Tuberculosis: Its Reemergence,
Resistance, and Therapies

Table of Contents

History of Tuberculosis
Epidemiology
Worldwide Incidence and Mortality of Tuberculosis
   into the New Millennium
Explanations for the Worldwide Increase in Tuberculosis
Pathophysiology
Natural History
Clinical Manifestations
Tuberculosis Control
Government Commitment to Tuberculosis Control
Passive Case Finding and Diagnosis
Treatment of Tuberculosis
Directly Observed Therapy
Continuous and Reliable Supply of Tuberculosis Drugs
Reporting and Recording
Other Interventions for Tuberculosis Control
Vaccination
Treatment of Latent Disease
Multidrug Resistant Tuberculosis

Readings

 

History of Tuberculosis

The irony of considering Tuberculosis (TB) among emerging diseases is that it is one of the truly historic diseases of our species, as illustrated by this little ceramic figurine. Produced in the 5th Egyptian dynasty, it shows a male figure with a deformity in the upper spine which is classic for Potts disease (TB of the spine).

Direct evidence of TB has been identified in Egyptian mummies by using DNA testing to find the causative organism, Mycobacterium tuberculosis, a species which spread from cattle to humans and became a persistent human pathogen.

Epidemiology

TB is a major health problem worldwide. It is estimated that about a third of the world's population is infected by Mycobacteria tuberculosis. In Africa and Asia, for example, between 50 and 70 percent of adults are infected. In Latin America, it is approximately 20 to 30 percent. About 8 million people will develop active TB worldwide and over 2 million people will die of tuberculosis every year. This is more deaths than are directly attributed to any other single infectious disease. It causes more deaths than any pregnancy-related conditions and is the single largest killer of young women.

Worldwide Incidence and Mortality
of Tuberculosis into the New Millennium

These are statistics from the World Health Organization (WHO) which are projections of the number of new TB cases and deaths from the year 1990. The projections show an increase of about 60% of new cases of TB by the year 2005. The death rate is not predicted since there are too many other factors involved. This illustrates the tremendous burden this single disease has globally.

Two thirds of the world's cases of TB are in Asia. Based on the WHO regions, the world TB rates break down as follows:

The highest incidence countries, however, are now in Africa. In Botswana where HIV infected rates are very high, the TB rate is 550 per 100,000 persons. What is the TB rate in the United States (US)? We are approximately 7 per 100,000 persons. In West Africa HIV infection is less, 100 per 100,000 persons; Asia has 200 per 100,000 persons. The former Soviet Union has approximately 50-70 per 100,000 and Latin America and the Middle East have 30-50 per 100,000 persons.

Explanations for the Worldwide Increase in Tuberculosis

• Demography: Population growth and increased longevity.
• The worldwide spread of HIV infection.
• Social injustice: the world's poor are disproportionately attacked.
• Population movement driven by social and economic factors.
• Breakdown or lack of public health infrastructure.

Why is TB increasing and why can we consider it among emerging infections? Much of the focus has concentrated on the global spread of HIV infection. HIV co-infection has been an important determinant in the increase in TB but it is not the only factor. First is simple demography. The world's population is increasing rapidly and currently stands at approximately 5-6 billion. An estimated 1 out of every 3 humans alive sustain a latent infection with Mycobacteria tuberculosis. Most of the 8 million active cases each year, arise when the latent infection activates. So if we have a disease that is very prevalent, and the population increases, and there is not good public health control, then the number of infected persons increases with the increasing population.

Social injustice refers to the fact that TB targets the most vulnerable members of the population. The world's poor have always been disproportionately affected by many diseases and the living circumstances for much of the world's population is deteriorating. TB is considered a disease of poverty but can be seen across all socioeconomic strata. Risk of TB does increase with poverty. This may be due to other factors such as crowding and malnutrition. TB is also seen more commonly in alcoholics and drug abusers.

In addition, there is increased mobilization of the world's population. People are moving to seek better economic opportunities and better lives for themselves and their families. There is also mass movement of people in time of civil violence and wars. Foreign born individuals account for 75% of the new cases of TB in Seattle, Washington in 1997.

The breakdown or lack of adequate public health infrastructure has been shown to contribute to resurgence of this disease. One of the best examples is the outbreak of multidrug resistant TB (MDRTB) in New York City in the mid-1980s. This occurred after funding for TB control had diminished significantly. We are also seeing the increase of TB in the former Soviet Union where 20-30% of prisoners are estimated to have active disease. If these numbers are accurate this is a worrisome trend.

