The Continuing Challenge of Tuberculosis

September 1993

OTA-H-574

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Recommended Citation:

U.S. Congress, Office of Technology Assessment, The Continuing Challenge of

Tuberculosis, OTA-H-574 (Washington, DC: U.S. Government Printing Office,

September 1993).

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Foreword

A

fter having declined for 30 years, the overall incidence of tuberculosis

in the United States has been on the rise since the mid- 1980s. In some

communities, the problem is extremely serious, compounding other

social ills, including AIDS, hopelessness, drug abuse, and poverty.

Particularly disturbing is the emergence of multidrug-resistant tuberculosis

(MDR-TB). MDR-TB has been directly linked to inappropriate and incomplete

treatment, which in turn has been linked, in part, to a lack of resources to ensure

the proper delivery of tuberculosis services.

At at a time when the Nation is focused on health care reform, the threat

of TB reminds us of the importance of maintaining a strong public health infrastructure. The Federal Government has a long history of providing resources

and leadership to State and local health authorities in the control of TB.

However, only in the past few years has the government begun to restore funding to TB programs that were cut during the 1970s and early 1980s.

OTA’s report synthesizes current understanding of TB in the United

States, including the extent of the disease, the state of research of new preventive, diagnostic, and therapeutic technologies to aid in its control, and the delivery of effective TB services. The report also provides an overview of Federal

involvement in these activities.

It was initiated in response to requests from three committees of

Congress: the House Committee on Energy and Commerce’s Subcommittee on

Health and the Environment, the House Committee on Government Operations’

Subcommittee on Human Resources and Intergovernmental Relations, and the

Senate Committee on Labor and Human Resources.

OTA was assisted in the study by a group of public health leaders from

academia, industry, government, and public interest groups who met in a workshop convened by OTA in March 1993. A large number of other experts provided detailed reviews of multiple drafts.

OTA gratefully acknowledges the contribution of these individuals.

with all OTA reports, the final responsibility for the content of these assessments rests with OTA.

As

Roger C. Herdman, Director

. . .

Ill
workshop Participants

Alan Bloch

Medical Officer

Surveillance and Epidemiology

Branch

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Barry Bloom

Professor

Department of Microbiology and

Immunology

Albert Einstein College of

Medicine

Yeshiva University

Bronx, NY

Wafaa E1-Sadr

Director

Division of Infectious Diseases

Harlem Hospital Center

New York, NY

Larry Gostin

Executive Director

American Society of Law,

Medicine and Ethics

Boston, MA

Margaret Hamburg

Commissioner of Health

New York City Department of

Health

New York, NY

Jeffrey Levi

Director

Government Affairs

AIDS Action Council

Washington, DC

Joan Otten

Director

Office of Tuberculosis Control

Jackson Memorial Hospital

Miami, FL

Lee Reichman

President

American Lung Association

New York, NY

Gisela Schecter

Tuberculosis Controller

Tuberculosis Control Division

Department of Public Health

City and County of San Francisco

San Francisco, CA

Peter Selwyn

Associate Director

AIDS Program

Yale-New Haven Hospital

New Haven, CT

Virginia Shubert

Director of Advocacy and

Public policy

Housing Works, Inc.

New York, NY

Jane Sisk

Professor

School of Public Health

Columbia University

New York, NY

Jeffrey Starke

Assistant Professor

Department of Pediatrics

Baylor College of Medicine

Houston, TX

OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the participants in OTA’S

workshop on Policy Issues in the Control of Tuberculosis, March 23, 1993. The workshop participants do not, however, necessarily approve, disapprove, or endorse this report, OTA assumes full responsibility for the report and the accuracy of its

contents.

iv
—.—

Clyde J. Behney

Assistant Director, OTA

Health, Life Sciences, and the

Environment

ADMINISTRATIVE STAFF

Beckie Erickson

Office Administrator

Daniel B. Carson

PC Specialist

Carolyn Martin

Word Processing Specialist

Eric L. Gille

Secretary

PUBLISHING STAFF

Mary Lou Higgs

Manager, Publishing Services

Denise Felix

Production Editor

Dorinda Edmondson

Typographer

Christine Onrubia

Graphic Designer

Preject Staff

PROJECT STAFF

MICHAEL E. GLUCK

Project Director

JULIA T. OSTROWSKY

Principal Contractor

Sharon Y. Hamilton

Research Analystl

Arna M. Lane

Research Analyst

Contractors

Sue Etkind

Massachusetts Department of

Public Health

Boston, MA

Lynn Powers

Editorial Consultant

Alexandria, VA

1 From August 1992 to May 1993
1 Summary and Policy Options 1

Scope of the OTA Report 2

Tuberculosis, Health Care Reform, and Public

Health Investments 2

What Is TB? 2

What Is the Risk of TB Infection? 3

Trends in the Incidence of Active TB 3

The Changing Demographics of TB 4

Multidrug-Resistant Tuberculosis 6

Three Strategies for TB Prevention 6

Diagnosis of Active TB 8

Treatment of Active TB 9

Delivering TB Treatment 10

Federal Involvement in TB Control 12

Policy Options for Congress 16

2 Etiology and Transmission of

Tuberculosis 27

Transmission and Infectivity 28

Factors Influencing the Probability of Acquiring

Tuberculous Infection 28

Factors Influencing the Development of Active

TB After Infection 30

Development of Tuberculosis and Its Clinical

Manifestations 30

Immune Responses to Tuberculous Infection and

Disease 31

Clinical Course in HIV-Seropositive Individuals 32

Clinical Course in Children 32

3 The Changing Epidemiology of

Tuberculosis 33

contents

Ii

Overall Trends in TB Incidence 33

Demographic Changes in TB 34

Geographic Distribution 35

Race, Ethnicity, Age, and Sex 37

High-Risk Populations 40

vii
4

HIV and AIDS: Epidemiologic Association With

TB 42

The Prevalence of TB Among Individuals With

MDs 43

Multidrug-Resistant Tuberculosis 44

Recent Outbreaks of MDR-TB in Institutional

Settings 46

Factors Underlying the TB Resurgence in the

United States 47

Strategies to Prevent Tuberculous Infection

and Active Disease 49

Infection Control 50

Infection Control Measures 52

Tuberculin Skin Testing and Preventive

Treatment 55

Identifying Individuals with Tuberculous

Infection 59

Isoniazid Preventive Treatment 61

BCG Vaccination 62

The Nature and Rationale for BCG Vaccines 63

Efficacy and Safety of BCG Vaccination 64

Impact of BCG Vaccination on the Incidence of

TB 65

BCG Vaccination Policy in the United States 66

Issues Concerning Future Use of Vaccination

Against TB 67

5 Diagnosis and Treatment of Active TB 69

Diagnosis of TB and Resistance to Anti-TB Drugs 70

Treatment of Active TB 72

Rationale for Antimicrobial Treatment of TB 74

Current Treatment Regimens 75

Treatment of TB in Individuals with AIDS 76

Treatment of Multidrug-Resistant TB 76

New Approaches to Treatment 78

The Cost of Drugs for Tuberculosis Treatment 79

6 Delivery of Treatment for Tuberculosis 81

Magnitude of the Problem 82

Factors Involved in Treatment Outcome 84

Provision of TB Control Semices 84

Medical Care Practices 86

Patient Behavior 87

Available Strategies for Improving Treatment

Delivery 88

. . . Vlll
7 Federal Involvement in Tuberculosis Control

and Research 91

Public Health Activities 92

The Centers for Disease Control and

Prevention 92

Occupational Health and Safety Administration 97

U.S. Departments of Justice and State 98

U.S. Department of Veterans Affairs 98

Indian Health Service 99

Federal Bureau of Prisons 99

U.S. Agency for International Development 99

Health Resources and Services Administration 100

Research and Development 100

National Institutes of Health 100

Regulation of Technologies 102

Health Services Research 102

Housing 103

Reimbursement for TB Services 103

Disability Programs Administered by the

Social Security Administration 103

The Role of Federal Health Insurance

Programs 103

A Acknowledgments 107

B Abbreviations and Glossary 112

REFERENCES 119

INDEX 141

ix
T

Summary

and

Policy Options 1

uberculosis (TB) is a contagious disease that has killed

millions of people worldwide over the centuries. The

lack of a reliable cure prior to this century and TB’s

perceived randomness made it a common theme in

literature and a metaphor for larger social and political ills

(84,299). Today, TB continues to be a public health threat in the

United States. After decreasing in the country as a whole for

many decades, rates of TB disease are again on the rise. In some

communities, particularly among economically disadvantaged

groups, TB rates have consistently remained high.

