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TUBERCULOSIS – AN INDIAN SCENARIO

ABSTRACT
Tuberculosis is a highly infectious disease caused by Mycobacterium tuberculosis. It has been present in Humans since antiquity, as the origins of the disease are in the first domestication of cattle. Several Egyptian mummies with severe skeletal deformities suggested that TB existed since long (Pott’s disease). TB was also known as Consumption, Phthisis, White-plague.

About a third of the world’s population is infected with Mycobacterium tuberculosis. Among communicable diseases, TB is the second leading cause of death worldwide after HIV/AIDS, killing nearly 2 million people each year. India accounts for one fourth of the global TB burden. India has highest burden of both TB and MDR TB based on estimates reported in Global TB Report 2016.
The aim of this review is to provide an update on the tuberculosis in an Indian scenario.

Key-words: Multi drug resistant TB, tuberculosis, white-plague

INTRODUCTION:
Tuberculosis is a highly infectious disease caused by Mycobacterium tuberculosis. It has been present in Humans since antiquity, as the origins of the disease are in the first domestication of cattle. Several Egyptian mummies with severe skeletal deformities suggested that TB existed since long (Pott’s disease). TB was also known as Consumption, Phthisis, White-plague.

Epidemiology:
About a third of the world’s population is infected with Mycobacterium tuberculosis. Among communicable diseases, TB is the second leading cause of death worldwide after HIV/AIDS, killing nearly 2 million people each year.  Approximately 13% of TB cases have co-existed HIV infection. More than a half of TB cases occur in the largest Asian countries (India, China, Indonesia, Bangladesh, Philippines, and Pakistan). Sub-Saharan Africa presents with the highest incidence rate (around 300/100,000 population per year).

Even though TB has declined in Western Europe and North America, the global TB burden appears on the hike, especially in the former Soviet Union, Eastern Europe, and Africa. HIV infection accounts for much of the recent increase in the global TB incidence. According to WHO, “it is estimated that between 2000 and 2020, nearly one billion people will be newly infected, 200 million people will get sick, and 35 million will die from TB – if control is not further strengthened”.

India accounts for one fourth of the global TB burden. In 2015, an estimated 28 lakh cases occurred and 4.8 lakh people died due to TB. India has highest burden of both TB and MDR TB based on estimates reported in Global TB Report 2016. An estimated 1.3 lakh incident multidrug resistant TB patients emerge annually in India which includes 79000 MDR-TB Patients estimates among notified pulmonary cases. India bears second highest number of estimated HIV associated TB in the world. An estimated 1.1 lakh HIV associated TB occurred in 2015 and 37,000 estimated number of patients died among them. The incidence of TB has reduced from 289 per lakh per year in 2000 to 217 per lakh per year in 2015 and the mortality due to TB has reduced from 56 per lakh per year in 2000 to 36 per lakh per year in 2015.

SOCIAL AND ECONOMIC BURDEN OF TB IN INDIA
Estimated burden per year
n    Indirect costs to society $3 billion
n    Direct costs to society $300 million
n    Productive work days lost due to TB illness  100 million
n    Productive work days lost due to TB deaths 1.3 billion
n    School drop-outs due to parental TB 300,000
n     Women rejected by families due to TB  100,000

On an average, 3 months of work time are lost if an adult has TB, resulting in the loss of 20-30% of annual household income and an average of 15 years of income is lost if the patient dies from the disease.

Causes for high prevalence in India
1. Large number of active cases
2. Overcrowding due to large population
3. Poverty and poor nutrition
4. Bad sanitation
5. Illiteracy – leads to stoppage of treatment
6. HIV cases – increasing in India – as a co-infection

Classification:
I. Based on organ involved:
Pulmonary TB & Extra pulmonary TB
II. Based on the type of Infection:
Primary, Secondary
III. Based on localization of infection:
Localized pulmonary TB and Disseminated / Miliary Tb
85% of the cases are reported are pulmonary and the rest 15% accounts for extrapulmonary type. The most common extrapulmonary sites include spine, genitourinary, lymph nodes, bone, meninges, peritoneum, pericardium.

The primary mode of transmission is by the inhalation of air bone particles containing Mycobacterium tuberculosis. These bacteria are then transported to the alveoli where they undergo multiplication and spreads all over the body through blood stream and lymphatic system. It can also be transmitted by drinking unpasteurised milk from cow infected with M.bovis. Ingestion of self sputum may cause gastrointestinal TB. Direct inoculation into skin or mucosa is also a possibility.

The clinical manifestation of pulmonary type include productive cough lasting for more than three weeks, dull aching chest pain, hemoptysis, fever, malaise, fatigue, night sweats, loss of appetite and weight loss. In case of extrapulmonary the manifestation depends on the organ involved.

