Pulmonary Tuberculosis – Diagnosis and Treatment

tuberculosis_tb_xrayPulmonary Tuberculosis or chest tuberculosis is a contagious disease caused by mycobacterium tuberculosis. When this bacillus is stained with carbol fuchsin it appears purplish red. The bacterium retains this dye even when it is washed with acid and alcohol. That is why it is called acid fast bacillus (AFB). Mycobacterium tuberculosis can remain dormant for many years in the lung without producing disease.

The spread of infection

The patient with pulmonary TB is the source of infection to others around him, especially when his sputum contains AFB. When such a patient coughs, he expels thousands of tiny droplets around him which have AFB in them.

Transmission of infection takes place when those around him breathe this contaminated air. Direct sunlight rapidly destroys AFB, but they can survive for long periods in darkness. Thus the risk of transmission of infection is highest in those persons who stay indoors with such a patient for long periods, e.g. family contacts.

The infection is largely spread in the community by patients whose sputum smear is positive for AFB. The chances of a sputum smear negative patient spreading infection are much less, and by those with extrapulmonary TB even lower.

The onset of disease

90 percent of the infected adults never develop TB. They remain asymptomatic but Mantoux positive throughout their liver.

The rate of progression of infection to disease is highest shortly after exposure to infection and it diminishes progressively as time passes. However, at anytime, weakening of immune responses and stress may cause multiplication and spread of the already present bacteria, resulting in the onset of tuberculous disease.

Making a Diagnosis

Cough, chest pain and fever are symptoms common to a variety of lung diseases. Most acute respiratory conditions subside within 3-4 weeks. When these symptoms persist for more than 3 weeks or if the patient has haemoptysis, a diagnosis of pulmonary TB must be considered in view of the high prevalence of this disease in our country. The above symptoms may or may not be associated with constitutional symptoms like malaise, loss of appetite and weight, and night sweats.

Pulmonary TB does not present with any specific physical signs. It cannot be distinguished from other respiratory disease on the basis of physical examination alone.

Diagnosis of Tuberculosis- Chest Skiagram and Computed Tomography

Chest skiagram

The radiological opacities in a chest x-ray are a result of the pathological processes taking place in the lungs. TB causes alveolar consolidation, necrosis, cavitation and fibrosis, features, which it shares with a variety of lung diseases. That is why TB also shares its radiological features with many other pulmonary diseases.

Hence, there is no radiological feature that is absolutely typical of pulmonary TB and other diseases may mimic TB radiologically. The following features, however, when seen on a chest skiagram, suggest a diagnosis of TB:

• Unilateral or bilateral upper zone opacities with or without associated fibrosis.
• Cavity lesions.
• Opacities with or without cavitation in apical segments of either lower lobe.
• Mediastinal and unilateral hilar lymphadenopathy.
• Bilateral miliary mottling.
• Pleural effusion.

The unreliability of radiological features in previously treated patients

TB, even after a complete cure, usually leaves behind residual opacities in the patient’s chest x-ray for life. That is why, when a previously treated patient presents with recurrence of respiratory symptoms, ATT should not be started on a radiological basis alone, without sputum smear or culture positivity for AFB.

His symptoms may be due to intercurrent bacterial infection in areas of post-tubercular bronchiectasis or due to some other lung disease. A significant radiological deterioration, from the chest x-ray taken on completion of previous treatment, may be made the basis of starting ATT only in the rarest case for pressing clinical reasons, i.e. the patient is seriously ill and needs urgent treatment.

Remember

There is no radiological feature that is diagnostic of pulmonary TB. A definite diagnosis can never be made on the basis of x-ray alone. It must be complemented with vigorous attempts to isolate AFB in sputum (by smear or culture) or directly from the lesion itself.

Also remember

Most patients with a cavity on an x-ray chest are smear positive for AFB. Thereafter, when the sputum of a patient with cavitary lesions on the x-ray is persistently negative, consider other diagnosis.

Computed tomography

Although computed tomography is currently an important investigation in the management of pulmonary diseases, it is practically of no value in the work up of a patient suspected to have TB. It should not be routinely ordered when investigating such a patient.

