FAQs
General Information/Disease
Demographic changes like increasing life expectancy, population growth, deterioration of living conditions in urban areas like over-crowding and epidemiological factors like HIV epidemic are expected to increase the incidence of TB, unless TB control efforts are intensified on a war footing. Poor treatment practices if continued may contribute to epidemic of multi-drug resistant TB (MDRTB) making the disease virtually incurable.
Fortunately, the ‘DOTS strategy’ now being expanded in the country has shown promise in terms of cure of infectious cases and hopes have been aroused of its control provided the strategy is implemented with full vigour.
Sputum smear positive cases of pulmonary TB are the main sources of transmission of infection. They are responsible for almost 95% of the transmission of infection in the community. They also suffer from more extensive disease and thus are at higher risk of dying. If not treated properly they become the sources of drug resistant bacilli.
Symptoms
About 84% of smear positive cases attending health institutions can be detected by screening of chest symptomatics of ³ 3 weeks cough alone, as revealed in operational research studies. Subjecting patients with cough of <3 weeks or those with other chest symptoms to sputum smear microscopy may increase the workload of laboratory by almost three times while adding little to the case yield.
Diagnosis
Of the total smear positive cases presenting at health Institutions, about 69% can be detected by smear examination of first sputum specimen and another 20% by examination of second specimen. The additional case yield by subsequent specimen is minimal. Therefore, a minimum of two specimens should be examined for obtaining acceptable sensitivity of smear microscopy as a case finding tool.
Further, there is likelihood albeit small of single positive sputum smear result to be false positive. However, the chances of two positive results to be false positive are practically non-existent. Therefore, the criteria of at least two smear positive results to label a case as smear positive increases the specificity of the test. Since the bacilli are not excreted consistently in all specimens, at least three specimens should be examined to satisfy the above criterion.
A sputum smear is spread over an area of 200 mm2 and contains about 0.01 ml of the specimen. Each oil-immersion field has an area of 0.02 mm2. Therefore, there are 10,000 fields on the slide. If a specimen contains 5000 bacilli/ml, there will be 50 bacilli distributed over entire smear and 1 bacilli over 200 fields.
Considering that the bacilli are not distributed evenly over the smear, there must be at least 10,000 bacilli/ml to detect 1 bacillus over 200 fields.
Rinse mouth before sputum collection or collect specimen before food.
Use separate wooden stick for each smear preparation and stain each slide separately on a rack.
Use new slides. Nevertheless, the scratches on the slide can be differentiated as these occur in parallel rows and are found deeper.
Use fresh stains and preferably filter the stains before use.
Preferably, use distilled water to avoid false positive result from environmental mycobacteria.
Do not touch the slide with the objective of the microscope or the oil dropper.
Clean lens with a lens cleaning paper (not cotton) after exam of each slide.
Improper guidance to the patient resulting in poor quality of the sputum sample is the most common reason of a false negative result.
Bacilli may loose acid fastness if exposed to excessive heat (over heating while fixing the slide), direct sunlight, or long period of storage in hot and humid conditions.
Smear not prepared from blobs that contain dead caseous tissue discharged from cavity.
Too thin or too thick smear
Improper fixing
To short carbol-fuchsin staining or boiling it
Intensive counter staining
To short carbol-fuchsin staining or boiling it
Intensive counter staining
Erratic and brief examination
Administrative errors
Chest X-ray has a role in differential diagnosis of pulmonary disease among chest symptomatic patients whose sputa are consistently negative on smear microscopy.
Smear positive cases do not necessarily pass through an early smear negative stage and only a few smear positive cases would be prevented by use of additional more sensitive methods for detecting pulmonary TB cases, which will also shift priority from detecting and treating most infectious cases.
A cavity of 2-cm diameter contains about 100 million organisms, easily detected by sputum smear microscopy. Almost the same number of new cases can be detected by the first two smears as by first 3-culture examination. Therefore, the additional yield of cases by culture is small. Only nodular lesions discharging small amounts of bacilli are negative by microscopy. Moreover, only culture positive TB cases (negative on microscopy) discharge bacilli intermittently, compared to smear positive cases, which discharge bacilli more consistently. Nevertheless, culture has a role in drug sensitivity testing, diagnosis of extra-pulmonary TB like lymph node TB and for differential diagnosis in a few cases after carefully evaluating microscopy and radiology.