About 0.1% to 5% of the cases have shown oral manifestation. It can occur either as a primary or secondary lesion. The most common form to occur in the oral cavity is the secondary type. The primary lesions are seen in younger individuals whereas the secondary lesions are seen in elderly individuals. The primary lesion mainly affects the gingiva and presents as a diffuse, hyperemic, nodular or papillary proliferation of the gingival tissues and regional lymphadenopathy. The lesion extends from the gingival margin up to the depth of the adjacent vestibule. The secondary lesions usually manifests as a chronic non healing painful ulcer. Tongue is the most common site, followed by palate, lips, buccal mucosa, gingiva, floor of the mouth and palatine tonsil.

The oral lesions can manifest in various forms, such as nodules, ulcers, periapical granulomas and tuberculomas. It can even involve the jaws in the form of TB osteomyelitis. Among the oral lesions, the ulcerative form is the most common form of manifestation. They are pale, indolent, irregular ulcers with inverted margins and the floor is covered with granulation tissue and slough.

The four components of diagnosing TB includes
1. History and Physical Examination
2. Tuberculin Skin Test
3. Chest Radiograph
4. Bacteriologic Examination of sputum

1. History and Physical Examination
History taking is very important in order to find out whether the person was exposed, has symptoms, had prior TB disease or has risk factors for developing TB. Most cases of TB are diagnosed when patients seek medical care for TB-related symptoms or other medical conditions.

2. Mauntoux test
The biologically active material in the liquid medium after growth of M.Tb was named tuberculin. This crude material was later called as Old Tuberculin. A purified protein derivative of tuberculin (PPD) was made by Siebert in 1924 by precipitating it with saturated ammonium sulfate. The WHO adopted a large batch of PPD and designated it as PPD-s, as international standard tuberculin. The Mountoux test or Intracutaneous test is performed by injecting 5 TU contained in 0.1 ml of solution intracutaneously with a needle and a syringe. This is known as intermediate strength test. It corresponds to 0.1 micro gm of standard preparation. PPD is also available in the dosage of 1-250 TU, but generally 5 TU is considered as standard and appropriate to obtain the required result.

Principle: when PPD is injected intradermally in a subject previously infected with M.Tb, a hypersensitivity reaction develops at the site of injection. This comprises an inflammatory response characterized by the accumulation of CD4 and CD8 cells and consequent release of inflammatory mediators, which presents as a rash clinically and it is interpreted.

Interpretation:
In a sensitized individual a reaction of redness, swelling and induration begins at about 6 hrs, reaches a maximum intensity at 36-60 hrs and then fades over next few weeks. The area of induration is measured in millimeters and a standard chart is used to compare the values to determine if the individual is positive. A positive reactive test, that is induration up to 10 mm or more, denotes previous infection with M.Tb. Induration of 5-9 mm signifies a probable prior infection. 0-4 MM – means previous infection unlikely.

False Positive reaction:
•    Prior BCG vaccination
•    Exposure to non-TB Mycobacteria
•    Factitious –caused by rubbing or scratching the area

False Negative results:
•    Viral infection, especially HIV
•    Severe and Overwhelming TB
•    Other bacterial Infections
•    Renal failure and Diabetes Mellitus
•    Disorders of Lymphoid organs: Leukemia, Lymphoma, Sarcoidosis
•    Immunosuppressive therapy: corticosteroid =/> 15 Mg/day, Anti-cancer drugs, Cyclosporins
•    Improper storage of PPD, denaturation/contamination

Mountoux is widely preferred and used method to detect TB exposure. Other tests that make use of same PPD but different injecting device are:
1. Heaf test
2. Tine tests
These tests are said to have poor sensitivity and specificity than Mountoux and hence not commonly used.

3. Chest Radiograph
Infiltrates or cavities can appear on a chest radiograph. However, a person with TB disease can have a “normal” chest radiograph.

4. Bacteriological Examination: Sputum Smear and Culture
Sputum can be collected for pulmonary and urine or spinal fluid can be collected for extrapulmonary type. It is examined for the presence of acid fast bacilli.

Transmission of TB occurs very frequently in the dental clinics either from patient to doctor or from doctor to patient. The possible routes are airborne transmission, which is the more common route or through direct contact either by contaminated instruments or mycobacteria on dentist’s fingers. Thus it is important that the office protocols are in place to prevent its transmission.

The guidelines for infection control in dental settings 2003 from the CDC reinforces the need for managing dental environmental surfaces and should serve as the standard for clinicians to follow regarding surface disinfection.

