|
 
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| SYMPOSIUM – POST SURGICAL SPINE INFECTION |
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| Year : 2018 | Volume
: 1
| Issue : 1 | Page : 24-31 |
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Atypical spinal infections in immunocompromised patients
Harvinder Singh Chhabra, Rajat Mahajan, Abhinandan Mallepally Reddy
Indian Spinal Injuries Centre, New Delhi, India
| Date of Web Publication | 17-Jan-2018 |
Correspondence Address:
Dr. Harvinder Singh Chhabra
Indian Spinal Injuries Centre, Vasant Kunj, New Delhi
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/isj.isj_19_17
Spinal infections in immunocompromised patients are a potential threat due to atypical presentations and delay in diagnosis. These patients often present with back pain, fever, and neurological deficits. It is crucial to have knowledge of atypical etiology of vertebral osteomyelitis. Immunocompromised status of the patients presumably prevents them from mounting an inflammatory or vascular response necessary to counter the disease process. The diagnostic delay of such disastrous conditions remains unsatisfactorily long. Identification of the causative microorganisms and timely initiation of treatment are of prime importance in the management of such infections. Magnetic resonance imaging with/without gadolinium contrast is the choice of noninvasive investigation in spinal infections, and an appropriate tissue biopsy for isolation of causative organism is required for confirmation of the diagnosis. Patients are best managed by a multidisciplinary approach. Surgical intervention may be necessary for effective management and prevention of complications due to atypical spinal infections.
Keywords: Atypical spinal infection, immunocompromised host, spondylodiscitis
How to cite this article:
Chhabra HS, Mahajan R, Reddy AM. Atypical spinal infections in immunocompromised patients. Indian Spine J 2018;1:24-31 |
| Introduction | |  |
The incidence of spine infections is on the rise, reported to be about one in 100,000–200,000 in the general population.[1],[2] Spinal infections in the immunocompromised patient population, though uncommon and not reported exclusively, are probably underestimated.[3],[4] Immunocompromised organ transplant patients have a 40-fold increased risk [5] for spinal infections. Human immunodeficiency virus (HIV) patients, intravenous (IV) drug users, alcoholics, cirrhosis patients, diabetes mellitus, malnutrition, cancer patients, immunosuppression associated with chemotherapy for cancer, transplantation, or autoimmune diseases are the commonly occurring immunosuppressive states making these patients prone to spinal infections [Table 1].[4],[5],[6],[7],[8] They are prone to frequent bacteremia episodes and subsequent hematogenous seeding of the spine. The infection can occur without a definite source or bacteremia, particularly in the setting of immunosuppression. The present review is an attempt to bring out the currently available literature on diagnosis and treatment of spinal infections in the immunocompromised host including some of the atypical spinal infections.
| Methods | | |
Although this is not a comprehensive review of the spinal infection literature for the immunocompromised conditions, a PubMed/Medline search and review of the English language literature on atypical spinal infection, including fungal and parasitic infections and spinal infections in the immunocompromised patients, was performed. Clinical presentation, diagnosis, and treatment aspects of spinal infections were correlated with immunocompromising medical comorbidities.
| The Immune System in the Immunocompromised Host | | |
The immune system can have a functional deficiency either in the humoral or in the cellular immunity. Deficiency in humoral immunity increases susceptibility to pyogenic organisms such as Haemophilus influenzae, Streptococcus, and Staphylococcus,[8] whereas abnormalities in cellular immunity may preferentially predispose to viral, fungal, and protozoan infections;[9] however, both mechanisms are interdependent and are affected together in a given immunocompromised state [Table 2]. HIV-infected patients are one of the most common groups to be affected with immune deficiency. Staphylococcus and tuberculosis are the most common organisms isolated in immunocompromised patients with HIV.[10] In India, tuberculosis is the main cause of spinal infections while the scenario is different in the Western world where pyogenic bacterial infection is much more common than tuberculosis.[10],[11] However, with the rise in immunocompromised patients and HIV patients, tuberculous spondylodiscitis has also shown an increasing trend in the Western world.[11] An HIV patient experiences a progressive decline and dysfunction of T-cells and monocytes with interleukin (IL)-15, interferon (IFN) alpha, tumor necrosis factor (TNF), IL-18, IL-10 cytokine dysregulation, leading to defective immune response.