Management of Tuberculosis: Diagnostic Approach

Accurate and timely diagnosis of Tuberculosis (TB) is a prerequisite for the treatment and control of spread of infection to other family members of the patient and health professionals dealing with patients. In the recent past several advances in the diagnosis and management of Tuberculosis (TB) have come out. Tools and technology are of great help in understanding of pathogenesis, demonstration of Mycobacterium, drug sensitivity testing and evaluation of prophylaxis.

Tuberculosis is a major health problem requiring early management at diagnostic and treatment level to bring down the mortality rate. In the developing countries the current mortality rate is 1 death per 100,000 population. The global incidence rate of Tuberculosis (TB) reported in the year 2010 was 128/100,000/year. To sustain the control and elimination of Tuberculosis (TB) there is a need for efficient testing and treatment regimens.

Diagnosis of Tuberculosis (TB) has conventionally been relied upon sputum microscopy of Micobacterium tuberculosis (an Acid Fast Bacilli) by Ziehl-Neelsen Staining Technique. The technique is very specific but has a poor sensitivity (around 50%). More sensitive technique used for demonstrating Acid Fast Bacilli (AFB) is by culture on Lowenstein Jensen Medium. Isolation of mycobacteria by culture method is considered to be gold standard in-spite of being time consuming.

The scenario of multi drug resistant TB (MDR-TB) has given a challenge to biomedical scientists to develop new drugs and diagnostic methods. Advances in molecular techniques for the diagnosis of TB have revolutionized diagnostic approach to this public health problem. Various new diagnostic modalities are based on the DNA extraction from the mycobacterial isolates. The nucleotide sequences of DNA are amplified and multiplied millions of times by polymerase chain reaction (PCR) for comparative diagnosis through detection of amplified DNA.

The tests that detect Mycobacterium tuberculosis antigens in clinical specimens could provide rapid and direct evidence of infection. The major targeted antigen of Mycobacterium tuberculosis is Lipo-arabino-mannan (LAM). LAM is detected in the urine of patients suspected of having pulmonary TB (Tuberculosis of lungs) as well as extra-pulmonary TB (Tuberculosis of organs other than lungs).

Molecular Tests are very sensitive and specific for diagnosis of infection and monitoring of treatment as well as for evaluating drug resistance. Uniplex-PCR (single insertion sequence IS6110 of 38 kDa)) or Multiplex-PCR (for multiplex targeting like IS6110 and MPB 64) are of great help for detecting drug resistance. Multiplex-PCR is more sensitive than Uniplex-PCR. Multiplex-PCR is useful in early detection, species differentiation (Mycobacterium tuberculosis or Mycobacterium avium) and epidemiology.

Two Molecular Assays used for rapid diagnosis of a case of TB and drug-resistance testing are:  i) X-pert MTB/RIF, and ii) Line Probe Assay (LPA)

i)                    X-pert MTB/RIF: X-pert MTB/RIF detects Mycobacterium tuberculosis (MTB) and resistance to Rifampicin (RIF) using Real-Time PCR (RT-PCR) Assay by amplifying MTB-specific sequence of the rpoB gene (inherent of MTB genome) that is probed with molecular beacons for mutations within the RIF-resistance determining region. Diagnosis of TB can be determined within 2 hours from the sputum samples with minimal health hazard. X-pert MTB/RIF test has 99% sensitivity and 100% specificity.

ii)                  Line Probe Assay (LPA):  Rapid detection of anti-TB drug resistance by Mycobacterium tuberculosis is the need of the hour for effective treatment and management of patient care. Line Probe Assays have been developed for rapid detection of rifampicin resistance and/or MTB-DR (especially rifampicin in combination with isoniazid). The Line Probe Assay (LPA) employs the hybridization of labeled PCR products with oligonucleotide probe on a strip and reading by colorimeter. The genotype MTB-DRplus Assay also simultaneously detects specific mutations in the katG gene conforming high level isoniazid resistance as well as in the inhA gene conforming low level isoniazid resistance.

The Molecular Assays are labeled for use on isolates from solid and liquid culture as well as directly on sputum smear positive pulmonary specimens. Mycobacterium tuberculosis ‘strain typing’ is very important for the analysis of the spread of tuberculosis as well as for monitoring the evolution of antibiotic resistance. These assays are also used to assess the bacterial load for monitoring of anti-TB treatment (ATT).

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Tuberculosis of Lymph Glands: A common type of surgical tuberculosis.

The tuberculosis in general comes under the domain of physicians, but several of its local manifestations are regarded as surgical tuberculosis. However, with powerful and effective anti-tuberculosis therapy majority of these cases can be treated without surgery. The tuberculosis of lymph glands is very common type of surgical tuberculosis. The lymph glands (filtering units of lymphatic system) commonly involved are those in the region of the neck; on one or both sides, above the clavicle. The affected lymph glands appear like a small or big lump with nodules. Initially the swollen lymph glands are painless, but later on the swelling may become soft due to breaking down of gland into a cheesy material and termed as 'cold abscess'.

