Transcript Case

Paradoxical Reaction in TB
Done by : Mazen Badawi
Supervised by : Prof. Tariq Madani
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.
Case
 There were no associated abdominal
pain or gastrointestinal or urinary
symptoms. Patient denied any history of
fever, weight loss or backache.
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.
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
Case
 Investigations:
 A biopsy from the hyoid bone revealed
caseating granuloma . No AFB or MTBPCR done
 CT of the head showed lytic lesions in the
mentioned bones
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
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.
Case
 Investigations:
 CBC, ESR, LFT, renal functions were
within normal
 CXR was within normal
 PPD >10 mm induration
 CT Abdomen showed bilateral psoas
abscess, the right one is bigger and
extending to the abdomen and pelvis
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
DD
 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
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
In this case:
 All bacterial, fungal and mycobacterial
cultures turned out to be negative!!
 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.
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.
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.
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
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 HIV+TB+ 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
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
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 <100
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 CD4<200
 HIV - : patients receiving infliximab (eg for
IBD)
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 host’s delayed
hypersensitivity response
3. decrease in suppressor mechanisms and
apoptosis of lymphocyte
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.
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.
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
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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)
Study: Paradoxical reactions during
tuberculosis treatment in patients with
and without HIV co-infection
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.
Method
 A study was undertaken to determine
the frequency of PR and its associated
features in a population of HIV+TB+
patients and a similar sized group of
HIV-TB+ individuals
Methods
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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:
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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.
METHODS
 The comparator population was selected by identifying consecutive TB
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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 Fisher’s exact test, x2 test,
Mann-Whitney U test, and Kaplan-Meier methods.
Results
Total pt
114
HIV + TB+
64
Excluded
14
HIV-TB+
50
HIV+ TB+
50
4 died
4 no mathcing criteria
3 no records
3 f/u outside
PR 5
PR 14
9 didn’t receive HAART
28 received HAART after TB Dx
2 pt. developed PR
before anti TB
Reason is
severe or
prolonged
symptoms
 ESR, CRP, LDH , Hb, Albumin
measured in all patients HIV+TB+
before and after PR developed. No
significant change between those who
developed PR and those who didn’t.
Analysis of data of the 28 HIV+TB+
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
30–143) and the viral load was 5.5 log copies/ml (range 5.2–
5.9).
 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 (p=0.03).
 PR was more common in those with disseminated disease (6/13
with dissemination v 2/15 without dissemination; p=0.09) and
viral load suppression to ,400 copies/ml within 6 months (p=0.3).
However, none of these reached statistical significance.
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.
 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
 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.
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Disseminated TB—which is seen more frequently in HIV infected TB patients17—was
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
Summary
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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
Don’t stop Anti TB
Don’t stop Anti retrovirals unless life was threatened
Steriods may help in individual cases
Larger sample studies are needed especially
regarding management
 Questions?
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 1998;158:157– 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; 40:1368–71.
Thank you!