Pathophysiology

TB is caused by Mycobacteria tuberculosis. The main site of the clinical manifestations is the lung. Approximately 85% of active cases have pulmonary manifestations, the other 15% are extra-pulmonary. It is transmitted by aerosolized droplet nuclei that are projected out from coughing, talking, and singing. These droplets containing the bacteria get suspended in the air and are inhaled by persons who come in contact with them. Actual contact with the patient is not always necessary to get infection. The risk of transmission increases with duration and intensity of exposure.

This is the primary scheme by which most people become infected with TB and go on to latent infection or active disease.

Natural History

Most people that develop the infection will never go on to get tuberculosis disease. The lifetime risk of progressing to active disease is about 10%, and this risk is greatest in the first two years after exposure. If you are infected, about 5% will go on to active disease within two years and 5% in the rest of their lifetime. Historically, 50% of the people with active TB died, 30% will cure spontaneously and 20% will enter a state of chronic infection. With resistant TB there is no reliable cure rate. Co-infection with HIV changes the historical situation greatly. In this case the annual risk of developing active TB is 8-10% instead of a lifetime risk of this percentage. This is illustrated in the following algorithm.

Clinical Manifestations

The most common symptoms are cough, fevers, night sweats and weight loss. Extrapulmonary TB can present as fever, meningitis, lymphadenopathy or spinal involvement known as Potts disease.

Who gets active disease? In developing countries, it is primarily a disease of adults in their most productive years, usually between ages 20 and 55. It is also seen in children, but much less so than in the adults. In developed countries, by contrast, it is increasingly a disease of the elderly, with the exception of those who are foreign born or who have HIV infection. The biggest increase in TB cases has been in females 15 to 19 and 20 to 24 years old, largely reflecting the patterns of HIV prevalence in those countries. In countries that are being infected by the HIV epidemic, the epidemiology of HIV is now driving the epidemiology of TB.

Diagnosis

Most people are symptomatic when they have active TB disease, and they do seek medical care. There is controversy in the TB control strategies about whether you should do active versus passive surveillance for TB cases. Studies in Europe and Africa have shown that active case finding is unnecessary with low yield of finding more cases than passive surveillance. There are also issues with how to do active case finding. What is the case definition? Do you do Xrays regularly? Currently active case finding is not recommended.

X-rays are probably the most overused and inappropriately used test to diagnose tuberculosis. A suspicious chest x-ray may assist in making an accurate diagnosis of TB but it can be normal as well. Because it can be so non-specific, it is not recommended as part of the TB diagnostic evaluation in low resource countries. The basis of international TB diagnosis for the WHO is sputum microscopy and staining for acid fast bacilli. Higher resource countries, like the US, use chest x-ray, sputum culture, and susceptibility testing.

Newer technologies like the polymerase chain reaction (PCR) and serologic tests are available but are not yet of proven value in low resource countries. More appropriate, less expensive technologies are under development.

TB skin testing, known as the purified protein derivative (PPD), is used primarily to identify persons with latent TB infection. This is especially important in the HIV-infected population to try and prevent development of active disease by treating latent disease with prophylactic medication such as isoniazid (INH). However, resource poor countries usually cannot undertake this approach and instead use passive case finding and appropriate treatment.

Tuberculosis Control

Tuberculosis control is a leading public health priority worldwide. WHO declared TB a global health emergency in 1993 and launched the Directly Observed Therapy Strategy (DOTS) for TB control. There are 5 basic elements of the WHO TB control strategy. First is government commitment to TB control. Second is passive case finding and diagnosis with smear microscopy. Third is standard, short-course chemotherapy with direct observation of the treatment. Fourth is continuous and reliable supply of quality drugs and fifth is an efficient recording and reporting system.

By 1993 when the WHO put out the global health emergency, there were about 20 countries implementing the WHO strategy. In 1997, about 100 countries out of approximately 212 countries worldwide are using the DOTS strategy. This does not mean there is 100% implementation in each of these countries but the process has started.

Government Commitment to Tuberculosis Control

This is absolutely critical to instituting a DOTS program. There has to be government commitment and political recognition of TB as a public health priority. You can have the best-meaning, non-government organization and people, but if the government from the top level on down is not committed to DOTS, it won't work effectively. TB is one of those diseases where a bad program can sometimes be worse than no program. Inadequate or partial treatment will only increase the incidence of multidrug resistant TB (MDRTB) and worsen the ability to control the disease. These chronically infected, many with resistant TB, can go on to infect new persons and the problem becomes compounded. Ultimately, you have created a bigger problem because these people go on to spread potentially non-treatable resistant tuberculosis.

