Unit (ICU) ( ). Up to 18% of patients who request consultation for Covid-19 compatible symptoms do not present radiological alterations. When these appear, the most frequent clinical sign is unilateral or bilateral ground glass opacification with an interstitial pneumonia pattern or bilateral patched consolidation, evident on plain radiography and on chest computerized tomography (CT) examination (56.4%) ( ; ). At diagnosis, more than 80% of patients present lymphopenia ( ), which is more severe and accompanied by neutrophilia in patients requiring ICU admission ( ). The main cause of death after Covid-19 infection is respiratory failure and fulminant myocarditis, ( ). In these patients, a highly exaggerated inflammatory response has been described known as hyperinflammatory syndrome, with a massive release of cytokines into the bloodstream ( ; ) similar to that observed in hemophagocytic syndromes caused by other virosis ( ). A series of clinical factors have been described, associated with symptoms of greater morbidity and mortality: male gender, age above 60 years—especially above 80 years old, where the fatality rate is close to 16%—and the presence of previous comorbidities such as: hypertension, ischemic heart disease, diabetes mellitus, lung disease, and various disease entities that lead to immunosuppression, such as autoimmune diseases or cancer ( ). Analytical markers associated with a higher risk of mortality are sustained lymphopenia and elevation of D-dimer, IL-6, ferritin, LDH, and troponin ( ).

The aim of this chapter is to analyze the clinical presentation of Covid-19 in spinal cord-injured patients (SCIP). The authors pretend to make pause to understand if this emergent disease, which is deadly hitting our general population, behaves in the same or different way as in these especial patients, in order to understand if the SCI condition is acting as a risk factor for morbidity or not, and why. For this purpose, we believe the immune system plays a significant role in infection, especially from our knowledge of other infections.

Immunosuppression due to spinal cord injury

Among non-specialist the most evident consequences of SCI is loss of mobility and sensibility. However, in spite of their dramatic effect on patient quality of life, this is only the tip of an iceberg compared to the other lifelong neurological and non-neurological sequelae. These patients have an immunodepressed state characterized by changes in the number and function of immune cells that render them highly susceptible to infections ( ; ; ). Indeed, these are the leading cause of morbidity and mortality after SCI ( ). In this chapter, we review why immunodepression occurs after SCI and how this affects the ability of patients to cope with the current Covid-19 pandemic and other infectious diseases.

Pathophysiology of spinal cord injury-induced immunodepression

The physiological responses to physical or psychological stress are mediated by the coordinated response of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. Both systems mediate the so-called fly-or-fight responses by setting the whole organism to cope with stressful stimuli at the expenses of arresting functions that are not indispensable for immediate survival. This physiological and evolutionary adapted response may, however, turn into a maladaptive chronic situation. Spinal cord injuries are a source of tremendous physical and psychological stress that unfortunately exemplifies the effect on the immune system of maladaptive SNS and HPA responses.

Dysregulation of the sympathetic nervous system

The main mechanism driving immunodepression after SCI is the dysregulation of the autonomic sympathetic nervous system. The cell bodies of the sympathetic preganglionic neurons (SPNs) are localized in the lateral horn of the spinal cord, in the intermedio-lateral nucleus. Classically, it has been considered as sympathetic the neurons located from T1 to the first lumbar segments (L2 − 3), although recently, the parasympathetic neurons located in the lateral horn of the sacral segments have been shown to have phenotypical and ontogenetic characteristics of SPNs ( ). In any case, SPNs synapse in sympathetic ganglia majorly with post-ganglionic noradrenergic neurons, which in turn release norepinephrine (NE) in the target organs, though a minority of post-ganglionic sympathetic neurons are cholinergic, as those innervating sweat glands ( ). The timing and intensity of SPNs activation is controlled by nuclei located in the brainstem, pons and hypothalamus that project inhibitory descendants into the spinal cord ( ). After a severe SCI, these supraspinal projections are interrupted and, thus, SPNs loss their inhibitory inputs. Consequently, when these neurons are activated, it may give raise to an exaggerated or more durable sympathetic response and, thus, to an excessive release of NA in the target organs. In addition, the sublesional spinal circuitry involved in the control of preganglionic neurons undergoes a remodeling process that favors the connectivity between activating interneurons and SPNs ( ). Overall, the resultant sympathetic overactivation below the lesion level underlies a plethora of autonomic dysfunctions after SCI, including the suppression of the immune system.

