1. Paradoxical Reactions DR RONAN BREEN CONSULTANT CHEST PHYSICIAN GUYS AND ST THOMAS’ NHS FOUNDATION TRUST

2. Paradoxical reactions  Definition  Patterns  Pathogenesis  Clinical Features  Role of HIV treatment (ART)  Management

3. SIMPLE PR Diagnosis of TB Starts treatment PR End of TB treatment

4. Paradoxical Reaction (PR) Definition  “a worsening of clinical findings following the initiation of appropriate anti-TB therapy in the absence of evidence of poor adherence, disease relapse or the presence of another diagnosis”  Diagnosis of exclusion

5. SIMPLE PR/IRIS Diagnosis of TB Starts treatment ART PR/IRIS End of TB treatment

6. SIMPLE PR Diagnosis of TB Starts treatment ART/stop anti- TNF/feeding PR End of TB treatment

7. SIMPLE PR Diagnosis of TB Starts treatment PR End of TB treatment

8. SIMPLE PR Diagnosis of TB Starts treatment PR End of TB treatment PR

9. SIMPLE PR Diagnosis of TB Starts treatment PR End of TB treatment

10. TB/HIV+ PR  54yo Caucasian male  6 months weight loss, sweats,  Recent nystagmus  Diagnosed miliary TB – starts anti-TB treatment  Diagnosed HIV infected  CD4 51 cells/ul  VL 5.8 logcopies/ml

11. TB/HIV+ PR  Returns to London  On reducing course of steroids  ART at Day 21  Stable at day 35 so discharged

12. TB/HIV+ PR  Day 49 – recurrent nystagmus and new confusion

13. TB/HIV+ PR  What is the problem?  Adherence?  Drug-resistance?  Another diagnosis?  PR/IRIS?

14. TB/HIV+ PR  Subsequent course  Continues ART  MTB sensitive to first-line agents  Steroids increased  X2 further PR as steroids reduced  Good long-term outcome

15. “I’m taking my treatment but my neck is swollen again!”  29yo Egyptian  Slight increase in swelling at week 3  Now at week 6

16. “I’m taking my treatment but my neck is swollen again!”  Initial cytology diagnosis of TB  MTB sensitive to first-line agents grown  TB-PCR positive at week 3 but culture negative  Re-aspirated and culture negative  Aspirated x3 and settled over 10 weeks

17. Early PR Reports  Choremis et al 1955 – Transitory exacerbation of fever and roentgenographic findings during treatment of tuberculosis in children  Silver, Steel 1961 - Mediastinal lymphatic gland tuberculosis in Asian and coloured immigrants  Campbell, Dyson 1977 - Lymph node tuberculosis: A comparison of various methods of treatment. 25% experienced PR  Chambers et al 1984 – Paradoxical expansion of intracranial tuberculomas during chemotherapy  Onwubalili JK et al. 1984 - Acute respiratory distress related to chemotherapy of advanced pulmonary tuberculosis. Postulated effect of stopping alcohol and being fed

18. Increasing SOB and fever – 3 week old baby doing well

19. Early IRIS  French et al 1992 – Zidovudine induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected cases  Race et al 1998 - Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease

20. TB “unmasking” IRIS

21. PR Pathogenesis – MTB  Fundamentally related to initiation of effective anti-TB treatment  Campbell and Dyson proposed PR due to release of cell wall antigens  Cell wall contains abundant insoluble, lipid-rich antigens  Antigen may be more likely to be trapped in nodes, CNS  More effective killing releases antigen more rapidly  Less/later PR if drug-resistance present?  More PR with treatment-shortening regimens?