Recent trends in the incidence of TB have been linked, in part,

to decreases in public health investment over the last two decades

(45,46,176). Other factors associated with the resurgence of TB

include the human immunodeficiency virus (HIV) epidemic,

foreign birth, substance abuse, poverty, and hopelessness. An

important complication is the emergence of TB strains resistant

to the most commonly used anti-TB drugs.

Unchecked, these recent trends in TB represent a serious threat

to communities already saddled with poor health, poverty, and

other social problems. Furthermore, this disease could become a

additional major burden to the Nation’s health care system.

Unlike the TB of past centuries, however, today’s TB is

amenable to human intervention, We know how it is spread. We

know how to cure it, and we know how to prevent it. Although

the primary governmental responsibility for controlling TB in the

NOTE: Because of the large amount of material synthesized to produce this report, most

citations to the literature underlying this summary chapter are omitted. However, the

detailed analysis presented in subsequent chapters is fully referenced, and the summary

in this chapter closely folIows the organization of the subsequent chapters. References to

ideas that are found only in this chapter are given where they occur.

1
2 | The Continuing Challenge of Tuberculosis

United States falls to State and local authorities,

the Federal Government has had, and continues to

have, a substantial role in eliminating this disease.

This report synthesizes scientific understanding

of TB in the United States in 1993 and considers

the Federal role in its control.

SCOPE OF THE OTA REPORT

Three congressional committees requested this

report: the Subcommittee on Health and the

Environment of the House Committee on Energy

and Commerce, the Subcommittee on Human

Resources and Intergovernmental Relations of

the House Committee on Government Relations,

and the Senate Committee on Labor and Human

Resources. The report provides information on

the problems posed by TB that Congress can use

in considering alternative Federal policy responses. Although the report gives an overview of

the direction and magnitude of Federal involvement in TB control and considers options for

Congress, the report does not evaluate in detail

the effectiveness of specific programs in individual communities or Federal agencies. Another

congressional research agency, the General Accounting Office (GAO), is currently evaluating

the effectiveness of efforts to control TB in

several communities hit hard by the disease (183).

One-third of the world’s population is infected

with the organism that causes TB. With significant migration to the United States by people

horn countries with high levels of TB, foreign

birth is a risk factor for the disease in this country.

Hence, controlling TB abroad could have some

impact on levels of TB in the United States.

Although this report briefly considers the Federal

Governrnent’s support of international organizations involved in TB control in developing

countries, it focuses on TB as it occurs in the

United States.

Tuberculosis, Health Care Reform, and

Public Health Investments

As policymakers focus on health care reform,

the analysis in this report indicates that TB will

not disappear with improved access and better

cost control of health care services alone. Even

with universal access to medical services, a

change in the organization and financing of health

care will not, in and of itself, eliminate the need

for Federal funding and coordination of the

infrastructure to conduct education, surveillance,

screening, diagnosis, research, and even treatment.

Furthermore, TB control is an exercise in

vigilance. With an estimated one-third of the

world’s population infected with TB and the

relative mobility of people in and out of the

United States through immigration and tourism,

the complete eradication of tuberculosis from this

country is unlikely in the foreseeable future. In

addition, people infected with the organism that

causes TB now may progress to active disease

many years in the fiture, after the current

epidemic is brought under control. Nevertheless,

TB control measures can lower disease rates and

minimize the public health threat posed by the

disease. Achieving such a goal will require a

properly targeted and sustained effort. Once this

goal is achieved, continued investment to identify treat, and prevent TB will be necessary to

maintain low disease rates. The current resurgence in TB is evidence that this last lesson was

not learned in the past. Even in the last year, the

Centers for Disease Control and Prevention

(CDC) noted its own failure to implement recent

TB control recommendations, due largely to a

lack of resources (337).

What Is TB?

In 1882, the German scientist Robert Koch

identified a species of bacteria, Mycobacterium

tuberculosis (M.tb. or tubercle bacilli) as the
Chapter l-Summary and Policy Options | 3

cause of TB. There are two general stages of the

disease: tuberculous infection (or “latent TB”)

and active tuberculosis. Individuals with tubercu10US infection are asymptomatic and not contagious, whereas individuals with active TB can be

symptomatic and contagious. Tuberculous infection is necessary to develop TB, but overall only

10 percent of those with the infection ever

develop active TB. Risk is higher for children and

for people with HIV and other disorders that

impair immunity. In immunocompetent individuals, the immune system is usually able to contain

most tuberculous infections. A tuberculin skin

test, which uses a substance known as purified

protein derivative (PPD), is used to detect tuberculous infection. In most immunocompetent people with the infection, this test produces a small

raised area on the skin within 48 to 72 hours of

administration.

While active TB can attack various parts of the

body, pulmonary TB is the most common and

leads to the destruction of lung tissue and

frequently death if untreated. Symptoms include

weakness, fever, chest pain, cough, and when a

small blood vessel is eroded, bloody sputum.

Active TB can also occur in other parts of the

body, with the brain (TB meningitis) being the

most serious. TB outside the lungs is more likely

to occur among children and people with HIV.

What Is the Risk of TB Infection?

People with TB are contagious when they expel

airborne particles containing viable tubercle bacilli through, for example, coughing, singing,

speaking, or sneezing. The likelihood of infection

depends mainly on the:

■

9

9

■

■

Probability of coming into contact with someone with contagious, active TB;

Closeness or intimacy of the contact;

Duration of the contact;

Number of viable bacilli present in the air;

Susceptibility of the uninfected case; and

■ Environmental conditions (e.g., volume of

airspace, ventilation with outside air, relative

humidity, presence of sunlight).

Health care workers (HCWS) are at increased

risk of infection, particularly if they perform

cough-inducing medical procedures on patients

with active pulmonary TB and if they work in

environments with inadequate infection control

measures.

Casual contact with an infectious person—i.e.

with active, untreated TB—in a public place such

as a movie theater or subway is unlikely to lead to

infection, although the risk is not zero. Although

infection occurs at a specific point in time when

an infectious particle is inhaled, the longer the

exposure, the greater the likelihood an infectious

particle will be inhaled. Hence, exposure to an

infectious person over a period of months is

usually necessary for transmission to occur.

In general, less than 30 percent of household

members become infected while living with an

infectious person, but the risk is highly variable.

Under extraordinary circumstances (when the

concentration of airborne infectious particles is

unusually high), exposures as brief as 2 hours

have reportedly led to infection.

Adequate anti-microbial or anti-tuberculosis

treatment can reduce the infectiousness of drugsusceptible TB within days. Although the exact

amount of time needed to eliminate the infection

completely varies by patient, it is about 6 months

or longer. While there is no evidence that

drug-resistant TB is more contagious than drugsusceptible TB, delays in diagnosis and treatment

allow patients to remain infectious for a longer

period of time, thus increasing chances of infecting others.

Trends in the Incidence of Active TB

Between 1953, when the Public Health Service

(PHS) first implemented a national reporting

system for active TB cases, and 1984, the number

of annually reported cases declined 74 percent

horn 84,304 (53 per 100,000 population) to
4 | The Continuing Challenge of Tuberculosis

Figure l-l—Reported Tuberculosis Cases in the

United States, 1953-92

100

80

0 +,,,,, 1 1 1 1 1 1 1 1 1 1 1 1 1 1953 1963 1973 1983 1992

SOURCE: Office of Technology Assessment, 1993, based on data

from U.S. Department of Health and Human Services, Public Health

Service, Centers for Disease Control and Prevention, 1992.