The recommended guidelines for dental management of tuberculosis patients are:
1. Limit the use of ultrasonic scalers and high speed hand pieces in actively infected patients. High volume suction is mandatory for carrying out any procedure to minimize aerosol generation.
2. Use rubber dam isolation with high vacuum suction. On the other hand, if the patient has productive cough it is better to avoid Rubber dam.
3. Maintenance of proper hand hygiene, personal protective equipments like eye shields, facemasks, head caps, gloves and surgical gowns.
4. Use a well constructed, soft pleated, high filtration face masks. Face masks should have at least 95% Bacterial filtration efficiency (BPE) for particles 3μm diameter (3M™ N95 Particulate Respirator). The operator should wear respirators while treating patients with symptoms of active TB.
5. Provide dental operatories with fresh, non recirculated outdoor air to dilute the contaminated operating air. TB rooms should have effective air evacuation with either exhausted or HEPA-filtered if re circulation is necessary.
6. Regular fumigation of dental operatories. Cleaning and disinfecting critical and semi critical contact surfaces like Dental chair and accessories. Anti bacterial sprays may be used.
7. Use of barrier techniques.
8. Use of high efficacy filters or UV light in the exhaust air ducts.
9. All dental settings should conduct an annual risk assessment for TB    transmission

Dental Management of patient with TB
Patients with active sputum-positive TB:
•    Consult a physician before treatment
•    Administer emergency care only
•    Treat in hospital setting with isolation, sterilization, gloves, mask, gown, special ventilation
•    If patient’s sputum is negative for AFB, treat as normal patient

Patients with History of tuberculosis:
•    Approach with caution; obtain thorough history of the disease and its treatment duration
•    Obtain chest X-ray, if necessary
•    Consult a physician if questionable history and if there is lack of medical supervision, if signs of relapse
•    If present status is free of active disease, treat as normal patient

Patients with recent conversion to positive tuberculin skin test:
•    Should be evaluated by a physician to rule out active disease
•    If no active disease, treat as normal patient

Patients with signs and symptoms of TB:
•    Refer the patient to a physician or a Primary health centre
•    Defer the treatment, provide only emergency treatment only

Multi drug resistant TB:
Drug-resistant TB is widespread and it emerges as a result of treatment mismanagement. It is passed from person to person in the same way as drug-sensitive TB.  Multidrug-resistant TB (MDR-TB) is a form of TB which does not respond to the standard treatment using first line-drugs (i.e. resistant to isoniazid and rifampicin).

Definition
Multi-drug resistant tuberculosis is defined as resistance to rifampicin and isoniazid whether there is resistance to other drugs or not. It is therefore incorrect, by this definition, to classify a patient has having multi-drug resistant disease if they have an infection with a bacterium susceptible to rifampicin but resistant to many other drugs.

However, treatment had to be continued with good quality drugs for as long six months to ensure cure. It can take two years to treat with drugs that are more toxic, and 100 times more expensive. If the drugs to treat MDR-TB are mismanaged, further resistance can occur. Extensively drug-resistant TB (XDR-TB) is a form of TB caused by bacteria resistant to all the most effective drugs (i.e. MDR-TB plus resistance to fluoroquinolone and  the second-line anti-TB injectable drugs: amikacin, kanamycin or capreomycin).

The difficulties in ensuring this occurs, especially in resource poor countries, has resulted in an increasing incidence of tubercle bacteria resistant to the most effective drugs.

In a country like India, MDR-TB is almost equivalent to a death sentence, as few patients have the financial capacity or resources to complete the required long term regimen.

Drug Resistance TB Survey Findings:
Fourthy five countries in the world with at least one case confirmed. In former Soviet Union countries, proportions of X (extensive) DR-TB among MDR-TB range from 4% in Armenia, to almost 24% in Estonia. The treatment of multi-drug resistant tuberculosis is specialised, complex and expensive and should only be undertaken at recognised centres with experience of managing such patients. But, for the clinician who is faced with a patient with tuberculosis, as no way of knowing that the patient has drug resistant bacteria until culture results are available and these may take some weeks. The clinician must therefore be aware of risk factors which may raise the possibility of drug resistant tuberculosis and put the doctor on his guard.

The following are the risk factors for drug resistance:
•    Previous treatment for tuberculosis especially if prolonged
•    Contact with another patient known to have drug resistant disease
•    Immigration from an area with a high incidence of drug resistance
•    HIV seropositivity
•    Drug  abuse

Treatment of MDR TB
With multiple drug resistance, use atleast three drugs to which the organism is sensitive. With resistance to one of the four main drugs use of other three drugs to be made. Therapy should be continued for upto 2 years and in HIV +ve patients with DR, therapy continued for at least 12 months after –Ve culture. Second line drugs available for treatment of resistant M.tb are capreomycin, cycloserine, clarithromycin, azithromycin, ciprofloxacin, ofloxacin, ethionamide, kenamycin and amikacin.

