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 Table of Contents  
ORIGINAL ARTICLES
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 176-180

Paradoxical reactions in spinal tuberculosis: A case series


Department of Orthopaedic Surgery, Jaslok Hospital and Research Center, Mumbai, Maharashtra, India

Date of Submission23-Sep-2020
Date of Decision22-Apr-2021
Date of Acceptance17-May-2021
Date of Web Publication16-Jul-2021

Correspondence Address:
Nitin P Jaiswal
Department of Orthopaedic Surgery, Jaslok Hospital and Research Center, 15 Dr G Deshmukh, Pedder Road, Near Haji Ali, Mumbai 400026, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ISJ.ISJ_77_20

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  Abstract 

Introduction: Clinical or radiological worsening of pre-existing tubercular lesions or appearance of new lesions in patients who have shown initial improvement following antitubercular chemotherapy (ATT) is termed as a paradoxical reaction (PR). The appearance of these lesions after spine surgery raises the possibilities of drug resistance, treatment failure, and surgical site infection. This retrospective case series aims to describe the presentation of PRs in spinal tuberculosis (TB), identify risk factors, and propose a treatment plan for PRs within the spine. Materials and Methods: Nine patients (2 males and 7 females; mean age 31.2 years), who underwent posterior transpedicular decompression and instrumented fusion for spinal TB, presented 4–7 weeks later with a soft, large swelling at the surgical site. In one patient, the swelling had burst through the skin resulting in a discharging wound. Two patients had screw pullout with local kyphosis. All patients had been started on ATT only after index surgery and had experienced improvement in constitutional symptoms, pain, and neurology. Magnetic resonance imaging showed large fluid collection at the surgical site without any new bony lesions. Results: All patients underwent surgical debridement with two patients requiring revision instrumentation. Examination of tissue and fluid revealed caseating granulomas and mycobacteria. Continuation of the same ATT led to uneventful healing. Conclusion: PRs in patients with spinal TB presented with a cold abscess at the surgical site between 4 and 7 weeks after starting ATT. Surgical drainage with debridement and continuation of ATT without changes to the regimen led to uneventful healing in all patients. Young age, female sex, thoracic lesions, and patients virgin to ATT prior to surgery were risk factors.

Keywords: Cold abscess, immune competence, paradoxical reaction, spinal tuberculosis


How to cite this article:
Zaveri GR, Jaiswal NP. Paradoxical reactions in spinal tuberculosis: A case series. Indian Spine J 2021;4:176-80

How to cite this URL:
Zaveri GR, Jaiswal NP. Paradoxical reactions in spinal tuberculosis: A case series. Indian Spine J [serial online] 2021 [cited 2021 Aug 4];4:176-80. Available from: https://www.isjonline.com/text.asp?2021/4/2/176/321582




  Introduction Top


Paradoxical reactions (PRs) in tuberculosis (TB) are characterized by clinical or radiological worsening of pre-existing tubercular lesions or the appearance of new tubercular lesions in patients who have shown an initial improvement following anti-TB treatment.[1],[2] Pornsuriyasak and Suwatanapongched[3] have proposed the following criteria to diagnose a PR:

  • (1) initial clinical/radiological improvement with adequate ATT;


  • (2) paradoxical clinical/radiological deterioration;


  • (3) no conditions interfering with efficacy of ATT should be present (compliance, malabsorption, or side effects);


  • (4) absence of other explanations for deterioration.


Additionally, Carvalho et al.[4] suggested that the clinical or radiological worsening should occur after receiving ATT for at least 1 month for it to be labeled as a PR. Deterioration prior to that could be attributed to delay in responding to treatment. Cheng et al.[5] conducted a systematic review of literature and reported that the median time to PR was 60 days from the start of ATT. Gupta et al.[6] have reported the occurrence of PRs as late as 17 months after initiation of ATT in their patients with central nervous system (CNS) TB.

A paradoxical response is seen in 2.4–30% of the patients receiving antitubercular therapy.[7],[8] It is more commonly described in HIV-positive patients with reported incidence of 11–36% in patients receiving highly active antiretroviral therapy (HAART).[9],[10] PRs have been observed following both pulmonary and extrapulmonary TB and they may occur at the site of primary diagnosis or in a new uninvolved site. The most common presentation is worsening of the original lesion (75%), especially with tubercular involvement of the CNS.[11] New lesions commonly involve the CNS, respiratory system, skin, and lymph nodes.[12] Cheng et al.[12] observed a high propensity for spinal and paraspinal involvement. Velivela and Rajesh[13] observed a 7.5% incidence of PRs among 80 patients who were treated for spinal TB.

