Paradoxical Reaction in TB

1
Paradoxical Reaction in TB

• Done by Mazen Badawi
• Supervised by Prof. Tariq Madani

2
Case

• 18 yr old Saudi female presented with
  intermittent right flank swelling for 1 month.
  This swelling is progressively increasing in size
  and it would appear on standing and disappear
  when lying down.

3
Case

• There were no associated abdominal pain or
  gastrointestinal or urinary symptoms. Patient
  denied any history of fever, weight loss or
  backache.

4
Case

• She was diagnosed 5 months earlier with
  multifocal skeletal TB in hyoid, right mastoid
  and right occipital bones as well as the first 2
  cervical vertebrae.

5
Case

• She presented at that time with fever, weight
  loss, hearing loss, purulent discharge from her
  right ear and swelling over the right side of the
  neck overlying the hyoid bone

6
Case

• Investigations
• A biopsy from the hyoid bone revealed caseating
  granuloma . No AFB or MTB- PCR done
• CT of the head showed lytic lesions in the
  mentioned bones

7
Case

• Patient was started on 4 anti TB medications for
  2 months and to continue on 2 medication for 4
  months
• Compliance was assured with regular follow ups
• Patient had good improvement in symptoms in 4
  months and then started to have right flank
  swelling

8
Case

• On examination the patient was afebrile, looked
  healthy. Abdominal examination showed non tender
  and soft fluctuant mass in the right flank which
  is prominent in standing position with no
  overlying skin changes. Examination of the spine
  was normal, and the rest of the physical
  examination was unremarkable.

9
Case

• Investigations
• CBC, ESR, LFT, renal functions were within normal
• CXR was within normal
• PPD gt10 mm induration
• CT Abdomen showed bilateral psoas abscess, the
  right one is bigger and extending to the abdomen
  and pelvis

10
Case

• CT- guided aspiration of the right psoas abscess
  was done. Gram stain was negative. AFB stain and
  MTB-PCR was positive.
• Pyrazinamide, ethambutol,moxifloxacin and
  amikacin was added for possible resistance

11
(No Transcript)
12

• DD

13

• DD
• Non tuberculous infection
• Bacterial superinfection
• New lesions of resistant TB
• Progression of pre-existing and clinically silent
  psoas abscess due to drug resistance,
  incompliance or malabsorption
• Drug fever , drug reaction, reduced drug levels
  due to drug- drug interaction
• Different disease etiology, eg lymphoma
• Paradoxical reaction to anti TB drugs

14
DD

• Paradoxical reaction Worsening of tuberculosis
  during appropriate anti TB therapy
• Treatment failure
• Mycobacterial cultures ve after 3 months or
• AFB stain ve after 5 months of appropriate
  treatment

15
In this case

• All bacterial, fungal and mycobacterial cultures
  turned out to be negative!!

16

• So, the additional drugs were discontinued , and
  the diagnosis of psoas abscess related to
  paradoxical reaction with anti TB was made
• Patient continued on 2 drugs to complete total of
  9 months. She was improving.

17
Definition

• Paradoxical reaction (PR) or immune
  reconstitution inflammatory syndrome (IRIS, in
  HIV-coinfected pt.) is defined as clinical, or
  radiological, or both, deterioration of
  preexisting tuberculous lesions, or the
  appearance of new lesions during the course of
  appropriate anti TB therapy in a patient who
  initially improves.

18
History It is not new!

• The first paradoxical drug reactions based on a
  possible immune response were reported by Robert
  Koch in 1890 when he attempted to treat
  tuberculous patients with injections of large
  amounts of killed tubercle bacilli (old
  tuberculin). This resulted in high fevers,
  ulcerating lesions, and increased morbidity and
  mortality.

