NATIONAL INTEGRATED VECTOR CONTROL PROGRAMME
NATIONAL INTEGRATED VECTOR CONTROL PROGRAMME
National Integrated Vector Control Programme is an expanded version of earlier National Malaria Eradication Programme. The Cabinet Committee on Economic Affairs has recently expanded the scope of earlier programme to cover 4 diseases i.e. malaria, filaria, dengue and Japanese encephalitis, after the growing menace of Japanese encephalitis acknowledged. The programme involves a total fund of Rs 1350 crores in the 10th Plan. One of the main targets of the Plan is to eradicate filaria by 2008.
- Reasons behind failure of Malaria Control Programme
- Due to the direct use of pesticides; the insecticides developed resistance in vectors.
- Malarial parasite became resistant to chloroquinine, the most commonly used medicine.
- Pesticides could not be made available at right time in affordable prices.
- Supervision mechanism has been ineffective.
- Administrative inefficiency and the lack of sufficient funds to operationalise the programme.
- Intensive research should be carried out to discover new insecticides and to develop their bio-control methods and immunizing agents so that vectors may not become resistant to the insecticides.
- Alternative insecticides like use of microbes and other biological agents should be promoted.
- Environmental method of controlling mosquito breeding should be used.
- Malaria control should not operate in isolation. It should be integrated to all other healthcare programmes.
- Continuous review and monitoring of the programme.
- DNA vaccines are also a promising mode of control by mediating T-cell mediated response.
Alexander the Great has been, indisputably, the greatest of conquerors mankind has witnessed since the dawn of human civilization. But unimaginably, the strength and valour of this all-time hero appears- stumpy when viewed against the triumphs of the single-celled bug that unleashes, across the globe, its tyranny spelled out as ‘tuberculosis’. The culprit, Mycobacterium tuberculosis, is for sure the most successful conqueror of human lives as it infects one in three people worldwide and kills about 3 million victims every year on a global scale. Nearly 9 million new TB cases add to the TB burden of our planet annually. To make matters worse, the TB bug is infamous for turning resistant to common drugs and invading almost every part of the human body.
TB – An Ancient Scourge
Affecting the poorest people in society who live in overcrowded areas and maintain poor hygiene, TB is an airborne communicable disease plaguing human populations since antiquity. Signs of tubercular decay have been found in bone fragments of 4000-year-old Egyptian mummies. Called variously as ‘consumption’ or ‘phthisis’ or ‘white plague’, TB was rampant in Europe and the US in 1600s. The stigma of being a victim of TB was so much that patients were made to live in total isolation until death, in places called sanitaria.
In 1882, Robert Koch made a breakthrough by discovering the tubercle bacillus through a staining technique for identifying this bug. He was awarded with the Nobel Prize in Physiology or Medicine in 1905 “for his investigations and discoveries in relation to tuberculosis.” Even today, despite the availability of a preventive vaccine and potent drugs to contain this disease, TB remains a daunting adversary. Although victims of TB occur all over the globe, this disease poses a tough challenge in the developing countries, which account for about 95% of all TB cases. South-east Asia, Western pacific and Africa are, in fact, the most severely hit regions. In India the bug kills 1000 people every day!
Journey of the Culprit
Mycobacterium tuberculosis is a microscopic, rod-shaped bacterium that is transmitted through the air when the infected person coughs, spits, or sneezes. It is a slow growing, acid-fast bacterium that .cart remain viable in dried aerosol droplets for as long as eight months. The dust from the dried saliva or sputum might also contain TB bacilli, which spread the infection. In fact, it is truly a dangerous gamble going to congested places in areas with high TB incidence.
This single-celled bug primarily attacks the lungs. TB infection is characterized by the formation of tubercles or hard nodules in the lungs that are the result of interaction between the bacteria and the host’s immune system. Basically, when M. tuberculosis enters the lungs, special cells of the host’s defence machinery called macrophages engulf the pathogen, but they are unable to dig’ the bacteria due to its waxy outer coat .This bug then begins to multiply within the macrophages, eventually killing these cells that are supposed to protect the host.
The infected macrophages result in an inflammatory response, which attract more macrophages until the site of infection is completely surrounded by large groups of these cells. Inflammation further triggers the deposition of collagen fibers around the packed macrophages, forming a site of enclosed infection within the lung called a tubercle. The cells at the centre of the tubercle may eventually die giving rise to necrotic/dead tissue. As more and more macrophages are affected by the TB bacilli, the victim begins to show the early signs of the disease.
