Transcript GUIDELINES TO THE MANAGEMENT OF HYPERLACTATAEMIA …

SMEAR NEGATIVE
TUBERCULOSIS
FAIEZA SAHID
DEPT. OF INFECTIOUS DISEASES
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BACKGROUND
STATISTICS
DEFINITIONS
WHO GUIDELINES
MODALITIES TO DIAGNOSE SMEAR
NEGATIVE TB
BACKGROUND
• In South Africa tuberculosis (TB) has reached crisis
proportions, being responsible for more than 80% of notifiable
diseases.
• KwaZulu-Natal is considered the epicentre of HIV associated
TB, where two thirds of all patients with TB are co-infected with
HIV.
• HIV/AIDS modifies the clinical and radiological presentation as
well as the diagnostic utility of sputum smears resulting in an
increase in smear negative pulmonary TB.
• Of importance, it has been demonstrated that smear negative
TB remains a public health risk with a transmission rate of 22 to
47% relative to smear positive cases.
Anastasis D et al 1997; Behr MA et al 1999
BACKGROUND
• Disproportionate increase in rates of smear negative
pulmonary and extrapulmonary tuberculosis in HIV
prevalent resource limited settings results in:
– Cultures frequently not available
– Delayed diagnosis
– May contribute to mortality
• Higher mortality in HIV infected, especially smear
negative patients.
• In the absence of rapid, simple, and accurate
diagnostic tools for smear-negative pulmonary and
extrapulmonary tuberculosis, diagnostic algorithms
have been recommended.
WHO GLOBAL TB REPORT
2008
• South Africa → highest TB incidence in the world
– 5 times the average incidence rate found in the 22
high-burden countries.
– 4th highest estimated total burden of TB for 2006,
behind only India, China and Indonesia, countries
with much larger populations.
• In 2006, South Africa with only 0.7% of the world’s
population had an estimated 28% of HIV-positive adult
TB cases reported globally.
STATISTICS (2006)
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Estimated 9.2 million new TB cases in 2006.
1.7 million deaths
200,000 in clients co-infected with HIV.
Incidence highest in the African region at 363
cases per 100,000 population compared to a
global figure of 139 per 100,000 population.
• Incidence in South Africa 940 per 100,000
population.
Table 1.1: TB Case Finding 2006
All TB
Cases
PTB
Cases
New
Smear
Positive
PTB
Cases
EASTERN
CAPE
48,512
41,558
19,527
8,473
3,615
9,943
2,805
6,954
687
589
FRRE STATE
23,374
19,058
9,553
2,840
2,479
4,186
2,295
4,316
789
643
GAUTENG
46,093
34,290
20,609
4,188
2,915
6,578
4,155
11,803
501
372
KZN
104,705
88,271
32,855
9,527
20,547
25,342
8,593
16,434
1076
907
LIMPOPO
17,301
14,118
7,574
1,323
1,305
3,916
1,069
3,183
305
249
MPUMALANGA
15,035
13,496
7,216
1,081
859
4,340
7,55
1,539
463
416
NORTH WEST
28,421
24,519
12,539
2,954
1,764
7,262
2,156
3,902
738
637
NORTHERN
CAPE
8,631
7,951
3,583
1,482
901
1,986
1,018
680
950
875
WESTERN
CAPE
49,093
43,296
17,644
8,563
8,366
8,723
6,955
5,797
1,033
911
SOUTH AFRICA
341,165
286,557
131,100
40,431
42,751
72,276
29,801
54,608
720
605
Retreatment
Smear
Positive PTB
Cases
Smear
Negative
PTB
Cases
No
Smear
PTB
Cases
Children
0-7
years
EPTB
Cases
Incidence
Incidence
All TB
PTB cases
cases per
per 100,000
100,000
REVISED CASE DEFINITIONS
(HIV ONLY)
• Smear-positive pulmonary tuberculosis only requires
one positive smear result.
• Smear-negative pulmonary TB:
– At least two sputum exams negative for AFB and
– X-ray consistent with active TB and
– Decision by clinician to treat with full course for TB
OR
– AFB smear-negative sputum with cultures that are
positive.
EXTRAPULMONARY
TUBERCULOSIS (EPTB)
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CRITERIA:
One specimen from an extrapulmonary site culturepositive
OR
Histological or strong clinical evidence consistent with
active extrapulmonary tuberculosis and
Decision by clinician to treat with full course for TB
and
Laboratory confirmation of HIV infection or
Strong clinical evidence of HIV infection
EPTB – CLINICAL FEATURES
EPTB
• Maintain high clinical vigilance for EPTB.
• Assess clinical response to TB treatment after one
month and seek alternative diagnosis if no
improvement.
EPTB
• HIV testing offered to all patients suspected of EPTB..
• This is because HIV-related EPTB is an indication for early
commencement of antiretroviral treatment (clinical stage 4 of
HIV disease).
• For HIV-related EPTB, the following interventions should be
carried out:
– refer for HIV care or start antiretroviral treatment according
to national guidelines.
– start co-trimoxazole preventive therapy.