19
You Need To Know

• Incidence 6-30 of patients receiving anti TB
  drugs
• Previously believed to be only in patients who
  are co- infected with HIV
• In HIV infected patients its found to be more
  with those receiving HAART , it can reach 30
• Might cause larger reaction to PPD skin test

20
You Need To Know

• Usually it is mild, transient and self-limited,
  might start anytime within anti TB course few
  days to many months and usually last 10-40 days,
  some studies suggest diagnosis to be made only
  after 30 days of initiation of treatment.
• In HIVTB PR may show from 10-180 days with mean
  of 60 days since HAART
• Patients tend to gain weight. Some studies showed
  weight loss.
• Usually complicates treatment TB lymphadenitis,
  cerebral dissimenated TB

21
You Need To Know

• Care should be taken in miliary PTB, expanding
  tuberculomas in brain, enalrging mediastinal LN,
  severe sepsis, uncontrolled high fever.
• In HIV paradoxical response can be seen
  following Rx of lepromatous leprosy, or following
  corticosteriod withdrawal, recovery of cytopenia
  after chemo, withdrawal immunosupp. In transplant
  recepient infected with Crypt. N. and engrafment
  of Stem C. T.
• In HIV there could be other co-infections that
  show paradoxical reaction MAC, Cryptococosis,
  CMV, Pneum. Jiroviichi, Herpes Z., HCV, HBV

22
You Need To Know

• Risk Factors ( HIV )
• Some studies relates timing of HAART initiation
  with concomitant treatment of opportunistic
  infections
• Other studies, concerned about CD 4 count lt100
  cells/microL at time of initiation, and use of
  powerful protease inhibitors and HIV RNA decline
  of more than 2.5 logs. In pre-existing TB it
  might happen with CD4lt200
• HIV - patients receiving infliximab (eg for
  IBD)

23
Pathogenesis

1. Enhanced inflammatory response as a result of
   increased MTB antigen exposure from rapidly dying
   MTB to sensitized lymphocytes following anti TB
   therapy and immune reconstitution (esp. HIV
   patients on HAART) which lead to increase in IL-5
   TNF-a
2. strengthening of the hosts delayed
   hypersensitivity response
3. decrease in suppressor mechanisms and apoptosis
   of lymphocyte

24
Pathogenesis

• In HIV , the half life of HIV is 1-4 days.
  HAART may give 90 reduction in viral load within
  1-2 weeks. This decline persists 8-12 wk then
  stabilizes. The increase in immune cells occurs
  in inverse proportion to the fall.

25
Clinical Manifestations

• Depends on HIV status, and site of infection
• ¾ of HIV TB will have fever
• PTB fever, malaise, ? wt loss, worsening resp.
  symptoms, trans. Worsening CXR new opacities,
  LN enlargment, ARDS
• Extra PTB lymphadenitis, Pl. effusion,
  tuberculoma expansion
• In some HIV there are reported cases of
  cutaneous lesions, peritonitis, epydidimitis,
  bowel perforation or granulomatous nephritis.

26
Diagnostic tests

• it is a diagnosis of exclusion!
• ve AFB stain , MTB PCR are NOT diagnostic (may
  be due to dead bacilli)
• PPD and caseating granulomatous inflammation on
  biopsy are NOT diagnostic as they may reflect
  enhanced inflammatory reaction to the antigen
  from dying bacilli and not active infection
• May cause increase in CRP
• Hawkey(3) associates high baseline monocyte count
  with increased PR incidence

27
Treatment

• no optimal treatment!
• Mild to moderate symptomatic treatment
• Severe Life threatening ? short course of
  steriods and monitoring the patient, suggested to
  be taken orally for 6 wk, however no controlled
  trial was done
• Surgical intervention?
• Anti TB Anti retroviral should not be stopped
  (HAART may be stopped only if life threatened)

28
Study Paradoxical reactions during tuberculosis
treatment in patients with and without HIV
co-infection
29
Background

• It has been suggested that deterioration of TB
  during appropriate treatment, termed a
  paradoxical reaction PR, is more common and
  severe in HIV positive individuals on HAART. A
  group of TB patients who are HIV ve were the
  cases and another group of TB patients who are
  HIV ve were the control in a retrospective study.

