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Paradoxical reaction in immunocompetent children with tuberculosis

Open AccessPublished:August 18, 2016DOI:https://doi.org/10.1016/j.ijid.2016.08.009

      Highlights

      • A paradoxical reaction (PR) is not an unusual occurrence in immunocompetent children with tuberculosis (TB); PR is defined as the clinical or radiological worsening of pre-existing TB lesions in a patient who has initiated anti-tuberculosis treatment.
      • During the study period, five of 51 children diagnosed with TB matched the definition of PR (9.8%), consistent with the results of previous studies.
      • There is no consensus regarding the use of corticosteroids in the treatment of PR.
      • Steroid treatment was administered to all of the patients in this study, and all had a favourable outcome.

      Summary

      Background

      A paradoxical reaction (PR) during anti-tuberculosis treatment is a phenomenon that is poorly studied in immunocompetent children. It is defined as a clinical or radiological worsening of pre-existing tuberculosis (TB) disease.

      Methods

      A retrospective descriptive study of children younger than 14 years of age was performed; these children developed PR during the years 2009 to 2014, following a diagnosis of TB. Demographic characteristics, microbiological results, treatment and outcome data were collected.

      Results

      Of 51 children diagnosed with TB, five (9.8%) developed a PR; four of these children had pulmonary TB and the remaining patient had miliary TB with central nervous system involvement. The PR occurred at a median of 42 days (range 23–53 days) after initiating therapy. Corticosteroids were started when PR was suspected, at a median dose of 1 mg/kg/day. Clinical and radiological improvement was noted in all cases, with a median clinical regression time of 10.5 days (range 3–15 days) and a median radiological regression time of 45 days (range 26–105 days). No sequelae were described in any patient.

      Conclusions

      PR in immunocompetent children during anti-tuberculosis treatment is not such an unusual reaction. Treatment with corticosteroids may be useful for the resolution of PR.

      Keywords

      1. Introduction

      Patients with tuberculosis (TB) can suffer an unexpected deterioration despite good therapeutic compliance. This phenomenon is known as paradoxical reaction (PR), defined as the clinical or radiological worsening experienced by patients with good adherence to treatment.
      • Meintjes G.
      • Lawn S.D.
      • Scano F.
      • Maartens G.
      • French M.A.
      • Worodria W.
      • et al.
      Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings.
      Such a reaction has been described extensively in HIV-positive patients, i.e. the immune reconstitution inflammatory syndrome (IRIS). Likewise, the emergence of PR has also been observed in the immunocompetent population.
      • Fernández-Fúnez A.
      Paradoxical response during anti-tuberculosis treatment in immunocompetent patients.
      With regard to children, PR has mostly been reported in isolated clinical cases,
      • Park J.A.
      • Park S.S.
      • Park S.E.
      A paradoxical reaction during antituberculosis therapy for congenital tuberculosis.
      • Del Rio Camacho G.
      • Jimenéz Jimenéz A.B.
      • Górgolas Hernández-Mora M.
      • Sanz Calvo M.L.
      • Montoro Chavarrias S.
      • Bernacer Borja M.
      Paradoxical reaction to tuberculosis treatment in an immunocompetent adolescent.
      and only two studies have been published to date.
      • Thampi N.
      • Stephens D.
      • Rea E.
      • Kitai I.
      Unexplained deterioration during antituberculosis therapy in children and adolescents: clinical presentation and risk factors.
      • Olive C.
      • Mouchet F.
      • Toppet V.
      • Haelterman E.
      • Levy J.
      Paradoxical reaction during tuberculosis treatment in immunocompetent children: clinical spectrum and risk factors.
      This article reports the cases of immunocompetent paediatric patients diagnosed with TB who developed PR over a period of 5 years.

