Tuberculosis is an ancient infection and has been around for 6000 years so why do we include this disease in a course on emerging infections?  

The definition of an emerging infection is a new, reemerging or drug resistant infection whose incidence in humans has increased within the past 2 decades or threatens to increase in the near future.

Given this definition, TB is both a reemerging infection and a drug resistant problem as well.

This lecture will review the pathophysiology, risk factors, global epidemiology, co-infection with HIV issues, and prevention and control strategies of TB.

Global TB Epidemiology

Worldwide there are more than 30 million people infected with latent TB. Of these, 10 million will develop active disease and 3 million will die from TB. This is the second most common infectious disease in adults and the fourth most common infectious disease worldwide.

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.

In the United States between 1985 and 1992 there was a 20% increase in active TB cases. A large majority of these cases were in association with a newly identified infection: human immunodeficiency virus (HIV). In 2000, there were over 16,000 cases of active disease. The majority of cases in the US are seen in the foreign born (25 per 100,000) compared to US born (3.5 per 100,000). With improvement and increase funding to the public health infrastructure TB rates in the United States has decreased by 7% from 1999.

In Seattle King County our reported TB cases from 1999 to 2000 increased from 104 to 127 cases. Of these 79% were in foreign born and 19% were in African immigrants. The incidence rates for Seattle King County were 7.3 per 100,000 persons.

Pathophysiology

Tuberculosis is an infection that has an important balance and involvement of the host, the agent and environmental factors.

[Figure:  Venn Diagram]

TB is spread by droplets and typically presents with fever, cough, night sweats and weight loss in active disease. The infectious agent is a mycobacterium called Mycobacterium tuberculosis. The majority of immune competent persons who become infected develop latent disease which is usually detected by the presence of a reaction to the TB skin testing. The induration of the skin test determines whether the person has been previously infected but may not have active disease. The size of the positive skin test varies depending on host risk factors. For an immune competent person, 15mm induration is considered positive. For a person who is foreign born from a high risk area, a recent contact to active TB, persons who live in higher risk institutions, a 10mm induration is positive; and for an immune suppressed patient or one with HIV-infection, a 5 mm induration is positive.

Host Factors

Immune compromise significantly increases the risk of reactivating latent infection and increasing initial active disease with new infections. It is unclear if previous infection and treatment confers any protective immunity. Foreign born from high risk areas have increased rates, close contacts of active case, intravenous drug users, residents of jails, shelters, and other institutions.

Agent factors

Emergence of multidrug resistant TB (MDR-TB) is one of the most important agent factors. There is an increase in random mutations. Greater inoculation of bacterium and diagnostic delays increase the risk of transmission. Treatment also requires multiple medications for an extended period of time from 6 months up to 2years or more depending on resistance patterns.

Environmental factors

TB is a disease of the poor, homeless, and malnourished. There is along latency period in the environment. Increased urbanization with increasing slum cities can increase risk of TB spreading.

The incubation period for TB infection is 2-10 weeks. Transmission and infection is dependent on where the organism is dispersed, the quantity of bacteria expelled, duration of exposure to bacterium, the hosts’ immune status, and the resistance patterns of the bacillus.

[Figure:  TB Exposure and Risk of Disease]

This slide depicts the outcome of TB infection in the immune competent person and the immune suppressed (with HIV) person. There is a 100-200 fold increased risk of active disease with HIV co-infection.

Tuberculosis and the Factors of Emergence

Human demographics and behavior:

TB is a disease of crowding, poverty, lack of sanitation, nutrition and access to care. Increasing urbanization can increase all of these human demographic factors and lead to an increase of TB. Increasing refugees and migration from wars, drought and persecution also contributes to the previously mentioned factors. Poor adherence to the medication regimen leads to treatment failure and increasing antibiotic resistance. In many countries partial treatment of TB is possible by the use of over the counter medications that contain active TB treatment. A delay in the diagnosis and appropriate treatment also increases the emergence of new infections.

Technology and Industry

Transmission has occurred in such diverse settings as hospitals through contaminated instruments, from cadavers to embalmers, and from medical waste to waste disposal workers.

On the positive side of technology there are newer more rapid diagnostic techniques such as DNA probes. This has reduced the time to accurate diagnosis from weeks to days and hopefully eventually to hours. Restriction fragment length polymorphism is a technique for strain identification and has been useful in outbreak situations within institutions and globally.

Economic Development

Usually with improved economics there is an eventual decline in infectious diseases. However, initially due to overcrowding and poor sanitation there may be increasing rates of some infections such as TB.

International Travel

There have been several cases of transmission of TB on airplane flights. The most notable study was by Kenyon et al which showed transmission of TB on 4 separate flights and infected person took. Concerns about the air quality on planes has come into question but studies have shown that the air flow exchange is every 3-4 minutes and air sampling shows less air contamination than one finds on buses, or in shopping malls.

Travel by immigrants, refugees, students, tourists, and business travelers can all pose a risk of transmitted disease if infected at the time of travel. The screening process of immigrants and refugees to reduce this risk is good but does not include the student, tourist or business traveler.

Microbial Adaptation and Change

There has been a worldwide increase in single drug and multidrug resistant tuberculosis. Multidrug resistance is defined as resistance to both isoniazid and rifampin. These are 2 of the most potent TB medications, so to lose them for treatment makes TB much more difficult to adequately treat. Globally there is 17-54% isoniazid resistance and 4-30% multidrug resistance. In the United States 8.4% of isolates are isoniazid resistant and 2% are multidrug resistant.