22. PR Pathogenesis - M Ulcerans  O’Brien et al 2013 – Australia  21% PR during treatment of Buruli Ulcer  Increased frequency with ART  Associated with amikacin use, older adults  Related to removal of inhibitory mycolactone toxin?  Steroid responsive  Better recognition of PR reduced use of surgery

23. Pathogenesis – Immune response Immune phenotypeParadoxical reactionParadoxical TB-IRISUnmasking TB-IRIS Adaptive responses Expansion of mycobacteria-specific Th1 CD4+ T cells Bourgarit et al. (2006)Wilkinson et al. (2012) Increased activation of circulating CD4+ T cells Antonelli et al. (2010)* Expansion of polyfunctional CD4+ T cellsMahnke et al. (2012)* Increased numbers of γδ T cellsBourgarit et al. (2009) Low expression of Mtb-specific anti- phenolic glycolipid antibody Simonney et al. (2008)

24. Pathogenesis – Immune response Innate responses Hypercytokinaemia/increased circulating pro- inflammatory cytokines/spontaneous cytokine production (IL-6 and CRP) Bekker et al. (1998) Andrade et al. (2014), Oliver et al. (2010), Tadokera et al. (2012, 2013) Increased MMP expressionTadokera et al. (2014) Increased numbers/activation of peripheral blood monocytes Hawkey et al. (2005)Andrade et al. (2014) Dysregulated complement component expression in monocytes Tran et al. (2013) High TLR-2 expression on monocytesTan et al. (2011) High rates of NK cell activationPean et al. (2012)Conradie et al. (2011) High neutrophil counts and TNFα at site of disease Jung et al. (2011)Marais et al. (2013, 2014) Immune phenotypeParadoxical reactionParadoxical TB-IRISUnmasking TB-IRIS

25. CRP and PR – London data CRP rose in 64% at time of PR compared to only 3% on starting treatment No association observed between baseline CRP and PR Is IL-6 a therapeutic target?

27. HIV Co-infection

28. TUBERCULOSIS & PR/IRIS CountryPopn.StudySizeIRIS (H+) PR (H-) Ref USWardProsp88 (33 HIV+) 36% 2%Narita, 1998 USClinicRetro82 (28 HAART) 7% (11% HAART) N/AWendel, 2001 SpainWard & Clinic Retro76 (17 HAART) 8% (35% HAART) N/ANavas, 2001 UKWard & Clinic Retro100 (50 HIV+) 28%10%Breen, 2004 FranceWard & Clinic Retro3743%N/ABreton, 2004 IndiaClinicRetro1448%N/AKumarasamy, 2004 ThailandClinicRetro16713%N/AManosuthi, 2006

29. TUBERCULOSIS & PR/IRIS

30. PR and ART  Concerns about  PR morbidity and mortaility  Over-lapping drug toxicity  Drug-drug interactions  Recommendations early in ART use included  treating TB and then HIV without overlap if at all possible  Avoiding rifamycins  No large RCT looking at mortality

31. BHIVA Audit 2005 Timing of HAART initiation & TB therapy Number of centres Timing of HAART start relative to TB therapy Freedman et al BHIVA 2005

32. Effect of ART on PR Frequency

33. PR and ART Timing  STRIDE, SAPIT, CAMELIA – large RCTs comparing early and delayed ART in TB endemic countries with mortality as primary end-point  Demonstrated mortality benefit in early ART if CD4 <50 cells/ul  IRIS/PR intensively investigated as secondary endpoint

34. PR/IRIS Definitions - INSHI

35. PR and ART Timing CAMELIA n=661STRIDE n=806SAPIT n=642 ART schedule2 weeks vs 8 weeksWithin 2 weeks vs 8-12 weeks Within 4 weeks vs 8-12 weeks vs with 4 weeks of end of TB Rx Median blood CD426 cells/ul77 cells/ul~150 cells/ul IRIS in early ART36%10.4%22% IRIS in late ART16%4.7%13% Median Time ART to IRIS14 days16 days17 days Mortality from IRIS3.9%0%2.5% Risks for IRISEarly ART, disseminated TB, EPTB, mediastinal nodes on CXR, CD4 6 logs Early ART, CD4<50, baseline HIV load Baseline HIV load, low CD4, WHO status