Grading assists in quality control and also saves time since fewer fields have to be examined for higher grades. It also assists in monitoring prognosis during course of treatment. A higher proportion of 2+ and 3+ smears are likely to remain positive at the end of intensive phase and may require additional one month of intensive Phase.
Bacilli are not evenly distributed in a specimen but are found in clumps. (Specimens consistently positive contain at least 105 to 106 bacilli per ml.
A scanty positive smear result should be supported by another positive smear (more than scanty positive) or by suggestive chest X-ray. Otherwise, repeat sputum collection and smear examination is preferable.
In hot & humid climates, the bacilli seem to loose their acid-fatness. Even the stained bacilli may also loose the stain by osmosis in such climates. Therefore, slides labeled positive for Acid fast Bacilli (AFB) by lab technician (L.T.) but negative by senior lab technician (STLS) should be re-stained.
The purpose of cross checking is to identify lab technicians that require retraining rather than identification of individual slide errors.
(i) Serological tests have poor sensitivity and specificity. Their sensitivity is highest in patients with smear positive disease and much lower among TB cases not detected by smear microscopy viz. sputum smear negative cases of pulmonary TB, extra-pulmonary TB, children diagnosed with TB and HIV infected TB cases. Also, these tests do not reliably distinguish active TB from dormant infection.
(ii) Amplification tests e.g. polymerase chain reaction (PCR) are 95% sensitive in smear positive cases and only 50% sensitive in smear negative and culture positive cases. Though specificity is high, it is lower under field conditions. In addition, inability to distinguish viable from dead bacilli and high cost dissuade their use in developing countries.
(iii) The Assay of cell-mediated immunity is highly complex.
(i) False positive smear result
(ii) Bacilli might have lost ability to grow in culture due to the following reasons:
– Bacilli killed or harmed by treatment
– Exposure to heat and sunlight
– Long storage of sputum specimen
– Excessive decontamination procedures while processing the specimen for culture
Patients with history of treatment of less than one month have been found to respond similarly, as those never treated before. Also, the chances of development of drug resistance with less than one month therapy are remote.
Though relative risk of acquiring infection and developing TB is higher among contacts, the case yield from contact tracing is low. However, the risk of breakdown is maximum during the period immediately following infection, especially among children. Therefore, all child contacts and symptomatic adult contacts of smear positive cases, irrespective of the duration of symptoms should be examined at the health centre, to identify and treat TB cases and to provide preventive treatment to children.
Chemotherapy/ Treatment Activities
At least one third of patients receiving self-administered treatment do not adhere to treatment. It is impossible to predict which patients will take medicines regularly. Therefore, directly observed treatment is necessary at least in the initial phase of treatment to ensure adherence and achieve sputum smear conversion. A TB patient missing one attendance can be traced immediately and counseled. No method other than directly observed treatment has been able to achieve 85% cure rate of new smear positive cases.
The tubercle bacilli when exposed to a drug do not multiply for varying duration, which is called lag period. This property of the bacilli is utilized as the basis of intermittent therapy.
Drug regimens are decided in consideration of the following facts:
Mode of action of individual drugs
The dose of each drug depends on minimum inhibitory concentration (MIC) i.e. the minimum drug concentration that inhibits bacterial growth in-vitro, and
Minimum Bactericidal Concentration (MBC) i.e. the concentration at which bacteria are killed. MBC is usually higher than MIC.
Prevention of drug resistance.
Demonstration of efficacy during drug trials and field trials in terms of sputum conversion and relapse.
Minimal side effects.
Cost effectiveness.
Operational feasibility.
INH has very high early bactericidal activity (EBA) and acts on rapidly multiplying extra-cellular bacilli. It accounts for 95% kill in bacillary population. Remaining bacilli metabolize slowly and are killed preferentially by ‘Rifampicin’. INH is also most effective drug for preventing resistance to other drugs. On the other hand, other drugs are not so efficient in preventing resistance to INH, which is therefore more common.
Rifampicin also has high bactericidal activity but starts acting little later. It acts on rapid as well as intermittently (found in caseous lesions) multiplying bacilli.
Pyrazinamide acts on intra-cellular bacilli that are particularly inhibited by acid environment inside macrophages.
Ethambutol is the companion drug to prevent drug resistance.
Rifampicin is the main sterilizing drug in this phase. The role of INH is mainly to prevent drug resistance to Rifampicin.