[12],[13],[14],[15] Infected patients experience rapid progression of disease and greater risk for life. Acquiring tuberculosis (TB) in HIV patients is independent of CD4-T-cells count although suppressed IL-12 and IFN alpha levels increase susceptibility to primary TB infection and reactivation of old disease. There is reversal of CD4:CD8 T-cell ratio and significantly reduced cytokine expression and increased TNF levels. There exists a linear relationship between CD4 count and severity of the spinal infections and other opportunistic infections. Further, CD4-lymphocyte count is a useful parameter in assessing risk of postoperative infections. A cell count <200/mm 3 is associated with a greater risk for postoperative infection,[13],[14] and hence, it is advisable to defer elective surgeries with low CD4 counts until the immune system recovers. | Table 2: Various immunodeficiency conditions are depicted along with the cause of immunodeficiency and the common organisms causing infections in these patients
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IV drug abusers are another group of patients which can present with spinal infections with these opportunistic pathogens. Classically, pseudomonas infection has been described in them.[16],[17],[18] Cervical spine involvement is seen more commonly in patients with IV drug users as compared to normal population.[16] Heroin users have direct immunosuppression with T-cell inactivation,[19],[20] and in the rest of the IV drug users, it is a combination of malnutrition and repeated bacteremia with needle pricks. Diabetes mellitus is another common disorder with deranged immune system along with complex metabolic derangement of glucose metabolism. Immune system in patients with diabetes shows changes in both humoral and cellular responses.[21],[22] There are alterations in antibody response to antigen and dysregulation of complement response (C3 and C4, C1 inhibitor).[22] Cellular immunity is also compromised with direct effects on T-cell population [23],[24] and secondary to alterations in cytokine signaling, TNF, IL-1β, IL-2, IL-6, IL-8, and insulin-like growth factor-2.[25],[26] The increased inflammation along with cytokine dysregulation may contribute to the immunocompromised state associated with diabetes.[3] There is a 5.7-fold increased relative risk for infection in these patients.[2]
Pharmacological agents such as methotrexate, corticosteroids, and chemotherapeutic agents cause direct marrow suppression and affect both the humoral and cellular immune response. Low-virulence, opportunistic, and often severe infections affect these patients frequently along with reactivation of occult previous infections.[27]
Chronic alcoholism induces a malnourished state, resulting in altered functioning of phagocytes and granulocytes and bone marrow suppression.[28],[29],[30] Alcoholic patients are predisposed to infections with tuberculosis and opportunistic bacterial and fungal species.[31],[32],[33] Alcoholism as an independent risk factor for spine infection was reported in two case series of more than 20 patients.[34],[35]
| Clinical Features | | |
Spinal infections in the immunocompromised may have insidious clinical presentations. Back pain may be the only presenting symptom unless progression of the disease results in neurological deficits. One of the major problems in the treatment of spondylodiscitis in the immunocompromised host is the relative delay in diagnosis as the presentation is vague. Routine radiographs are of little help for the back pain in early stages, making the diagnosis a challenge. On an average, the time interval between symptom to diagnosis range from 2 weeks to 9 months.[36],[37] Delay in diagnosis of spine infection in these patients may lead to permanent disability with spinal cord injury.[38] Spondylodiscitis should always be a differential diagnosis in the setting of a new-onset back/neck pain in these high-risk group patients. Though fever is a common feature of spine infections, it is inconsistent in such high-risk groups [Table 3] and less so in fungal, mycobacterial, and Brucella More Details infections.[39] Rarely, patients present with an acute-onset severe back pain in the setting of a chronic low back pain along with fever and radicular symptoms or neurologic deficits [40],[41],[42]. It is not uncommon to see a patient with neurological deficit in tubercular spondylitis with minimal back pain. Facet joint septic arthritis is one of the conditions to look for in an immunocompromised host.[43] | Table 3: Clinical presentation of spinal infections in the immunocompetent and the immunocompromised host
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| Diagnosis | | |
Routine screening investigation for infections, such as erythrocyte sedimentation rate (ESR), C-reactive protein, white blood cell (WBC), and complete blood count in an immunocompromised host, may not reveal an elevated WBC or ESR due to patient's decreased ability to mount a immune response (only 27%–30% showed elevated WBC count [1]). Protocol for evaluating patients with suspected spinal infections in immunocompromised status starts with detailed history for known immunocompromised states and any addictions such as IV drug abuse or alcoholism, along with laboratory tests and imaging of the spine.
