Identification and Management of Paradoxical Reactions in Pediatric Tuberculosis

Worsening of clinical, radiologic or laboratory parameters while receiving appropriate antituberculous therapy (ATT) is broadly classified as a “paradoxical reaction” (PR). In this review, we refer to PR as a dysregulated inflammatory response following the institution of appropriate ATT after initial clinical improvement or stability that is typically seen in children not living with HIV. PR is similar yet distinct from immune reconstitution inflammatory syndrome (IRIS) observed in people with HIV and tuberculosis (TB) coinfection. In IRIS, there is a clear immune reconstitution event following initiation of antiretroviral therapy (ART), which can lead to a worsening of symptoms of TB that is being treated (“paradoxical TB-IRIS”), or a new presentation of TB shortly after ART is commenced (“unmasking TB-IRIS”). The presentations of PR include clinical deterioration, radiographic evidence of worsening disease and laboratory evidence of an acute inflammatory response. PR is a diagnosis of exclusion, and the findings should not be explained by TB relapse or drug resistance, newly acquired infection, expected clinical course or drug side effects. In practice, differentiating these possibilities is often difficult. Incidence The reported frequency of PR in children varies widely. A recent systematic review of retrospective cohort studies found that PR occurred in 8.8% (95% confidence interval, 2.9%–14.6%) of HIV-negative children treated for TB.1 The estimated incidence of TB-IRIS in adults with HIV is about 18% but is uncertain in children.2,3 Risk Factors and Pathogenesis Both immune suppression and multibacillary TB diseases are 2 key risk factors for the development of PR.4 Identified risk factors for PR in children include the presence of multisite disease, absence of BCG vaccination5 and body weight <25th centile.6,7 Two studies showed an increased incidence in younger children, but one found that PR was more common in older children and adolescents.5–7 PRs are more commonly reported in those with TB of the central nervous system (CNS) and extrapulmonary lymph node disease, but this may be due to publication bias and more obvious clinical presentations at those sites. Pathogenesis The pathogenesis of PR needs to be better characterized. Similar to IRIS, patients with PR are thought to have underlying immune dysfunction due to either host factors or pre-existing lymphopenia from TB itself alongside a higher burden of mycobacterial disease followed by restoration of immunity upon starting ATT.4,8–13 In patients with IRIS, following initiation of ART, myeloid activation via inflammasome pathways alongside the expansion of a dysregulated polyfunctional antigen-specific response in T cells leads to an aberrant inflammatory response to multibacillary disease.14–17 Underlying host genetics may also play a role in addition to the immune dysfunction from HIV.18 These pathways are not fully interrogated in patients with PR; however, similar polyfunctional antigen-specific responses and myeloid activation have been reported.19–21 Clinical Features The timing of PR is variable but may occur months into therapy. PR has been described between 10 and 365 days after treatment initiation in children, with reported median intervals of 32 to 80 days.1 PR can manifest in various forms; common presentations in children are discussed in Table, Supplemental Digital Content 1, https://links.lww.com/INF/G149. Typically, PR presents as an exacerbation at the site(s) affected at the initial diagnosis of TB although some patients may present with fever alone or exhibit involvement at a new site. Often presentations are mild and self-limiting, but some cases present with excessive inflammation and even features of hemophagocytic lymphohistiocytosis. In individuals with intrathoracic TB, symptoms may include new or worsening cough, wheeze or stridor, which can arise from airway compression due to enlargement of intra thoracic or extrathoracic lymph nodes, new extension of disease into the bronchus or from worsening of existing endobronchial disease. Hemoptysis can occur from expanding intrathoracic lymph nodes eroding into the surrounding vessels or endobronchial TB eroding through the bronchial wall into vessels. New or worsening pleural/pericardial inflammation may lead to an expanding effusion. In CNS-TB, PR may result in the exacerbation or new onset of arachnoiditis, particularly in the optochiasmatic region, which can lead to visual disturbances and potentially blindness. An increase in basal exudates may obstruct cerebrospinal fluid (CSF) drainage, resulting in worsening or new-onset hydrocephalus or elevated intracranial pressure. PR can lead to the formation or enlargement of existing tuberculomas, causing