      2. Patients and methods

      A retrospective descriptive study was performed of patients under 14 years of age diagnosed with TB who developed a PR; these patients presented to the study tertiary care hospital during the years 2009 to 2014.
      PR was defined as a clinical or radiological worsening of pre-existing TB lesions or the development of new lesions, in a patient who had initiated TB treatment at least 2 weeks before and in whom a clinical improvement had been observed. The diagnosis of the PR was made during outpatient visits. The exclusion of a bacterial or viral infection, poor compliance to treatment, and resistance to the therapeutic drugs used was required for the diagnosis.
      • Meintjes G.
      • Lawn S.D.
      • Scano F.
      • Maartens G.
      • French M.A.
      • Worodria W.
      • et al.
      Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings.
      • Graham S.M.
      • Ahmed T.
      • Amanullah F.
      • Browning R.
      • Cardenas V.
      • Casenghi M.
      • et al.
      Evaluation of tuberculosis diagnostics in children: 1. Proposed clinical case definitions for classification of intrathoracic tuberculosis diseases. Consensus from an expert panel.
      The time to onset of the PR was considered as the number of days between the initiation of TB treatment and the diagnosis of PR. The time for PR regression was defined as the number of days between the diagnosis of PR and the first signs of clinical or radiological improvement.

      3. Results

      During the study period, 51 children were diagnosed with TB disease; none had congenital or acquired immunosuppression. Five of these patients matched the definition of PR (9.8%): four had pulmonary TB and the remaining one had miliary TB with central nervous system involvement. All patients were autochthonous and Caucasian. The characteristics of these patients are detailed in Table 1.
      Table 1Characteristics of paediatric patients with TB who developed a paradoxical reaction
      PatientTB formAge, yearsSexIsolation of MTTB regimenRadiology at diagnosisPR onset, daysPR symptomsPR radiologyPR treatmentDosage, mg/kg/ daySteroids duration, daysPR clinical regression, daysPR radiological regression, days
      1Pulmonary2.3FYes6 months

      H,R,Z,E
      Parenchymal infiltration in right upper lobe42NoWorsening of parenchymal infiltrationPrednisolone1.534-38
      2Pulmonary2.1MNo
      This case was exposed to a confirmed TB case, in which no resistance was observed.
      6 months

      H,R,Z,E
      Unknown50Fever, cough, and respiratory failureHilar adenopathy; right upper lobe infiltration; bronchial compressionPrednisolone11093105
      3Pulmonary2.6MYes6 months

      H,R,Z,E
      Right paracardiac infiltration42Worsening coughMiddle lobe atelectasisPrednisolone1.5331526
      4Pulmonary1.6MYes6 months

      H,R,Z,E
      Parenchymal infiltration in right upper lobe (Figure 1)23Fever and coughRight upper and middle lobe atelectasis (Figure 2)Prednisolone123645
      5Meningitis7.2MYes12 months

      H,R,Z,E
      CT chest: miliary pattern

      Brain MRI: supratentorial and infratentorial tuberculomas
      53Fever recurrenceIncrease in number and size of tuberculomasPrednisone1301575
      TB, tuberculosis; MT, Mycobacterium tuberculosis; PR, paradoxical reaction; F, female; M, male; H, isoniazid; R, rifampicin; Z, pyrazinamide; E, ethambutol; CT, computed tomography; MRI, magnetic resonance imaging.
      a This case was exposed to a confirmed TB case, in which no resistance was observed.
      The TB disease was treated with first-line drugs in all cases, and no adverse reaction was observed. The PR occurred at a median of 42 days (range 23–53 days) after the initiation of anti-tuberculosis drugs. The diagnosis was made on the basis of radiological worsening in all cases, as well as clinical deterioration in four cases.
      Of those with the pulmonary forms, two required admission at the time of PR and received systemic antibiotics for a suspected associated bacterial infection; there was no improvement after initiating the antibiotics and no microbiological isolation in either case .
      The same TB treatment was maintained for all patients, and systemic corticosteroids were administered in every case for an average duration of 46 days (range 23–109 days) at a median dose of 1 mg/kg/day, which was gradually tapered off. A clinical and radiological improvement was noted in all cases following corticosteroid treatment. The median clinical regression time was 10.5 days (range 3–15 days) and the median radiological regression time was 45 days (range 26–105 days). There were no sequelae after treatment completion.
      To investigate possible predictors of deterioration, patients who developed PR were compared with those who continued to improve. No statistically significant difference was found for any of the parameters analyzed (Table 2).
      Table 2Baseline characteristics of the patients
      Data are presented as number (%) or median (range). The statistical analysis was done using the Student t-test or Mann–Whitney U-test for medians and proportions, according to the variable distribution. Categorical variables were compared using Fisher's exact test. The confidence interval was 95%.
      No paradoxical reaction