Unlike an abscess or a boil due to acute infection, the glandular abscess is not 'warm' to touch. The abscess may break down, develop into a sinus and start discharging pus. The discharging sinus refuses to heal for a long time unless the patient is treated properly. It is worth remembering that every form of tuberculosis, in any part of the body leads to signs and symptoms of 'tubercular toxemia'. The 'tubercular toxemia' causes evening rise of temperature, weight loss, loss of appetite (anorexia), general weakness and sweating of body at night. The consultation of physician is must for early diagnosis and treatment of tuberculosis of lymph glands if above mentioned symptoms are there.

Tuberculosis: A killer of the poor !

The human race is indebted to Dr. Robert Koch of Germany for his landmark discovery of causative bacillus of tuberculosis in 1882. This discovery later won him (Dr. Robert Koch) the Nobel Prize. Dr. Koch worked on many other diseases also. He discovered the causative agent of Cholera in 1883 in Egypt. Both the discoveries of this renowned microbiologist are remarkable and revolutionary in the field of medical science. Dr. Robert Koch’s fundamental discovery of causative agent of tuberculosis set the pace of efforts worldwide to eradicate tuberculosis on the pattern of smallpox. Many nations in the world have already done so. Developing countries are still putting in efforts to eradicate the killer disease of the poor who cannot afford timely diagnosis and treatment in-spite of the free supply of anti-tuberculosis drugs.

Tuberculosis is still on the top of communicable diseases in many countries. Lack of awareness, poverty and associated malnutrition are the invitation for this communicable disease. BCG is the vaccination used to generate immunity against tubercle bacilli, but unfortunately the same has been failed to provide effective immunity in some geographical areas. The laboratory diagnosis of tuberculosis is largely based on x-ray study of the chest and examination of sputum for tubercle bacilli. Once diagnosed, the disease is curable.  Home-based treatment of tuberculosis is as effective and safe as the isolation ward of a hospital. At present the standard-regimen for treatment of tuberculosis is for six-months. However, a re-investigation and follow-up is must.  Extra-pulmonary tuberculosis can be diagnosed by cytological evaluation of 'fine needle aspirate' for tubercle bacilli. Polymerase chain reaction (PCR) is newer diagnostic method for Extra-pulmonary tuberculosis.

Participation of community is must for successful eradication of tuberculosis. If somebody is under treatment at a home, he/she should be confined to a room for at least two months of treatment, and all members of the family should bear mask in case of pulmonary tuberculosis. The preventive and curative efforts should move 'hand-in-hand' for successful eradication of tuberculosis.

Children’s health, growth and immunization: Our role in preventing preventable diseases

Unless we look after our women and children in a programmed manner in the field of health, we cannot have a happy world around us. Children are still killed or disabled each year by diseases that could have been prevented by immunization. The World Health Organization (WHO) is doing its best to eradicate/eliminate a variety of infectious diseases, but involvement of every citizen of the world is must for compliance of various programs of the WHO. The measles, mumps and rubella triple vaccine (MMR) should be included in the EPI (Expanded Preventable Immunization) program of every country. We should not ignore the facts that measles and mumps can cause considerable morbidity and mortality which could be prevented with optimum immunization. Optimum immunization means full course of vaccination schedule without missing any booster dose.

Apart from vaccination child nutrition and general health must be taken care of. The child health reminds me the efforts of Mr. James P Grant, the Director of United Nations' Children's Fund (UNICEF, 1984), who in 1984 brought out a Report on the State of World's Children, and forwarded a mnemonic GOBI-FFF to remember the techniques which could reduce sadness of the world. In GOBI-FFF, "G" stands for growth monitoring, "O" stands for oral rehydration therapy, "B" stands for breastfeeding, and "I" stands for immunization. The three Fs (FFF) stand for 'family spacing', food supplements and female education. The methods represented by GOBI-FFF are the simplest methods which could help us in tiding over the state of health of children and preventing diseases and saving lives. Consequent upon the compliance of GOBI-FFF, lives of millions of children are saved every year and the health and growth of millions more is protected. Still there is need to protect the children from episodes of common childhood diseases like measles, respiratory infections and diarrhoeal infections.

Various infections also interfere with physiological and psychological development of children. The malnutrition and infections perpetuate each other and may lead to suboptimum brain development. The GOBI methods are not so expensive. Community health workers can be assigned the responsibility of growth monitoring through periodic recording of weight and height of a child. The oral rehydration salts (ORS) should be supplied at cost price to prevent the dehydration caused by diarrhoea. The breastfeeding should be encouraged since it provides ideal nourishment to the child and saves from the infectious hazards of bottle feeding. Immunization against tuberculosis, diphtheria, pertusis (whooping cough) tetanus, polio, measles, mums and rubella protects the child against these serious as well as disabling diseases. Attention should also be given to the health education of mothers. Awareness about the child's health in mothers would definitely make all the healthcare and immunization programs successful. It is well established fact that proper spacing between child births decreases the risks to the heath of the mother and the infant. Food supplements should regularly be supplied to the mothers during pregnancy and vaccination against tetanus should be done. We must put in our best efforts to prevent the preventable diseases since prevention is better than cure.