36. Time from ART to PR CAMELIA SAPIT

37. Manifestations of HIV+ PR/IRIS CAMELIA (Cambodia) SAPIT (South Africa) STRIDE (Multi- national) ROYAL FREE (London) Fever68%2.5%59%93% RespiratoryNot reported72%34%43% CXR worsening53%56%41%Not reported Nodal swelling77%22%59%21% Abdominal49%2.5%Not reported14% Neurological5%<10%Not reported7% Steroids used15%10%54%71% Severe IRIS/PRNot reported35% early group vs 22% vs 16% 31%57%

38. Severity of PR according to HIV status

39. Effect of ART on PR Frequency

40. Manifestations of PR – London Cohort

41. Time to PR from starting anti-TB Rx

43. Treatment of PR  Reassurance  Exclude other possibilties

44. AFRICAN WITH COUGH, WEIGHT LOSS

45. Says he was a bit better but now worse at week 8. PR?

46. Treatment of PR  Reassurance  Exclude other possibilties  Helpful if you have mentioned the possibility of PR at start of treatment  Observation if possible  Don’t stop anti-TB medication  Don’t stop ART  Aspiration if painful/tense/pointing

47. Treatment of PR  NSAIDs – widely used but questionable effectiveness  Corticosteroids  effective at low doses: pred 20mg daily?  Probably modulating innate not adaptive immunity  Reduce node swelling but may not aid healing  Not always effective in CNS even at high dose  Unclear how long to treat  PR may recur at end of steroids

48. Treatment of PR  Poor evidence base if severe and recurrent  Make sure PR definition is fulfilled. Beware PR followed by relapse/new infection  Think hard before retreating  Consider resection if localised eg peripheral lymph node, focal CNS lesion  Unclear what to use other than corticosteroids  Azathioprine, thalidomide, cyclophosphamide all reported  Montelukast reported in HIV IRIS  Infliximab - Blackmore et al CID 2008 reported successful use in severe case of severe CNS and lymph node PR not responding well to steroids and cyclophosphamide

49. Late PR – Case 1  28yo from Ethiopia presents with node in right supra-clavicular fossa  FNA shows granulomas and necrosis – starts anti-TB therapy  Mild swelling at week 4 diagnosed as PR – aspirate culture negative  M Bovis cultured – continuation phase 7 months RH  Returns 3 months after treatment completion with swelling superior to baseline site  What are the options at this time?

50. Late PR – Case 1  28yo from Ethiopia presents with node in right supra-clavicular fossa  FNA grows M Bovis and treated for 9 months  Mild swelling at week 4 diagnosed as PR – aspirate culture negative  Returns 3 months after treatment completion with swelling above baseline site  What are the options at this time?  Re-sample for cytology and culture  Discuss adherence  Reassure - review original results  Observe? Re-treat? Steroids?

51. Late PR – Case 1  28yo from Ethiopia presents with node in right supra-clavicular fossa  FNA grows M Bovis and treated for 9 months  Mild swelling at week 4 diagnosed as PR – aspirate culture negative  Returns 3 months after treatment completion with swelling above baseline site  What are the options at this time?  Re-sample for cytology and culture  Discuss adherence  Reassure  Observe

52. Late PR – Case 1  Swelling settles after 8 weeks without treatment  FNA shows granulomas and necrosis but culture negative  Presents again 10 months later with new swelling medial to original site  What to do this time?  Re-sample for cytology and culture  Discuss adherence  Reassure (yourself?)  Observe? Re-treat? Steroids? Resect?

53. Late PR – Case 1  Swelling settles after 8 weeks without treatment  FNA shows granulomas but culture negative  Presents again 10 months later with new swelling medial to original site  What to do this time?  Re-sample for cytology and culture  Discuss adherence  Reassure  Steroids

54. Late PR – Case 1  Settles more quickly than before with prednisolone 10mg od for 4 weeks  FNA shows granulomas and necrosis but culture negative  Reassured  Will PR occur again?