22,255 (9.4 per 100,000). Beginning in 1985, this

decline slowed and then reversed (figure l-l).

The number of new cases reported in 1992 was

26,673 (10.5 per 100,000), a 20 percent increase

over 1985.

The Changing Demographics of TB

Over the years, TB has gradually shifted from

a disease broadly distributed over the whole

population to one that is more narrowly concentrated among certain portions of the population.

Although the rapid increase in the overall number

of new cases suggests a potential threat to the

population as a whole, the current concentrations

of the disease offer TB-control experts and

policymakers a guide in targeting resources for

controlling TB. Groups with particularly high

rates of TB can be described according to

geography, race, ethnicity, and factors causally

related to the disease.

Heavy Concentrations in Certain Parts

of the Country

The most populous States have the largest

number of cases. In 1991, over half of all TB cases

came from California, New York, Texas, Florida

and Illinois. Urban areas with populations over

250,000 contained 18 percent of the country’s

population but 43 percent of its new TB cases in

that year. The number of new TB cases per

100,000 of population in the South has always

been above the national average, although New

York, Hawaii, and California have the highest

rates. Among cities, Atlanta (76.4 per 100,000),

Newark (71.8 per 100,000), New York (50.3 per

100,000), Miami (48.5 per 100,000), and San

Francisco (46.0 per 100,000) had the highest case

rates 1 during 1991.

Accounting for 14 percent of the total number

of new TB cases reported in the United States

during 1991 and with a TB case rate five times the

national average, New York City alone has a

significant, concentrated portion of the Nation’s

entire TB problem. In one part of the city, Central

Harlem, the case rate was 169.2 per 100,000 in

1989 and has never dipped below 52 during the 40

years that data have been kept (45).

Heavy Concentrations Among Minorities

and the Young

Within a given geographic area, certain demographic groups are more likely than others to

produce new cases of TB. In 1991, 71 percent of

new cases occurred in racial and ethnic minorities. Hispanic Americans, Black Americans, and

Americans of Asian or Pacific Island2 origin

showed relatively large increases in TB during the

1985-91 period. Although the risk of TB in adults

increased with age, this pattern was not consistent

across different racial and ethnic groups. Among

white, non-Hispanic Americans, most TB cases

occurred among elderly people, while among

~ A “case rate” k defined as the number of cases of active TB diagnosed in a given year per 100,000 population.

2 Terms used to describe these demographic groups are tbose used in the original studies from which the epidemiologic findings are drawn.
Black and Hispanic Americans, the bulk occurred

in the 25 to 44 year-old age group.

Rates of increase have been disproportionately

high among children; this trend is also concentrated among racial and ethnic minorities, who

accounted for 86 percent of all childhood cases in

1991. Childhood cases of TB are strong evidence

of recent transmission of the disease, suggesting

contact with other infectious individuals in the

community and possibly more, undetected cases

of infection. High rates of TB among immigrants

and increases in TB among parents in the 25 to 44

age group may account for the observed increases

among children. Furthermore, children infected

now could suffer active disease years in the

future.

High Rates Among Immigrants, Prisoners,

Drug Users, Migrant Workers, and

Homeless People

Being born outside the United States, being

homeless, a substance abuser, being incarcerated,

or being a migrant worker is a risk factor for

tuberculous infection. In addition, being confected with HIV increases one’s risk of progressing from infection to active disease. The overlap

among these groups reinforces the concentration

of TB within the United States population and the

particular risk for members of these groups.

Given the high prevalence of TB infection in

many other parts of the world (171), a large

percentage of new TB cases in the United States

occur among individuals born elsewhere (27

percent in 1991). Among homeless populations,

several studies have found latent TB infection to

be as high as 50 percent. Impaired immunity due

to poor overall health, substance abuse, or HIV

infection may cause homeless people with tuberCUIOUS infection to progress to active disease. In

addition, homeless shelters can generate new

transmissions, due to crowding and poor ventilation. Twenty percent of newly diagnosed TB

cases in New York City in 1991 were homeless.

Chapter l-Summary and Policy Options | 5

Substance-abusing populations overlap with

other groups at high risk of TB, especially with

homeless and HIV-infected people.

The prevalence of TB in prisons is related to the

close living quarters, poor ventilation, and other

risk factors that inmates may possess. In some

States, epidemiologists have estimated that TB

may be as much as 6 to 11 times more prevalent

among prisoners than among the general population. Prison populations comprise other groups at

high risk of TB--drug users, HIV-infected people, and individuals homeless prior to incarceration. Persons with active TB in prisons cannot

only spread the disease among other prisoners,

but they also place at-risk prison staff and family

or friends with whom they have close contact

upon their release.

Among migrant workers, lack of access to

health services and lack of adequate working and

housing conditions are believed to contribute to

the heightened risk of TB as noted among some

limited recent studies, Many members of this

group are also poor, minorities, foreign born, or

former homeless shelter residents.

People With HIV Have High TB Rates

HIV is the pathogen that causes acquired

immunodefiency syndrome (AIDS). Because

HIV-related immunosuppression impairs the body’s

ability to fight a tuberculous infection, individuals infected with both tubercle bacilli and HIV are

estimated to have a risk of as high as 8 percent per

year of progressing rapidly to active TB disease,

compared with a 10 percent lifetime risk for

HIV-negative individuals.

Epidemiologic evidence has consistently shown

a higher prevalence of TB among individuals with

AIDS compared with the general population,

even after adjustment for age, race, and sex. In

addition, more than one-half of deaths with TB in
6 I The Continuing Challenge of Tuberculosis

individuals 20 to 49 years old appear to occur in

people who also have AIDS.3

Multidrug-Resistant Tuberculosis

When a patient takes TB medication erratically

or when an inadequate combination of drugs is

prescribed, active, infectious TB can recur in a

form resistant to one or more of the drugs used in

the original treatment.4 As described later in this

chapter and in detail in chapter 4, cases of

MDR-TB are far more difficult and costly to treat

than drug-sensitive TB, and can be fatal despite

the best available treatment. CDC began regularly

collecting drug susceptibility data on each reported case of TB in 1993, a practice done

periodically with surveys prior to 1986.

Preliminary data from a 1991 CDC survey

indicate that drug resistant TB cases have been

reported in all regions of the country, but are most

heavily concentrated in a few States. Cases

resistant to at least one drug were found in 36

States and to two or more drugs in 13 States. Of

the cases found to be resistant to the two most

commonly used drugs, isoniazid (lNH) and rifampin (RW), over half were in New York City.

In a separate study, 33 percent of the 466 TB cases

reported in New York City during April 1991

were resistant to one or more drugs, and 19

percent were resistant to both INH and RIF.

Since 1990, there have been at least 9 outbreaks

of MDR-TB among 297 individuals in prisons

and hospitals. Most of these people were HIVinfected. As many as 89 percent of those with

MDR-TB (including 6 health care workers and 1

prison guard) have died from their TB.5 Delayed

or inadequate infection control measures, premature discontinuation of patient isolation, delayed

reporting of drug resistance, and lack of isolation

facilities were major factors in the spread of

MDR-TB in these institutions.

Three Strategies for TB Prevention

Under public policy discussion are three strategies for preventing the spread of T’B-infection

control, finding and offering preventive treatment

to infected high-risk populations, and bacillus

Calmette-Gu&in (BCG) vaccination.

Infect/on Control

Although tuberculous infection has long been

known as an occupational hazard for health care

workers, and although there is some evidence that

HCWS in some jobs (e.g. pulmonary medicine)

are at greater risk than other HCWS, the actual

magnitude of the risks have not been well

documented in recent years.

CDC updated its guidelines for preventing TB

transmission within hospitals in 1990 and is

expected to do so again in the near future (79).