Magnetic resonance imaging (MRI) best visualizes typical findings in spinal infections such as abnormal signal enhancement in the involved intervertebral disc and adjacent vertebral body marrow, loss of disc space, and epidural and paraspinal abscess.[44] It has sensitivity of 96% and specificity of 93%. MRI findings suggestive of infection include hypointense signal of disc and end plate on T1, hyperintense signal from disc and end plate on T2, loss of disc height, epidural abscess, and prevertebral and paravertebral collections. Gadolinium contrast enhancement is of value in differentiating infection from Modic changes (Type 1) and tumors. It is hence necessary to look for other signs which suggest infection, such as intradiscal hyperintense signal on T2-weighted images, epidural and paraspinal fluid collections, and loss of degenerative disc vacuum, so as not to delay the diagnosis.[45],[46],[47] However, it is important to be aware of atypical presentations of spinal infections, such as lack of enhancement of involved areas.[46] Patients' immune compromise status may prevent them from mounting the inflammatory and vascular response necessary to produce such enhancement.[47] Gadolinium contrast helps in delineating a phlegmon and a formed epidural abscess. It increases specificity as the end plate enhancement can be the earliest sign of acute spondylodiscitis.[47],[48] In patients where MRI is contraindicated, contrast-enhanced computed tomography/positron emission tomography (CT/PET) scan or a bone scintigraphy may be able to establish the diagnosis.[49] 18F-fluorodeoxyglucose (18F-FDG) PET can differentiate active from inactive disease in patients with TB, and this is potentially an important clinical application in these patients. There is overlap in the standardized uptake values of TB and malignant lesions on 18F-FDG PET, which limits its usefulness in distinguishing them. Further, a study reported that 18F-FDG PET/CT was more effective than MRI in distinguishing between tuberculous and pyogenic spondylitis.[50] Another review by Rivas-Garcia et al.[51] on the image findings in Pott's disease emphasizes the role of advanced imaging such as 18F-FDG-PET in the assessment of lesion extent, as a guide to biopsy, to assist in surgical planning, and to contribute to follow-up evaluation.
Blood cultures should be a routine investigation to be done in high-risk group patients with fever and back pain as they are roughly positive in 60% of bacterial spondylodiscitis cases.[52] CT-guided biopsy plays an important role for diagnosis with accuracy of 30%–75%, especially in patients with negative blood cultures.[53],[54],[55] Standard protocol should include aerobic/anaerobic, bacterial, mycobacterial, fungal stains and cultures with a biopsy for histopathological examination, especially in culture-negative cases to confirm diagnosis. Biopsy yield is affected by prior antibiotic use. Molecular diagnosis with polymerase chain reaction (PCR) techniques may help in the isolation of organism in paucibacillary infections such as Mycobacterium tuberculosis and other infections as well. GeneXpert test may also help identify resistance to rifampicin in addition to isolating the organism by PCR technique. Serological tests are of value in diagnosing Brucella infections.
| Treatment | | |
Conservative treatment consists of antibiotic administration, appropriate to the culture, and sensitivity with restricted activity. Surgical intervention is indicated in the presence of neurological deficits, failure to respond to conservative treatment, progression of disease/deformity, and need to identify positive pathogens in case of negative cultures and percutaneous biopsy.[56]
Systemic antibiotics for 6–8 weeks is sufficient for most cases.[57],[58] Monotherapy is better avoided, especially for organisms such as Staphylococcus aureus species known to show resistance.[59] Response is monitored using serial inflammatory markers along with clinical improvement. Relapse of spine infections are very high in immunocompromised patients and morbidity from the condition is also very high.