Risk factors for multidrug resistance (MDR) are:

• Delayed diagnosis of active tuberculosis
   
• Delayed identification of species and drug sensitivities
   
• Prolonged infectivity due to inadequate early treatment or poor adherence to anti-TB therapy
   
• Co-infection with HIV with high risk of activating disease
   
• Inadequate environmental hygiene practices

There have been several institutional outbreaks of MDR-TB. One of the first identified was in a New York hospital in 1991. Twenty three patients were affected of which 21 had co-infection with HIV. Nineteen of 23 (83%) died from TB. There were 12 of 79 health care workers who seroconverted from this exposure. Second was an outbreak in a Florida hospital. Of 140 active TB cases, 62 had MDR-TB. Of these 62, 47 had co-infection with HIV. It was noted that the time to diagnosis of the MDR-TB cases was 635 days compared to 167 days in the controls. The third outbreak was in an Argentine hospital. Of 1253 active TB cases, 272 of these were co-infected with HIV. Of the 272 co-infected, 124 had MDR-TB. Of the 124, 101 of these were resistant to 5 or more drugs. The median survival for was 33 days.

[Figure:  Cure Rates]

This slide shows the various cure rates between susceptible, single drug resistance and multidrug resistant TB with the approximate cost of treatment and care. This data is for Seattle King County and may vary in other places.

Breakdown of Public Health

TB funding was decreased in the United States in the mid-1980’s due to a decrease in the number of active TB cases. It was felt by many that TB was going to continue to decline and attention and money was spent on other diseases. In the late 1980’s we started to see the rise of TB cases and specifically of MDR-TB. A huge influx of financial support for TB control was needed to get these outbreaks under control and continue to monitor for these problems.

For many countries appropriate and sufficient TB medications are not universally available. There is widespread use of single drug therapy due to lack of medications and lack of adherence. Many countries do not have access to rapid diagnostic techniques and are dependent of sputum AFB staining and chest radiograph findings. Many countries and US counties lack capacity to do the entire contact tracing to try and find secondary infections from an index case.

In 1993, the World Health Organization made TB treatment and control a priority and developed the DOTS strategy.

The DOTS is comprised of 5 major components.

1. Government commitment to effective TB control program
    
2. Case detection through passive case finding: active case finding was found to not be cost effective or cost beneficial
    
3. Administration of standard short course chemotherapy to all sputum smear positive cases under direct supervision. This is to include 4 drug therapy whenever possible.
    
4. Establish and maintain a system of regular TB medication supply
    
5. Establish and maintain an effective monitoring system for program management and evaluation

How the DOTS strategy is implemented in each country should have some flexibility to allow for country differences. Many countries have already begun to do this and developed ways to try and make the DOTS strategy work for them. Some countries are using the traditional healers to deliver the medicine, others are using local business people and others are using the standard Western model of the health care worker distributing medication to those in need.

Surveillance is another key component to effective TB control and prevention.

The WHO has come up with global surveillance objectives which include:

1. Implement surveillance in a number of countries under the guidance of a network of supranational reference laboratories
    
2. Standardize susceptibility testing with use of internally accepted methods and with monitoring for quality control
    
3. Assurance that data collected are representative of population. There is a need to distinguish between primary and acquired infections.
    
4. Establish a consistent case definition for active TB that is appropriate and acceptable worldwide

New technology is now available to make a more rapid and accurate diagnosis of active tuberculosis. Nucleic acid amplification has a sensitivity of 83% and specificity of 97%. It has a higher positive predictive value (59% vs. 36%) in low risk persons compared to AFB smear. The negative predictive value was 91% compared to 37% with AFB smear.

Whole blood assay for gamma interferon helps to detect cell mediated immunity to tuberculin. Comparing this new technique to the standard diagnostic test of latent infection, the purified protein derivative (PPD) showed that this test was equivalent to the PPD for detecting latent infection. Advantages include only requiring a single patient visit, results in less than 24 hours, and elimination of subjectivity with the skin test reading.

Vaccination for Tuberculosis

The currently available vaccine for TB is called the BCG (Bacille, Calmette, Guerin). This vaccine is given at birth in most countries outside of the United States for control of TB. The efficacy of this vaccine to prevent active disease however is extremely poor with efficacy rates in studies ranging from 0 to 60 percent. There are currently no new vaccines in the immediate future but some research is being done to try and clone the complete genome of Mycobacterium tuberculosis.

Prevention of Tuberculosis

The best way to prevent TB is do identify and treat latent infection in high risk individuals, specifically those with HIV infection and foreign born. Second is to identify contacts to active TB cases and treat them in a timely fashion. Third would be to educate health care workers and the public on the clinical manifestations of active TB, know who to screen, and know the appropriate treatment for latent infection and active TB treatment with or without directly observed therapy.

In summary, TB is one of the top public health infectious disease problems worldwide. Continued and improved global surveillance is needed. Diagnosis, treatment and prevention require significant resources and training. Co-infection with HIV has led to increased active cases, emergence of MDR-TB, and increased mortality. TB is one of the diseases targeted by the Global Fund for AIDS, TB and Malaria. Newer treatments and more rapid diagnostics are needed and will assist in better control of TB. Vaccine development is necessary but is years away from being realized.

Resources

TB prevention and treatment guidelines can be found at the Center for Disease Control web site.

• http://www.cdc.gov

Information on WHO DOTS strategy can be found at the WHO web site.

• http://www.who.int

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© 2002 University of Washington Department of Health Services Box 357660, Seattle, WA 98195-7660 e-mail: carrieho@u.washington.edu