In rare situations it can be used to define mediastinal and pulmonary lesions more clearly. Wherever computed tomography is resorted to, it must be complemented, wherever possible, with a guided fine needle aspiration biopsy to arrive at a definite pathological or microbiological diagnosis.

mantoux_tuberculin_skin_test1Mantoux Test In  Tuberculosis

The Mantoux test is very widely used test for tuberculosis. Its interpretation however complex. It is also called tuberculin test.

Tuberculin is a glycerol extract of the tubercle bacillus. Purified protein derivative (PPD) tuberculin is a precipitate of non-species-specific molecules obtained from filtrates of sterilized, concentrated cultures.

The test is named after Charles Mantoux, a French physician who developed on the work of Koch.

Procedure

A standard dose of 5 Tuberculin units (0.1 mL) is injected intradermally and read 48 to 72 hours later. A person who has been exposed to the bacteria is expected to mount an immune response in the skin containing the bacterial proteins.

The reaction is read by measuring the diameter of induration (palpable raised hardened area) across the forearm (perpendicular to the long axis) in millimeters. If there is no induration, the result should be recorded as “0 mm”.

Erythema (redness) should not be measured.

If a person has had a history of a positive tuberculin skin test, another skin test is not needed.

Interpretation of tuberculin reaction

The results of this test must be interpreted carefully. The person’s medical risk factors determine at which increment (5 mm, 10 mm, or 15 mm) of induration the result is considered positive.

A positive result indicates an exposure with mycobacterium tuberculosis.

Normally generalised interpretation of Mantoux test are

Induration 0-5 mm  – Negative

Induration 6-9 mm  – Weak positive

Induration > 10 mm – Positive

However depending upon risk factors the interpretation is considered positive as follows

Induration of 5 mm or more is positive in

  • HIV-positive person
  • Recent contacts of TB case
  • Persons with nodular or fibrotic changes on chest x-ray consistent with old healed TB
  • Patients with organ transplants and other immunosuppressed patients

Induration of 10 mm or more is positive in

  • Recent arrivals (less than 5 years) from high-prevalence countries
  • Injection drug users
  • Residents and employees of high-risk congregate settings (e.g., prisons, nursing homes, hospitals, homeless shelters, etc.)
  • Mycobacteriology lab personnel
  • Persons with clinical conditions that place them at high risk (e.g., diabetes, prolonged corticosteroid therapy, leukemia, end-stage renal disease, chronic malabsorption syndromes, low body weight, etc)
  • Children less than 4 years of age, or children and adolescents exposed to adults in high-risk categories

Induration of 15 mm or more is positive in

  • Persons with no known risk factors for TB

False positive result

A false positive result may be caused by nontuberculous mycobacteria or previous administration of BCG vaccine. Prior vaccination with BCG may result in a false-positive result for many years afterwards.

False negative result

Those that are immunologically compromised, especially those with HIV and low CD4 T cell counts, frequently show negative results from the PPD test. This is because the immune system needs to be functional to mount a response to the protein derivative injected under the skin.

Patients with highly active TB infection may also show false negative results.

Anergy testing

In cases of anergy, a lack of reaction by the body’s defence mechanisms when it comes into contact with foreign substances, the tuberculin reaction will occur weakly, thus compromising the value of Mantoux testing. For example, anergy is present in AIDS, a disease which strongly depresses the immune system. Therefore, anergy testing is advised in cases where suspicion is warranted that it is present. However, routine anergy skin testing is not recommended.

This induration is a result of the hypersensitivity that the individual develops to the bacilli. Hence a positive Mantoux test only indicates that the individual got infected with Mycobacterium tuberculosis sometime during his life. It should not be misinterpreted as a sign of tuberculous disease and ATT should not be started in adults solely on the basis of a positive Mantoux test.

More than 50 percent of Indian adults are Mantoux positive, indicating a high prevalence of infection with Mycobacterium tuberculosis. 90 percent of those infected do not develop pulmonary TB in their lifetime. It is clear that a positive Mantoux test does not indicate and is not a sign of disease in adults.

A test is either positive or negative depending on whether the induration is less than or more than 10 mm in diameter. There is no added significance of a “strongly positive” reaction.