Numerous novel drugs have been introduced in the market in recent times which promise to be a better alternative like Nitroimadazoles group, Diarylquinolines, Oxazolidinones, Phenothiazines, for effective treatment of TB.

Drugs used in the treatment of TB are basically classified as
•    First-line agents
a.    Essential drugs
b.    Supplemental drugs
•    Second-line agents
First-line essential drugs are highly effective and are a necessary component of any therapeutic regimen. The first line supplemental drugs are also effective, and infrequently toxic. Second line drugs are clinically less effective and frequently cause severe adverse reactions.

First-line Essential drugs: Rifampicin (R), Isoniazid (H) and Pyrazinamide (Z).
First-line supplemental drugs are: Ethambutol (E), Strptomycin (S).
Second-line drugs are: para-Amino salicyclic acid (PAS), Ethionamide, Cycloserine, Kanamycin, Amikacin, Capreomycin, Viomycin and Thiacetazone.
Newer Anti-tubercular Drugs: Rifapentine, Refabutin and quinolones such as Ciprofloxacin, oflaxacin and Sparfloxacin.

Direct Observed Treatment Short Course (DOTS)
•    Directly Observed Therapy Short course is a program to cure TB.
•    A DOT Lay Worker meets with clients to help with TB medication, and provide support and education.
•    DOT by definition means watching clients swallow each dose of anti-TB medication
Intensive phase ( 2-3 months): under direct supervision of a health worker or trained person
Continuation phase (4-6 months): a multiblister combipack with drugs for 1 week is given of which the first dose is taken under supervision

Category I
Color of box: RED
Type of Patient: new sputum smear positive, new sputum smear negative, new extra pulmonary.
Regimen: 2 (HRZE)3, 4 (HR)3
Duration in months: 6

Category II
Color of box: BLUE
Type of Patient: Sputum Positive relapse, Sputum Positive failure, Sputum Positive treatment after default
Regimen: 2 (HRZES)3, 1 (HRZE)3, 5 (HRE)3
Duration in months: 8

Category III
Color of box: GREEN
Type of Patient: Sputum Negative, extra pulmonary not Seriously ill
Regimen: 2 (HRZ)3, 4 (HR)3
Duration in months: 6
Multi Drug Resistant TB (MDR-TB) : atleast resistant to Isoniazid and Rifampicin
Treatment based on dots – plus

Intensive phase 6-9 months
Kanamycin
Ofloxacin
Cycloserine
Ethinamide
Ethambutol
Pyrazinamide
Continuation phase :- 18 months
Ofloxacin
Cycloserine
Ethionamide
Ethambutol
Extensively Drug Resistant TB (XDR TB): Resistance to Isoniazid and Rifampicin + resistance to any of the Fluoroquinolones + resistance to any one of the injectible second line drugs.

Intense phase:- 6-12 months
•    Caperomycin
•    Para Aminosalicylic acid
•    Moxifloxacine
•    Clofazimine
•    Linezolid
•    Amoxicillin / Clavulanate

Continuation phase :- 18 months
•    Para Aminosalicylic acid
•    Moxifloxacine
•    Isoniazid
•    Clofazimine
•    Linezolid
•    Amoxicillin / Clavulanate

Adverse reactions to anti-TB drugs
•    Isoniazid- Peripheral neuropathy, hepatitis
•    Rifampicin – Vomitting , abdominal pain, hepatitis
•    Pyrazinamide – Joint pains , hepatitis
•    Ethambutol – Optic neuritis
•    Streptomycin – Renal damage, auditory & vestibular nerve damage

Government initiatives:
Revised National Tuberculosis Control Program aims to eliminate TB in India by 2025. The government has implemented various projects like “Universal Access to TB care” which plans to   link access to services and IT support with private sector for attracting TB notification from private hospitals in Patna, Mehsana, and Mumbai. They have developed “NIKSHAY” – a web based TB surveillance system to aid in notification. They have also reduced the price of various laboratory investigations and free medications for TB patients.

Conclusion:
Tuberculosis is one of the oldest and a well known disease. It was almost eradicated from most of the countries in the recent past but now has re-emerged as one of the chronic infections affecting mankind. Its presence as a co-infection with HIV needs special attention. The disease can be well controlled and cured by proper medical care. Dentist can be the first to recognize TB where only oral manifestations are present, which helps to prevent further spread of the disease to the community and hence knowing this disease in detail is of utmost importance. At the same time even dentist should be aware of the precautionary measures that should be undertaken while treating a patient diagnosed with TB as there is high risk of transmission in the dental setting through the generation of aerosols.

References:
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2.    Government of India. Revised national tuberculosis control programme. Annual status report 2017.
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