Surgical management becomes necessary for patients with a neurologic deficit, uncontrolled infection, or instability of the spine due to extensive bone destruction.[60] The surgical intervention must achieve the goals of rigid 3-column stabilization of the spine with adequate decompression of the spinal cord, along with debridement and material for biopsy. This can be achieved either with anterior approach, posterior approach, or a combined approach. Anterior approach involves thoracotomy, decompression of the cord with corpectomy, and spinal stabilization with cage and anterior instrumentation,[61] whereas a posterior-only approach involves pedicle screw-rod stabilization with corpectomy and cage insertion via the retropleural approach.[62],[63] Combined approach is usually avoided in these patients due to the associated increase in morbidity and mortality in the already immunocompromised host. Use of instrumentation in the active infective stage is no longer prohibited, and the stability achieved along with good debridement of infective focus usually aids in faster resolution of the infective focus.[60],[64] Septic infections of facet joints can be treated along the same lines of vertebral osteomyelitis. A CT-guided purulent aspiration from facet joint is known to help with faster pain relief.[65]
| Fungal Infections | | |
Patients with altered immune status related to diabetes mellitus, corticosteroid usage, chemotherapy, malnutrition, HIV, and organ transplantation are predisposed to fungal infections of the spine.[66],[67] Fungal spinal infections can range from a simple discitis to more complicated and destructive multifocal osteomyelitis with huge abscess and sometimes deformity. In a large review from 1948 to 2010, a total of 157 cases of fungal infections affecting the spine were recorded.[68] Aspergillosis was the most common fungal infection affecting the spine, followed by the Candida species. Other less common fungal infections were coccidioidomycosis, cryptococcosis, histoplasmosis, and blastomycosis.[69],[70],[71] Aspergillous infections of the spine had concomittent pulmonary infection in more than 70% of the patients and also had high mortality (60%).[68],[72]Candida infections were less severe with an average of 19.3% mortality.[73] Rare infections such as histoplasmosis in HIV patients had higher mortality ranging from 50% to 100%.[70] Neurological deficit at presentation was seen in 41.7% of patients with aspergillous infections with 81% requiring surgical intervention.[68] In patients with spinal candidiasis, 22.9% had neurological deficit at presentation with 54.3% requiring surgical intervention.[68] Diagnosis of fungal spondylodiscitis is usually delayed in immunocompromised patients.[66] A high index of suspicion with appropriate investigation is essential for early diagnosis. The histopathological confirmation of the presence of fungal hyphae (true septate in aspergillosis and pseudohyphae being nonseptate in Candida) is essential for diagnosis.[68] In disseminated invasive infections, blood cultures are positive, especially in aspergillosis.[72] Antifungal treatment with the advent of ozoles in 1985[68],[74] has decreased the morbidity and mortality, which was more with single drug treatment using amphotericin-B.[75]
Drug regimen recommended by the Infectious Diseases Society of America.
Candida spinal infections
Fluconazole 400 mg (6 mg/kg) daily for 6–12 months or liposomal formulation of amphotericin-B 3–5 mg/kg daily for 2–4 weeks and then fluconazole for 6–12 months were recommended.[76]
Aspergillus infections
Voriconazole 6 mg/kg IV 12 h for 1 day followed by 4 mg/kg IV 12 h was recommended; oral dosage is 200 mg every 12 h for a minimum of 6–8 weeks.[77]
| Parasitic Spinal Infections | | |
These are rare infections of the spine but can have significant complications due to delay in diagnosis and frequent neurological deficits at presentation. The most common parasitic infection of the nervous system is cysticercosis.[78]
Cysticercosis
Cysticercosis is caused by implantation of the cestode Taenia solium (pork tapeworm) in humans, serving as an intermediate host. It has a prevalence of 3%–6% in endemic areas and affects approximately 50 million people worldwide, including Central and South America, Eastern Europe, Africa, and Asia.[79] 95%–98% of cysticercosis involves the central nervous system and spinal involvement is reported to be around 1.2%–5.8%. Spinal intradural-extramedullary infection is mostly due to downward migration of larvae from the intracranial compartment to the spinal subarachnoid space.[80] Neurologic manifestations is caused by a combined inflammatory reaction and mechanical compression from intramedullary or extramedullary cysts, leptomeningitis, and ischemia.[81] Treatment involves surgical decompression with albendazole chemotherapy for 6–12 weeks.
Schistosomiasis
It usually occurs in humans with exposure to freshwater snails. Approximately 200 million people worldwide are afflicted with schistosomiasis, and approximately 20 million develop severe disease, most commonly central nervous system infections.[82] Since the first description of this disease in the 1930s, approximately 800 cases have been reported, most of them due to Schistosoma manson.[83] Neurologic symptoms are secondary to deposition of eggs with granulomatous reactions in areas of the brain or spinal cord.[84] The medullary form is generally associated with a rapid course and severe weakness. By contrast, in conus-cauda equina syndrome, the symptoms develop more slowly, the distribution of the sensorimotor alterations is predominantly asymmetric, and weakness is less severe.[83] Surgical decompression with laminectomy and biopsy gives the diagnosis.