Pyrizinamide has no additional benefit if given beyond 2-3 months, as seen in clinical trials. Ethambutol is not required because the chances of drug resistant to INH or Rifampicin developing in continuous phase is negligible as the number of bacilli is drastically reduced in this phase.
Streptomycin has limited penetration to membranes, however it can be given intra-thecal in case of serious cases of TBM.
The re-treatment cases are more likely to harbor drug resistant bacilli, at least to INH. Therefore, ethambutol is added to prevent drug resistance to INH or Rifampicin.
Smear negativity means there are few bacilli and thus negligible chances of resistant mutant bacilli being present.
Most common reason of treatment failure is the failure to observe drug administration, which commonly results in treatment failure.
Rifampicin should be protected since resistance to it results in much higher
failure and relapse rates. Cross-resistance also occurs to all other Rifamycins. It should never be used without direct observation. Its use should preferably be restricted to public health Institutions and experts. The regimens, which minimize risk of resistance to Rifampacin, should only be used.
This information is essential for prolongation of intensive phase by one month, which reduces risk of failure and relapse.
It is an important management tool and reflects on the quality of lab, quality of treatment observation during Intensive Phase and proportion of defaulters.
The smear status at the end of Intensive Phase also predicts the probability of cure.
If error is detected at the time of diagnosis, check for other smear results, X-ray and whether patient has been started on treatment. If the patient was missed on diagnosis, he should be traced and put on treatment.
If an error is detected on follow-up smear examinations, no change in treatment is undertaken based on the results of cross examination. To some extent, there are built-in mechanisms to handle this problem for e.g., re-examination of sputum smears after 5 months of treatment among those who are smear positive at 4 months. However, full efforts must be made to keep the errors on follow-up examinations to be minimum.
With treatment of high efficacy, smears can be positive at 2-3 months due to presence of dead bacilli. Therefore, treatment failure based on smear examination is not considered until 5th month of treatment.
The treatment during continuous phase is partially supervised and adherence is sustained by continued motivation and health education of the patient. Operationally, it may not be feasible to supervise each dose of continuation phase. However, all those patients who have a history of being irregular, alcoholics etc., should be fully supervised. Other cases that are willing to be fully supervised during continuous phase should be encouraged.
Assuming that the history of previous treatment was taken properly at the time of diagnosis, most patients who continue treatment get cured, though relative risk of failure among such cases is higher compared to those who are smear negative at the end of intensive phase.
Only a proportion of patients put on re-treatment regimen are failure cases and likely to be resistant to one or more drugs. Cohort analysis of patients treated so far in our country shows that two-thirds of the patients remaining smear positive after 5 moths of treatment on Cat I and subsequently treated with Cat II have been successfully treated.
In twice weekly regimen, if patient misses one dose, it amounts to once weekly medication, which is more than lag period for most drugs and increases the risk of development of resistance. Twice weekly regimen are also more toxic because of immunologically mediated adverse effects.
Continuation Phase may be prolonged upto 7 months with INH & Rifampicin in cases of TBM, Miliary and Spinal TB
(i) Pyridoxin supplementation to pregnant females, diabetics,chronic alcoholics.
(ii) Discourage alcohol consumption during treatment
(iii) Monitor for symptoms and signs consistent with hepatic damage
(iv) Liver function tests every 2 – 3 months for those at high risk
(v) Sterptomycin is contra – indicated during pregnancy
(vi) Monitor side effects of sterptomycin specially in elderly: tinnitus,
vertigo, hearing tests for higher frequencies which are affected first,
Romberg’s Test
(vii) Avoid loop diuretics, which potentiate side effects of ‘Streptomycin’.
(viii) Analgesics for arthralgia which usually does not require withdrawal of
anti-TB treatment.
(ix) In case of suspected preexisting ophthomological disease, assess visual
acuity and colour vision before starting treatment
(x) Stop ethambutol in case of side effects, which are reversible
(xi) Avoid ethambutol among children < 6 years
(xii) Avoid ‘Streptomycin’ and ‘Ethambutol’ in renal disease
(xiii) Avoid Antacids that decrease drug absorption
(xiv) Women to use non- hormonal contraceptive methods
(xv) In case of hypersensitivity reaction, withdraw treatment completely and desensitize later
(xvi) Monitor steroids, oral anti-coagulants, anti-convulsants, oral hypoglycaemics, tranquilizers, theophylline, beta-blockers, calcium channel blockers, digoxin when given concurrently with Rifampicin.