30
Method

• A study was undertaken to determine the frequency
  of PR and its associated features in a population
  of HIVTB patients and a similar sized group of
  HIV-TB individuals

31
Methods

• Patients diagnosed with TB between February 1997
  and February 2002 were identified from the Royal
  Free Hospital TB database which records all
  patients diagnosed with TB in our urban teaching
  hospital. Treatment was initiated either as an
  inpatient or an outpatient depending on symptom
  severity.
• All patients in the clinic received
  self-administered treatment. Clinical information
  was validated against patient case notes.
• Diagnoses were accepted if the patient had
• a positive culture for Mycobacterium
  tuberculosis
• had been culture negative but AFB smear and/or
  nucleicacid amplification assay positive (TB
  Strand Displacement Amplification assay,
  Becton-Dickinson, NJ, USA) with
  clinicoradiological features and response to
  treatment consistent with TB
• histological findings consistent with TB and
  response to treatment consistent with TB.
• Patients were excluded if they were followed up
  for less than 6 months or never started TB
  treatment.

32
METHODS

• The comparator population was selected by
  identifying consecutive TB patients who satisfied
  the definition of diagnosis, did not meet the
  exclusion criteria, and had a documented negative
  HIV antibody test.
• PR was defined as a worsening of clinical or
  radiological findings following the initiation of
  appropriate antituberculous treatment in the
  absence of evidence of disease relapse or the
  presence of another diagnosis.
• Dissemination was defined as clinically or
  radiologically apparent disease at more than one
  site, with or without laboratory confirmation.
• Dual antiretroviral therapy was defined as the
  use of two nucleoside reverse-transcriptase
  inhibitors (NRTIs). HAART involved the use of two
  NRTIs with either a protease inhibitor (PI) or a
  non-nucleoside reverse-transcriptase inhibitor
  (NNRTI).
• Statistical analysis was performed using
  Fishers exact test, x2 test, Mann-Whitney U
  test, and Kaplan-Meier methods.

33
Results
34
(No Transcript)
35
9 didnt receive HAART 28 received HAART after TB
Dx
2 pt. developed PR before anti TB
Reason is severe or prolonged symptoms
36

• ESR, CRP, LDH , Hb, Albumin measured in all
  patients HIVTB before and after PR developed.
  No significant change between those who developed
  PR and those who didnt.

37
(No Transcript)
38
Analysis of data of the 28 HIVTB patients who
received HAART only after TB dx

• 8 of the 28 patients (29) had PR.
• Their median CD4 count at TB diagnosis was 58
  cells/ml (range 30143) and the viral load was
  5.5 log copies/ml (range 5.25.9).
• No association was found between PR and baseline
  CD4 count or CD4 response on HAART in this study
• In this group PR was significantly associated
  with starting HAART within 6 weeks of TB
  diagnosis (p0.03).
• PR was more common in those with disseminated
  disease (6/13 with dissemination v 2/15 without
  dissemination p0.09) and viral load suppression
  to ,400 copies/ml within 6 months (p0.3).
  However, none of these reached statistical
  significance.

39
DISCUSSION

• Our results, based on a population of patients
  with a range of clinical disease, suggest that PR
  during treatment for TB is common in both HIV
  infected and uninfected individuals.The observed
  frequency of 28 in our HIV positive patients is
  lower than some groups have reported since the
  introduction of HAART, while our rate of 10 in
  HIV negative patients is higher than the rate of
  2 reported by Narita et al in their HIVnegative
  comparison group.5 We believe these
  differencesmay be due to patient selection. We
  have investigated a typical mixed inpatient and
  outpatient study population with a range of TB
  presentations. All patients received daily
  selfadministered treatment and, although not
  formally assessed in this study, adherence to
  treatment in our cohort is generally excellent.
• The main differences between our HIV positive and
  HIV negative groups were with respect to
  ethnicity and the presence of disseminated TB.
  The former reflects the demographic
  characteristics in our practice as a whole. We
  observed PR in all ethnic groups with no
  difference in frequency according to race,
  although the sample size for this analysis was
  small. However, there have been no reports of
  ethnic differences in the occurrence of PR and we
  do not believe that ethnicity explains the
  increased frequency in the HIV positive group.