The current study is a retrospective case series that aims to describe the clinical presentation of PR in spinal TB, identify risk factors, and outline our management strategy.


  Materials and Methods Top


Between March 2002 and July 2018, 978 patients were treated for spinal TB. Of these, 10 patients were HIV-positive. 353 patients were treated surgically and 625 patients received non-operative treatment. Nine out of 353 patients, 7 females and 2 males, mean age 31.2 years (14–66 years) who were treated surgically subsequently developed a PR. Eight patients had initially been treated for thoracic/thoracolumbar TB, while one patient had involvement of the lumbar spine [Table 1] and [Table 2]. Seven patients were HIV-negative and two were HIV-positive. Both the HIV-positive patients were on antiretroviral therapy and had a CD4+ count >50 preoperatively. None of the nine patients had received antitubercular chemotherapy (ATT) prior to the surgery. All patients had initially undergone a posterior stabilization with pedicle screws, laminectomy with transpedicular decompression, drainage of prevertebral abscess, and anterior column reconstruction when necessary. Gene Xpert revealed that two patients were rifampicin-resistant, six patients were rifampicin-sensitive, and mycobacteria could not be isolated in one patient. Histopathological examination revealed caseating granulomas in all nine patients. ATT (isoniazid + rifampicin + ethambutol + pyrazinamide) was started on postoperative day 2/3 in patients who were rifampicin-sensitive and in those without mycobacterial growth. Patients with rifampicin resistance were started on a seven-drug ATT regime recommended by an infectious disease specialist. Antiretroviral therapy was started on fourteenth postoperative day.
Table 1: Demographics of patient population in the study

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Table 2: Lab parameter at diagnosis of index disease and at time of paradoxical reaction

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All patients experienced significant reduction in the preoperative pain, improved appetite, and weight gain along with improvement in the preoperative neurologic deficit over the first 3–4 weeks following surgery.

Patients who suffered from the PR presented with soft swelling at the surgical site between 4 and 7 weeks after the index operation. The surgical scar did not show evidence of inflammation, was non-tender, and had healed primarily. In one patient, the swelling burst through the skin forming a discharging sinus with an ulcer [Figure 1]A–G. None of the patients developed fever, decline in appetite, weight loss, or worsening of neurologic deficit when they developed the PR. None of the patients developed any clinical symptoms and signs indicating TB at other spinal or non-spinal sites. The total white blood cell count was within the normal range, and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated in all patients. X-rays revealed loosening or partial pullout of pedicle screws in two patients with recurrent kyphosis. Magnetic resonance imaging (MRI) showed no worsening of the vertebral lesion, nor any fresh vertebral lesion in any of the patients. It simply showed a large fluid collection that extended dorsally from the surgical site up to the skin. The fresh fluid collection was observed even in patients who did not have a significant pre/paravertebral abscess preoperatively.
Figure 1: (A-C) Preoperative (A) anteroposterior X-ray, (B) lateral X-ray, and (C) T1-weighted sagittal MRI of 16yF with D9-12 tuberculosis with no significant pre/paravertebral abscess. Patient presented with severe back pain and kyphosis without neurologic deficit. (D) Postoperative AP and lateral X-rays. (E) Clinical picture and (F) MRI, 6 weeks after index surgery when patient presented with an ulcer over the lower part of the incision. (G) Intraoperative picture following debridement and closure of wound after debridement

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Aspiration of the swelling with an 18 no. needle was unsuccessfully attempted in two patients. All patients were re-explored. None of the patients showed evidence of slough or significant infective granulation tissue. No biofilm was noted over the implants. The common finding was collection of a large amount (approx. 300cc) of sticky, viscous, clear-to-semi-translucent fluid. Smear of the fluid revealed Mycobacterium tuberculosis. Histopathology revealed marked inflammation along with caseating granulomas. Loose implants were replaced, and wound was thoroughly irrigated and debrided and closed over a large bore drain. The drain was maintained postoperatively till the daily drainage reduced to <20 mL/24 h. The ATT that was given earlier was continued without adding new drugs to the regime. All patients went on to heal uneventfully. ATT was stopped at one year in the non-rifampicin-resistant group and continued for 18 months in the rifampicin-resistant group. None of these nine patients has had a relapse of the disease since stopping the ATT.


