MCF COUNSELORS TRAINING FOR TUBERCULOSIS HELPLINE

VENUE:MCF OFFICE, PUNE5TH NOV 2012 TO 9TH NOV 2012

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Why helpline for TB?Tuberculosis (TB) remains a major global health

problem. It causes ill-health among millions of people each

year TB ranks as the second leading cause of death from

an infectious disease worldwide, after HIV1

Tuberculosis is a treatable and preventable disease. What is needed is knowledge about the disease.Stigma, discrimination and fear : TB has all as HIV Strong referral services availableSo helpline for TB makes sense

1: Source: http://www.who.int/tb/publications/global_report/gtbr12 2www.mcf.org.in

What is tuberculosis?• TB is a chronic bacterial infection. • The great majority of infections in people are

caused by Mycobacterium tuberculosis (M. Tuberculosis or tubercle bacilli).

• M. tuberculosis and seven very closely related mycobacterial species like M. bovis and others together comprise what is known as the M. tuberculosis complex.

• M. Bovis can cause TB in people who drink unpasteurised milk from infected cows.

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TB: Global Scenario

• About 1 in 3 of the world’s population is infected with tubercle bacilli.

• There were an estimated 12 million prevalent cases in 2011

• 170 cases per 100 000 population

• Incidence: 90 lakh new cases

• Someone is newly infected every second

• Mortality: Nearly 14 lakh TB deaths every year

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• About 95% of the world’s cases of TB occur in South East Asia, sub-Saharan Africa and the Western Pacific.

• The five countries with the largest number of incident cases in 2011 were India (approx 2.0 million), China (approx–1 million), South Africa (approx 0.5 million), Indonesia (approx 0.5 million) and Pakistan (approx 0.4 million).

• India and China alone accounted for 26% and 12% of global cases, respectively.

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TB in IndiaNearly 40% of the Indian population is infected

with the MTB bacillusApprox 30 million people in India are infected

with TBIn 2011, with 2 million cases of TB, India alone

accounted for 26% of global cases.4 lakh deaths occur from TB every year. Everyday 5000 develop TB disease and 1000

people die of TB TB kills more adults in India than any other

infectious disease.

(2 deaths every 3 minutes).6www.mcf.org.in

Who are getting infected?

Of the 9 million incident cases in 2011

1 million (13%) were among people living with HIV

0.5 million were children 3 million were women.

TB affects mostly adults in the economically productive age groups.

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Drug resistant TB Globally, 3.7% of new cases and 20% of

previously treated cases are estimated to have MDR-TB.

Estimated 310 000 of MDR-TB cases in 2011. Almost 60% of these cases were in India,

China and the Russian FederationOf MDR-TB cases, Extensively drug-resistant

XDR-TB is 9.0%Treatment success rate of MDR TB is 50%

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Microbiology

Rod-shaped bacterium of 2-4 x 0.2-0.5 μm.

Obligate aerobe found in the well-aerated lungs.

Slow growing (dividing only every 16-20 hours)

Lives within tissue macrophages.

Humans are the only reservoir of M. Tuberculosis

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Microbiology

• Peculiar cell wall that consists of peptidoglycan and complex lipids.

• The cell wall is a major factor in the virulence of the organism.

• Once stained (e.g. with carbol fuchsin: Z N Staining), it retain dyes when treated by acidified organic compounds.

• Therefore, it is classified as an “acid–fast” bacterium.

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How is TB transmitted?

Nearly all TB infection is acquired by inhalation of respiratory droplets from people with TB in the lungs or throat.

Air droplets 3-5 μm diameter are coughed, sneezed or spat-out by an “open” case of TB.

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Other modes of transmission Ingestion of the organisms leads to development

of tonsillar or intestinal tuberculosis. This mode of infection of human tubercle bacilli is from self-swallowing of infected sputum of an open case of pulmonary tuberculosis, or ingestion of bovine tubercle bacilli from milk of diseased cows.

Inoculation of the organisms into the skin may rarely occur from infected pus tissue.

Transplacental route results in development of congenital tuberculosis in foetus from infected mother and is a rare mode of transmission.

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How is TB not transmitted?People cannot get infected with TB bacteria

throughHandshakesSitting on toilet seatsSharing dishes , mattresses with someone

who has TB.From insect bitesFrom touching surfaces that are

contaminated with M. tuberculosis.