Tuberculosis is clinically categorized into primary TB, secondary reactivated TB and disseminated TB.
Primary Tuberculosis: The first infection with TB bacilli, which gears the body’s immune system to either eliminate the pathogen fully or prevent the spread of bacteria and progression of the disease. With most TB infections, our body’s defence machinery is able to contain, although not eliminate, the TB bacilli within the tubercle. It is here that the bug remains dormant for years together.
Secondary or Reactivated Tuberculosis: In case the TB bacilli suddenly awake inside a lung tubercle and reactivate to rupture the tubercle and spread through the lungs, it is called secondary infection or reactivated TB. This reactivation invariably occurs in people with a weakened immune system.
Disseminated Tuberculosis: It is that stage of TB when the bacilli rampantly spread within the body as infected macrophages move through the blood and lymph. As the bug gets lodged in different sites of the body, infection occurs in these organs and symptoms of TB begin to show up.
The early symptoms of TB include fatigue, recurrent fever, unusual loss of weight and coughing. An infected person normally has night sweats and sometimes there is blood in cough. In advanced stages, the patient shows prolonged coughing for more than three weeks, breathlessness, and recurrent fever. This is pulmonary TB where the bacterium resides primarily in the lungs. The severity of TB infection depends on whether the bug has spread from the lungs to other parts of the body. The diseases is most serious when the Bacterium infects blood, bones, the meanings (membranes around the brain and spinal cord), or the kidneys.
Despite being infected with TB bug, most people do not show active disease, which only gets triggered when the person’s immune system is weakened due to many factors like malnutrition, alcohol abuse and infection with human immunodeficiency virus (HIV/AIDS virus). This is latent tuberculosis infection (LTBI), where the victims have the TB germ in their body (usually lungs), but have yet to develop clear- cut symptoms. In fact, no TB bacilli are found in the sputum of such persons, which is why latent infection is not enough to spread the disease. In many persons with latent infection, TB may last for a lifetime without developing into full-fledged disease. Most cases of active disease occur through the conversion of latent infection to active disease.
Normally, TB is diagnosed by tuberculin skin test, chest X-ray and microscopic analysis of sputum smear/ culture. A repertoire of new methods for molecular detection of the TB bug is also available and still better diagnostic tools suiting the needs of poor countries are under development.
The most common tuberculin skin test is the Mantoux test, which consists of injecting a small amount of protein from the TB bacilli into the forearm. A reddening and swelling of the area after 24-72 hours signals the presence of TB. This is not a definitive diagnosis of TB. Persons with latent and active TB cannot be differentiated with this test. The skin test often remains positive for life after initial infection with TB, which is why the test can be false positive in patients successfully treated for TB in the past. However, all victims of this disease show a significant reaction to a Mantoux skin test and the TB bug is found in their sputum.
The diagnosis of TB largely depends on the microscopic demonstration of acid-fast bacilli (AFB) in sputum samples using Ziehl-Nielsen stain, described by two German doctors, Franz Ziehl and Friedrich Nielsen. It is the simplest laboratory test for detecting TB bacilli. This diagnostic test is cheap and fast but cases of non- pulmonary TB cannot be detected as infection occurs in different organs of the body. Besides, acid-fast bacilli other than M. tuberculosis could also be stained which means that the specificity of sputum test is not 100%.
The auramine fluorescence staining method that requires fluorescence microscopy is more sensitive than AFB staining as the fluorescence is easier to see than the coloured stain. Smear microscopy has for long been the gold standard of TB diagnosis, and is employed under the DOTS (directly observed therapy) strategy for TB control, that is internationally recommended by the World Health Organization (WHO).
Chest X-ray and CT Scan
Chest X-ray is used to check for any lung abnormalities in people who have symptoms of TB. The results of a chest X-ray are not specific as many other diseases can produce similar changes in the lungs. The test is not useful if the TB is not in the lungs. So in 40% of all cases of active TB where the disease is not found in the lungs, the chest X-ray is of no use. Besides, Computerized Tomography (CT Scan) and Magnetic Resonance Imaging (MRI) have proved useful for imaging tuberculosis lesions, particularly those in the brain and spine.
A gold standard for active TB, culture based detection is extremely sensitive if TB bacilli are present in the sample. TB bacilli can be cultured from a variety of specimens including sputum, central spinal fluid (CSF), pleural effusion etc., and can thus be used to detect, pulmonary as well as non-pulmonary disease.
