Transcript Latent tuberculosis infection new Saudi guide lines

Dr Wafa Ababtain ,MD
Int medicine department,KFHU
January,31,2011
Outlines
•
•
•
•
•
•
•
•
•
•
•
•
Global and local epidemiological data
Latent TB infection
Why and how to identify LTBI
BCG and TST interpretation
Technique ,reading and interpretation of TST
Serial tuberculin testing
IGRA and Saudi recommendations
Indication for TST and who should be treated
Recommended regimen for LTBI
Special situations with LTBI
Cases study
conclusion
Global TB statistics
• one third of world's population or two billion
people carry the TB bacteria.
• more than 9 million become sick each year with
“active” TB which can be spread to others.
• about 2 million deaths/year due to TB, > 90%
deaths in low- and middle-income countries .
• 22 countries account for 80% of all new TB
cases,> 50% in 5 countries .India, China, South
Africa, Nigeria, and Indonesia.
• TB is leading cause of morbidity and mortality
among HIV-infected persons
the Kaiser Family Foundation’s The Global Tuberculosis Epidemic fact sheet June 2010
- 1.7 million people died from TB (including
380 000 women) in 2009, including 380 000
people with HIV, equal to 4700 deaths a day.
- The TB death rate has fallen by 35% since 1990
- There were 9.4 million new TB cases (including
3.3 million women) in 2009, including 1.1 million
cases among people with HIV
- Most cases were in the South-East Asia, African
and Western Pacific regions (35%, 30% and 20%,
respectively).
- An estimated 11–13% of incident cases were HIVpositive, the African Region accounted for
approximately 80% of these cases.
- Multidrug-resistant TB (MDR-TB) is a form of TB
that is difficult and expensive to treat and fails to
respond to standard first-line drugs
- There were an estimated 440 000 new MDR-TB
cases in 2008, and 150 000 deaths from MDR-TB
- In 2010, the largest WHO MDR-TB survey
reported
the highest rates ever of MDR-TB, with peaks of
up to 28% of new TB cases in some settings of the
former Soviet Union
- Extensively drug-resistant TB (XDR-TB) occurs
when resistance to second-line drugs develops
on top of MDR-TB
- XDR-TB cases have been confirmed in 58
countries
WHO
Tuberculosis profile in Saudi Arabia
Saudi ArabiaTuberculosis profile
Population 2009 (millions) 26
Country profile 2008-2009: SAUDI ARABIA
TB Unit of the WHO Regional Office for Eastern-Mediterranean Region
Saudi Arabia
Tuberculosis profile
Country profile 2008-2009: SAUDI ARABIA
TB Unit of the WHO Regional Office for Eastern-Mediterranean Region
Major challenges still exist:
• Deaths - 1.7 million died in 2009 from what is a curable
disease.
• Incidence - though falling, it is falling too slowly. Under
the current rate of decline, TB will not be eliminated in
our lifetime.
• MDR-TB response - the response is still insufficient and
more efforts are needed to scale up and strengthen
programmes, especially with 440 000 new cases
emerging each year, and that less than 5% of those
cases being properly treated.
Scanning electron micrograph of Mycobacterium tuberculosis bacilli.
Latent tuberculosis (LTB)
Definition
• mycobacterial infection, dormant state,
diagnosed by positive skin test (PPD)
• people with latent tuberculosis infection retain
viable M. tuberculosis bacilli within their lungs,
even though they are asymptomatic and not
infectious.
• When becomes immunosuppressed , the
dormant bacteria can reactivate within the
calcified tubercles and develop active TB disease.
GIT
Why to identify Latent Tuberculosis
• Identification and treatment of latent
tuberculosis infection can reduce the risk of
development of disease by as much as 90
percent
• to protect the health of the individuals as well
as the public by reducing the number of
potential sources of infection
Latent Tuberculosis
• most cases of tuberculosis in saudi arabia are
due to reactivation of latent infection
• targeted testing of individuals at high risk of
disease progression is a key component of
tuberculosis control
• many practitioners remain reluctant to use the
TST, and therefore, do not give therapy for
latent TB infection even to patients at high risk
of reactivation.
Diagnosis of LTBI
• active tuberculosis be excluded by medical
evaluation
• medical history and a physical examination to
check for suggestive symptoms and signs
• chest radiograph
• testing of sputum or other clinical samples for the
presence of M. tuberculosis.