The sympathetic nervous system innervates both the primary and the secondary lymphoid organs, and modulates all the immune processes, from hematopoiesis to immune responses ( ; ). Immune cells sense NE majorly through beta-2-adrenergic receptors, although monocytes/macrophages also express lower levels of alpha-1- and alpha-2-adrenergic receptors ( ). The overall effect of adrenergic receptor activation on physiological conditions over innate immune cells is anti-inflammatory ( ; ). On B cells, NE participates in T-cell mediated IgG production ( ; ), while the effects of NE over T lymphocytes is more complex and varies according to the cellular stage of maturation and timing of exposure. Depending on the stage of maturation of T CD8 ⁺ cells, exposure to NE may either promote or decrease their cytolytic activity ( ). Similarly, exposing Th1 cells to NE before their activation decreases the synthesis of IL-2 and IFN-gamma, while exposing them to NE after activation increases the synthesis of IFN-gamma ( ). In any case, the overall effect of NE over adaptive immune responses is also considered to be anti-inflammatory, inhibiting Th1 cell differentiation and promoting Treg-suppressive activity ( ; ).

After SCI, immune cells may be subjected to persistent or more intense exposure to NE, which results in immunosuppression ( ). A factor that may dramatically affect the sympathetic dysregulation-induced immunodepression is the lesion level, being lesions at T5 or above associated to a greater impairment of the immune system both in patients and in experimental animal models ( ; ; ). This observation coincides with the fact that most of the sympathetic innervation of immune organs arise from preganglionic neurons located below T5. The innervation of lymph nodes is not resolved, but it is considered to originate from spinal segments close to their location in the body ( ). Thymus receives most of its innervation from above T5, specifically between T1 and T7 ( ). In any case, the sympathetic dysregulation induced by SCI suppresses immune cells in the decentralized lymphoid organs. This statement is supported by direct experimental evidence showing that immune suppression effects depend on beta-2-adrenergic stimulation and may be reverted by receptor antagonists ( Table 1 ). Indirect evidence is further provided by the observation of a relationship between lesion level and extent of immunodepression ( Table 2 ).

Table 1

Effects of SCI over immune cells with experimental evidence of dependence on beta-2-adrenergic receptor stimulation.

Cell type	Effect	References
B cells	(1) Impaired primary humoral responses (2) Apoptosis	(1) , (2)
T cells	Apoptosis
CD8 ⁺ T cells	T cell exhaustion

Experimental evidence shows that SCI-induced immune suppression effects depend on beta-2-adrenergic stimulation and may be reverted by receptor antagonist. SCI: spinal cord injury.

Table 2

Effects of SCI over immune cells dependent on lesion level.

Cell type	Effect	References
B cells	Decreased number	, ,
T cells	Decreased number
CD4 ⁺ T cells	Decreased number
NK cells	Decreased number
Dendritic cells	Decreased number

The observation of a relationship between the injury level and severity and the extent of immunodepression highlights the effects of SCI over immune cells. SCI: spinal cord injury.

There is evidence of the contribution of sympathetic overactivation to immune depression after SCI results from autonomic dysreflexia crises, potentially triggered by any sustained sensory stimuli entering the spinal cord below the lesion level. This occurs mainly in patients with severe lesions above T5 because these injuries render without inhibitory supraspinal inputs the SPNs that control abdominal circulation ( ). As a consequence, SPNs overactivation occurs and results in vasoconstriction and hypertension. As a counteractive measure it is triggered a vagal response that induces vasodilatation (only successful above the lesion level) and bradycardia, which may be life-threatening if derives into a cardiac arrest. It has been experimentally proved that in these crises, the overactive sympathetic response further aggravates immunodepression in animals with high thoracic (T3) SCI ( ), which may help to explain why infections result in morbidity and mortality among patients with tetraplegia compared to patients with paraplegia.

Another potential symptom of immunodepression driven by the autonomous nervous system is the “inflammatory reflex” ( ). When the vague nerve is stimulated, spleen macrophages are polarized into an anti-inflammatory profile. Evidence shows that the spleen does not receive parasympathetic innervation. However, the vagus nerve synapses with sympathetic post-ganglionic neurons in the celiac ganglion, eliciting the release of NE in the spleen. In response, T lymphocytes produce acetylcholine, which acting on alpha-7-nicotinic receptors expressed by macrophages inhibits the production of TNF-alpha, IL-1 beta and IL-18 by these cells. The contribution of the inflammatory reflex to SCI-induced immunodepression is not elucidated, but it seems reasonable to believe that it could be triggered by the vague nerve reflex that takes place during autonomic dysreflexia crises.