Evaluate each patient by interview and clinical examination for emergence of side effects at the end of each month.
These drugs are moderately effective with other drugs for MDRTB and should only be given if standard drugs not tolerable.
(i) These drugs are less efficacious and more toxic.
(ii) They possess cross resistance to first line drugs
(iii) Most patients needing such treatment are difficult to hold e.g. alcoholics, drug addicts, migrants etc,
(iv) Hospitalization is a must for observation and regularizing treatment. Ambulatory treatment is possible only after tolerance and regularity assured.
(v) It is irrational for any country to divert resources to treating with second line drugs until full potential of SCC regimen has been achieved.
Requirement of the reserve drugs indicates poor program.
If a child is diagnosed to have tuberculosis, a full course of treatment has to be given. Children rarely suffer from smear positive disease. As a result, there are few bacilli in the lesions and no chance of resistant mutants being present. The recommended regimen is Cat III. The dose of drug has to be calculated in mg per kg body weight and given from loose drug stock. For patients with military or meningeal TB, a fourth drug, streptomycin can be added and the total duration made to 9 months.
The history of previous treatment should be elicited clearly for deciding on the proper category of treatment for the patient. Otherwise, cases may be given wrong treatment that may lead to treatment failure.
In chronic liver disease, 2 EHRZ / 6 HR can be given unless there is severe liver damage. If ascitis and portal hypertension are present, treat with 2 SHE / 10 HE.
In case of acute hepatitis, the treatment may be deferred. If TB is serious, treat with 3 SE or 3 SE + ofloxacin followed by 6 HR when hepatitis is recovered.
Stop all drugs and monitor serum transaminases. Usually treatment can be re-started with the same regimen after the serum levels of transaminases return to normal. In serious cases, Ethambutol and Streptomycin which are least hepato-toxic can be given.
Drugs eliminated by non-renal routes – INH, Rifampicin, Pyrazinamide and Thioamides may be given in normal doses.
2 HRZ / 4 HR is safe.
Decrease dose of Streptomycin & Ethambutol and adjust by renal function tests.
HIV and TB
Cough is reported less frequently among HIV positive TB cases, since there is less cavitation, inflammation and endo-bronchial irritation because of impaired cellular immunity.
Majority of HIV positive pulmonary TB cases is smear positive though their proportion is less than among HIV negative pulmonary TB cases.
The main types of Extra-pulmonary TB seen among HIV positive patients are – lymphadenopathy, pleural effusion, pericardial effusion, miliary TB and tuberculous bacteraemia.
Same regimen is used, as for HIV negative TB cases, since sputum conversion rates and cure rates are similar if effective chemotherapy is given. However, the treatment in Continuation Phase should also be fully supervised since lower rates of adherence and higher fatality rates have been observed among such patients.
Prevention and Control
Risk of breakdown from infection to disease is maximum during the period immediately following infection especially among young children. So, asymptomatic child contacts less than 6 years old are routinely recommended chemoprophylaxis.
Tuberculin test may be negative in the window period. Since the risk of breakdown is maximum during the period immediately following infection especially among young children, asymptomatic child contacts are recommended chemoprophylaxis irrespective of the tuberculin test result. INH given for 3 months reduces the tuberculin size considerably, so a low cut off is used for further continuation.
The only effective means of preventing MDRTB is to prevent emergence of such cases by DOTS. The proportion of cases with MDR has been demonstrated to come down with implementation of DOTS, in a number of places all over the world viz. Texas, New York, Peru. In Botswana where DOTS is being implemented, the proportion of MDRTB is one twentieth of that in other African countries where DOTS is not being implemented. At RNTCP sites in India, the proportion of patients put on cat II has been seen to reduce gradually. Experience shows if we make sure that patients receive every dose of drugs, the emergence of MDR TB can be prevented.
BCG prevents childhood form of TB like disseminated and miliary TB, but has no role in preventing TB in adults especially cavitary forms.
Evaluation
Because of high cure rates, the proportion of re-treatment cases should decrease. There should be decline in prevalence of initial drug resistance.
In the community, the impact of any change in disease situation is first reflected in a change in annual risk of infection (ARI) rates. Therefore, repeated ARI surveys along with age distribution of cases can be relied upon for assessment of disease trends in the community.
The decline in prevalence of disease occurs next and decline in disease incidence takes much longer.