• Neither an IGRA nor TST can distinguish LTBI
from active tuberculosis.
Saudi guidelines for testing and treatment of
latent tuberculosis infection
Ann Saudi Med. 2010 Jan–Feb; 30(1): 38–49
Al Jahdali, H. Baharoon, S. Abba, A. Menzies, D.
• the Saudi Thoracic Society (STS)
• the Saudi Society of Medical Microbiology and
Infectious Disease (SSMMID)
• Saudi Association of Public Health (SAPH)
• Society of Family and Community Medicine
provides the first national recommendation for targeted
tuberculin testing and treatment regimens for person
with latent tuberculosis infection in Saudi Arabia.
Prevalence of LTBI in Saudi Arabia
The prevalence of LTBI at 10 and 20 years is
3.4% and 6.7% respectively, placing Saudi
Arabia in the intermediate prevalence
(2%-14%) category
Making the diagnosis
methods of detection of latent TB
• PPD skin test
- induration ≥ 5 mm in immunocompromized or
exposed persons
-induration ≥ 10 mm in high risk persons
-induration ≥ 15 mm in persons with no risk factors
• interferon-gamma blood test
• chest x-ray
- may not be helpful as most latent TB is clinically
inapparent
BCG and TST interpretation
• BCG vaccination was started in 1964 in Saudi
Arabia and a 95.9% coverage rate was
achieved by 2007
• Al Kassimi et al in 1993 –
the first comprehensive and nationwide
tuberculin survey in Saudi Arabian general
population with urban/rural stratification.
33% of the subjects had a positive TST, and
56% were aged 45 years and older.
al-Kassimi FA,Tuber Lung Dis. 1993
BCG and TST interpretation
• A meta-analysis including more than 24 studies
found that only 1% of patients who received BCG
during infancy were TST positive if tested more
than ten years after BCG vaccination
• longer-lasting effect on TST if BCG was given later
in life
• Most of the international guidelines recommend
ignoring BCG's effect on the interpretation of TST
in persons at increased risk of developing active
TB.
Technique for the TST
• A standard tuberculin
syringe with a 27-gauge
needle is used to inject 5
tuberculin units of
purified protein derivative
(PPD) intradermally.
• The inner surface of the
forearm is used. . A small
wheal 5 mm in diameter
should be elicited at the
time of injection.
• If incorrect administration is suspected, a second
test dose can be given immediately at a site that
is at least 5 cm away from the first one.
• It should be administered as soon as feasible
after filling the syringe, ideally within 20 minutes.
• Long-term storage of prefilled syringes is not
recommended. Tuberculin material should be
kept refrigerated but not frozen, and most
importantly, kept protected from light
Reading the TST
• a delayed hypersensitivity
immune reaction.. Reading is
done between 48 and 72
hours.
• The transverse diameter of
the induration, but not
erythema, is demarcated
The induration is measured
and recorded in millimeters.
If there is no reaction, the
size should be recorded as 0
mm and not simply as
“negative”.
Causes of false-negative tuberculin skin testing
Technical : (potentially correctable)
Tuberculin material• Defective antigens because of improper storage
(exposure to light or heat) or manufacturing
Contamination
• improper dilution
Adminstration
• Injection of too little tuberculin, or too superficial, or
too deeply (should be intradermal)
• Prolonged storage within the syringe before
administration (more than 20 minutes)
Reading
• Inexperienced or biased reader
• Error in recording
Causes of false-negative tuberculin skin testing
Biological factors: (not correctable)
Infections
-activeTB (more advanced diseas )
•
•
•
•
•
-Viral, bacterial, or fungal infections
-HIV (especially if CD4 count <200)
Live virus vaccination within the past two months
Metabolic derangement, protein depletion, chronic renal
failure, severe malnutrition, stress (surgery, burns)
Concurrent use of immunosuppressive drugs:
(corticosteroids, TNF inhibitors, and others)
Very young <6 months or elderly
Diseases of lymphoid organs: (lymphoma, chronic
lymphocytic leukemia, sarcoidosis
Causes of false-positive tuberculin skin testing
• Nontuberculous mycobacteria
– Reactions caused by nontuberculous
mycobacteria are usually  10 mm of
induration
• BCG vaccination
– Reactivity in BCG vaccine recipients generally
wanes over time; positive TST result is likely
due to TB infection if risk factors are present
Serial tuberculin testing (conversion
or boosting)
When repeated tuberculin testing has been
performed, some individuals may manifest an
increased tuberculin reaction on their second
test in the absence of any obvious exposure.