      (n = 46)
      Paradoxical reaction

      (n = 5)
      p-Value
      Median age, years4.5 (0.1–13.9)2.6 (1.6–7.2)0.46
      <3 years of age16 (34.7%)3 (6.5%)0.34
      Male to female ratio25/213/21.00
      Weight percentile ≤25%16 (34.7%)2 (40%)1.00
      History of TB contact22 (47.8%)1 (20%)0.35
      TST median, mm1211.50.79
       Negative5 (10.8%)01.00
       5–14 mm28 (60.8%)4 (80%)0.64
       ≥15 mm13 (28.4%)1 (20%)1.00
      Pulmonary TB31 (67.3%)4 (80%)
      Extrapulmonary TB15 (32.7%)1 (20%)1.00
       Endobronchial30
       Pleural20
       Disseminated40
       Lymph node30
       Abdominal10
       Meningeal21
      Mycobacterium tuberculosis-positive culture21 (45.6%)4 (80%)0.19
      Median lymphocyte count, ×109/l3.120 (0.200–11.900)3.150 (0.120–5.870)1.00
      Cases with lymphocyte count <1.5 ×109/l5 (10.8%)1 (20%)0.42
      Median haemoglobin level, g/dl11.9 (7–13.5)11.2 (9.3–13.5)0.76
      Median treatment duration, months6 (6–12)6 (6–12)0.83
      Number of cases with steroid treatment6 (13%)5 (100%)<0.001
      TB, tuberculosis; TST, tuberculin skin test.
      a Data are presented as number (%) or median (range). The statistical analysis was done using the Student t-test or Mann–Whitney U-test for medians and proportions, according to the variable distribution. Categorical variables were compared using Fisher's exact test. The confidence interval was 95%.