By assessing the effect of antibiotics on the cultured bacilli, this technique can also identify the antibiotic susceptibility of the particular strain of TB infecting the patient. It is, therefore, the main method for identifying if a person has MDR-TB. But as it is not always possible to obtain mycobacteria in the sample, especially in non-pulmonary TB, the culture method is not a sensitive test. The culture test is also time-consuming as it takes about 2 to 6 weeks. More importantly, good laboratory facilities requiring expensive equipment and high maintenance are a prerequisite for performing culture-based diagnosis and drug-resistance testing. That is why the culture method for TB Y detection does not suit resource-poor settings.
Global research efforts have paved the way for revolutionary, molecular- based techniques for the diagnosis of TB that have opened the door to rapid TB detection for initiating timely treatment.
Nucleic acid amplification (NAA) tests: These techniques include polymerase’ chain reaction (PCR), Amplicor MTB Test (Roche Diagnostic Systems Inc, New Jersey, USA) and the Amplified MTB Direct Test (MTD; Gen-Probe, California, USA). The PCR method is based on identifying the species-specific DNA segments of the TB bacillus from a given sample. The Amplicor is a DNA- based test that amplifies and detects the presence” of a specific ribosomal RNA of TB bacilli in a colorimetric reaction. The MTD test is based on the amplification of the same ribosomal RNA of the TB bug but its detection is with a DNA probe. Both these methods are approved for the direct detection of M. tuberculosis in smear-positive cases. These methods confirm the presence of M. tuberculosis within 1 to 3 days as compared with 2 to 6 weeks with culture techniques. Moreover, these methods are being used to identify MDR-TB as mutations in the DNA of MTB, which confer drug resistance, have been discovered.
Interferon Gamma Assay: Called QuantiFERON®-TB (QFT-G) Gold test, it is a highly specific test for detecting MTB infection, and was approved by the U.S. Food and Drug Administration (FDA) in 2005. Blood samples are mixed with antigens (substances that can produce an immune response) and controls. For QFT-G, the antigens include mixtures of synthetic peptides representing two M. tuberculosis proteins. After incubation of the blood with these antigens for 16 to 24 hours, the amount of interferon-gamma (IFN- gamma) is measured. If the patient is infected with M. tuberculosis, their white blood cells will release IFN-gamma in response to contact with the TB antigens The QFT-G results are, therefore, based on the amount of IFN-gamma that is released in response to the TB antigens. Clinical evaluation and additional tests (such as a chest X-ray, sputum smear, and culture) are needed to confirm the diagnosis of latent TB or active TB. This test reduces the number of false-positive results suspected to be cases of latent TB.
In addition, this test may increase the identification of more cases of latent TB before progression to active disease. However, it requires laboratory equipment and trained personnel thus increasing the operational cost. Moreover, the sensitivity of this test for particular groups of TB patients (e.g., young children and immunocompromised patients) has not been determined.
Drugs to Combat TB
The first tuberculosis patient was treated in 1944, thanks to Selman Waksman who in 1943 discovered the antibiotic ‘streptomycin’ from a fungus called Streptomyces griseus. For this discovery, Waksman was awarded the Nobel Prize in Physiology or Medicine in 1952. Two other drugs, ‘para- aminosalicylic acid’ (PAS) and ‘isoniazid’ were also developed at this time that were effective in TB therapy. Even today, TB treatment regimen involves the intake of strong antibiotics, mainly rifampicin and isoniazid, which are the standard or first-line-drugs against TB.
As drug-resistant TB strains are widely prevalent, it is important to grow the patient’s bacteria in a culture and test with a variety of drugs to determine the most effective treatment. The chosen drugs then need to be continued without fail for the entire duration of treatment that normally extends from about six months to two years. Failing to complete treatment with these drugs hot only retards the recovery process but also allows the TB bug to smartly alter its outer coat, which is the first step towards development of MDR-TB. Use of fake or poor quality drugs also can result in development of MDR form of the disease.
MDR-TB takes longer to treat and can only be cured with second-line drugs, which are more expensive and have more serious side effects. The misuse of these second-line drugs results in extensively drug-resistant TB (XDR-TB), which is resistant to both first- and second-line drugs. The most widely accepted drug regimen is the combination of isoniazid, rifampicin, pyrazinamide and ethambutol or streptomycin daily for two months, followed by isoniazid and rifampicin daily for four additional months.