Boosting
• the restimulation of previously acquired immunity from
earlier exposure.
• the risk of developing active tuberculosis actually lower
than those with an initial positive TST, and much lower than
in persons with tuberculin conversion
Tuberculin conversion
• occurs after an initial tuberculin infectiona, TST reaction of
10 mm or more plus an increase of 6 mm or more from the
previous TST results within a two-year period.
• the risk of disease is between 5% and 20% over the next
two years alone
• The ATS/CDC/IDSA definition of conversion requires an
increase of 10 mm or more from the previous TST result.
boosting
conversion
there is no
intervening
exposure
if the second
reaction is
>15 mm
If the second
TST is
performed
soon (within
two weeks)
after the first
one
there has been exposure
to MTB
If the second test is performed months to
years after the first TST
Two-step testing protocol
1st TST*
Negative TST (< 10 mm)
1 to 4 weeks later
2nd TST
Negative (<10 mm), then it’s
truly negative
*TST_tuberculin skin test
TST -tuberculin skin test
If retesting after a period is
Positive (≥ 10 mm ), it is a true
conversion should be treated.
Patient history
• 36-year-old Asian female
• Moved to U.S. from Philippines > 15 years ago
• Plans to work in a correctional facility
• TST result negative 1 year ago
• TST for pre-employment physical = 26 mm of
induration
• CXR normal
• No symptoms of TB disease
• No known contact with a TB patient
• Patient’s TST converted from negative to
positive (within a 2-year period)
• TST conversion increases risk for progressing
from LTBI to TB disease
• Foreign-born status is less of a risk factor, i.e.,
she immigrated more than 5 years ago
IGRA
• Interferon
Gamma
Release
Assay
• in-vitro tests that measure the levels of interferon-g
released by sensitized T lymphocytes after
stimulation with antigens of M. tuberculosis.
• These (IGRA) do not present cross-reaction with
(BCG), nor with the majority of nontuberculous
mycobacteria
IGRA
•
•
•
•
provide results in a single patient visit.
They do not have a ‘booster’ effect
can be repeated without the need for two-step testing.
They have excellent specificity and are unaffected by
BCG and NTM (estimated specificity >98%).
• IGRA sensitivity in active TB has been found to be
comparable to the sensitivity of TST (up to 30%
negative).
• IGRAs are NOT recommended for the diagnosis of
active TB
IGRA
• the CDC guidelines recommend using either
TST or IGRA for LTBI testing.
• UK, Canada, Spain, Italy recommend a twostep approach where TST is done first,
followed by IGRA.
• There is a potential boosting effect of TST on
IGRA results, it may be best to collect blood
for IGRA at the time the TST is read (i.e.,
within three days of placing PPD)
IGRA
Disadvantages
• higher material cost
• the need for an equipped laboratory
• requirement to draw peripheral blood.
• interpretation of IGRA conversions and
reversions is unclear
• evidence is rather limited in children and
immunocompromised populations.
Recommendations
• IGRAs should not be used to diagnose active TB in adults. In
children, they may be used as an adjunct test, in
combination with TST, chest x-ray, and microbiological
investigations. A negative IGRA alone should not be used to
rule out active TB.
• In BCG-vaccinated individuals (adults and children), IGRAs
may be used to confirm a positive TST result (i.e., to check
if the TST result is a false positive). If a positive TST result is
confirmed by a positive IGRA result, LTBI treatment should
be initiated after ruling out active TB.
• In immunocompromised patients, if a false-negative TST
result is suspected, IGRAs may be used to rule out LTBI.
Indication for TST and who should be treated
1. high risk of recent infection.
2. who are at high risk of progression from LTBI
to TB disease.
• High-risk individuals –risk for reactivation is
6 x higher than for normal
• Moderate-risk - 3 - 6 X normal
• Low-risk individuals - 1.5 – 3X normal
High risk
Moderate
risk
Low risk
indications and precautions in LTBI testing
and treatment
• Testing is not recommended for individuals
≥65 years unless they are at high risk for
reactivation.