 

stethoscope_routine-investigation1Investigations That Aid In Diagnosis of Pulmonary Tuberculosis

Routine blood and urine examinations in pulmonary tuberculosis are as non-specific as those of physical examination. The patient may be found to be anaemic with a normal or raised WBC count.

Erythrocyte sedimentation rate (ESR)

ESR is o a non-specific investigation which may become rapid in a large variety of clinical conditions ranging from anaemia to any chronic infectious, inflammatory or malignant disease.

ESR has absolutely no diagnostic value for TB and should not be given any weightage at all towards its diagnosis as a standalone criteria. But in conjunction with other clinical parameters, its raised value can indicate possibility of tuberculosis

Sputum examination

Examination of the sputum is the only way by which a definitive diagnosis of pulmonary tuberculosis can be made. You can be absolutely certain that your patient has pulmonary TB only when his sputum smear is positive for AFB. The importance of this investigation cannot be overstated. Vigorous efforts should be made to isolate AFB in sputum before initiating treatment.

Useful tips

  • The patient should preferably give samples on three days. In case of inconvenience, a ‘spot’ sample to the laboratory on the first day, return the next day with an early morning sample and give a third, ‘spot’ sample, the same day. The chances of finding AFB in sputum are much higher with 3 samples than with 2 or 1 sample
  • Give clear instructions to the patient to give sputum and not saliva for examination. Instruct the patient to produce the specimen by a vigorous cough and give the thick, white, yellow or green sputum thus expectorated from the lower respiratory tract.
  • It is preferable to transfer the sample to the laboratory on the same day in a clean, wide mouth glass container.
  • Send samples to a reliable laboratory that routinely handles a large number of sputum specimens every day.
  • Wherever there is a high index of suspicion, but the first two samples are negative for AFB by smear, and a reliable laboratory is available, send the third sample for both smear and culture examination.

Common reasons for a negative report

  • Poor or no instructions by doctors to patients
  • Poor staining the smear also contributes towards underdetection of AFB in sputum.
  • Too few or no bacilli in the sputum

The patient whose sputum smear is persistently negative may have some other disease. However, if you still strongly suspect pulmonary TB clinically and radiologically, repeating sputum smear examination after 3-4 weeks may be worthwhile.

Polymerase chain reaction

polymerase_chain_reactionWith the help of PCR, millions of identical copies of any specific DNA or RNA sequence can be made. This sequence may be a gene, or a part of gene, or simply a stretch of nucleotides.

This is done by using highly specific oligonucleotide primers to amplify the target nucleic acid by repeated rounds of denaturation, primer annealing and amplification. The target DNA is amplified a billion fold within 2-4 hours, and becomes quantitatively enough to be detected by a variety of detecting system.

The principle is used to target the DNA of even very small number of mycobacteria available in the specimen, amplify it and detect the material, now available in a detectable quantity. The whole process takes about 24 hours. It can detect less than 10 organisms in the specimen.

It is a very sensitive and specific test.

However, even a slight contamination can result in a false positive result.

Enzyme linked immunosorbent assay (ELISA)

Due to the highly complex nature of both Mycobacterium tuberculosis and the human immune response to it, there is no known 100 percent diagnostic serological test for confirming the presence of tuebrculous disease in an individual.

ELISA techniques have been in use for some time to now to detect antibodies against various mycobacterial antigens in serum of patients suspected to have TB. The commonly done tests detect antibodies (IgG, IgM,) against cytoplasmic antigen 60 (A60) of mycobacteria.

These tests are sensitive towards infection with Mycobacterium tuberculosis but may not be specific in differentiating tubercular infection from tubercular disease. Although some people have claimed a specifically of upto 90 percent for ELISA testing, there is not enough data to define the right cut off value (which may even vary from population to population) which can differentiate between mere infection with, and disease caused by Mycobacterium tuberculosis. In addition, the test may cross react with other mycobacteria and other bacterial antigens.

ELISA is not recommended at present for sue in the routine work up of a patient suspected to have TB.

What is Short Course Chemotherapy For Tuberculosis?