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Factors that determine transmission risk

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Characteristics of a Patient with TB Disease that Are Associated with Infectiousness

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Environmental Factors that Enhance the Probability that M. tuberculosis Will Be Transmitted

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Proximity and Length of Exposure Factors that Can Affect Transmission of M. tuberculosis

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What happens when TB bacilli is inhaled? Between 70-90% of individuals exposed to TB

will not develop the infection. This is because

• inhale too few organisms to cause infection• have sufficient immunity to prevent an

infection becoming established

Any factor associated with impaired immunity, such as extremes of age, malnutrition and HIV/AIDS will increase the risk of developing infection.

No infection in 70 to 90 % exposed people

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What happens when TB bacilli is inhaled?

In those 10-30% who develop infection, TB infection begins when the mycobacterium reach the lung alveoli.

In the alveoli, TB enters macrophages and with other cells form a shell called granuloma.

The granuloma prevents dissemination of the mycobacteria.

Bacteria inside the granuloma can become dormant, resulting in a latent infection.

It may remain latent lifelong or may reactivate to active TB when immunity fails.

Of the 10 to 30% of the exposed who develop infection, 90% people have

latent infection 19www.mcf.org.in

What happens when TB bacilli is inhaled? Active TB InfectionActive TB disease occurs if

the immune system cannot keep the tubercle bacilli under control.

Bacilli begin to multiply rapidly and break free from the shell of granuloma.

Active clinical disease can be pulmonary or may be systemic ( Brain Larynx Lymph node Lung Spine Kidney , etc)

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Pathogenesis 5

What are the likely outcomes following exposure to open TB?

Dormant TB (90%)• well• no TB disease • not infectious to others

Active TB (10%)• ill and likely to die if untreated • infectious

Infection(10-30%)

No infection(70-90%)

Exposure to TB

Activation of infection results in disease

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Clinical stages or states of Mycobacterium tuberculosis infection

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Who is at risk of TB infection?Contacts ChildrenElderlyAll householdWorkplaceHIVPrevious TBMalnourishedSmokers

Low body weight Certain medical

treatments (such as corticosteroid treatment

PrisonsUrban slumPoor areasMigrantsDrug abusersDiabetics

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Distribution of tuberculosis cases by anatomical site in HIV-negative patients.

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Distribution of tuberculosis cases by anatomical site in HIV-positive patients

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Clinical features of lung TB

Cough That Last For More Than Two Weeks

Chest painBreathlessnessCoughing up blood

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HIV AND TB

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Miliary TBExtensive TBMay present only as fever and weight loss

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Common symptoms with TB at any site

Weight LossLoss Of Appetite

FeverNight SweatsWeakness

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TB lymphadenitis

Painless nodes in neck commonly

Non-tender, matted together and rubbery

May ulcerate and discharge.

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Abdominal TBWeight lossDiarrhoea or

constipationAbdominal distension

(from ascites) or chronic intestinal obstruction

Enlarged abd lymph nodes may be palpable as multiple intra-abdominal masses

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Pleural effusionExtrapulmonaryPain,

breathlessness, cough

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Brain TB Meningitis or intracranial tuberculomas

Headache, neck stiffness, altered mental status, and cranial nerve abnormalities, convulsions.

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TB spine Especially seen in young children

Presents as a pain and/or swelling on the back or neck

Loss of limb function

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Pericardial TBPatient presents with breathlessness and chest pain.

Chest x-ray shows cardio-megaly and pleural effusion

Changes on ECG are common.

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Diagnosis of TB: Latent and Active

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Diagnosis of active TBSputum Examination for pulmonary TBExamination of ascitic fluid, pleural fluid,

CSF, joint fluid, pus, etc for type of cells and AFB

Culture for AFBNAAT for TBADA testUrine test: LAMAntibody testsBreath tests

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Sputum Smear Examination for pulmonary TBSputum is a thick fluid that is produced in the lungs Sample of sputum is usually collected by the person

coughing. Earlier 3 morning sputum samples were

recommended, but now two spot specimens are collected on the same day.

To do the test a very thin layer of the sample is placed on a glass slide, and this is called a smear.

A series of special stains ( Zeihl Neelson or ZN stain) are then applied to the sample, and the stained slide is examined under a microscope for signs of the TB bacteria.

Ziehl-Nielsen stain demonstrates the presence of the acid and alcohol fast bacilli (AFB). 39www.mcf.org.in

How to collect sputum?Patient is instructed to inhale deeply two to three

times with his/her mouth open, cough out deeply from the chest, open the container, spit out the sputum into it and close the container tightly

The health worker or the laboratory technician should stand behind the patient.