The TB diagnosis and treatment programs are costly, complicated and labor-intense. It requires mobilization and commitment to both staff and resources to effectively function. Government needs to create an identifiable TB control program with a program manual, that everyone is trained to use and follow.

What are some of the obstacles to getting this government commitment? One reason is that the problem of TB is underestimated. It is thought to be a disease that has been around for a long time and we cannot do much about it. It also does not have a voice in many societies. It is a disease of the poor, the disenfranchised, and those with less political power. Another issue is that the treatment itself is relatively costly, even though it is very cost-effective. The minimum 6 month course of treatment for new diagnosis of TB ranges from $11 to $30 per person in many developing countries. When your per capita health expenditure is only $1-$2 per person, the price for TB treatment is a huge financial burden. A third obstacle is lack of donor support and contributions to make this sustainable. Donors may be willing to purchase TB drugs for two to three years but will not buy them forever. A fourth obstacle is that TB requires a fair number of vertical supervisory components and specifically dedicated people at various levels in health systems. This is at a time when health systems are trying to decentralize this care.

Passive Case Finding and Diagnosis

People who are AFB smear positive are four to twenty times more infectious, and each one of these patients may go on to infect 10-15 persons every year if they are not treated appropriately. Sputum cultures and individual drug susceptibility testing, which is part of every patient's evaluation in the US, is logistically and economically difficult in developing countries. This requires an infrastructure that can support laboratory-based diagnosis with trained personnel. Smear microscopy is personnel, equipment and time intensive. You need to have trained technicians to spend time looking at each slide. You need to have good microscopes and an ongoing supply of diagnostic materials, such as sputum cups, slides and reagents. Also, you need to have in place a system of supervision and quality control. The biggest obstacles to improved smear microscopy are lack of funding, lack of commitment, and lack of trained personnel.

Treatment of Tuberculosis

Current recommendation for active TB treatment is called short course chemotherapy. This short course consists of taking 3-4 drugs every day for 2 months followed by 2 drugs for an additional 4 months, for a total of 6 months of treatment. The most common first line drugs for treatment are isoniazid (INH), rifampin, pyrazinomide (PZA), and ethambutol (EMB). The priority for treatment should be given to those patients who are AFB smear positive on microscopy.

The key to success is to use standard therapies that are well established and followed to avoid treatment irregularities and failures due to drug resistance. These regimens have been shown in clinical trials to produce good treatment outcomes and cure. To fail the first line treatment increases the risk of multidrug resistant tuberculosis (MDRTB). The possibility of cure goes from almost 100% to almost 50% with a multidrug resistant strain. The cost increases exponentially as well.

This table shows the cure rate and cost of drug sensitive, INH resistant, and MDRTB in Seattle.

Directly Observed Therapy

The idea of directly observed therapy is to observe the patient swallow their tablets and insure that the patient is treated with the correct dose of medication at the correct intervals. It is an essential part of the TB program. The reason for implementing DOT is that many patients are not reliable with taking their medicines, even with good health education. Also who will be reliable cannot be predicted. DOT has to be acceptable to the patient. It has to be monitored carefully for adherence. It should be seen as a service to patients and providers and not as punishment. In the US, each health department had decided on their own approach. Some give DOT to all TB cases, others are on a case-by-case basis.

What are the obstacles to DOT? First determining a standard regimen for each country or provinces. Second, convincing the health care system, including doctors, that a standard regimen is necessary to treat this disease and reduce drug resistant rates. Third, there is a need to organize a system for delivery of daily medication to be directly observed. Rural areas in many countries pose a very difficult obstacle and creative solutions are needed. Some places are using family members or community leaders as the delivery system with variable success. Fourth, the need to lessen the stigma of TB. Fifth, the need to convince patients of the importance of treating TB with directly observed therapy.

In rural Uganda, the village leaders are being responsible for patients getting their medicines. This has had 2 benefits: where this has been implemented not one patient has left treatment and the active case finding has doubled. The leaders are now aware of the symptoms of TB and refer patients for diagnosis.

In the US, DOT is implemented in 2 different ways. One is where people come to the health care facility, usually the local TB control program to receive their medicine. Second is to bring the medicine to the patient either at home or a designated site.

Continuous and Reliable Supply of Tuberculosis Drugs

Regular and uninterrupted supply of quality drugs is necessary for DOTS. Drug interruption can lead to treatment failure and development of drug resistance. For example, in the former Soviet Union there was disruption of the health system and only a few drugs were available at a time. So when INH was available everyone got that, then rifampin was available and everyone got that. To give drugs in succession is a set up for developing significant drug resistance.