Short course chemotherapy is the treatment of TB using a combination of new antitubercular drugs in a fixed regime for a set duration. These regimes have shortened the duration of treatment of TB from the 12-18 months of old regimes using streptomycin, isoniazid, thiacetazone or PAS to 6-9 months.

These new regimes with nearly 100 percent cure rates are much more potent than the older regimes and fewer relapses are reported with them. Their potency, shorter duration of treatment and fewer relapse rates make them a very cost effective treatment of choice for TB.

The regimes essentially consist of treating TB in two phases.

Initial intensive phase (for rapid killing)

Several drugs are given in the initial intensive phase to rapidly reduce the bacillary population in the tubercular lesion. This results in the destruction of drug resistant mutants in the bacterial population and prevents their selective proliferation. In addition, the rapid killing also results in very early sputum conversion, which dramatically reduces the risk of transmission of infection.

A tubercular lesion has four different types of bacilli:

Group 1: Rapidly growing, active bacilli (most bacilli in the lesion belong to this group)

Group 2: Those in the acidic environment inside cells and in cavitary walls.

Group 3: Semidormant bacilli which show occasional spurts in growth (mostly responsible for relapses)

Group 4: Few dormant bacilli. (no drug is yet available against this group)

Each of the 4 drugs used in the initial intensive phase acts on different populations in the tubercular lesion.

Isoniazid kills 90 percent of all bacilli during the first few days. It is most active against group 1. Rifampicin is not only most effective against group (3), but also acts on group 1.

Pyrazinamide acts on group 2.

Ethambutol or streptomycin are added to the regime to prevent emergence of MDR strains of Mycobacterium tuberculosis in countries like India, where the prevalence of initial bacterial resistance is high.

This potent combination of drugs rapidly decimates the bacillary population which results in the virtual treated by a combination of these drugs become smear negative by the end of two months.

Continuation phase (to prevent relapse)

The rapid decrease in the population also ensures elimination of drug resistant strains. That is why ethambutol or streptomycin, are withdrawn at the end of 2 months. In addition, in the first 2 months pyrazinamide has destroyed the intracellular and extracellular bacilli in acidic pH, against which it acts specifically. It has no further role and is also withdrawn at the end of 2 months.

A small population of intermittently multiplying bacilli still remains in the lesin at the end of the intensive phase. This population is responsible for relapses. A protracted treatment with sterilizing drugs that act specifically against these bacilli is necessary to prevent relapses.

Isoniazid and rifampicin are continued for four months in the continuation phase. They are very potent bactericidal drugs and continue to destroy bacilli. In addition, rifampicin continues to destroy semidormant, intermittently multiplying bacilli which cause relapses.

Currently available standard daily short course chemotherapy regimes

1. Six months duration: (2+4)

  • 2 EHRZ/ 4HR
  • 2 SHRZ/ 4HR
  • 2 HRZ/ 4HR

2. Nine months duration (2+7)

  • 2 SHR/ 7 HR
  • 2 HER/ 7 HR

E: ethambutol, S: streptomycin, H: Isoniazid, R: rifampicin, Z: pyrazinamide

Prefix numerals indicate the number of months for which the drugs have to be given.

