Tuberculosis (TB) is the number 1 cause of infectious disease mortality worldwide and is recognized as significant cause of under-5 mortality.1,2 Young children have a high risk of disease progression following primary Mycobacterium tuberculosis infection, with up to half of infants less than 12 months of age developing disease compared with approximately 5% in adults.1,3
Paradoxical TB reactions occur in up to a quarter of patients, usually within 2–3 months of starting treatment.4 A paradoxical reaction is defined as worsening of clinical or radiologic findings or new lesions following a period of initial improvement after starting appropriate TB treatment, having excluded drug-resistant disease, poor treatment adherence, drug toxicity and potential alternative reasons for deterioration. Paradoxical TB reactions are proposed to be secondary to an exaggerated immune response to mycobacterial antigens and are associated with significant morbidity and mortality.5 We describe the first reported pediatric use of infliximab, a tissue necrosis factor α (TNF-α) inhibitor, for a severe paradoxical reaction during treatment for TB meningitis and review the literature regarding use of infliximab for this indication.
A 7-year-old previously well girl was admitted to hospital with a 7-day history of fever, vomiting and headache. Her examination was normal with no meningism. Initial investigations revealed a lymphopenia (1.12 × 109/L), hyponatremia (133 mmol/L) and normal C-reactive protein level, with a normal chest radiograph and noncontrast head computed tomography. She was started on intravenous (IV) ceftriaxone 24 hours before a lumbar puncture which revealed 7 × 106/L polymorphs, 122 × 106/L lymphocytes, 15 × 106/L red blood cells, protein 1.10 g/L (normal range: 0.20–0.40 g/L) and glucose 2.0 mmol/L (2.8–4.0 mmol/L). cerebrospinal fluid (CSF) India ink staining and antigen testing for Cryptococcus spp. were negative.
Further history revealed she had traveled to Vietnam at 2 months of age for 2 weeks but reported no known TB contact. There was an insufficient volume of CSF to do an Xpert Ultra mycobacterium tuberculosis (MTB)/rifampicin (RIF) resistance assay. During the first 3 days of admission, she had persisting fever and headache, increasing combative behavior, and her serum sodium fell to 127 mmol/L despite fluid restriction. On day 4 of admission, she had reduced consciousness (Glasgow Coma Score 12) associated with a new left convergent squint, urinary incontinence and bradycardia with a normal blood pressure (100/70 mm Hg). Urgent magnetic resonance imaging (MRI) brain with angiography revealed 3 foci of abnormal contrast enhancement within the right frontal lobe sulci. Two of the lesions appeared contiguous with a blood vessel, raising the possibility of mycotic aneurysms. There were also parenchymal abnormalities in the right frontal operculum, left pars opercularis (Broca area) and splenium. There was no leptomeningeal enhancement or visible hydrocephalus. Ophthalmology review revealed no papilledema.
On day 5, the patient developed further clinical features suggestive of raised intracranial pressure including bradycardia (heart rate 70/min while febrile), bradypnea (respiratory rate 10/min) and bilateral sixth nerve palsies. An external ventricular drain confirmed an elevated opening pressure of 25 cm H2O (normal <15 cm H2O), which normalized with simple neuroprotective measures and continuous drainage. Transesophageal echocardiography showed no vegetation, and an MRI spine was normal. Autoimmune antibody and HIV serology testing were negative, and a QuantiFERON-TB Gold result was indeterminate. On retrospective review of her initial chest radiograph, a subpleural nodule in the right lung field was noted. A computed tomography chest revealed localized tree-in-bud nodules around a calcific focus in the right middle lobe with calcified right hilar lymph nodes consistent with previous TB infection with reactivation. In light of this, treatment for TB meningitis was started while awaiting further results (isoniazid 15 mg/kg daily, rifampicin 15 mg/kg daily, pyrazinamide 35 mg/kg daily and moxifloxacin 10 mg/kg daily, with IV dexamethasone 0.15 mg/kg 6 hourly). The Xpert MTB/RIF result on a repeat CSF sample was subsequently positive with no rpoB gene mutation detected. The external ventricular drain was removed on day 17 and steroids weaned over 8 weeks with resolution of bilateral sixth nerve palsies.
