Key Issues in TB and HIV Co-Infection in the setting of HIV

1
Key Issues in TB and HIV Co-Infection in the
setting of HIV infection

• Dr. Daniel Park
• University of California, San Diego
• ITECH

2
Clinical Presentation of TB in HIV Infection
South African National Tuberculosis Control
Programme Practical Guidelines 2004
3
Extra pulmonary TB

• 50-70 of TB cases in HIV infected patients are
  extra-pulmonary
• Common presentations of extra-pulmonary TB
• Meningitis
• Lymphadenitis
• Miliary
• Pleural effusion
• Empyema
• Pericardial Effusion
• Peritoneal
• Skeletal

4

• Post-primary Pattern
• Consolidation in the upper lobes /- cavitation.
  No adenopathy. Bronchogenic spread included.
• Primary Pattern
• Air space consolidation in the middle or lower
  lobes. Interstitial changes, including miliary
  pattern also considered to be primary.
  Adenopathy and pleural effusion may be present

5
Radiological Patterns in HIV

• Retrospective study of 209 HIV patients
  diagnosed with Cx pulmonary TB
• 01/1987 12/2001
• CT Scan performed in 42 patients
• Patients on HAART 33/209 (16)
• CD4 350
• Patients not on HAART 176/209 (84)
• CD4 64

6

• CXR CD4 lt 200 CD4 gt 200
• (158) (51)
• Consolidation 90(57) 44 (86)
• Upper lobes
• Cavity 31(20) 28 (55)
• Pleural effusion 12(7) 7 (14)
• Adenopathy 18 (11) 3 (6)
• Miliary 88 (57) 4 (8)

7
From Emedicine
8
(No Transcript)
9
Performance Characteristics of Diagnostic Tests
for TB Chest Radiography

• 4 (10/250) asymptomatic HIV infected patients
  with normal chest xrays and negative sputum
  smears were culture for TB1
• Prior to preventive therapy
• Yield very low unless symptomatic2,3
• But has not been evaluated in setting immediately
  prior to HAART initiation

10

• Summary
• CXR findings correlate with degree of immune
  suppression. CXR may appear atypical at higher
  degrees of immunosuppression.
• Primary TB infection is more common in advanced
  HIV patients.
• Extrapulmonary TB disease is more common in HIV
  patients.

11
Diagnosis

• TB is harder to diagnose in patients with HIV
  infection
• Increased prevalence of extrapulmonary TB
• Shed less tubercle bacilli, so less positive AFB
  sputum smears
• Do symptom screen.

12
Symptom Screen

• Cough gt 3 weeks
• Fever
• Night sweats
• Fatigue
• Weakness

• Weight loss
• Poor appetite
• Chest wall pain
• Coughing up blood

13
South African National Guidelines for Diagnosis
of Tuberculosis

• Sputum collection
• 2 expectorated for microscopy
• 1 expectorated for CS (re-treatment cases only)
• Indications for culture
• Hx previous unsuccessful TB Rx
• Drug susceptibility necessary
• Smear at 2 or 6 months
• 2 smears negative, no response to antibiotics,
  clinical suspicion TB

• Indications for CXR
• When sputum AFB
• Suspected complications
• Haemoptysis
• Diagnose other lung diseases
• Only 1 of 2 sputum AFB smears
• When sputum AFB
• During end of Rx
• If response not satisfactory

South African National Tuberculosis Control
Programme Practical Guidelines 2004
14
South African National Tuberculosis Control
Programme Practical Guidelines 2004
15
Source WHO
16
WHO TB Diagnosis Algorithm
Source WHO
17
Acid fast bacilli with ZN stain
18
Sputum Microscopy
19
Sputum AFB Smear

• Several quantitative studies have shown that
  there must be 5,000 to 10,000 bacilli per
  milliliter of specimen to allow the detection of
  bacteria in stained smears.
• In contrast, 10 to 100 organisms are needed for a
  positive culture.
• Concentration procedures in which a liquefied
  specimen is centrifuged and the sediment is used
  for staining increases the sensitivity of the
  test thus, smears of concentrated material are
  preferred.

20
Performance Characteristics of Diagnostic Tests
for TB

• Sensitivity of expectorated sputum1 for PTB
• 55 (1 sputum)
• 70 ( 2 sputa)
• 70 (3 sputa)
• Auramine staining increases yield by 182

21
Performance Characteristics of Diagnostic Tests
for TB

• Sputum induction in patients with negative smears
  or unable to expectorate has positive yield
  varying from 13.23 294
• Sputum concentration by centrifugation and NaOCl
  liquefaction increases sensitivity from 54.2 -
  67.5 to (conventional direct microscopy) to
  63.15 -87.16

22
Are sputum smears graded as scanty false-positive?

• Abuja, Nigeria, sputum smears from 1068 patients
• One specimen was cultured.
• 824 (26) smears were positive, 137 (4) scanty
  and 2243 negative.
• One hundred and thirty (95) scanty and 809 (98)
  positive smears were culture-positive.
• lt5 scanty results, lt1 of the patients treated
  for TB, are false-positive.