Prescribing the Treatment In Tuberculosis – Points To Remember

  • Meticulously take a history of any previous ATT, that the patient may have received prior. This is the single, most vital parameter
  • Write the regime and date of starting ATT on each prescription slip so that precise durations are clearly recorded and not left to vagaries of memory.
  • Always calculate the drug doses according to the weight of the patient before prescribing a particular ‘kit’ or fixed drug.
  • Patients should be forcefully instructed to meticulously take the prescribed drugs daily in adequate doses for the complete duration. This is most vital in ensuring compliance and treatment completion.
  • Antitubercular drugs are most effective when given once, in full doses in the morning.
  • The patient has to take 4 drugs in the initial intensive phase.
  • Warm all patients that rifampicin colours the urine, sweat and tears reddish orange.
  • Reduce doses of anticonvulsants during treatment with isoniazid.
  • Oral contraceptives become unreliable when taken with rifampicin. Advise the patient to change the method of contraception.
  • Rifampicin is a potent inducer of liver enzymes. Hence the doses of corticosteroids, oral anticoagulants, oral antidiabetic agents, digoxin, phenobarbitone, morphine, dapsone and ketoconazole may need to be increased when taken concomitantly with rifampicin and reviewed once rifampicin is discontinued.
  • The dose of rifampicin should be reduced in patients with cirrhosis.
  • Streptomycin may cause vestibular damage especially with high doses and in the elderly. This results in giddiness, nystagmus and rarely, deafness. Stop streptomycin when these symptoms occur.
  • Ethambutol rarely causes retrobulbar neuritis which results in progressive loss of vision. It is best to tell patients that ethambutol may affect vision. Wherever possible, they should be told to check visual acuity by reading fine print regularly. They should be instructed to stop taking ethambutol and report, should the vision deteriorate. Always assure the patients that the risk is very small. This will check possible non-compliance.
  • Ethambutol should not be given to patients with very weak eyesight as they may not notice a minor diminution of vision early enough.
  • Rest and nutritious food are not important in the treatment of TB. Adequate, regular chemotherapy, taken for the prescribed period results in cure and prevention of relapse.

Common Problems During Treatment of Tuberculosis

Arthralgia

Arthralgia occurs in upto 21 percent patients on regimes that contain pyrazinamide. Pyrazinamide also inhibits the renal excretion of uric acid. Mild arthralgia should be managed with reassurance and when it is more severe and when associated with arthritis, a non-steroidal anti-inflammatory drug should be administered.

In severe cases, high serum uric acid levels can precipitate gout. However, joint symptoms should never necessitate withdrawal of pyrazinamide, especially as the drug is withdrawn after 2 months in any case.

Peripheral neuropathy

This is the main form of chronic toxicity induced by isoniazid. It is seen more commonly in poorly nourished patients, especially when isoniazid is given in high doses. Others at risk are the elderly, alcoholics, diabetics, pregnant women, HIV positive patients and those with chronic liver disease.

Clinically, the symptoms and signs are predominately sensory. The patient usually present with a burning sensation in the feet and hands which may progress to paraesthesia and subsequently to a full blown neuropathy. Muscular weakness may also be present.

The group of patients at risk, should always be given 20mg of pyridoxine daily along with ATT. 100-200 mg daily pyridoxine must be given to patient with established neuropathy. Routine use of pyridoxine with ATT, however, is not recommended.

Itching

Without or with transient minimal rash

In a small number of patients an itch occurs very early on in treatment. It is occasionally accompanied with a transient minimal rash. The itch and rash are both always self limiting and should be treated with reassurance and an antihistamine. Do not stop ATT.

Merely observe the patient more frequently till his condition subsides, which usually does within a fortnight, after which the antihistamine can be withdrawn safely without recurrence of the condition.

Remember

In case there is a rash, always tell the patient to observe it himself and discontinue treatment and report back immediately if it progresses rapidly.

With rash and/or fever

A progressive rash accompanied with itching is very rarely encountered in patients receiving short course chemotherapy. The rash can be maculopapular and erythematous, and if severe, urticarial. It’s often pleomorphic and in some cases may become confluent and accompanied by fever with chills and rigours, periorbital oedema, lymphadenopathy, hepatosplenomegaly and even encephalitis.

In the most severe cases, extensive exfoliative dermatitis with mucus membrane involvement (Stenven Johnson syndrome) and shock may occur. Fortunately, such severe cases are very rare with the newer drugs used drugs used in short course chemotherapy. They are usually seen with thiacetazone. Thiacetazone should never be given again to a patient who has had any reaction with this drug.

Whenever a persistent progressive rash appears in a patient on ATT, stop all drugs immediately. Treatment with lotion calamine application and an oral antihistamine is usually sufficient.

However, in a severe case with exfoliative dermatitis and or mucus membrane involvement with or without shock, intravenous hydrocortisone (200mg-800mg daily) or oral prednisolone (40—60 mg daily) are also given immediately, till such time that the condition improves.

Skin Reactions During Treatment of Tuberculosis

In such cases withdraw and do not restart ATT till the rash has subsided completely. Once the rash has subsided, the offending drug has to be first identified.