The guidelines call for a‘ ‘hierarchy of controls,’

including limiting exposure to the source of

infection (through identification, respiratory isolation, and prompt treatment of infectious patients), implementing environmental measures,

and using individual protective devices. None of

these measures are believed to have been widely

adopted by hospitals or other institutions.

Although implementing combinations of these

measures appears to have been effective in ending

the recent outbreaks, there are few data on the

effectiveness of individual measures under conditions of actual use (79). 6 In practice, decisions

q Despite the prevalence of TB among those with HIV, M.rb. may represent only 10 percent of mycobacterial infections in this patient group.

Non-tuberculous mycobacteria (e.g., M. avium) is very common among AIDS patients; these infections occur in later stages of AIDS (when

CD4 cell counts are below 100/mm3), are untreatable, and maybe fataL

4 Srrains of TB treatable with available anti-TB medications are called ‘drug sensitive. ” Strains resistant to at least one anti-TB medication

are called “drug-resistant.”According to the CDC, strains resistant to, at Ieas$ isoniazid and rifampin are referred to as MDR-TB.

5 It is unknown whether the high rate of mortality observed in these outbreaks applies to other HIV-infected populations or to HIV-negative

individuals.

6 CDC currently has some such research underway with plans to begin more in the future (see chapter 7).
-— —— —-—

Chapter l-Summary and Policy Options | 7

about the adoption of individual measures depend

not just on their efficacy in controlled experiments, but also on their feasibility given the

physical characteristics of the relevant facility,

the patient population, and available resources.

Another basic component of CDC’S guidelines

is achieving adequate ventilation, which can be

difficult in modern facilities designed for energy

conservation or in older buildings without central

air circulation. New devices are under development to filter and recirculate air within individual

rooms. Also, germicidal ultraviolet-C (W-C)

light has been advocated as an adjunct to ventilation controls, as have masks designed to fit tightly

around the mouth and nose (called disposable

particulate respirators); but data on the effectiveness of each under actual conditions of use are

lacking.

In 1992, the National Institute of Occupational

Safety and Health (NIOSH), a part of the CDC,

recommended that HCWS who come in contact

with infectious TB patients should wear ‘‘powered air purifying respirators” (PAPRs), devices

commonly employed in industrial settings to

protect workers from toxic fumes and other

substances. Other TB experts at CDC criticized

the NIOSH recommendation, arguing that PAPRs

are unnecessary and interfere with the provision

of clinical care. TB experts outside of CDC report

that these contradictory recommendations have

caused confusion among HCWS, patients, and

those charged with controlling infection in facilities with TB patients (304). The divergent recommendations may reflect the different missions of

NIOSH and the rest of CDC. While NIOSH is

mandated to seek zero occupational risk, the

position of the others at CDC on PAPRs reflects

an attempt to balance worker safety with the

provision of feasible effective treatment to patients (79). Whatever the intent or impact of these

recommendations, however, there is currently no

evidence on the effectiveness of PAPRs.

Skin Testing and Preventive Treatment

For several decades, it has been theoretically

possible to prevent most new cases of TB with

available diagnostic and preventive treatment

methods. As TB has retreated from the general

population and become more concentrated among

subset populations, such targeted efforts should

have become more feasible. Indeed, CDC has

long recommended screening for tuberculous

infection among groups with high rates of TB,

with HIV, or with other risk factors for developing active disease and INH preventive treatment

(IPT) for those found to be infected. The ability

to implement these recommendations has been

limited largely by the availability of funding,

other resources, and knowledge about the most

cost-effective methods of providing these services to high-risk groups.

In order to prescribe IPT, one must first detect

a TB infection, usually with the PPD tuberculin

skin test. For otherwise healthy people, the test

detects an existing infection about 95 percent of

the time with a variable false positive rate. For

people with HIV and other immune deficiencies,

the test is much less likely to detect tuberculous

infection (due to a condition called anergy),

reducing its effectiveness as a screening tool in

these populations and thus limiting the use of IPT.

For those with tuberculous infection the preventive use of the anti-TB drug isoniazid (INH) has

been shown in large, randomized clinical trials to

be as much as 90 percent effective in eliminating

the bacilli from the body and preventing subsequent development of active disease. Between 2

and 3 percent of adults over age 50 receiving INH

develop liver inflammation that can lead to

hepatitis if the drug is not stopped when blood

tests reveal the condition.

BCG Vaccination

Since the early 1950s, the World Health

Organization (WHO) has advocated widespread

vaccination with BCG as a preventive measure

against TB in countries with a high prevalence of
8 I The Continuing Challenge of Tuberculosis

the disease. Currently, about 70 percent of the

world’s children receive BCG. However, BCG

has never been widely used in the United States

due, in part, to controversy over its efficacy and

low expected utility in populations in which the

rate of TB transmission is relatively low.

BCG refers to several strains of bovine tubercle

bacilli derived from a single strain produced

about 70 years ago in France. One form of BCG

is currently manufactured and sold with Food and

Drug Administration (FDA) approval in the

United States, Instead of preventing initial TB

infection, BCG is believed to enhance the body’s

immune response to the infection and prevent the

multiplication and dissemination of bacilli to

various parts of the body.

Several studies, including randomized clinical

trials, have produced estimates of the preventive

efficacy of BCG that range from zero (or negative) to 80 percent. It is also unclear how long

BCG might enhance immunity and whether

HIV-related irnmunodeficiency inhibits the vaccines’ usefulness. Attempts to interpret the existing data and understand the differing results

continue. Some research does suggest that BCG

may be more effective in preventing the more

serious extrapulmonary forms of TB among

children than in preventing the pulmonary forms

of the disease. Although side effects are rare and

data are insufficient to make actual risk estimates,

there have been published case reports of BCG

complications among HIV-infected individuals.

BCG vaccination may itself cause subsequent

tuberculin skin tests to show up as positive for 3

to 5 years, thereby complicating public health

efforts to detect actual infections and offer

preventive treatment. Framed as a policy choice

among alternative strategies for prevention”on,

Federal policy in the United States has long

favored strong infection control, skin testing,

and preventive treatment. However, CDC does

recommend selected use of the vaccine in

high -tisk infants and children for whom preventive treatment is infeasible or culturally unacceptable.

Diagnosis of Active TB

At present, diagnosis of active TB is based on

a combination of clinical symptoms, laboratory

tests, and chest x-ray findings. Although these

technologies have been generally adequate, their

deficiencies have grown in the face of rising drug

resistance and the need to prevent the rapid spread

of TB among patients who have HIV or who live

in congregate settings.

The TB skin test used for detecting tuberculous

infection is considered inadequate for diagnosing

active disease, partly because of its unreliability

with imrnunocompromised and other sick people

and with the minimum of 48 hours required for

results. The initial diagnostic laboratory test is the

sputum smear in which a sample of the patient

sputum is stained with a dye for acid fast bacilli

(AFB) and is examined under a light microscope.

However, only 50 to 80 percent of patients with

active TB have positive sputum smears, and the

rate may be even lower for people with HIV.

Hence, negative smears cannot be used to rule out

TB. Chest x-rays are also used to detect signs of

the presence of TB in the lungs or the damage

caused by the disease.

Definitive diagnosis of TB has been traditionally based on culturing and identifying tubercle

bacilli from a patient’s sputum, body fluids, or

tissue in the laboratory. This test takes 3 to 6

weeks given the bacilli’s slow rate of growth. A

relatively new, automated, radiometric device

(known by the trade name of BACTECT M

)

reduces testing time to about 10 days by measuring carbon dioxide given off by the tubercle

bacilli. Other diagnostic technologies are under

development.

Effective treatment depends on determining

the susceptibility of a patient’s TB to antituberculosis drugs. Delayed diagnosis and drug

susceptibility testing were considered to be one of

the main factors contributing to the recent outbreaks of MDR-TB and continue to represent a

major impediment in the control of TB. Conventional methods of drug susceptibility testing
Chapter 1-Summary and Policy Options | 9

typically require 8 to 12 weeks. Newer radiometric techniques used with direct testing can determine susceptibility to the five first-line drugs

within 3 weeks, although these tests are relatively

expensive and not yet widely available.