  Discussion Top


The phenomenon of PRs in TB is well described in literature. In patients with TB, there is often a significant suppression of immunity.[14] Administration of ATT results in improvement of the general condition of the patient and a gradual restoration of immunity. ATT also results in lysis of the pathogen and release of mycobacterial debris which stimulates the immune system to launch an inflammatory response. This inflammatory response can result in worsening of the existing lesion or appearance of new lesions.[13] In HIV-positive patients with low CD4+ T cell counts who are coinfected with TB, the simultaneous initiation of ATT and HAART results in a rapid bolstering of the immune system, which is also increasingly activated by destruction of the mycobacteria. Immune reconstitution inflammatory syndrome (IRIS) has been observed in 10–43% of the patients with HIV–TB co-infection.[15],[16] The World Health Organization recommends a period of anti-TB treatment before initiation of HAART to avoid IRIS. If the CD4+ count is less than 50, HAART should be commenced within 2 weeks after TB medication. If the CD4+ count is >50, the initiation of HAART should be deferred for 8 weeks after initiating anti-TB care.[15],[17] In our series, none of the nine patients had received ATT prior to surgery. ATT was started from the 2nd/3rd postoperative day onwards and antiretroviral therapy after 2 weeks.

PRs in spinal TB are uncommon.[13],[18] Ours is possibly the only series that describes the presentation of a paradoxical response following surgery for spinal TB. All the patients who suffered from PR in our series presented with a large soft swelling at the surgical site without any local signs of infection, any constitutional symptoms, significant pain, or neurological deterioration. None of the patients had developed fresh spinal lesions or any symptomatic extraspinal lesions. MRI revealed an abscess dorsal to the dural sac often extending up to the skin. There was no increase in size of pre/paravertebral abscesses or worsening of the pre-existing vertebral lesions. Although ESR and CRP were elevated, the total leucocyte count was normal.

After ensuring compliance to ATT and antiretroviral therapy, the following differential diagnoses were considered: progression of existing tubercular lesions due to drug resistance, pyogenic surgical site infection, PR, and pseudomeningocele. The diagnosis of PR was made only after obtaining negative pyogenic cultures from the wound, isolation of mycobacteria on smear or culture, and presence of chronic inflammatory granulomas with caseation.

We elected to perform surgical debridement in all patients because aspiration of the swelling was unsuccessful in two patients, two patients required revision of loose implants, and one patient has a discharging wound that needed excision. Although patients with CNS and pulmonary TB who have developed PRs have been treated with steroids or anti-inflammatory medication,[19],[20] none of our patients was put on these drugs and this did not seem to negatively influence the eventual outcome. As reported by Im et al.,[18] continuation of ATT without change in the regime led to uneventful recovery.

A review of literature has identified young age, anemia, lymphopenia, high serum albumin levels, short duration of illness, HIV-positive status, disseminated TB, and extrapulmonary location as risk factors for PRs in TB.[21],[22],[23],[24] In our series, female sex, younger age group, thoracic or thoracolumbar involvement, and patients virgin to ATT prior to surgery were identified as risk factors for developing a paradoxical response.


  Conclusion Top


A PR is an uncommon but not rare occurrence of fresh lesions or worsening of a previous lesion while on ATT. In patients with spinal TB, a PR typically presents between 4 and 7 weeks after initiation of ATT with a cold abscess at the surgical site without constitutional symptoms, deterioration in neurology, or local signs of wound infection. No fresh lesions or worsening of existing vertebral lesions was noted. Pyogenic surgical site infection, pseudomeningocoele, multidrug resistance, and inadequate index surgery must be considered in the differential diagnosis after patient compliance with ATT is ensured.

We recommend open drainage, irrigation, and debridement with revision of loose implants. Continuation of same ATT should result in uneventful healing. The routine use of steroids or prolonged course of anti-inflammatories was found to be unnecessary.

Patients virgin to ATT, female sex, young age group, and thoracic/thoracolumbar involvement were identified as risk factors.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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3.
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4.
Carvalho AC, De Iaco G, Saleri N, Pini A, Capone S, Manfrin M, et al. Paradoxical reaction during tuberculosis treatment in HIV-seronegative patients. Clin Infect Dis 2006;42:893-5.  Back to cited text no. 4
    
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[PUBMED]  [Full text]  
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Shankar EM, Vignesh R, Ellegård R, Barathan M, Chong YK, Bador MK, et al. HIV-Mycobacterium tuberculosis co-infection: A “danger-couple model” of disease pathogenesis. Pathog Dis 2014;70:110-8.  Back to cited text no. 15
    
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