Dysregulation of the hypothalamic-pituitary-adrenal axis

The activation of the HPA axis after SCI is well documented by the increase of blood serum glucocorticoids (GCs) in patients and in experimental animals. Besides the direct immunosuppressive actions of GCs on immune cells, glucocorticoids (GCs) and NE synergize to modulate immune cell function. GCs increase the affinity and persistence in the cell membrane of beta-2-adrenergic receptors ( ; ) while NE potentiates GCs signaling ( ). As such, when cortisol and the NE analog terbutaline are added together, they synergize to induce apoptosis of B and T cells in vitro ( ). Notably, the spleen atrophy and the decrease in the number of splenocytes induced by an experimental SCI in T3 is partially reverted by the join administration of antagonists of beta-2-adrenergic and GC-receptors ( ). In addition, it should also be considered that adrenal glands are innervated by the SNS, which induces the release of GCs.

Leading infection diseases in spinal cord-injured patients

Infection is one of the leading complications of inpatients, especially severe for SCIP due to the risk of death when it occurs a progression to a bloodstream infection. These patients have a greater predisposition to suffer infectious diseases because of their required use of medical devices such as intravenous and urinary catheters or ventilators. Special conditions suffered by these patients such as lack of mobility or bladder and respiratory dysfunctions contribute to a higher level of infection ( ).

There are two main features that make diagnosis of infection particularly challenging in SCIP. First, their loss of feeling can mask standard symptoms which make its diagnosis more difficult to diagnosis. Second, there are also some other described conditions that can simulate an infection, but they are really the manifestation of another disease with no infection as it occurs in hyperthermia, abdominal retention, and pulmonary embolism or collapsed lung ( ).

In general terms for treatment, it is strongly recommended to use narrow-spectrum and less toxic antibiotics to avoid eliminating patient’s native bacterial flora. It is also important to choose an appropriate directed antibiotic therapy to avoid the appearance of resistant bacteria.

The major infections that suffer SCIP are explained below ( Table 3 ).

Table 3

Principle infection features in SCIP.