If a patient coughs out only saliva, (s)he should be asked to try again to bring out sputum.

If a specimen cannot be sent to laboratory immediately, it should be stored in a refrigerator or in another cool place.

Sputum specimens should be examined immediately whenever possible and not late than a week after collection.

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Sputum Smear Examination for pulmonary TB Simple, inexpensive, requires minimum training High specificity High reliability with low inter-reader variation Can be used for diagnosis, monitoring and defining cure Results are available quickly Feasible at peripheral health institutions Correlates with infectivity in pulmonary TB casesBut the sensitivity though is only about 50-60%. I.e. the

test is often falsely negative in patients with TB. When positive, the patient is “smear-positive” or “open

TB” and the risk of transmission of infection to others is very high.

The yield of the test is higher in patients with lung cavities.

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Sputum-smear microscopy with LED=light-emitting diode Instead of simple

microscope, benefits of low cost, durability, faster and ability to use without a darkroom.

WHO issued a policy statement recommending that conventional microscopy should be replaced by LED microscopy

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How is sputum smear test interpreted?

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Sputum culture

Culturing is a method of studying bacteria by growing them on media containing nutrients.

It provides a definitive diagnosis of TB and can significantly increase the number of cases found.

Culture can also provide drug susceptibility testing, showing which TB drugs a person's bacteria is resistant to.

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Sputum cultureSolid culture

medium Egg-based Lowenstein Jensen (LJ medium) or Agar-based medium

Diagnosis can take 4 weeks to get a conclusive result with another 4-6 weeks to produce drug susceptibility results.

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Liquid culture medium

BACTEC MGIT 960.This can detect growth of mycobacteria as early as 4 days from inoculation and drug susceptibility will be available in 21-28 days.

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Microscopic observation of drug susceptibility assay (MODS) MODS has been described for the early

detection of M. tuberculosis growth in liquid medium, allowing a more timely diagnosis and drug susceptibility testing.

The method is based on the observation of the characteristic cord formation of M.tuberculosis visualized microscopically in liquid medium with the use of an inverted Microscope

Sensitivity of MODS (92 %) Turnaround time of nine days.

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NAATs=nucleic acid amplification tests (MTB PCR)Currently available NAA tests are

not sufficiently sensitive (detecting 50%--80% of AFB smear-negative, culture-positive pulmonary TB cases) to exclude the diagnosis of TB in AFB smear-negative patients suspected to have TB

NAATs have high specificity. Cannot be used for treatment

monitoring.

Culture, supported by microscopy, still remains the gold standard

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Xpert MTB/RIFIt is rapid NAAT test Uses PCR technique for diagnosis of Mycobacterium

tuberculosis and rifampicin resistanceXpert MTB/RIF has the advantage of detecting TB

with equivalent sensitivity to culture on solid media and of simultaneously detecting rifampicin resistance with high sensitivity (95%) and specificity (98%)

Turnover time less than 2 hours Another advantage is that it performs equally well

among HIV-negative and HIV-positive individuals. It is therefore a useful tool to improve early case

detection of MDR-TB and HIV-associated TB.

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CDC recommendations For NAAT

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Serological (antibody) detection tests for pulmonary and extrapulmonary tuberculosis

Commercial serological tests (Ig G, Ig M tests) for both pulmonary and extrapulmonary tuberculosis produce highly inconsistent estimates of sensitivity and specificity

None of the assays do well enough to replace microscopy.

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ADA for tuberculosis pleuritis, pericarditis, peritonitis

Measurement of ADA concentrations in pleural, pericardial, and ascitic fluid has high

Sensitivity and specificity for extrapulmonary tuberculosis.

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Diagnosis of latent tuberculosis

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Mantoux or tuberculin skin test (TST) or TT or PPD TEST0.1 ml PPD is injected

intradermally and the injection site is inspected 48-72 hours later.

Erythema and induration at the site signify an immune response and, therefore, previous exposure to mycobacteria.

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Mantoux or tuberculin skin test (TST) or TT or PPD TESTFalse positive: a skin reaction in people

who do not have TB because of exposure to non-pathogenic mycobacteria and also due to the immune response following BCG immunisation

False negative: a negative result in a person with TB in early primary infection or because they are immunocompromised – for example, due to HIV/AIDS, malnutrition or people who develop disseminated TB.