Eight weeks after starting TB treatment, on the day her steroids were due to cease, she reported recurrence of headache, “sore eyes” and nocturnal polyuria. On examination, she had Cushingoid features with normal neurology and no signs of raised intracranial pressure. A formal ophthalmologic assessment showed reduced visual acuity of 6/12 bilaterally (baseline visual acuity right 6/7.5−1; left 6/9.5−2). An urgent MRI brain revealed a new hyperintense mass lesion in the suprasellar cistern extending into the sella and the anterior recess of the third ventricle. The mass encased the optic chiasm and optic tracts, extending into the Sylvian fissures, consistent with optochiasmatic arachnoiditis (Fig. 1). Bilateral areas of subcortical white matter edema were also noted. Due to the significant risk of further vision impairment related to this inflammatory mass, she was restarted on IV dexamethasone 0.15 mg/kg 8 hourly as well as infliximab 5 mg/kg. Repeat MRI brain 1 week later showed significant reduction in the size of the inflammatory mass and her visual acuity returned to baseline. She received 2 further doses of infliximab 5 mg/kg after 2 and 6 weeks and continued prednisolone 2 mg/kg/d for 2 weeks before slow weaning over 8 weeks. The patient remained well with no visual symptoms at 6-month follow-up.
Inflammatory complications, termed paradoxical reactions, can occur weeks or months after starting treatment for TB meningitis and any clinical deterioration during TB treatment should be carefully evaluated. Optochiasmatic arachnoiditis is a severe vision-threatening inflammatory reaction and represented 12 of 44 paradoxical reactions in 1 large case series of 144 adults with TB meningitis.5 Eye pain has not been commonly reported in optochiasmatic arachnoiditis but was a prominent symptom in our patient. It is more typically associated with insidious progressive visual loss and, in a case series of 101 adults, was found to be a predictor of blindness at 6 months into TB meningitis treatment with a relative risk of 2.01 (confidence interval: 1.05–3.02, P = 0.001).6 Outcomes are poor: in 1 case series only 4 of 21 adults with visual impairment due to TB optochiasmatic arachnoiditis improved despite steroid therapy.7
Paradoxical inflammatory complications of TB treatment are often steroid resistant. In a randomized trial of adjunctive prednisolone in 141 children with TB meningitis, treatment with steroids did not reduce the risk of raised intracranial pressure or incidence of basal ganglia infarction.8 Patients with TB meningitis, have elevated CSF inflammatory markers such as TNF-α, interferon-γ, interleukin-8, interleukin-10 and matrix metalloproteases and inhibitors, throughout the first weeks of treatment.9 While steroids are the mainstay of management for severe paradoxical reactions, they have been shown to only marginally reduce CSF interferon-γ levels with no reduction in other cytokines.10 Animal models implicate levels of CSF TNF-α in the severity of inflammation in TB meningitis, suggesting immunomodulatory therapy targeted against this cytokine is likely to be beneficial.11
Thalidomide has multiple anti-inflammatory effects including suppression of TNF-α production and has been used in the treatment of life-threatening paradoxical TB reactions in children. In 1 study of 15 children with TB meningitis, adjunctive thalidomide resulted in a significant decline in CSF TNF-α levels and more favorable clinical outcomes compared with controls who received corticosteroids alone (5/15 had improved motor outcome, remainder no worsening at 6-month follow-up and no patients developed new infarcts).12 Adjunctive thalidomide was also effective in a case series of 4 children with blindness due to TB meningitis-related optic neuritis, all of whom regained good visual acuity.13 However, in addition to TNF-α suppression, thalidomide has a range of other immunomodulatory actions that may be unnecessary for the successful treatment of optochiasmatic arachnoiditis. Furthermore, at higher doses (24 mg/kg/d), deaths and adverse events were observed in a pediatric randomized trial of adjunctive thalidomide for TB meningitis, that necessitated termination of the trial.14
Infliximab is a specific TNF-α antagonist. There have been no trials of the use of infliximab for paradoxical reactions in TB meningitis, but favorable outcomes have been reported in 6 adults.15–18 As summarized in Table 1, these paradoxical reactions were refractory to steroids or other immunomodulatory therapy such as cyclophosphamide or methotrexate, and there were no infliximab-related adverse events.16–19 Additional evidence supporting the use of TNF-α blockade in this setting comes from reports of severe paradoxical TB reactions after infliximab was stopped in patients who were diagnosed with TB disease while receiving immunomodulatory treatment for underlying autoimmune disease.19,20
Our patient fully recovered after treatment with infliximab and high-dose steroids with no adverse events. It is possible that infliximab contributed to the preservation of vision given the severity of optochiasmatic arachnoiditis in this case. This is the first reported use of infliximab for this indication in a child and further highlights the role of TNF-α in the pathogenesis of paradoxical reactions in TB meningitis.
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