40

• We and others have shown a strong association
  between the use of HAART and PR.10 The underlying
  mechanism for this is unclear. Our data suggest
  that PR is independent of both baseline CD4 count
  and HAART mediated recovery of CD4 cells as
  measured in peripheral blood. However, these may
  not accurately reflect local immune responses in,
  for example, the lung which are probably more
  relevant.11 This might explain the reported slow
  recovery of M tuberculosis specific T cell
  responses in blood from patients starting
  HAART.12 13 There is a suggestion that a rapid
  reduction in HIV plasma viral load may be
  associated with PR, as found by Navas et al.10
• In practice, the association between early
  initiation of HAART and PR creates a dilemma for
  the clinician treating TB/HIV co-infection.
  Against this must be balanced the risk of further
  opportunistic infections if HAART is delayed. A
  large study of co-infected patients showed that
  four of 188 had a further AIDS defining illness
  (ADI) within the first 2 months of TB
  treatment.14 Those at particular risk of further

41

• Although our study could not investigate the
  reasons which lead physicians to decide when to
  prescribe HAART after TB treatment and hence we
  cannot rule out confounding factors, our data
  suggest that delaying HAART to avoid PR may be
  advisable in the presence of disseminated TB but
  not necessary in those with low CD4 counts alone.
  A flaw in this strategy may be the difficulty in
  accurately assessing the TB burden in
  manypatients with advanced immunosuppression.
• In HIV negative patients admitted for treatment
  of TB, restoration of skin test responses to PPD
  after 2 weeks of antituberculosis treatment have
  been reported.15 This has been ascribed to
  reversal of immunosuppression due to TB itself.
  However, improved nutritional status and alcohol
  cessation, which might be most marked in those
  admitted for treatment, have been shown to affect
  cell mediated immunity 16 and thus may also play
  an important part.

42

• Disseminated TBwhich is seen more frequently in
  HIV infected TB patients17was associated with
  PR, although this did not reach statistical
  significance. This may not only reflect the
  importance of immune status, as discussed above,
  but also suggests that overall mycobacterial load
  can influence the development of PR. Campbell and
  Dyson3 proposed that rapid killing of bacilli by
  effective antituberculous treatment can cause the
  release of large amounts of tuberculoprotein and
  other cell wall products. The ability of such
  materials to elicit a severe and potentially
  fatal inflammatory response was described first
  by Koch himself.18 It is logical to assume that
  the overall inflammatory response to M
  tuberculosis reflects both the number and
  function of appropriate immune cells and the
  amount of antigen that they encounter.
• The severity and frequency of PR would therefore
  be expected to increase if disseminated or
  extensive single organ disease was present. We
  have shown that PR is a common phenomenon during
  TB treatment in a combined inpatient and
  outpatient population, regardless of HIV antibody
  status. However, it is seen more frequently in
  co-infected patients receiving HAART. The reasons
  for this remain unclear, although the timing of
  HAART initiation in relation to TB diagnosis
  appears to be important, as does the presence of
  disseminated disease. Our study is limited by its
  retrospective nature and relatively small size.
  Results that do not achieve statistical
  significance at the 5 level may become
  significant with a larger sample. We believe that
  this warrants further prospective,clinical, and
  laboratory investigation

43
Summary

• PR is a serious, easily missed phenomenon
• Diagnosed by exclusion
• Higher association with HIV
• Suggestion of starting HAART after approx.1- 2
  months of OI treatment (TB, HBV)if AIDS is
  severe give 2 week gap
• Dont stop Anti TB
• Dont stop Anti retrovirals unless life was
  threatened
• Steriods may help in individual cases
• Larger sample studies are needed especially
  regarding management

44

• Questions?

45
REFERECES

• 1- Fayez H,Imad M, TB paradoxical reaction,
  clinical note. Saudi J M 2007
• 2- Narita M, Ashkin D, Hollender ES, et al.
  Paradoxical worsening of tuberculosis following
  anti-retroviral therapy in patients with AIDS. Am
  J Respir Crit Care Med 1998158157 61.
• 3-Hawkey C, Yap T, Pereira J, et al.
  Characterization and management of paradoxical
  upgrading reactions in HIV-uninfected patients
  with lymph node tuberculosis. Clin Infect Dis
  2005 40136871.

46

• Thank you!