Newer diagnostic technologies under study

include a genetic technique called polymerase

chain reaction (PCR) to amplify the amount of

deoxyribonucelic acid (DNA) material specific to

tubercle bacilli. PCR-based diagnosis has reportedly produced results in research conditions

within 48 hours. However, PCR techniques currently carry a high risk of operator error, and TB

diagnosis using this technology is not yet available for nonexperimental use (29,30).7 A recently

reported method uses the light-producing enzyme

from fireflies to distinguish drug-resistant and

drug-sensitive tubercule bacilli in 2 to 3 days.

However, this technology has not yet been

adapted for clinical use. Other quick diagnostic

technologies are in various stages of development.

Treatment of Active TB

The introduction of antibiotic drug treatment in

the 1940s dramatically changed the practice and

outcome of TB treatment. Over the past 20 years,

no new drugs have replaced or supplemented the

five main frost-line drugs-INH, RF, pyrazinamide (PZA), ethambutol (EMB), and streptomycin (SM)--although other drugs of lesser

effectiveness and greater toxicity are available as

second-line drugs. In addition, clinical research

has permitted abetter understanding of how drugs

eliminate TB from the body as well as the

refinement of drug treatment regimens.

Combinations of antimicrobial drugs with overlapping functions are used in current treatment

regimens to attack tubercle bacilli in the body.

Anti-tuberculous drugs are generally classified as

bactericidal (producing rapid killing of bacilli) or

sterilizing (killing the last surviving, slowly

Treatment of drug-susceptible TB involves taking three

or four drugs together on a daily, two-, or three-time a

week basis for 6 months. However, hospitalization is

usually not necessary after a few weeks of treatment

renders the patient noninfectious. Treatment of drugresistant TB can involve more drugs for a Ionger period

of time and potentially longer hospital stays.

metabolizing bacilli over the long-term), INH is

the major bactericidal drug. RIF and PZA are the

most potent sterilizing drugs.

Current regimens usually consist of two phases

and can, if taken fully, produce cure rates of 98

percent with relapses among less than 3 percent.

During an initial 2-month bactericidal phase, the

daily use of INH, RIF, PZA, and SM or EMB is

intended to eliminate quickly the bulk of tubercle

bacilli. During the second 4 to 5 month sterilizing

phase, patients take INH and RIF on a daily

schedule or a two- to three-time a week schedule

to eliminate remaining bacilli. These drugs can

cause side effects, the most serious of which is

hepatitis, an inflammation of the liver.

By comparison, treatment of MDR-TB is

longer, potentially more toxic, less effective, and

significantly more costly. Drug regimens for

MDR-TB are determined on a case-by-case basis

using information on the patient’s prior drug

therapy, drug-susceptibility testing of the pa-

? One manufacturer, Hoffman LaRoche, offers this test as a service for laboratories that provide it with patient tissue samples; however,

the cost is approximately $175 per specirneq making it relatively expensive (29,30).
10 I The Continuing Challenge of Tuberculosis

tient’s bacilli, and the patient’s tolerance of

adverse effects. Cases resistant to two or more of

the first-line drugs would be treated with combinations of drugs selected from among the firstand second-line drugs, often for 18 to 24 months

or longer.

The arsenal of second-line TB drugs includes:

capreomycin, kanamycin, ethionarnide, cycloserine, and p-aminosalicyclic acid. Reliable data to

judge the effectiveness of these second-line drugs

are lacking, but anecdotal experience suggests

that they are much less effective and more likely

to lead to serious toxic effects. Adjunctive surgery to remove heavily infected tissue (usually in

the lung) is sometimes used as a last resort when

drug treatment is inadequate in patients with

localized pulmonary TB.

Current evidence suggests that drug-sensitive

TB is curable in many individuals with HIV, even

some with advanced stages of immunodeficieny.

Most documented cases of treatment failure in

patients with HIV have been linked with incomplete treatment or poor absorption of antituberculosis drugs. The major problems in treating TB in HIV-infected people are drug side

effects and interactions with other treatments or

conditions.

Recently, the FDA has worked with drug

manufacturers to rectify shortages of some drugs.

Public health officials have also expressed concern over increases in the price of antituberculosis drug treatments. Table 1-1 shows the

results of a recent CDC survey of the prices paid

by State and local health departments for drugs

they purchase for two common TB drug regimens. Table 1-1 suggests drug price increases of

about 9 percent per year on average between 1986

and 1992 for treating an uncomplicated case and

about 12 percent per year for treating a patient

resistant to INH and RIF.

Current research is focused on developing new

drugs, shorter regimens, and better methods of

drug delivery. A number of individual drugs are

being investigated for anti-TB activity, but so far

there is limited or no data about their efficacy and

safety from controlled clinical trials. Among such

drugs not yet approved for TB treatment in the

United States are clofazamine and the classes of

drugs known as quinolones, rifamycin derivatives, and phenazines.

Combination tablets containing INH and RIF

(known by the trade name RifamateT M

) are

approved by the FDA but not widely used in the

United States. In 1993, the FDA received an

application to market RifaterTM, a combination of

INH, RIF, and PZA, in the United States.

Implantable devices containing anti-TB drugs for

slow release similar to the contraceptive

NorPlantTM are not yet ready for clinical evaluation. Irnmunotherapeutic approaches to treating

TB are also under investigation.

Delivering TB Treatment

Because current TB treatment involves taking

multiple drugs over many months, complete,

appropriate treatment can be hard to achieve.

Hence, the delivery of treatment is as important

for TB control as is the arsenal of available drugs

themselves. Current programs to deliver treatment and other TB services are heterogeneous

and can vary across and with communities.

Data based on samples of TB case reports

suggest that about 75 percent of U.S. patients

being treated for TB complete treatment within a

year and that 80 percent take their medication on

a continuous basis. However, these national

averages obscure wide variation among different

areas of the country. For example, in the late

1980s, cities such as Chicago, New York, and the

District of Columbia reported completion rates

ranging from 54 to 60 percent, while Dallas, San

Francisco, and El Paso had rates above 94

percent.

While much public discussion has focused on

patient behavior as the cause of treatment failure,

evidence suggests that the availability and quality

of TB control services as well as prescription of

optimal treatment regimens may be equally important in determining whether patients are cured.
Chapter I-Summary and Policy Options I II

Table l-l—Trends in Drug Costs for Treating Tuberculosis in a 165 lb (75 kg) Patient,

1986-92: An Uncomplicated Case Versus a Case Resistant to INH and RIFa

Uncomplicated case:

Drug Daily dose Duration 1986 cost 1990 cost 1992 cost

Isonizaid 300 mg 180 days $ 5.04 $ 6.50 $ 8.50

Rifampin 600 mg 180 days 106.20 159.30 165.30

Pyrazinamide 25 mg/kg 60 days 98.00 160.00 179.20

$209.24 $325.80 $353.00

Average annual percentage increase in cost, 1986-92: 9.1 Yo

A case resistant to INH and RIF:

Drug Daily dose Duration 1986 cost 1990 cost 1992 cost

Pyrazinamide 25 mglkg 540 days $882.00 $1,440.00 $1,613.00

Ethambutol 15 mgfkg 540 days 690.00 1,246.00 1,610.00

Streptomycin 15 mgfkg 120 days 138.00 192.00 206,00

Ethionamide 20 mg/kg 540 days 890.00 1,458.00 1,691.00

Ciprofloxacin 1500 mg 540 days NA 3,000,00 3,600.00

$2,600.00 $7,338.00 $8720.00’

Average annual percentage increase in cost, 1986-92 (without Ciprofloxacin): 12.0%

*Add ofloxacin=$4,080 .00

Add amikacin=$27,648 .00

Add clofazimine=$71 .00

KEY: NA - not available.

a Treatment costs based on median prices given in table 5-1. Costs are for an entire recommended treatment CYde.

Estimates include drug casts only.