Hydatid disease
Hydatid disease (echinococcosis) is a parasitosis caused by the larval stage of Echinococcus, the dog tapeworm. Humans act as accidental intermediate hosts and are secondarily infected via the ingestion of food or water contaminated by eggs of the parasite. Lungs and liver infections constitute more than 90% of hydatid disease with 1%–5% involving the bone.[80] Spinal involvement constitutes 50% of bony infections with the thoracic segment of the spine affected in 50% of cases, followed by the lumbar (20%), sacral (20%), and cervical (10%) segments.[85] Marked eosinophilia should be useful in confirming a suspicion of parasitic disease. Casoni test and Elisa test for Echinococcus granulosis IgG are useful for confirmation of the diagnosis.[86] Long-term albendazole with surgical excision of the cyst is recommended. Intraoperative use of scolicidal agents such as 10% betadine or hypertonic saline is recommended to avoid recurrence of hydatid cyst.[87]
| Discussion | | |
Incidence of spinal infections is estimated to be around 5% of all osteoarticular infections.[2],[40] Favorable treatment outcome depends on early diagnosis, which is often delayed for an average of 6–12 weeks due to ambiguous symptoms,[88] especially in the immunocompromised host. As in an immunocompetent host, the most common organism encountered in immunocompromised patients is typical bacteria; however, a high index of suspicion must be maintained for atypical organisms.[5] In patients growing multiple organisms on biopsy/culture, all organisms identified should be treated in combination with adequate multidrug therapy. Spondylodiscitis caused by nontuberculous mycobacteria (NTM) is on the rise in immunosuppressed patients and are frequently misdiagnosed as Mycobacterium tuberculosis because of similar clinical and radiographic characteristics and indolent clinical course.[89] It is important to differentiate NTM from M. tuberculosis as antituberculous drugs do not cover NTM sufficiently.[90]
In India, most common cause of spinal infections is M. tuberculosis, while in Western world, S. aureus is the most common cause of spondylodiscitis.[90] Fungal infections are very rare cause of spinal infections and are reported mostly as case reports or series. There can be marked delay in diagnosing these infections and average delay in diagnosing them can be as much as 2 months.[67] Common fungal infections reported in the literature are with Aspergillus species, followed by Candida, Coccidioides, Blastomyces, etc.[68] Major problem of spine infections in the immunocompromised host is not about the treatment but establishing an early diagnosis before major neurologic deficits occur, which dramatically increase the morbidity and mortality. As it may take up to 6 weeks for bony erosive changes to manifest on plain radiographs,[46],[47] contrast-enhanced MRI is the modality of choice for imaging in the patients with suspicion of spinal infections. Incidence of these infections has been rising steadily because of better modalities to diagnose spine infection as well as decline in immune status of the ageing population.
Blood cultures should be a routine investigation to be done in high-risk group patients with fever and back pain. The chances of a positive blood culture are about 60% in bacterial spondylodiscitis cases.[52],[55] Every effort should be made to establish a microbial diagnosis. Currently, long-term combination chemotherapy with tailored antibiotics would be considered the standard medical treatment. However, the optimal therapeutic regimen and duration of treatment for infective spondylitis in immunocompromised patient have not been determined. Empirical treatment should be withheld in all but critically ill and high-risk patients with signs of sepsis or those requiring urgent surgical decompression for neurological compromise. Resolution of symptoms and declining values of CRP correlate well with clinical improvement more than radiological changes on MRI.[56] Specific association has not been demonstrated between follow-up MRI and clinical condition of patients. However, follow-up MRI may be required in case of deterioration or lack of clinical improvement.[91]
The decision to undertake spinal surgery in an immunocompromised patient for infective spondylitis is complex due to their poor immune response, which adversely affects their nutrition, wound healing potential, and life expectancy. The general medical condition of the patient is also considered, and the benefits of surgery are weighed against the patient's ability to tolerate surgical intervention.
Surgical treatment is necessary for patients with a neurologic deficit, uncontrolled infection, or instability of the spine due to bone destruction.[60] Various surgical options are available for vertebral osteomyelitis, and the optimal modality needs to be individualized. The surgical intervention must achieve the goals of rigid 3-column stabilization of the spine with adequate decompression of the spinal cord, along with debridement and material for biopsy. Percutaneous procedures such as discectomy, debridement, drainage, and percutaneous pedicle screw-rod instrumentations provide a minimally invasive surgical choice in these high-risk group of patients for the treatment of infectious spondylodiscitis.[92],[93]
| Conclusion | | |
Immunocompromised patients with spinal infections are best managed by a multidisciplinary team including an infectious disease expert. High index of suspicion is the key to early diagnosis and isolation of organism causing the infection is essential for appropriate chemotherapy and resolution of infection. MRI is the imaging modality of choice and biopsy as a routine is encouraged. Medical and surgical treatment in this group of patients needs to be individualized as patients with immunocompromise have poor healing ability along with decreased ability to fight infectious agents. Atypical infections including fungal, opportunistic bacterial, or viral infections are more common in this group of patients and need to be considered in the differential diagnosis.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]
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