If thaicetazone was used, it should not be used again. Other drugs should be reintroduced one by one  first in small doses.

The order of reintroduction of the drugs depends on the relative likelihood of the drugs to cause a skin reaction. The least likely drug is introduced first. The chart suggests a practical approach to identify the offending drug.

If the initial skin reaction was severe, start with approximately 1/10th of the dose shown for the first day. If no reaction occurs to this dose, the schedule for the 2nd and 3rd day should remain as shown above.

If possible, give two anti-TB drugs which the patient has not had before, while identifying the offending drug. This will prevent the emergence of drug resistance during the period in which the patient is being challenged. When restarting treatment, always consider it as a start of fresh treatment.

Options for alternate regimes

  • In case pyrazinamide is the offending drug, switch the regime to either of the 9 month regimes.
  • If ethambutol or streptomycin is the offending drug withdraw it and replace it by the other.

Rarely, a patient may develop a skin reaction to isoniazid or rifampicin. These drugs are both irreplaceable in short course chemotherapy. Hence desensitisation has to be done in such a patient. This is best left to the specialist and the patient should be referred to him.

without any deleterious effect to the patient. The eruption subsides on cessation of treatment.

Rule out other skin conditions like furunculosis, scabies and taeniasis before making a diagnosis of drug induced rash. These conditions are common in our country and may afflict the patient receiving ATT.

 

Monitoring The Therapy Of The Patient of Chest Tuberculosis

It is important to monitor the patient of tunerculosis. Once the patient is put on treatment do not expect any dramatic improvement in his clinical condition. Symptoms improve gradually over weeks. It is a good idea to explain this to the patient so that he is reassured and confident about his treatment.

About the regime

Four drugs are given daily for 2 months in the initial intensive phase. At the end of 2 months you have to take an important decision of withdrawing 2 of the 4 drugs.

You have to be certain that 3 sputum smears are negative before you do that. Hence, 3 sputum smears are negative before you do that.

Hence, 3 sputum smear examinations are done in the 8th week, while the patient is taking the 4 drugs. This may be supplemented by an x-ray. In case the smears are negative (which will be the case in more than 95 percent patients), pyrazinamide and ethambutol are discontinued after completing 8 weeks. Rifampicin and isoniazid are continued in the same doses daily for another 4 months.

In case the patient, despite best efforts (both of the patient and the physician), cannot produce any phlegm at the end of 2 months, clinical and radiological assessment should form the basis of withdrawing pyrazinamide and ethambutol.

Sputum examination should be repeated at the end of 4 months and again at the end of 6 months, supplemented with an x-ray at the end of 6 months, wherever convenient. If the smears are negative for AFB at the end of the 6th month, isoniazid and rifampicin are also discontinued and the treatment concluded after completing 4 months of the continuation phase, making a total treatment duration of 6 months. This policy is adopted irrespective of whether the smears were positive or negative for AFB when treatment was started.

Smear positive at two months

In case the smear is positive for AFB at the end of 2 months, extend the duration of the intensive phase by another month by not discontinuing pyrazinamide and ethambutol. Repeat smear examinations at the end of 3 months.

Withdraw pyrazinamide and ethambutol in case the smears are now negative for AFB. Then continue isoniazid and rifampicin in the same doses, daily for another 3 months so that the total duration of treatment remains 6 months.

There is no added advantage of extending the regime beyond the recommended duration. Do not continue the treatment on the basis of changing residual radiological opacities. Healed tubercular lesions, many a time, leave behind radiological opacities, depending on the extent of pulmonary necrosis and resultant fibrosis and bronchiectasis.

As fibrosis progresses, these opacities change, even over years, and remain with the patient for life. Rely more on sputum examination and insist on it from the patient. For some reason, both the patients and doctors find an x-ray examination more convenient. Desist from it and get at least 3 sputum smears done when indicated and not just 1. One won’t do, as many a time only one of the three may be positive!

Remember

The total duration of treatment with the 2HRZE/4HR regime is 6 months, out which 4 drugs are given daily for 2 months and two drugs for 4 months. Follow the regime meticulously.

Sputum status is the best guide to treatment.

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