Poor quality drugs may contribute to failure and resistance. There have been some problems with quality control in low-cost preparations. TB medications must also be available at an acceptable cost, or in some cases supported by government payment. In lower resource areas cost would be an additional barrier to coming for treatment.

There are a limited number of effective TB drugs available. Many countries have these medicines available without prescriptions at pharmacies. There are even countries that have vitamins with TB medicines in them, such as the Philippines. An important part of the solution would be to license the TB medicines and only make them available through a national TB program. Most of the first line TB medicines are off-patent and are on the UNICEF essential drug list. This keeps the cost of the medication reasonable. The second line TB medicines to treat drug resistance are more costly and less effective.

Reporting and Recording

The TB division has an excellent system of recording and reporting that if used well is the best management tool in a health system. TB maintains a series of registries at the district level. There is a registry of suspect cases and a laboratory registry of smear and culture positives. The TB registry keeps a record of when they were diagnosed, what treatment was given and for how long, when they became smear negative and the ultimate outcome. There is also information on drug susceptibility. Registries try and capture all of the cases in a lineless fashion, differing from a surveillance system which measures events or visits for a certain condition.

The TB registry relies on the passive surveillance system already in existence in most places. Once a diagnosis of TB is made the registry system comes into play. A quarterly report is produced that shows the number of new cases registered, the resistance pattern and the demographics of the cases. They can register patients by cohort, by part of the year, by gender or age, or by resistance patterns. Strict supervision of the staff and the record keeping is essential to maintaining accuracy. Faster technology such as new computer software is needed to streamline this process and make it more accessible for use and quality assurance.

Other Interventions for Tuberculosis Control

There are at least potential interventions in all three steps to control TB transmission. We have discussed treatment of active disease. The other control strategies are vaccination and treatment of latent disease.

Vaccination

BCG (Bacille, Calmette, Guerain) vaccination is one of the oldest vaccines and is on the Expanded Program of Immunization (EPI) list. It is usually given at birth in most developing countries. It's overall efficacy ranges from 0 to 60% at preventing active TB, but has been found to be effective at preventing serious TB manifestations such as meningitis. It has been shown to prevent the spread of bacilli from the lungs after the initial infection and prevents initial dissemination of the bacilli. Why BCG is not more effective is not completely known. There appears to be enough protection against the severe pediatric manifestations that it is still a useful preventive strategy.

BCG is not used in the US primarily because early studies failed to show adequate efficacy in our population. Whether BCG should be given to the HIV-infected or immunocompromised population has been debated. BCG is a live virus vaccine and those who are immunocompromised might be at increased risk of infection from the vaccine strain of BCG and possible disseminated disease. Because the US has other methods of treatment and prevention it is not given to our immunocompromised population.

Treatment of Latent Disease

Treating a person who has evidence of previous TB infection but not active disease with isoniazid is another acceptable control strategy. One is identified with latent infection by use of the PPD skin test. If someone does not have active disease, is under the age of 35 (for a low risk individual), and has a PPD test of 15mm or greater, then treatment with 6 months of INH can markedly reduce the risk of activation. Persons who are foreign born or HIV-infected and have a PPD test of 5-10mm of induration should also be treated. The age cutoff for the higher risk population is less rigid and needs to be considered on a case by case basis.

Multidrug Resistant Tuberculosis

Multidrug resistant TB is defined as resistance to isoniazid and rifampin, the two most potent anti-TB medicines. Etiologies for the increase of MDRTB are poor prescribing practices, drug shortages, poor quality of medication, and poor adherence to therapy. Treatment for MDRTB is even more costly and problematic as shown earlier. Instead of a 6 month treatment course you typically need 18-24 months of 4-7 drugs and in many cases may be an untreatable condition. MDRTB also has significant mortality associated with it as seen in the nosocomial outbreaks in the US in the late 1980s to early 1990s.

MDRTB is an increasing problem throughout the world and particularly in the former Soviet Union and Asia where drugs are readily available and poorly prescribed. This is a major public health problem and emphasizes the need for better TB control programs worldwide.

In conclusion, TB is one of the biggest public health problems worldwide and requires a collaborative effort to get it under control. The WHO, with country agencies, is working hard to implement the DOT strategy, improve surveillance, laboratory diagnostics and medication accessibility.

Readings

Dye C et al. "Consensus statement. Global burden of tuberculosis: estimated incidence, prevalence, and mortality by country. WHO Global Surveillance and Monitoring Project." JAMA, 1999 Aug 18; 282(7): 677-86.

Pablos-Mendez A et al. "Global surveillance for antituberculosis-drug resistance, 1994-1997. World Health Organization-International Union against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance." N Engl J Med, 1998 Jun 4; 338(23): 1641-9.

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