• In newly detected LTBI ,no treatment to be
started before excluding active TB disease
• Medical examination,symptoms and chest xray with radiographic signs, sputum smear
microscopy and culture to rule out active TB.
• If the radiograph is normal but the patient has a
clinical presentation consistent with TB, further
workup is indicated and treatment of LTBI should
be delayed
• If the radiograph is abnormal and consistent with
TB sputum for AFB stain and culture should be
obtained.
-Starting treatment pending the culture results
or
-waiting for culture results before starting
therapy dependent on benefit-risk.
Recommended regimens for
treatment
• Four basic regimens are currently
recommended
• Completion of therapy is based on the total
number of doses administered, not the
duration of therapy alone
• Treatment interruptions of more than two
months require another evaluation to exclude
active TB before restarting therapy.
• Isoniazid alone—preferred regimen
Isoniazid alone
• Daily INH for 9 months is the preferred regimen for the
treatment of LTBI for
- children and adolescents (up to age 18 years).
-HIV-infected persons or persons suspected of having
HIV infection.
- immunocompetent adults.
• Intermittent (twice weekly) INH for 9 months (DOTS)
acceptable alternative, provided all doses of therapy
are directly observed.
• Six months INH alone if there are any concerns about
side effects or adherence
Rifampin
Rifampin for 4 to 6 months
– Patients who cannot tolerate INH
– persons exposed to cases with resistance to INH,
but susceptible to RIF.
– Rifampin (RIF) alone for four months for adults.
– Rifampin alone for six months for children.
– Rifabutin (RFB) may be substituted for rifampin
where it cannot be given, such as in HIV-infected
persons taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors.
• Rifampin and pyrazinamide for two months—
NOT recommended due to fatal hepatotoxicity.
Follow-up evaluation at least monthly
- careful questioning
- brief physical examination
-assess for adherence to the regimen
-symptoms and signs of adverse drug reactions.
Clinical Monitoring
• Incidence of hepatitis in persons taking INH is
lower than previously thought (0.1 to 0.15%)
• Hepatitis risk increases with age
– Uncommon in persons < 20 years old
– Nearly 2% in persons 50 to 64 years old
• Risk increased with underlying liver disease or
heavy alcohol consumption
• Indications for monthly LFTs
serum bilirubin and either AST or ALT
– Abnormal baseline LFT
– Chronic liver disease
– Regular alcohol use
– Current use of hepatotoxic drugs
withholding INH if
– serum transaminase concentrations > 3x the
upper limit of the normal range when
accompanied by symptoms
– 5x the upper limit of the normal range in
asymptomatic patients.
Treatment of latent tuberculosis in special situations
Pregnancy/lactation
• There is no risk of progression of LTBI to active disease
during pregnancy
• treatment can be delayed until 2-3 months after
delivery.
• HIV-positive or other high risk factor of progression to
active disease, therapy should not be delayed on the
basis of pregnancy alone, even during the first
trimester.
• INH is not toxic to the unborn child, even during the
first 4 months of gestation and breastfeeding is not a
contraindication
HIV-infected persons
• INH nine months of therapy is recommended
rather than six months.
• rifampin should generally be avoided in persons
who are taking protease inhibitors (PIs) or
NNRTIs.
• management of persons co-infected with HIV and
LTBI can be highly complex.it has to be done by
physicians who are experts in the treatment of TB
and HIV.
Persons with fibrotic lesions/suspected disease
• upper lobe fibronodular changes or scarring and a
positive TST (>5 mm) without evidence of active
disease and no history of treatment for TB, are
considered at high risk of reactivation and should
receive treatment.
• evidence of healed, primary TB (i.e., calcified solitary
pulmonary nodules, calcified hilar lymph nodes, and
apical pleural capping) have only slightly increased risk
for TB (about double that of the healthy). Their risk for
TB and need for treatment of LTBI should be
determined by considering other risk factors
Renal failure
• at a high risk of reactivation (relative risk, 10.025.3)
• all patients with positive reaction (10mm) are
recommended for therapy.
• anergic reaction is common so that TST may not
be very sensitive to detect LTBI
• In the absence of randomized trials that are
specific for this population, nine months of
isonizid (INH) is recommended.