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Mantoux or tuberculin skin test (TST) or TT or PPD TESTIndividuals who had received BCG vaccination

are more likely to have a positive TSTThe effect of BCG on TST results is less after

15 yearsPositive TST with indurations of >15 mm are

more likely to be the result of tuberculosis infection than of BCG vaccination.

Non tuberculous mycobacterial infection can cause positive test, esp in areas where MTB is less.

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IGRAs=interferon-γ release assays. T-SPOT.TB Test, QuantiFERON-TB Gold

testIGRAs have excellent specificity (higher

than the TST), and are unaffected by previous BCG vaccination.

IGRA sensitivity varies across populations and tends to be lower in high-endemic countries and in HIV-infected individuals.

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Diagnosis of drug-resistant tuberculosisThe INNO-LiPA Rif assayGenoType MTBDR assaysCRI=colorimetric redox indicator methodNRA=nitrate reductase assaysMODS=microscopically observed drug

susceptibilityXpert MTB/RIF

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Different tests for drug resistanceThe INNO-LiPA Rif assay is a highly sensitive

and specific test for the detection of rifampicin resistance in culture isolates. The test has lower sensitivity when used directly on clinical specimens.

GenoType MTBDR assays have excellent sensitivity and specificity for rifampicin resistance, even when directly used on clinical specimens.

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CRI=colorimetric redox indicator method

Colorimetric methods are sensitive and specific for the detection of rifampicin and isoniazid resistance in culture isolates.

CRIs use inexpensive non-commercial supplies

and equipment and have a rapid turnaround time (7 days).

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NRA=nitrate reductase assays

NRA has high accuracy when used to detect rifampicin and isoniazid resistance in culture isolates.

NRA is simple and inexpensive Turnaround time 7–14 days

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MODS=microscopically observed drug susceptibility

MODS for rapid detection of rifampicin and isoniazid resistance

MODS has high accuracy when testing for rifampicin resistance, but shows slightly lower sensitivity when detecting isoniazid resistance.

MODS seems to do equally well with use of direct patient specimens and culture isolates.

MODS uses non-commercial supplies and equipment, and has a rapid turnaround time (10 days) compared with conventional methods.

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Diagnosis using urine sampleUrine-Based Assay for Lipoarabinomannan (LAM)Urine LAM test detects a subset of TB patients

who have severe TB, advanced AIDS, and are not detected by sputum smear microscopy

The combination of smear and LAM (either positive = TB) detects about 75% of TB cases

Urine LAM test is promising for use in conjunction with smear microscopy in settings of HIV high prevalence

Lacks infection control issues of blood, sputum

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The tuberculosis diagnostics pipeline

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Prevention of Tuberculosis

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Patients are more likely to be infectious if they:

Have TB of the lungs or throatHave a cavity in the lung Are coughing or undergoing cough-inducing

procedures Are not covering their mouth when coughing Have acid-fast bacilli on the sputum smear Are not receiving adequate treatment

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What care a TB case should take to prevent transmission of TB?

The most important thing is to take REGULAR medicine.TB patients who may be infectious should be instructed

to cover their mouth and nose with a tissue when coughing or sneezing. Put the tissue in a closed bag and throw it away.

Adequate (ventilated and sunny) site for sputum collection, preferentially outdoors

Avoiding the use of ceiling fansUse of a standing fan either to direct the air flow

towards the window (or door) or to produce an air "barrier" between the contacts and the patient

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What care a TB case should take to prevent transmission of TB?Avoid going to work or school. Sleep in a bedroom away from other family

members.If in a hospital and also in home if possible, TB

patient must be given a separate room, with the door closed and windows that can be opened.

This is to be followed for a period of 2 weeks after starting TB treatment after which infectiousness appears to decline very rapidly.

Close contacts should wear N99 masks, if available.

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BCG Vaccine

Bacille Calmette-Guerin is an live vaccine available for TB.

BCG appears to reduce the risk of serious childhood forms of TB, including miliary TB and extrapulmonary TB

BCG does not seem to be highly effective as people move into adulthood.

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BCG VaccineWHO recommends that BCG be given to

infants and young children in countries where TB is common.

It should not be given during pregnancy or to children with symptomatic HIV infection.

If you were vaccinated with BCG, you may have a positive reaction to a TB skin test. This reaction may be due to the BCG vaccine itself or to a real TB infection.