– remain vigilant for clinical deterioration of EPTB after the
start of antiretroviral treatment (immune reconstitution
inflammatory syndrome – IRIS) and take appropriate
measures.
LATENT VS ACTIVE TB
Maintained =
TB remains dormant
or latent
Cleared =
No infection
TB exposure
Adequacy of
Innate
defences
Not cleared =
Primary Infection
Contained = Latent
Infection (LTBI)
Development of
Acquired
defences
Not contained =
Progressive Primary
Disease
Maintenance of
Acquired Defences
Not maintained =
Late reactivation or
Post primary TB
TESTS FOR LATENT TB
• TST
– Standardised screening test for detecting LTBI in
high risk groups
– A negative skin test never excludes TB
• Interferon gamma release assays
– Quantiferon (based on PPD)
– Quantiferon Gold (based on ESAT 6 and CFP 10)
CULTURE
SMEAR
DIAGNOSIS
OF SNTB
CLINICAL
FEATURES
MOLECULAR
TECHNIQUES
CLINICAL FEATURES
• Clinical features not sensitive or specific to distinguish TB from
non-TB.
• Studies aimed to identify frequently occurring clinical features in
smear negative TB in areas with high prevalence of HIV and
TB:
– Hospital based study in Ethiopia, loss of appetite, weight
loss, fever, night sweats, chest pain, haemoptysis and
breathlessness were more common in patients with PTB
(smear pos and smear neg) than in those without PTB. Pts
with smear negative TB had night sweats for a longer period
of time. Smear pos pts were more likely to have fever and
weight loss than the smear negative group.
CLINICAL FEATURES
• Tanzania and Burundi identified 4 clinical criteria for diagnosis
of SNTB
– presence of cough for longer than 21 days (odds ratio
5·43[1·95–15·1]);
– presence of chest pain for longer than 15 days (1·98 [0·77–
5·12]);
– absence of expectoration (odds ratio for expectoration 0·42
[0·15–1·18]);
– absence of shortness of breath (odds ratio for
breathlessness 0·26 [0·01–0·66]).
• Diagnosis of smear negative tuberculosis by any two of these
criteria had a sensitivity of 85% but a low specificity of 67%
(positive predictive value 43%, negative predictive value 94%).
SMEAR
• Despite its limitations, smear microscopy remains the primary
diagnostic tool because it is inexpensive, specific in endemic
regions and identifies patients that pose the greatest public
health risk.
• Processing methods:
– NALC method – improves sensitivity by 66 to 83% compared
to direct microscopy.
– Bleach method – favoured in resource limited settings
because bleach kills mycobacteria, eliminating the need for
biosafety cabinets. It was shown that bleach and
centrifugation increased sensitivity by 18%.
Perkins M 2000, Best et al 1990, Steingart K 2006
CULTURE
• Most sensitive of currently available tests (sensitivity
of 98% have been reported), and also permits
identification and drug sensitivity tests to be made.
• Specificity is higher → each live bacillus forms
colonies on culture.
• Requires up to 6–8 weeks for the isolation of M. TB
from a clinical specimen and in 10–20% of cases the
bacillus is not successfully cultured.
• Estimated that 10% of smear-negative patients are
also culture negative.
• Not all patients with clinical TB will have positive
cultures.
CULTURE
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Solid medium :
 Lowenstein Jensen Medium – egg based.
 Middle Brook 7H10/7H11 – agar based.
 Simple and cost effective to use.
 Slow bacterial growth therefore detection of bacilli occurs within 3 – 4
weeks.
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Liquid medium :
 Semi – automated Radiometric System BACTEC 460 – uses radiation
technology.
 Automated Non-Radiometric Systems (MGIT) – uses fluorometric
technology
 Detection of bacilli occurs within 7 – 14 days.
NB!! Liquid medium is used in conjunction with solid medium as back up.
The detection of bacilli occurs within 7 to 14 days in liquid medium.
The major limitation to the use of these methods is the high cost
involved.
MOLECULAR TECHNIQUES
• The NAAT tests provide a reliable way of increasing the specificity of
diagnosis (ruling in disease) but sensitivity is too poor to rule out disease,
especially in smear-negative (paucibacillary) disease where clinical
diagnosis is equivocal and where the clinical need is greatest.
• Nucleic acid amplification tests:
– Gen -Probe Amplified M.TB direct test (sensitivity of 70.2% and
specificity of 94.6% in smear negative patients)
– Roche Amplicor M.TB test (sensitivity of 57.5% and specificity of 95.5%)
– HAIN’s PCR
• Mycobacteriophage based method
– Alternative to PCR
– Detect only viable mycobacteria and can yield antibiotic sensitivities
within 2-3 days
– Not clear whether these tests have sufficiently high sensitivity in smear
negative samples to recommend their routine use in practice
Dinnes et al 2007
CONCLUSIONS
• New diagnostic techniques are required in addition to AFB
microscopy for the identification of smear-negative tuberculosis.
• These need to be appropriate for use in low income countries.
• However, until such tests are widely available, algorithms must
be developed and validated to assist clinicians working in
resource-poor settings.