Lawson et al. Int J Tuberc Lung Dis 20059933-935
23
Smear Negative TB

• Disproportionate increase in rates of
  smear-negative pulmonary and extrapulmonary
  tuberculosis in HIV-prevalent and
  resource-constrained settings
• Higher mortality in HIV-infected, especially
  smear negative
• Over twice the risk of death in Malawi study with
  7 years of follow-up data (Kangombe CT, et al.
  Int J Tuberc Lung Dis 20048829-36.)
• Smear negative status leads to delayed diagnosis
  and may contribute mortality.
• Cultures frequently not available

• Getahun H, et al. The Lancet 3692042 - 2049

24
Smear Negative TB

• Infectivity of smear-negative tuberculosis
• 22 relative transmission rate compared to smear
  positive Siddiqi K, et al. Lancet Infect Dis
  20033288-296.

25
Smear Negative PTB
Colebunders et al. Int J Tuberc Lung Dise
2000497-107
26
South African National Tuberculosis Control
Programme Practical Guidelines 2004
27
Antibiotics Trial

• Primary role should not be as a diagnostic aid
• Treat concomitant bacterial infection
• Common both with and without tuberculosis
• Non-response increases the likelihood of TB but a
  response to antibiotics should not exclude TB
• Antibiotic choice should cover typical causes of
  community acquired pneumonia but should NOT
  INCLUDE FLUOROQUINOLONE

28
Antibiotics trial

• Validation of antibiotic algorithm
• Patients TB suspects
• respiratory symptomsgt3 weeks, abnormal CXR
  consistent with TB
• OR
• acute pneumonia and failed outpatient
  antibiotics
• Patients with Negative AFB smears treated with
  amoxicillin x 5 days and erythromycin x 5 days if
  not improved.
• 120 patients evaluated

Wilkinson D, et al. 2007. Int J tuberc Lung
Dis4513-518
29
Antibiotics trial

• Non-response increases the likelihood of TB
• PPV 73
• Response to antibiotics should not exclude TB
• NPV 61
• Sensitivity 55, Specificity 77

30
Etiology of pneumonia

• Prospective study to evaluate etiology of AFB
  sputum smear negative pneumonia in HIV-infected
  patients
• BAL in 71 and 75 in Senegal and CAR

31
Cases from the Field

• A man dies of unrecognized pulmonary KS while
  being repeatedly treated for tuberculosis
• A child dies of an undiagnosed abdominal
  malignancy after being diagnosed with
  extrapulmonary TB on the basis of abdominal
  ultrasound and treated for gt 12 months for TB
  with no improvement
• A women is diagnosed with extrapulmonary TB based
  on abnormal liver chemistries with normal chest
  xray, no cough, no fever, no lymphadenopathy? she
  actually had lactic acidosis from stavudine
  therapy

32
Isoniazid Preventive Therapy
South African National Tuberculosis Control
Programme Practical Guidelines 2004
33
Isoniazid Preventive Therapy
South African National Tuberculosis Control
Programme Practical Guidelines 2004
34
South African National Tuberculosis Control
Programme Practical Guidelines 2004
35
Immune Reconstitution Inflammatory Syndrome (IRIS)

• Paradoxical reaction temporary exacerbation of
  symptoms, signs, or radiographic manifestations
  of TB after beginning TB treatment, may include
• High fever
• Increase in size of lymph nodes
• New lymphadenopathy
• Worsened CNS lesions
• Worsened pulmonary infiltrates
• Increasing pleural effusions
• Occurs in HIV-uninfected patients, but more
  common in HIV-infected patients, especially those
  on ART

36
Type 1 IRIS
No HAART
Pre-Clinical OI
Clinical OI
HAART
Clinical
OI
Pre-Clinical
OI
HAART
37
Type 2 IRIS
No HAART
Clinical OI
Maintenance
Treatment
Phase
HAART
Clinical OI
HAART
Maintenance
IRIS
Treatment
Phase
38
Time of onset of IRIS

• IRIS associated with Mycobacterium tuberculosis
  occurs within 2 months of starting antiretroviral
  therapy, usually within the first 2-3 weeks
  (French et al, AIDS 2004, 1816151627)
• But a recent case series suggested a broader
  range on time of onset (Shelburne et al. AIDS
  2005, 19399406)

39
Shelburne et al. AIDS 200519399-406
40
French et al. AIDS 2004, 1816151627
41
Paradoxical Reaction
Worsening Radiograph
42
Buckingham et al. Clin Radiol 2004 59505-513
43

• May be difficult to distinguish IRIS from
  worsening of TB, treatment failure, new
  infection, adverse drug reaction, etc
• Evaluate thoroughly for other causes
• Can be prolonged and severe

44
Management of IRIS

• Management
• Mild-moderate reactions
• Symptomatic treatment, NSAIDs
• Continue TB therapy and ART
• Severe reactions (eg, high fever, airway
  compromise from enlarging lymph nodes, enlarging
  serosal fluid collections, sepsis syndrome)
• Not studied consider prednisone or
  methylprednisolone(1 mg/kg daily, with taper
  after 1-2 weeks)
• Continue TB therapy
• Continue ART if possible (unless IRIS is life
  threatening)

45
Summary

• TB and HIV coinfection is common and associated
  with higher mortality rates
• TB in the setting of HIV may often have atypical
  presentations, especially with lower CD4 counts
• Smear Negative TB is common and clinician should
  not be hesitant to make the diagnosis.
• IRIS is a common complication occurring after
  initiation of ARV treatment in pts undergoing
  treament for TB.

46

• Thanks to Dr. Mathews, Shimbakuro, Dr. Campbell
  who provided some of the slides used in this
  presentation.