The focus of present research is on developing less-toxic yet potent drugs to combat TB, which could shorten the treatment span. According to WHO estimates, there are about 4 lakh new cases of MDR-TB globally each year.
Although XDR-TB cases have been recorded in 37 countries, it is the lack of accurate diagnosis that makes it difficult to estimate such victims. Certainly, the treatment options for XDR-TB are very limited making the disease invariably fatal.
TB and AIDS – Twin Terror
Globally more and more AIDS patients are getting infected with TB bacilli. According to the National AIDS Control Organization (NACO), 60% of AIDS patients contract and ultimately die of TB. Actually, the deadly AIDS virus (HIV) damages the body’s natural defence machinery and accelerates the speed at which TB progresses from harmless infection to a life-threatening condition. The worse happens when the MDR-TB strains join hands with HIV and co-infects an individual, as it then seriously undermines all scientific efforts to contain this scourge. In this lethal partnership with HIV, both deadly partners speed up each other’s progress. The opportunistic TB bacilli simply spread like wildfire and kill the off-guard HIV-infected people. There are about 15 million people co-infected with TB-HIV in the world.
TB Burden on Poor Nations
Stalking the poor populations in different parts of the world, TB mainly spreads due to lack of proper nutrition and cramped living conditions with poor personal hygiene. Without financial support, the economic burden of TB in badly hit countries including
China and India could reach up to a whopping $1.2 trillion between 2006 and 2015.
Tuberculosis often goes undetected in developing countries, as due to limited resources people seeking treatment are not tested for drug sensitivity – a strategy fundamental to the control and treatment of drug- resistant TB. The need of the hour is to provide these most affected countries a quick, cheap and technically reliable diagnostic test for TB for rapid identification of drug-resistant strains. This calls for support of policy makers in increasing funding for research into TB diagnostics, and improving laboratory facilities for making TB diagnosis and drug-sensitivity testing accessible in the low resource settings of remote, rural areas of developing countries.
Yet another concern is the non- adherence to TB treatment, especially among the poor, which encourages development of resistant TB strains. This needs to be checked.
Under the Revised National Tuberculosis Control Programme (RNTCP) that began in 1993, every Indian state has a State TB Centre under which there are several district TB centres and each district TB centre has many TB units that have microscopy and DOTS centres. The RNTCP network had spread across the entire nation by 2006. Supervised individual-specific DOTS in conjunction with focussed radiological and bacteriological follow up and use of surgery whenever required are indeed crucial for the clinical management of TB.
The current BCG (Bacille Calmette Guerin) vaccine, administered .intramuscularly in a single shot at birth, is not really effective in terms of preventing TB as evident from the rapidly increasing TB cases globally. This vaccine, developed by Albert Calmette and Camille Guerin in 1921, comprises live, weakened strain of the bovine tubercle bacillus called M. bovis, which is responsible for causing TB in cattle. Although BCG vaccine is widely employed in childhood immunization programmes, the world today needs a new TB vaccine that is more potent against the TB bacilli.
Among the various concerted efforts being made the world over to design new vaccines against TB, the most clinically advanced vaccine candidate – called MVA85A – is under clinical trials in South Africa. Designed by Dr Helen McShane, Wellcome Trust’s Clinician Scientist Fellow and researcher at Oxford University’s Centre for Clinical Vaccinology and Tropical Medicine, this subunit vaccine -comprises select proteins of the TB bacilli, and works well along with BCG vaccine. Actually the new vaccine boosts the protective power of BCG vaccine by augmenting the response of T-cells, already stimulated by the BCG vaccine. This vaccine has been developed by the South African Tuberculosis Vaccine (SATVI), with support of the Aeras Global TB Vaccine Foundation (AERAS), an organization that is dedicated to HIV/TB research.
Global Efforts for TB Control
The global scientific community is all set to meet the United Nations Millennium Development Goal of bringing down, by 2015, TB prevalence and death rates to half of the figures reported in 1990 (6.6 million cases). The Stop TB Partnership; hosted by WHO in Geneva, Switzerland, is a network of more than 500 international organizations, countries, donors from the public and private sectors, and nongovernmental and governmental organizations that are working together to eliminate TB.