      4. Discussion

      Although PR is poorly described in the paediatric population, Thampi et al. reported an incidence of 14% among 112 children with TB in Canada,
      • Thampi N.
      • Stephens D.
      • Rea E.
      • Kitai I.
      Unexplained deterioration during antituberculosis therapy in children and adolescents: clinical presentation and risk factors.
      and Olive et al. reported an incidence of 10% in 130 patients in Belgium.
      • Olive C.
      • Mouchet F.
      • Toppet V.
      • Haelterman E.
      • Levy J.
      Paradoxical reaction during tuberculosis treatment in immunocompetent children: clinical spectrum and risk factors.
      In the present study, 9.8% of the children with TB developed a PR, consistent with the results of these previous studies.
      The pathophysiology of PR in the immunocompetent population remains unclear . It has been proposed that in the initial moments of infection, the bacillus is phagocytosed by lung macrophages; the triggering of a bactericidal reaction is therefore avoided, favouring a certain state of immunosuppression. An increase in production of interleukin 10 (IL-10) and transforming growth factor beta (TGF-β), which induces the apoptosis of T lymphocytes and reduces the production of interferon gamma (IFN-γ) , decreases the recruitment of new macrophages and promotes this level of immunosuppression. After the initiation of treatment, the immune system improves, either as a consequence of the therapy or spontaneously, and this is the main cause of TB worsening .
      • Fernández-Fúnez A.
      Paradoxical response during anti-tuberculosis treatment in immunocompetent patients.
      • Campbell I.A.
      • Dyson A.J.
      Lymph node tuberculosis: a comparison of various methods of treatment.
      The two previous studies conducted in children analysed the risk factors for developing PR.
      • Thampi N.
      • Stephens D.
      • Rea E.
      • Kitai I.
      Unexplained deterioration during antituberculosis therapy in children and adolescents: clinical presentation and risk factors.
      • Olive C.
      • Mouchet F.
      • Toppet V.
      • Haelterman E.
      • Levy J.
      Paradoxical reaction during tuberculosis treatment in immunocompetent children: clinical spectrum and risk factors.
      The main risk factors identified were a weight below the 25th percentile, the involvement of more than one site at initial presentation, and the presence of more serious symptoms at diagnosis. Olive et al. also described a lower age at diagnosis as an independent factor.
      • Olive C.
      • Mouchet F.
      • Toppet V.
      • Haelterman E.
      • Levy J.
      Paradoxical reaction during tuberculosis treatment in immunocompetent children: clinical spectrum and risk factors.
      The risk factors analyzed in the present sample were found not to be statistically significant, probably due to the small sample size.
      A change in the anti-tuberculosis therapy used, or in the duration of this therapy, is not recommended during the treatment of PR. The use of corticosteroids has been proposed by several authors, with different results obtained.
      • Park J.A.
      • Park S.S.
      • Park S.E.
      A paradoxical reaction during antituberculosis therapy for congenital tuberculosis.
      • Del Rio Camacho G.
      • Jimenéz Jimenéz A.B.
      • Górgolas Hernández-Mora M.
      • Sanz Calvo M.L.
      • Montoro Chavarrias S.
      • Bernacer Borja M.
      Paradoxical reaction to tuberculosis treatment in an immunocompetent adolescent.
      • Olive C.
      • Mouchet F.
      • Toppet V.
      • Haelterman E.
      • Levy J.
      Paradoxical reaction during tuberculosis treatment in immunocompetent children: clinical spectrum and risk factors.
      Although there is no clear indication, most authors agree that clinical observation may be sufficient in mild cases and that steroids could be beneficial for severe forms.
      • Fernández-Fúnez A.
      Paradoxical response during anti-tuberculosis treatment in immunocompetent patients.
      • Cheng V.C.
      • Ho P.L.
      • Lee R.A.
      • Chan K.S.
      • Chan K.K.
      • Woo P.C.
      • et al.
      Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients.
      • Link-Gelles R.
      • Moultrie H.
      • Sawry S.
      • Murdoch D.
      • Van Rie A.
      Tuberculosis immune reconstitution inflammatory syndrome in children initiating antiretroviral therapy for HIV infection: a systematic literature review.
      With regard to the dose used, most studies have recommended an initial dose of 1 mg/kg/day, with a progressive tapering off over 4 or 6 weeks.
      • Fernández-Fúnez A.
      Paradoxical response during anti-tuberculosis treatment in immunocompetent patients.
      • Park J.A.
      • Park S.S.
      • Park S.E.
      A paradoxical reaction during antituberculosis therapy for congenital tuberculosis.
      • Del Rio Camacho G.
      • Jimenéz Jimenéz A.B.
      • Górgolas Hernández-Mora M.
      • Sanz Calvo M.L.
      • Montoro Chavarrias S.
      • Bernacer Borja M.
      Paradoxical reaction to tuberculosis treatment in an immunocompetent adolescent.
      • Cheng V.C.
      • Ho P.L.
      • Lee R.A.
      • Chan K.S.
      • Chan K.K.
      • Woo P.C.
      • et al.
      Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients.
      Corticosteroid treatment was given to all of the patients in this study, with good results. Some of them did not present with a severe form of PR; therefore, it is possible that their outcomes would have been equally successful without corticosteroid treatment.
      This study has several limitations. It was retrospective in design and included a small patient sample. Furthermore, one patient in whom Mycobacterium tuberculosis was not isolated was included among those with PR, as the bacillus was isolated in the index case Figure 1, Figure 2.
      Figure thumbnail gr1
      Figure 1Chest X-ray done at diagnosis of pulmonary tuberculosis in a 2-year-old boy (patient 4, ), showing a right upper lobe infiltration. .
      Figure thumbnail gr2
      Figure 2Chest X-ray done in the same patient (patient 4, ) at the time of diagnosis of the paradoxical reaction: a radiological worsening with an increase in parenchymal infiltration and atelectasis in the right upper and middle lobes can be seen.
      In conclusion, PR is not such an unusual occurrence in immunocompetent children with TB. It is important to consider PR when other causes of clinical or radiological worsening have been ruled out.
      Funding: None.
      Conflict of interest: The authors have no conflicts of interest to report.

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