Pulmonary tuberculosis or chest tuberculosis is a contagious disease caused by Mycobacterium tuberculosis.
Mycobacterium tuberculosis appears red when it is stained with carbol fuchsin. The bacterium retains this dye even when it is washed with acid and alcohol in contrast to others which do not retain. That is why it is called acid-fast bacillus or AFB. Mycobacterium tuberculosis can remain dormant for many years in the lung without producing disease.
Transmission of Infection of Pulmonary Tuberculosis
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.
Development of Infection
90 percent of the infected adults never develop TB. They remain asymptomatic but Mantoux test is positive throughout their life.
The rate of progression of infection to disease is highest shortly after exposure to infection and it diminishes progressively as time passes. But, as bacteria lie dormant for a long time, at any time, weakening of immune responses and stress may cause multiplication and spread of the already present bacteria, resulting in the onset of tuberculous disease.
Symptoms of Pulmonary Tuberculosis
Tuberculosis has symptoms similar to other diseases of the lung. Cough, chest pain and fever are symptoms common to a variety of lung diseases. But most of the respiratory conditions subside within 3-4 weeks. When these symptoms persist for more than 3 weeks or if the patient has hemoptysis, a diagnosis of pulmonary TB must be considered in view of the high prevalence of this disease in endemic countries. The above symptoms may or may not be associated with constitutional symptoms like malaise, loss of appetite, weight loss, and night sweats.
Pulmonary TB does not present with any specific physical signs. It cannot be distinguished from other respiratory diseases on the basis of physical examination alone.
Imaging in Pulmonary Tuberculosis
Chest X-ray or Skiagram Chest
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 x-ray, 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.
There is 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.
A significant radiological deterioration, from the chest x-ray taken on completion of previous treatment, may be made the basis of starting drugs only in the rarest case for pressing clinical reasons, i.e. the patient is seriously ill and needs urgent treatment.
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.
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, other diagnoses should be considered.
Computed tomography (CT scan)
Although computed tomography is currently an important investigation in the management of pulmonary diseases, it is practically of no value in the workup 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 Test In Tuberculosis
The Mantoux test is very widely used test for tuberculosis. Its interpretation, however, is 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 tuberculin reaction was first described by Robert Koch. The test is named after Charles Mantoux, a French physician who developed this test based on the work of Koch.
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 generalized interpretation of Mantoux test is
- 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.
In cases of anergy, a lack of reaction by the body’s defense 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 adults in endemic countries 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.
Routine blood and urine examinations in pulmonary tuberculosis are as non-specific as those of physical examination. The patient may be found to be anemic with a normal or raised WBC count.
ESR is a non-specific investigation which may become increased in a large variety of clinical conditions ranging from anemia 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 stand-alone criterion. But in conjunction with other clinical parameters, its raised value can indicate the possibility of tuberculosis
Examination of the sputum is the only way by which a definitive diagnosis of pulmonary tuberculosis can be made. Vigorous efforts should be made to isolate AFB in sputum before initiating treatment.
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 1 or 2 sample.
The sputum should be produced by vigrous cough and sputum expectorated from the lower respiratory tract should be submitted to the laboratory. Saliva should not be confused with sputum.
It is preferable to transfer the sample to the laboratory on the same day in a clean, wide mouth glass container.
If clinical suspicion is high and the first two samples are negative for AFB by smear, the third sample should be tested for both smear and culture examination.
The patient whose sputum smear is persistently negative may have some other disease. In cases of strong clinical and radiological suspicion, repeat sputum smear examination after 3-4 weeks may be worthwhile.
Polymerase Chain Reaction (PCR)
With 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 a 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 large enough to be detected by a variety of detecting systems.
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 present 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 tuberculous disease in an individual.
ELISA techniques can be used to detect antibodies against various mycobacterial antigens in serum of patients suspected of having 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 addition, the test may cross-react with other mycobacteria and other bacterial antigens.
ELISA is not recommended at present for use in the routine workup of a patient suspected of having TB.
Treatment of Pulmonary Tuberculosis
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: Semi-dormant 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 the 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 a virtual cure. When treated by a combination of these drugs, the patient becomes smear negative by the end of two months.
Continuation phase (to prevent relapse)
The rapid decrease in the population also ensures the 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 destroys 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 lesion 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 the tubercle bacilli. In addition, rifampicin continues to destroy semi-dormant, intermittently multiplying bacilli which cause relapses.
Currently available standard daily short course chemotherapy regimes
- Six months duration: (2+4)
- 2 EHRZ/ 4HR
- 2 SHRZ/ 4HR
- 2 HRZ/ 4HR
- 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.
Common Problems During Treatment of Tuberculosis
Arthralgia occurs in up to 21 percent patients on regimes that contain pyrazinamide. Pyrazinamide also inhibits the renal excretion of uric acid. Mild arthralgia should be managed with reassurance but when it is more severe and is 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.
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 presents 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 20 mg of pyridoxine daily along with ATT (Antitubercular treatment). 100-200 mg daily pyridoxine must be given to the patient with established neuropathy. Routine use of pyridoxine with ATT, however, is not recommended.
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.
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 rigors, periorbital edema, lymphadenopathy, hepatosplenomegaly, and even encephalitis.
In the most severe cases, extensive exfoliative dermatitis with mucous membrane involvement (Steven Johnson syndrome) and shock may occur. Fortunately, such severe cases are very rare with the newer 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 calamine lotion application and an oral antihistamine is usually sufficient.
However, in severe cases with exfoliative dermatitis and or mucous membrane involvement with or without shock, specialized treatment is required.
Rule out other skin conditions like furunculosis, scabies, and taeniasis before making a diagnosis of drug-induced rash. These conditions are common and may afflict the patient receiving ATT.
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 thiacetazone 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.
If the initial skin reaction was severe, start with approximately 1/10th of the dose given on the first day. If no reaction occurs to this dose, the schedule for the 2nd and 3rd day can be given.
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 with the other.
Rarely, a patient may develop a skin reaction to isoniazid or rifampicin. These drugs are both irreplaceable in short course chemotherapy. Hence desensitization has to be done in such a patient. This is best left to the specialist and the patient should be referred to him.
Monitoring The Therapy Of The Patient of Chest Tuberculosis
It is important to monitor the patient of tuberculosis. 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/she is reassured and confident about his/her 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 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!
The total duration of treatment with the 2HRZE/4HR regime is 6 months, out of 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.