	UTI	PI	Covid-19
Frequency	It is the most frequent cause of infection (95%) in SCIP	The 50% of SCIP who suffer acute tetraplegia develop pneumonia during acute hospitalization PI and respiratory failure are the major causes of death in this population	Unknown but lower than expected
Pathogens	Escherichia coli Klebsiella pneumoniae Proteus mirabilis	Pneumococcus, Pseudomonas (outpatients) No data (inpatients)	SARS-CoV-2
Etiology	Changes due to neurogenic bladder produce an overdistension of the bladder, high intravesical pressure and bladder compliance decrease that can lead to an UTI Medical devices that are used for facilitating bladder voiding can lead to an UTI as well	The dysfunction of inspiratory and expiratory muscles, the increased risk of dysphagia disorders and the changes inside lung that produces a neurogenic pulmonary edema can lead to a PI Medical devices to assist with breathing can lead to a PI as well	Immunosuppression induced by SCI Neuromuscular respiratory failure due to respiratory muscles weakness and clearance secretions’ decrease in SCI levels of injury above T6–T8
Diagnosis	It is necessary to differentiate between: - Asymptomatic bacteriuria/bladder colonization: - ≥ 10 ² cfu/mL bacteriuria at sediment - or any bacteria detected at sediment when using IUC - no symptoms - ^a UTI: - bacteriuria (with one primary organism detected at culture) - one bladder symptom at least: - hematuria - new/increased incontinence - change in urine odor/clarity - pyuria - one general symptom at least: - fever - acute autonomic dysreflexia - acutely increased spasticity - sepsis - persistent fatigue - vomiting When symptoms appear, urine and blood cultures are required When symptoms persist, it may be necessary to carry out additional test as ultrasounds, cystoscopy or kidney scan, to rule out complications (hydronephrosis, vesicoureteral reflux, urinary lithiasis or kidney abscesses) Blood biomarkers (procalcitonin and interleukin-6) has shown poor evidence in ITU detection	Clinical symptoms: fever, dyspnea, secretions Chest X-ray that shows infiltrates within lungs Alterations in blood gas analysis Leukocytosis Culture and sputum Gram stain: − when NOT wearing an artificial airway: Sputum culture (> 25 polymorphonuclear leukocytes and < 10 epithelial cells per field) − when wearing an artificial airway: - bronchoalveolar lavage sample: > 10 ⁴ cfu/mL - tracheal aspiration sample: > 10 ⁶ cfu/mL	Mild symptoms of onset: hypoxia, secretion clearance impairment could be the only symptoms of onset; but SCIP can also present fever, dyspnea, fatigue, anosmia, ageusia, arthromyalgias, and headache Close observation to neurofunctional outcomes, especially with the help of the International Standards for Neurological Classification of the Spinal Cord Injury (ISNCSCI) Worksheet, is needed to know if this infection produces sensory and motor deficits in these patients Whenever those symptoms are suspected, it is needed to make a RT-PCR SARS-CoV-2 from nasopharyngeal or bronchial aspiration test to confirm the infected condition Other paraclinical tests: Chest X-ray (to explore infiltrates at lungs), gas blood analysis (to explore ventilation perfusion state), and a blood analysis (to rule out lymphopenia, increase of d -dimer, ferritin and IL-6 After 7–14 days from the onset of the symptoms, if patient presents a favorable clinical evolution, a serological SARS-CoV-2 should be done to look for IgM and IgG levels
Treatment	The choice of the most appropriate antibiotic treatment depends on culture results Long-term antibiotic treatment (from 7 to 14 days) is recommended	Prompt empirical antibiotic treatment is needed - ^b Community acquired pneumonia - empiric anti-pseudomonal coverage is recommended - optimize secretion mobilization: Multi-modal treatment Quad coughing Mechanical insufflator-exsufflator - ^b Early hospital-acquired pneumonia - empiric antibiotic treatment depends on most common pathogens for each hospital, ICU and anti-microbial susceptibility patterns of each community It is recommended to use agents from a different antibiotic class than the patient has recently received	The same as general population In these patients, respiratory rehabilitation is especially important due to their condition of respiratory muscle weakness (secretions’ clearance therapies, lower and upper active-assisted or passive kinesiotherapy, and relaxation exercises, and a positive expiratory pressure exercises with a Threshold PEP device to optimize the alveolar recruitment) It is mandatory that Physiotherapists use PPE for self-protection
Prevention	Minimize urinary retention: anti-cholinergic medications or onabotulinum toxin A (Botox) injections for overactive bladders Change bacterial flora of the bladder: - urine acidification (methenamine hippurate) - bacterial interference Strengthen the host: - probiotics - proanthocyanidins (cranberry extracts) - immune biotherapy Reduce biofilm formation: - D-mannose - nanoparticles - to cover the catheter with hydrophilic material - bacteriophages	^b Outpatients: - annual Influenza and Pneumococcal polysaccharide vaccines - aggressive mobilization of secretions ^b Inpatients: - standard precautions - hand washing - gloving and gowning - to perform tracheal and nasopharyngeal respiratory techniques and cares under aseptic conditions - to consider non-invasive positive-pressure ventilation instead of invasive ventilation - to perform orotracheal rather than nasotracheal intubation whenever possible - to clear secretions - to avoid saliva or respiratory secretions microaspiration by raising the head of the bed from 30 to 45 degrees - to perform pre-operative breathing exercises and post-operative incentive spirometry - to remove patients out of bed as soon as possible - to prevent hospital-acquired, ventilator associated, and healthcare-associated pneumonia	Isolation and hygienic measures, the same as in general population. Caregivers and health workers need to use PPE for self-protection.

Pathogens, frequency, etiology, diagnosis, treatment, and prevention strategies of the main infections that affect SCIP. Covid-19 : coronavirus disease 2019; ICU : intensive care unit; PEP : positive expiratory pressure.; PI : pulmonary infections; PPE : personal protective equipment; SARS-CoV-2 : severe acute respiratory syndrome coronavirus 2; SCIP : spinal cord-injured patients; UTI : urinary tract infections.

a Modified from: Craven, B. C., et al. (2019). Conception and development of urinary tract infection indicators to advance the quality of spinal cord injury rehabilitation: SCI-high project. Journal of Spinal Cord Medicine , 42 (sup1), 205–214.

b Modified from: Burns, S. P. (2007). Acute respiratory infections in persons with spinal cord injury. Physical Medicine and Rehabilitation Clinics of North America , 18 (2), 203–16.

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