SOURCE: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and

Prevention, Division of Tuberculosis Elimination, 1993.

State statutes authorize State and local health

agencies to control TB and other communicable

diseases. Most of these agencies, in turn, contract

with local hospitals and clinics to provide TB

services. It is widely held, though infrequently

documented, that these public health services

have generally not kept pace with health problems

in recent years, resulting in part from dwindling

funds, lack of expertise, and outdated technologies. In addition,

ble environment

flexible service

clinics may also

ment.

long waiting times, an inhospitafor personal care, and lack of

hours in many public health

contribute to inadequate treatAs many specialized TB facilities closed during the 1960s and 1970s, much of the job of TB

diagnosis and treatment has shifted to private

primary care physicians, many of whom are

unaccustomed to seeing patients with active TB

or MDR-TB. These physicians maybe less likely

to suspect TB, diagnose it quickly, and prescribe

the most efficacious treatment regimen. Recently

collected data suggest that as many as 40 percent

of physicians would unknowingly prescribe an

inappropriate TB regimen, an error which could

lead to treatment failure and emergence of drug

resistance.

Even when an optimal drug regimen is prescribed, available, and feasible, patients do not

always complete treatment. A very small percentage of patients do refuse or are mentally unable to

follow treatment. Still, available evidence suggests that most patients would complete treatment

if it were feasible to do so or if encouraged to do

so through incentives and progressively more

stringent measures as allowed by law to protect

the public health.
12 I The Continuing Challenge of Tuberculosis

The Centers for Disease Control and Prevention,

headquartered in Altanta, has primary responsibility

within the Federal Government for TB control.

A central issue in treatment delivery concerns

the degree to which supervision by HCWS is

necessary to bring about higher rates of treatment

completion. One form of supervised treatment is

directly observed treatment (DOT), which CDC

defines as observation of the patient by a health

care provider or other responsible person who has

frequent contact with the patient as the patient

ingests anti-TB medications. Although the concept of DOT is often proposed in policy and

clinical discussions, often as an alternative to

more restrictive forms of ensuring treatment

completion, DOT can take many forms. Some

programs limit DOT to health care facilities,

while others send workers to patients’ homes or

other places. All DOT programs are laborintensive and require skill, diligence, perseverance, and funds.

While some groups, including CDC and ALA,

have recommended DOT be considered for every

patient, others have argued that its use for most

patients is wasteful and needlessly restrictive

since they would complete therapy anyway. Most

of the existing literature of different treatment

delivery strategies are only descriptive in nature.

Little systematic research has been done on the

effectiveness or cost effectiveness of individual

DOT strategies or of DOT compared to less

supervised treatment for different patient populations. A more complete assessment of costs and

outcomes is needed to generate useful information for public policy.

Federal Involvement in TB Control

Primary responsibility for designing and carrying out TB control services rests with State and

local health departments, not the Federal Government. Still, the Federal Government does provide

the major funding, other resources, leadership,

and coordination to the Nation’s TB control

efforts through several agencies. Only a few of

these agencies are able to estimate spending for

TB as distinct from funds for other responsibilities.

Public Health Activities

The Centers for Disease Control and Prevention make up the lead Federal agency for TB

control. Out of its $79 million TB budget for

fiscal year 1993, CDC gave $34.3 million in

grants to State and local health departments.

Another $39.2 million constituted emergency

funds that Congress separately appropriated for

TB control in six States and seven cities most

heavily affected by TB. The remaining $5.2

million supported TB program operations at CDC

itself. CDC also used $25.4 million designated for

HIV activities for HIV-related TB efforts. Table

1-2 breaks down CDC’S TB spending for fiscal

year 1993 by function. These appropriations

represented a major increase in TB funds over

previous years (see figure 1-2). In addition, the

President’s fiscal year 1994 budget request includes $50 million over fiscal year 1993.

Following a drastic scaleback in Federal TB

funding in the 1960s and 1970s, CDC restarted

many of its activities in the early 1980s and

developed a comprehensive “Strategic Plan for

the Elimination of Tubeculosis in the United

States’ with the goal of lowering the incidence to

3.5 per 100,000 by the year 2000 and 0.1 per
Chapter l-Summary and Policy Options I 13

Table 1-2—U.S. Centers for Disease Control and Prevention Spending for

Tuberculosis by Function, Fiscal Year 1993

Dollars Percent

($ millions) Of budget

Community-based control programs (screening, treatment, prevention,

infection control)

Outreach and service linkage (implementation of directly observed

therapy)

Research and demonstration

Surveillance, epidemiology and data systems

Laboratory services

Public education and information

Professional competence assurance (training for service providers,

physicians, researchers, and laboratory personnel)

Leadership and administration (technical assistance to improve

management of State and local TB control programs)

Community protecition/regulatory programs

Total

$36. 9

36.7

9.8

7,0

4.8

4.4

2.2

2.2

NA

$104.0

35!40

35

9

7

5

4

2

2

NA

100?40’

NA = not available.

a Corn ~nent percentages do not add up to 100 percent due to r0undin9 error.

SOURCE: Office of Technology Assessment, 1993, based on data from C. Bozzi, Assistant to the Director for

Tuberculosis Coordination, Division of Tuberculosis Elimination, Public Health Service, Centers for Disease Control

and Prevention, U.S. Department of Health and Human Services, Atlanta, GA, personal communication, July 9, 1993.

Figure 1 -2—Tuberculosis Funding, U.S. Centers for Disease Control and Prevention,

Fiscal Years 1960-93

120 -–- —-

[

‘-- 1

cl

100

80

Q-J c

: 60

E

w

40

20

0

b

■ , a m,

1960 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 9293

a Fi~l years 1972 through 1982 categorical grants ceas~, funds to states were in block grants not specific for TB.

b Fiscal year f992in~ludes $26 million in human immun~eficienq virus (~1/) funds, used for HIV-re[ated TBactivities.

C Fisml year 1 ggs includes $25 million in Hlv fun~ used for HIV-relat~ TB activities.

SOURCE: Office of Technology Assessment, 1993, based on data from the U.S. Centers for Disease Control.
14 I The Continuing Challenge of Tuberculosis

100,000 by 2010. In 1992, CDC headed a task

force of Federal agencies and other public health

groups that issued a complementary “National

Action Plan to Combat MDR-TB. ” The task

force plan, which targets all forms of TB, not just

drug-resistant forms, details an exhaustive array

of government and private responsibilities in TB

control and research.

CDC estimates that Congress would need to

increase CDC’S budget for TB control by $380

million for fiscal year 1994 to implement fully

CDC’S responsibilities under the MDR-TB Action Plan. This amount is $330 million more than

the amount actually requested in the President’s

1994 budget. Estimates of money necessary for

other agencies to implement their responsibilities

under the action plan are not currently available.

Other Federal agencies run health care facilities that provide TB treatment. These agencies

include the Department of Veterans Affairs, the

Indian Health Service, and the Federal Bureau of

Prisons. In addition to supporting some anti-TB

drug research and the development of educational

materials on TB for health professionals, the

Department of Health and Human Services’ (U.S.

DHHS) Health Resources and Services Administration (HRSA) funds TB services through State

and locally run clinics that serve disadvantaged

and underserved populations. The U.S. Agency

for International Development (U.S. AID) gave

over $8 million for TB control in developing

countries, most of which supported BCG vaccination of children. Other agencies with roles in TB

control include the U.S. DHHS Substance Abuse

and Mental Services Administration (SAMHSA),

Department of State’s consular offices and embassies abroad, the Department of Justice’s Immigration and Naturalization Service (INS), and the

Department of Labor’s Occupational Safety and

Health Administration (OSHA).

Research and Development

Most Federal TB-related research and development R&D is conducted or funded by the

National Institutes of Health (NIH). Its spending

for TB research has increased dramatically from

$4.2 million in fiscal year 1991 to $35.9 million

in fiscal year 1993, with an additional $10 million

requested by the President in his fiscal year 1994

budget proposal.8 The bulk of NIH’s funding (57

percent) for fiscal year 1993 is administered by

the National Institute of Allergy and Infectious

Disease (NIAID), although a total of 17 NIH

institutes and centers within NIH report ongoing

TB research.