The basic approach qfJ5top TB Partnership initiative is to reduce die burden of TB by concerted expansion of DOTS, addressing the lethal co-infection of TB /TTTV, MDR-TB, and strengthening the primary health care facilities in rural areas of affected countries as well as promoting research for designing better vaccines and new drugs to treat TB. Besides, a thrust on advocacy, communication and social mobilization (ACSM) activities is poised to empower populations to tackle the TB threat. The Stop TB Partnership has seven working groups each focusing its efforts in a particular strategy to control TB namely, designing new diagnostics, new vaccines, new drugs, DOTS expansion, addressing MDR-TB, addressing HIV- TB and engaging in ACSM activities.
The Partnership’s ‘Global Drug Facility’ as well as the ‘Global Fund’ together provide countries with anti-TB drugs ensuring continuous drug supply so that more TB patients take a full course of treatment. Moreover, all drugs supplied to countries by the Global Drug Facility are pre-qualified by the WHO- led TB Pre-qualification Programme. So, every batch is independently tested’ before being shipped to ensure it meets quality standards. Global Drug Facility is also working to provide the new TB detection tools to various TB affected countries of the world.
Another commendable initiative is the Foundation for Innovative New Diagnostics (FIND), which is working with nearly 40 companies, academic institutions and government bodies to develop simple diagnostic tests for TB that can be used in the field on large scale. A large part of funds available for TB research worldwide are being pumped in by the Bill & Melinda Gates Foundation.
Thanks to the Global Alliance for TB Drug Development (TB Alliance), a not-for-profit product development partnership, many global drug discovery collaborations are in pipeline for developing compounds active against drug-resistant TB strains.
“These partnerships show that the TB Alliance is aggressively increasing the depth and strength of its portfolio to ensure that promising new TB drug candidates continue moving toward the clinic,” says Dr. Mel Spiderman, CEO of the TB Alliance. For example, efforts are on to develop drugs that inhibit menaquinone biosynthesis – a key component of the energy generation system in M. tuberculosis. These novel drugs put a full stop to bacterial growth and are poised to be highly effective against drug-resistant TB as well.
Similarly, in a unique attempt, anti- TB agents from natural sources, including microbial metabolites and traditional Chinese medicines are being designed. Yet another drug target to combat MDR-TB is looking for inhibitors of the enzyme, type 1 topoisomerase, which is essential for the unwinding of DNA and, therefore, required for normal cell processes. The focus of all these efforts is to find new faster-acting, simpler drug regimens for both drug-sensitive and drug-resistant TB.
The drug, designated TMC207, discovered at the Belgian Research Laboratory of Tibotec, may one day be the front-line treatment for tuberculosis, for this new drug cripples the activity of ATP synthase, an enzyme that plays a key role in biological energy metabolism. It does that only in the TB bacterium, and not in other cells. In one clinical trial, 47 people with MDR-TB were given either the usual cocktail of TB drugs and TMC207 or the usual cocktail and a placebo. After eight weeks, the TB bacteria was not found in 48% of those getting TMC207, compared to 9% of those getting conventional treatment.
The best way to break the back of the present TB epidemic is undoubtedly by the three-fold strategy of improving TB diagnosis through simple, fast and reliable screening tools that suit low resource settings; providing anti-TB drugs to the patients making sure they complete their treatment and lastly by designing more potent yet safe vaccine(s) to prevent TB in healthy people. Notwithstanding the current repertoire of strategies being worked out feverishly to contain the TB epidemic, the battle against the TB bug is very challenging and only time will tell as to who enjoys the last laugh.
A World Free of TB
The key to the Stop TB Strategy is the strengthening of DOTS (directly observed therapy), which has five basic components: Political Commitments concerted, a national TB control programme requires adequate funding, from domestic as well as international sources, for which government support is indispensable. Diagnosing TB: A wide network of well-equipped laboratories with trained personnel is necessary for making quality-assured sputum testing accessible to all. Diagnosis of TB among HIV-positive adults and children, as well as detection of MDR-TB cases that respond poorly to the first-line drugs, are essential components of TB detection. Standardized TB Treatment: The mainstay of TB control is to supervise the treatment making patients take their drugs regularly, so as to prevent the development of drug resistance. Effective Drug Supply: For an uninterrupted and sustained supply of essential anti-TB drugs a reliable system of procurement and distribution of drugs is required. An effective case recording and reporting system is also necessary to maintain adequate stocks of anti-TB drugs. Effective Monitoring: This involves the compilation and careful evaluation of individual patient data with treatment outcomes.