Children and adolescents
• Infants and young children (younger than five
years) with LTBI are at high risk of progression to
active TB. If untreated, they have up to 40%
likelihood of developing active TB.
• more likely than older children and adults to
develop life-threatening forms of TB, especially
meningeal and disseminated disease.
• 9 months INH therapy for LTBI is more effective
for children than adults, with risk reduction of 7090%.
Liver disease
• special problem, as all available regimens are
potentially hepatotoxic
• Four months of RIF may be safer although the
efficacy of such a regimen has not been
established.
• frequent clinical and laboratory monitoring for
drug side effects is prudent.
Solid organ transplantation
• very high risk of LTBI reactivation to active TB.
• The incidence of infection is estimated to be 20-74 x
the general population.
• Safety of INH remains a concern, especially in liver
transplant recipients, but is generally safe as long as
pretreatment liver transaminase levels are normal.
• INH for nine months or RIF for four months.
• Patients should be treated during the pretransplant
period, if possible.
Contacts of patients with drug-susceptible
tuberculosis index case
• positive TST reactions should be treated with one of
the recommended regimens.
• TST negative close contacts at high risk to develop
severe active disease (e.g., children younger than five
years of age) should be treated and another skin test
performed a few weeks after contact has ended.
• repeat skin test is negative, the treatment should be
discontinued
• Immunosuppressed persons, including HIV, with close
contacts with active TB, should receive treatment, even
if repeat skin testing remains negative.
Contacts of index cases with isoniazid-resistant
tuberculosis
• TST-positive contacts - recommend treatment
with four months of RIF
• If RIF cannot be used, rifabutin can be
substituted.
Contacts of patients with a multidrug-resistant
tuberculosis index case
• has not been evaluated in a randomized trial
• preventive therapy with two drugs to which the
organism is expected to be susceptible is
recommended.
• Pyrazinamide (PZA) and ethambutol (EMB) for 6
to 12 months for adults and for 9 to 12 months
for children
• PZA and fluoroquinolones (FQN) have been
recommended. however, it is very poorly
tolerated and is contraindicated in pediatric
• Saudi guide lines recommend FQN (levaquin or
moxifloxacin) and EMB as the preferred regimen
for adults.
• followed for at least two years
Management of Patient Who Missed Doses
• Extend or re-start treatment if interruptions
were frequent or prolonged enough to
preclude completion
• When treatment has been interrupted for
more than 2 months, patient should be
examined to rule out TB disease
• Recommend and arrange for DOT as needed
Case Study
Patient history
• 29-year-old saudi female
• History of diabetes
• 35 weeks pregnant
• TST = 20 mm of induration
• No symptoms of TB disease
• CXR, CBC, LFTs normal
• No known contact with TB patient
• Persons with diabetes mellitus are 2 to 4 times more likely
to develop TB disease than those without diabetes
• Risk may be higher in insulin-dependent diabetics and those
with poorly controlled diabetes
• Pregnancy has minimal influence on the pathogenesis of TB
or the likelihood of LTBI progressing to disease
• Pregnant women should be targeted for TB testing only if
they have specific risk factors for LTBI or progression to
disease
management
• Some experts prefer to delay treatment until after the early
postpartum period, unless the person has recent TB
infection or HIV infection
Patient history
• 47-year-old indian male
• Moved to saudi arabia 4 years ago
• Known contact of infectious TB case
• TST = 5 mm of induration
• 3 months later TST = 23 mm of induration
• No symptoms of TB disease
• Normal CXR, CBC, AST, and bilirubin
• Patient is a contact of an infectious TB case
• Recent entry to saudi arabia from a country
with a high prevalence of TB
• Should be treated for LTBI if TST reactions  10
mm of induration
• As a contact of an active TB case, 5 mm of
induration is considered positive
• This patient should have been treated for LTBI
immediately after the first TST
Conclusions
Saudi Arabia is a country of medium prevalence
for TB infection. The TST remains a useful tool in
the identification of subjects with latent TB
infection. NTM infection and BCG vaccination
(routinely given in infancy) do not interfere with
the interpretation of the test in adolescents and
adults. Patients at high risk of developing active
TB should be treated with the standard regimens
advocated in this statement after due care is
taken in excluding active TB disease.