NIAID estimates that fill finding of those

activities in the MDR-TB National Action Plan

that fall within NIAID’s purview would cost

$45.6 million in fiscal year 1994, $20.6 million

above NIAID’s spending in fiscal year 1993. In

spring 1993, an NIH Executive Committee identified and prioritized new TB research opportunities for all of NIH. Fully funding this research

agenda would cost an estimated $102 million

above fiscal year 1993 funding.

Areas of NIH research include development of

new diagnostic tools, drugs, and vaccines as well

as behavioral issues on prevention of transmission and adherence to treatment. NIH is also

spending $2.3 million to convert an existing

building into a containment laboratory that allows

for the safe handling of drug-resistant strains of

tubercle bacilli. Too few containment laboratories at NIH and other research institutions limit

the amount of TB research scientists can conduct

(29,30).

The Office of Technology Assessment (OTA)

found a lack of systematic research on the

effectiveness or cost-effectiveness of individual

interventions to control TB infection in hospitals

or to ensure that patients in different communities

or treatment settings complete anti-TB therapy. In

addition, little effort in health services and health

8 The 1993 budget includes $14.1 million also counted as HIV spending and $4.8 in one-time funds transferred by the NIH director from

her discretionary budget.
Chapter l-Summary and Policy Options I 15

economics research has been devoted to understanding variation in the use of hospitalization

and costs of treating TB, especially during the

disease’s acute, infectious period.

Although CDC and some institutes at NIH are

conducting studies on the effectiveness and appropriateness of TB services, U.S. DHHS’S Agency

for Health Care Policy and Research (AHCPR)

takes the lead in conducting and supporting

federally sponsored health services, health economics, and medical care effectiveness research.

AHCPR’S main efforts so far on TB were its

participation in developing the MDR-TB National Action Plan and a 1993 workshop for

judges on HIV and TB.

Regulation of TB Technology

The Food and Drug Administration ensures the

safety and effectiveness of drugs used to treat TB.

It also regulates and approves BCG and other

vaccines, tuberculin skin tests, other diagnostic

reagents used to detect M.tb. or to deterrnine drug

susceptibility, and devices used to prevent the

spread of the disease. In recent years, FDA’s role

in TB control has focused on alleviating shortages

of some TB drugs and expediting the approval of

new TB drugs. The FDA recently helped make

available an interim supply of SM and PAS for

MDR-TB patients through CDC when adequate

amounts of the drug could not be obtained

privately. The FDA is also working with companies to encourage development of combination

drugs and new technologies such as implantable,

slow-release formulations.

Federal Disability Programs

The Social Security Administration (SSA)

administers two programs for people unable to

work due to disability-the Disability Insurance

(DI) program for those who have paid the

requisite social security taxes over the course of

their careers, and the Supplemental Security

Income (SS1) program for very low-income

individuals. While SS1 pays a set amount each

month and can begin once the beneficiary is

forced to stop work, DI benefits depend on the

amount of social security taxes paid by the

beneficiary; DI has a 5-month waiting period after

the onset of disability.

By law, both programs require that an applicant

be unable to work due to a physical or mental

impairment expected to result in death or to last

at least a year. SS1 and DI are not available for

most patients with drug-susceptible TB because

they are usually able to work once a few weeks of

treatment renders them noncontagious. However,

TB patients can quilify for SSI or DI if they also

have concurrent HIV or if they have some other

disabling condition.

Medicaid and Medicare

While many medical services for people with

active TB are provided directly in outpatient

clinics through State and local programs that do

not necessarily charge patients, third-party health

insurers also pay for some TB services for their

beneficiaries. Little if any systematic research has

been done on the role of insurance in financing

care for TB. However, indirect evidence does

suggest a significant role for Federal insurance

programs. Figure 1-3, which breaks down all

hospitalizations for TB in 16 States in 1990

according to payer, shows that Medicaid was the

single most likely payer (36 percent), with

Medicare paying for another 17 percent. In total,

government pays for almost three-quarters of TB

hospitalizations in these States.9

Medicaid, aState-administered program funded

jointly by the Federal and State governments,

provides health insurance to certain categories of

low-income individuals, including recipients of

SS1, many poor women and children, and, in some

States, people whose high medical bills make

them poor or almost poor. The minimum set of

9 Although not necessarily representative of the entire country, the States presented do include several with the highest TB burdens, most

notably New York and California.
16 I The Continuing Challenge of Tuberculosis

Figure 1-3-Hospital Admissions With a Diagnosis

of Tuberculosis in 16 Statesa by Payer, 1990

Medicaid Medicare

36

Self payl

no charge

11% I

Other

government

programs

2 0

a States are Arizona, California, Colorado, Florida, Massachusetts,

Maine, New Hampshire, New Jersey, Nevada, New York, Oregon,

Pennsylvania, South Carolina, Vermont, Washington, and Wisconsin.

SOURCE: Office of Technology Assessment, 1993 based on data

derived from State hospital discharge abstracts covering 100 percent

of acute short-stay hospitals and U.S. Department of Veterans Affairs

hospitals. Data prepared by Codman Research Group, Inc., Lebanon,

New Hampshire.

benefits provided under Medicaid covers inpatient, outpatient, laboratory, and other services for

TB patients at approved facilities.

With approval from the Federal Health Care

Financing Administration (HCFA) that administers Medicaid and Medicare, New York’s Medicaid program pays for directly observed therapy for

Medicaid-eligible TB patients with reimbursement amounts dependent on the intensity of effort

necessary to provide and supervise therapy. No

other State has yet attempted innovative approaches to providing TB services with Medicaid

funding. HCFA estimates that in 1991, the

Federal Government’ sportion of Medicaid spending for TB totaled $45 million, while the States’

portion totaled $30 million.

Medicare provides health insurance to individuals who are over age 65, who have end-stage

renal disease, or who have received Social

Security DI benefits for 2 years. Medicare pays

for inpatient services provided in short-stay

hospitals and ambulatory services provided in an

office or clinic under a physician’s supervision.

Although Medicare does contain some limited

home health care benefits and long-term care and

skilled nursing services in certain types of approved facilities, DOT in the home and long-term

care facilities dedicated to TB care would most

likely not qualify for Medicare reimbursement.

HCFA estimates that Medicare spending for TB

totaled $65 million in 1991.

Policy Options for Congress

Through its analysis, OTA has identified 11

options for congressional consideration (box

l-A). Each option has the underlying goal of

improving TB control capabilities in the United

States. They fall into three categories that affect:

The public health infrastructure for combating

TB;

The research, development, and availability of

technologies for combating TB; and

The financial security and financial access to

health care services for persons with, or at risk

of, TB.

The focus of this discussion is on potential actions

of the Federal Government in providing leadership and resources for the Nation’s TB control

activities, rather than on potential actions of the

State, local, and private authorities that carry out

many of the programs to fight this disease. A

fuller discussion of these options and their

potential implications follows.

Options That Affect the Public Health Infrastructure

for Comating TB

OPTION 1. Fully fired the public health activities

identified in the CDC’S 1992 National Action Plan to

Combat Multidrug-Resistant Tuberculosis.

CDC estimates that full implementation of all

activities in its 1992 National Action Plan to

combat MDR-TB (described in box 7-B) for

which it would be responsible would require

appropriations of $380 million during the first

year over and above the $105 million appropriated in fiscal year 1993. This estimate includes
———

Chapter l-Summary and Policy Options I 17

Box l-A—Policy Options for Congressional Consideration

option 1. Fund fully the public health activities identified in the CDC’S 1992 National Action Plan to Combat

Multidrug-Resistant Tuberculosis.