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Treatment of Active TBhttp://www.lifehugger.com/doc/2224/RNTCP_

Current_guidelines_2011

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Anti-Tuberculosis TherapyFirst-Line Drugs

IsoniazidRifampinPyrazinamideEthambutolStreptomycin

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D Dormant (No cure)

B Acid

inhibition

C Spurts of

metabolism

А Continuous

growth

RIF PZA

INH (RIF, SM)

High

Speed of bacteria growth

Low

Mitchison, Tubercle 66: 219-226

Special bacterial population hypothesis

and action of the specific drugs

(From Mitchison, 1985)

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Side effects of ATT drugsNo appetite, nausea,

vomitingYellowish skin or eyesHepatitisAbdominal painSkin rashPatients on

Rifampicin can have red colored urine, saliva, or tears.

Easy bleedingAching jointsDizzinessBlurred or changed

visionRinging in the earsTingling fingers or

toes or around mouth

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Principles of TherapyInsure that patient is taking medication

properly (Directly Observed TherapyDirectly Observed Therapy).

Always use at least 2 drugs to which the organism is susceptible.

Never add a single drug to a failing regimen.

Monitor clinical response to therapy.

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What is MDR/XDR TB?MDR-TB occurs when the TB bacteria are

resistant to at least isoniazid and rifampicin, the two most powerful anti-TB drugs. 

Extensively drug-resistant tuberculosis XDR-TB is TB that is resistant to any fluoroquinolone, and at least one of three injectable second-line drugs, in addition to MDR-TB

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Criteria to label a patient as MDR-TB suspect.A new smear-positive patient remaining

smear-positive at the end of fifth month.A new smear-negative patient becoming

smear-positive at the end of fifth month.A patient treated with regimen for previously

treated remaining positive at fourth monthSmear-positive contacts of an

established/confirmed MDR-TB case

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MDR is more common in people whoHave spent time with someone with drug-

resistant TB diseaseDo not take their medicine regularlyDo not take all of their prescribed medicineDevelop TB disease again, after having taken

TB medicine in the past

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Contributing Factors for MDR TBHigh prevalence of HIV.

Delayed diagnosis.

Delays in adequate therapy (in part due to unknown drug susceptibilities).

Inadequate isolation procedures.

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Deadly MistakesNot knowing MTB drug

susceptibilities.

Inadequate therapy.Ineffective drug regimen.Inadequate length of treatment.Sub-therapeutic drug level.

Lack of patient monitoring.DOT.Clinical Response.

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Reason for AlarmAlarm

1.6

5.5

0

1

2

3

4

5

6

With Good TBControl

With Poor TBControl

%

%

Prevalence of Multi-Drug Resistant TB*

*The WHO/IUATLD Global Project on Anti-TB Drug Resistance

Surveillance (1994-1997)

Countries with good TB control = >33% DOTS coverage.>33% DOTS coverage.

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Management of MDR/XDR TB

For MDRIntensive Phase (IP) of 6 drugs should be

given at least 6 months. Continuation Phase, 4 drugs are given for

18 months.For XDR:

At least three to four drugs to which the strain is sensitive need to be used for effective treatment

Surgery of lung

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Treatment for Latent Tuberculosis Infection (TLTBI)

Isoniazid preventive therapy (IPT), is given to people who have latent TB infection to prevent them from developing TB disease.

The usual regimen for IPT is isoniazid given daily for 6 months for all patients.

Patients she should be screened for activeTB (current cough, fever, weight loss or night sweats ) to rule out active TB before starting IPT.

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Who should be offered IPT?ALL HIV patients should be given IPT irrespective

of the degree of immunosuppression, and also to those on ART, those who have previously been treated for TB and pregnant women.

IPT is administered to all the children aged 6 years , in risk groups such as household contacts, individuals with chronic renal or respiratory disease

Patients should be clinically evaluated every month for signs of hepatitis and other adverse reactions like tingling numbness in legs due to isoniazid.

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Referenceswww.tuberculosistextbook.comRevised National Tuberculosis Control Programme

(RNTCP) Training Module for Medical PractitionersExtrapulmonary tuberculosis Indian J Med Res 120,

October 2004, pp 316-353The Situation of HIV/M. tuberculosis Co-Infection in India.

The Open Infectious Diseases Journal, 2011, 5, (Suppl 1-M5) 51-59

WHO Policy on TB Infection Control in Health-Care Facilities, congregate Settings and Households

Biomarkers and diagnostics for tuberculosis: progress, needs, and translation into practice( Lancet) Questions and Answers About Tuberculosis, CDC 2009

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