localizing signs depending on location. Increased inflammatory exudates surrounding nerves may result in cranial nerve palsy, while stroke may occur due to inflammatory vasculitis.22 Abscesses (which can also be present at initial presentation) may also develop due to PR and have been described at different sites, including retropharyngeal, peritoneal, retroperitoneal, intrathoracic and viscerally. These cold abscesses can occur from the rupture of an enlarging adjacent lymph node, spread from surrounding structures (eg, vertebral TB resulting in psoas or epidural abscesses) or from hyperinflammation surrounding hematogenous disseminated TB (eg, in the brain or spleen). A common manifestation of PR is an enlargement of peripheral lymph nodes, which may compress surrounding structures and/or form cold abscesses that may spontaneously rupture resulting in draining sinuses.23 This may occur both during and after completion of adequate ATT.23 PR-IRIS Reactions in Patients Living With HIV Mycobacterial infections are the most common cause of IRIS [including paradoxical-IRIS (PR-IRIS) and unmasking TB-IRIS] in children living with HIV in both high- and low-burden settings.24,25 PR-IRIS may occur early in the treatment course of TB and even prior to initiation of ART.13,26,27 Reactions are often seen 4 to 8 weeks following initiation of ART and manifest with new fevers, weight loss or worsening radiogram findings and lymphadenopathy, including with bronchial compression.26–28 Based on limited evidence, PR-IRIS is more common in children with severe immunosuppression and low CD4 counts, malnutrition and with initiation of ART after a shorter duration of ATT. Diagnosis is challenging given the broad differential for clinical deterioration.27 Monitoring of CD4 count and viral load may aid assessment. Diagnosis PR is usually suspected when there is clinical, radiologic or laboratory (inflammatory marker) deterioration in a patient diagnosed with TB on appropriate ATT after showing initial improvement, and other causes have been excluded, including noncompliance to ATT, incorrect drug dosing, poor drug absorption, drug resistance and other coinfections (Fig. 1).1,4,7,29 Where possible, microbiologic and histopathologic sampling is important for diagnosis. Pathogen persistence on sampling may still be evident, but, typically, there is a reduction of burden (eg, lesser grade of smear positivity). In addition, histopathologic specimens may show increased inflammatory infiltrate compared to initial samples.FIGURE 1.: An approach to deterioration during treatment of pediatric TB.Lower absolute lymphocyte counts and elevated erythrocyte sedimentation rates have been associated with PRs. Elevated C-reactive protein and D-dimers, together with anemia and low body mass index, are predictive of IRIS; this may also be relevant to PR, but data are scarce.30 Treatment The optimal treatment for various forms of PR/TB-IRIS is uncertain and is dependent on the clinical situation. Most nonsevere cases are managed by observation and continuation of ATT. Most cases of PR involving lymph nodes resolve spontaneously.31 As PRs are strongly driven by a high bacterial burden and cannot easily be differentiated from inadequately treated TB disease, optimizing ATT is essential. Measures include ensuring patient adherence using directly observed therapy wherever possible, inquiring about vomiting and gastrointestinal intolerance and ensuring correct weight-based doses of medication. Therapeutic drug monitoring is useful if available. A significant proportion of pediatric TB cases are not bacteriologically confirmed, especially in low- and middle-income countries where suitable testing may not be available. Excluding ATT resistance wherever possible is important prior to any change in the drug regimen. In severe cases, adding at least 2 additional drugs to the existing regimen may be considered in cases with unknown susceptibilities and after further samples have been obtained. Drugs for PR management are summarized in Table, Supplemental Digital Content 2, https://links.lww.com/INF/G150. Corticosteroids are the most commonly used drugs for symptomatic PR through their wide range of effects on the immune system with subsequent suppression of hyperinflammation. The usual corticosteroids used in children are prednisolone or prednisone, but dexamethasone is an alternative, especially for CNS disease due to better penetration. The usual dose of prednisolone/prednisone varies between 1 and 2 mg/kg/day, while dexamethasone is usually prescribed at a maximum dose of 0.6 mg/kg/day. There are limited reports on pulse dose methylprednisolone for controlling initial severe symptoms. The initial corticosteroid dose should be maintained for 1 to 2 weeks pending initial clinical response with a tapering regimen over ≈6 to 8 weeks, reassessed at weekly intervals. Assessments of clinical symptoms and signs of PR, white blood cell count and/or C-reactive protein and imaging findings can guide when and how to taper. It is prudent to taper as quickly as the clinical presentation allows; however, there are many cases where steroid therapy may need to be prolonged due to relapse of PR symptoms during tapering or upon discontinuation of steroids. Prolonged corticosteroid therapy should prompt monitoring of blood pressure, weight, height and glucose levels. Optimizing bone health including vitamin D levels, ensuring gastrointestinal protection, monitoring for mood changes and excessive weight gain and managing immunosuppression and adrenal suppression (including stress dosing when unwell) are important.32 In cases with features of hemophagocytic lymphohistiocytosis at the time of PR, or where steroid side effects are severe or weaning steroids repeatedly leads to clinical worsening, alternative agents should be considered early (Table, Supplemental Digital Content 2, https://links.lww.com/INF/G150). Tumor necrosis factor-alpha inhibitors such as infliximab have been successfully used as steroid-sparing agents in PR and IRIS, especially in CNS-TB disease, but also for pulmonary and extrapulmonary PR.33 Most data on infliximab are from case series and reports; one retrospective cohort study showed improved disability-free survival.34 Infliximab has a long half-life and is associated with infusion reactions and the reactivation of endemic mycoses and other infections (and potentially worsening of TB if the treatment regimen is inadequate). Doses of 5 to 10 mg/kg for 3 doses have been used with consideration for additional doses if PR or IRIS symptoms recur. Thalidomide has been used in optochiasmatic arachnoiditis where vision is threatened, and for enlarging tuberculomas, and dural lesions causing seizures.35,36 It is highly teratogenic and should be used with extreme caution and safeguards in females of childbearing age. Side effects include rashes and peripheral neuropathy.35 Very high doses (24 mg/kg/day) have been associated with a marked increase in mortality.35 Doses of 3 to 5 mg/kg/day for 1 to 3 months have produced favorable responses with few side effects reported in the largest cohort.36 Advantages for use in low- and middle-income countries include low cost and oral administration. Emerging therapies include interleukin-1 receptor antagonists such as anakinra and Janus kinase inhibitors such as ruxolitinib; however, data are limited to case series and reports in adults.12,37 Interventional procedures are sometimes useful in the management of PR. Bronchoscopy with the removal of the endobronchial disease may allow the re-expansion of a collapsed lobe and prevent permanent lung damage.38 Surgical removal of steroid unresponsive intrathoracic nodes causing critical airway obstruction was helpful in a large prospective study of young children.39 Excisional surgery may be needed in cervical node TB if recurrent draining nodes persist despite treatment.23 Psoas or paraspinal abscess causing symptomatic compression of surrounding structures may also require drainage.40 In cases of CNS-TB where PR causes obstruction to CSF flow or compression on vital structures either CSF diversion or drainage of abscess or mass removal may be considered: the risks and benefits need to be carefully assessed and may be dependent on the available local expertise. Outcomes and Prognosis The sparse literature suggests that the occurrence of PR may prolong the duration of treatment41,42 and can cause adverse effects such as visual loss and developmental delay in CNS-TB.1 PR may lead to permanent pulmonary damage through lobar collapse and has been associated with reactive airway disease.7 In many cases, it is difficult to attribute the outcomes to the occurrence of PR versus TB disease itself. Research Gaps and Opportunities As PR may occur in about 9% of HIV-negative pediatric patients treated for TB, we recommend patients and families be counseled about the possibility of these reactions at the start of ATT. Critical research gaps include better defining which pediatric patients are most at risk for PR, understanding pathogenesis and short- and long-term consequences, and identifying opportunities in the management of TB to prevent PR. Further work is required to identify biomarkers and supportive laboratory investigations to aid in the diagnosis of PR. There is currently little evidence regarding optimal dosing and duration of corticosteroids and the role of corticosteroid-sparing agents in managing PR, particularly in steroid-refractory cases. Multicenter collaborations are urgently needed to make progress in the diagnosis and management of this poorly understood and clinically important phenomenon.