55. Late PR – Case 2  18yo from India with swelling in right high cervical chain and left SCF  FNA shows necrosis and starts anti-TB treatment  Presents at week 3 with increased swelling in left SCF and new right sided nodes  What are the options at this time?  Repeat FNA  Chase culture results  Discuss adherence  Reassure  Observe

56. Late PR – Case 2  Node swelling settles after 4 weeks  MTB sensitive to first-line agents at baseline but culture negative at PR  One month after end of treatment swelling at original site of right cervical nodes  What are the options at this time?  Repeat FNA  Discuss adherence  Observe? Re-start previous anti-TB drugs ? Steroids? New anti-TB drugs? Resection?

57. Late PR – Case 2  Node swelling settles after 4 weeks  MTB sensitive to first-line agents at baseline but culture negative at PR  One month after end of treatment swelling at original site of right cervical nodes  What are the options at this time?  Repeat FNA for cytology and culture  Discuss adherence  Observe? Re-start previous anti-TB drugs ? Steroids? New anti-TB drugs? Resection?  Observe

58. Late PR – Case 2  Culture positive! – sensitive to first-line agents again (phew)  Admits that adherence had been poor after month 2 (why?)  Re-treated and cured (eventually)

59. Late PR – Case 3  31yo Bengali with right SCF nodes  FNA shows granulomas and MTB sensitive to first-line agents  Starts anti-TB treatment and mild swelling at week 4 (aspiration)  Finishes treatment and re-presents 4 months later with swelling again at original site  Very worried that has cancer as this is what happened to his uncle  What are the options?  Repeat FNA for cytology and culture  Discuss adherence  Reassure – review original results  Observe? Steroids? Re-start anti-TB drugs - which? Resection?

60. Late PR – Case 3  Re-started on same 4 drug therapy  Further swelling at week 5 treated with steroids  Repeat cultures negative  Node keeps swelling on treatment and after treatment  Repeat FNAs culture negative and granulomas seen  What are the options?  Repeat FNA  Discuss adherence  Reassure?  Observe? Continue treatment? Steroids? New anti-TB drugs? Resection

61. Late PR – Case 3  Re-started on same 4 drug therapy  Further swelling at week 5 treated with steroids  Repeat cultures negative  Node keeps swelling on treatment and after treatment  Repeat FNAs culture negative and granulomas seen  What are the options?  Resected – granulomas and necrosis but culture negative

62. Late PR – Case 4  24yo GP receptionist presents fevers, weight loss and miliary change  Diagnosed TB and starts therapy including steroids  Week 6 presents following a seizure (now off steroids)  Increased size of tuberculomas  Re-starts steroids with seizures +/- mood change when dose reduced  Completes 12 months of anti-TB treatment (supervised by father)

63. Late PR – Case 4  Off anti-TB treatment re-presents with seizures and psychosis  Tuberculomata swollen again especially in temporal lobe  Refuses brain biopsy and re-starts anti-TB therapy including moxifloxacin (DOT)  Only controlled by high dose of steroids and does not like side-effects  Symptomatic of PR whenever steroids reduced  What are the options?

64. Late PR – Case 4  What are the options?  Discuss adherence  Extend length of treatment?  Change treatment? – injectable? Prothionamide?  Steroid-sparing agents? Azathioprine, thalidomide, cyclophosphamide, MMF  Montelukast – some evidence in HIV IRIS

65. Late PR – Case 4  What are the options?  Extend length of treatment?  Change treatment? – injectable? Prothionamide?  Steroid-sparing agents? Azathioprine, thalidomide, cyclophosphamide, MMF  Montelukast – some evidence in HIV IRIS  Resection – successful in this case in relieving temporal lobe symptoms  Infliximab - Blackmore et al CID 2008 reported successful use in severe case of severe CNS and lymph node PR not responding well to steroids and cyclophosphamide

67. Conclusions  PR is a common event during anti-TB treatment  Pathogenesis involves both pathogen and host immune factors with recent data suggesting importance of innate immunity  All PR may share a common signal amplified (revealed) by reversal of immune-suppression  Although timing of ART is better defined PR/IRIS remains a frequent event with significant morbidity and resource implications  If observation not appropriate then low dose steroids are usually effective  Management of late events remains problematic  PR still has lots of questions to be answered!