Option 2. Establish a mechanism for direct Federal intervention in cities and other jurisdictions with

extraordinarily high levels of active tuberculosis, multidrug-resistant TB, or HIV and TB

confection.

option 3. Require universal directly observed treatment (DOT) through legislation, regulation, or as a

condition of receiving Federal TB control funds.

option 4. Require periodic TB skin testing, active case finding (by chest x-ray), and preventive treatment in

Federal hospitals, prisons, and other facilities.

option 5. Purchase directly anti-TB drugs and distribute them to State and local authorities.

Option 5a. Purchase directly anti-TB drugs with State and local authorities reimbursing the

Federal Government.

option 6. Increase support for international TB control activities.

Option 7. Make a concerted effort to develop health Services research relevant to the fight against TB.

Option 8. Fully fund basic and clinical TB research as outlined in the CDC’S 1992 National Action Plan to

Combat Multidrug-Resistant tubererculosis and NIH’s 1993 Tuberculosis Research Opportunities.

Option 9. Support the creation of additional regional “centers of excellence” for TB treatment and research.

Option 10. Expand the Federal Government’s definition of disability to include active TB as a disabling

condition for the purposes of Supplemental Security Income (SSI) and Disability Insurance (DI)

benefits.

option 11. Provide States with the option to expand categorical Medicaid coverage to persons without other

forms of health insurance who have tuberculous infection or active TB.

Option ha. Limit the option of expanding categorical Medicaid eligibility to those with active

disease only.

Option llb. Limit categorical Medicaid eligibility to TB-related services only.

SOURCE: Office of Technology Assessment 1993.

$62 million in R&D expenditures, with the OTA found that CDC and other TB experts

remainder allocated toward various forms of

public health activities. Although CDC currently

has no estimates of amounts that would be

required for subsequent years, the $380 million

increase would include some one-year-only spending as well as some spending that would be

continued subsequently (35). No estimates currently exist of the cost of fully implementing

activities in the National Action Plan that are the

responsibility of other Federal agencies.

agreed on the need for increased Federal involvement and resources. However, some of the

options that follow in this section highlight major

policy questions that would need answers to fully

implement the CDC plan. In addition, because

CDC has given only rough indicators of priority

among all of the actions it recommends, Congress

and other policymakers cannot evaluate in detail

how CDC and other Federal agencies would

propose to allocate funding increases if Congress
18 I The Continuing Challenge of Tuberculosis

appropriated less than the amount required for full

implementation.

Immediate full funding of the plan may not be

more effective or more efficient than a more

incremental phase-in. On the one hand, such a

dramatic increase in funding would alert the

country to the threat of TB to affected communities and the value the Federal Government places

on TB control.

On the other hand, the public health and

research system may not be able to absorb such a

large influx of cash as efficiently as it could if the

increases came more gradually. In the course of

OTA’S analysis, public health officials pointed

out the highly regulated and slow process some

State and local governments face in hiring qualified individuals to administer TB therapy and to

perform other public health functions (29,30).

Additional Federal grants would not immediately

increase the supply of qualified public health

workers or speed up local governmental hiring

processes. Also, this report highlights the lack of

information about the relative effectiveness of

individual infection control procedures. Without

frost developing better experimental data on these

technologies, 10 some money devoted to retrofitting hospital rooms and other facilities to serve

active TB patients would probably be spent

inefficiently or unnecessarily. In an era of limited

Federal resources and many competing public

health needs, policymakers may wish to weigh

the value for spending some TB control dollars

better in the future against the value of providing

maximum resources for TB now.

OPTION 2. Establish a mechanism for direct Federal

intervention in cities and other jurisdictions with

extraordinarily high levels of active TB, MDR-TB, or

HIV and TB confection.

Support for this option would rest on the

assumption that TB can pose a significant enough

threat in some communities that State and local

authorities alone are unable to respond quickly

and sufficiently, even with Federal financial

support. One TB expert suggested to OTA that the

magnitude of drug resistance, HIV dual infection,

substance abuse, hopelessness, and incomplete

TB treatment is great enough in New York City

to warrant the formation of a Federal task force to

supply personnel and expertise from elsewhere on

a short-term, emergency basis (29,30).11 Such a

plan would extend the technical expertise that

CDC routinely provides to State and local health

authorities. Federal personnel would help provide

TB treatment, find cases of TB in facilities that

public health officials suspect to harbor the

disease, and perform other TB services needed in

the community.

This option raises several questions. First, by

what criteria would the Federal Government

decide to intervene? Given that most legal authority to protect the public health has been traditionally vested in State and local governments (125),

any Federal intervention would almost certainly,

at a minimum, require a request from the relevant

local governments. Second, Federal officials

would need to develop epidemiologic or other

criteria for judging that TB has reached levels

high enough to justify this Federal action. These

criteria would need to be measurable and perhaps

flexible. Inclusion of TB and HIV confection

rates or numbers of foreign-born residents, if

measurable, could make this option available for

communities with low rates of existing TB but the

potential for high rates in the future. The emphasis of Federal intervention in these communities

may be on screening high-risk groups and preventive treatment, rather than on providing resources

for treating active disease.

Decisionmakers would also want to question

whether Federal Government intervention would

actually be more effective than the local governments and private organizations acting alone. As

noted, the ability to bring in Federal persomel

10 me fitiation of such re=h is itself included b the Action pl~.

11 ~ssugg~tion was not made by an official of the New York State or City gOWmentS.
Chapter l-Summary and Policy Options I 19

may offer a significant advantage for State and

local governments that face limitations in hiring,

although the Federal Government may also face

hiring restrictions. Reassignment of professionals

from the Commissioned Public Health Service

Corps would mean these individuals would be

unable to continue to fulfill their current responsibilities,

The cost of hiring additional Federal personnel

on a short-term basis would depend on the

number hired, their qualifications, the duration of

their employment, and perhaps whether they

currently reside in the targeted community or

must relocate. Another possibility would be to

make voluntary service on such task forces one

means of paying back government loans for

health professional education and training as was

done in greater numbers during the 1970s and

1980s under the National Health Service Corps.

There is also precedent for providing special visas

for qualified foreign medical personnel to fill

positions in undeserved areas.

OPTION 3. Require universal directly observed treatment (DOT) through legislation, regulation, or as a

condition of receiving Federal TB control funds.

The American Lung Association recently recommended DOT for all persons with active TB

(244). In contrast, CDC has recommended that

DOT be considered for active cases,

Supporters of universal DOT point to the

practical difficulty of predicting a priori which

patients will complete treatment without supervision. These supporters argue that human nature

should lead health professionals to expect that

patients will forget to take medication without

reminders. Universal DOT proponents also argue

that some health authorities may be more likely to

assume that homeless individuals, drug users, and

people without access to regular health care

would be less likely than other TB patients to

complete therapy. These groups may be subjected

to more restrictive treatment measures without a

strong medical or public health rationale. Requiring universal DOT helps insure that all TB

patients are treated in an equitable manner.

Opponents of requiring universal DOT point

out that despite the difficulties in predicting who

is unlikely to complete treatment, between 1976

and 1990, over 80 percent of persons with active

TB in the United States completed treatment

without DOT (9). One estimate for New York

City suggests that DOT costs may fall between

$2,000 and $3,000 per person excluding the cost

of drugs (29,30). Opponents argue that universal

DOT is a wasteful use of limited resources and

needlessly intrusive for most patients.

In addition, Federal policymakers would need

to define exactly what State and local governments would have to do to conform to the Federal

requirement. DOT can take many different forms

and degrees of restrictiveness, require varying

intensities of resources, and be combined with a

variety of complementary programs such as

incentives or inducements to complete therapy.

As suggested in chapter 6, there are more

options available to policymakers than just requiring DOT for everybody or trying to predict a

priori which TB patients will not complete

therapy. One alternative, used in some communities, is to monitor all patients’ therapy, but allow

their behaviors to be indicators of the need for

more intensive supervision of therapy. Only when

patients do not show up for medical appointments

or give other evidence that they might not

complete therapy would public health officials

require patients to be observed taking their

medications. Although this alternative to universal DOT requires that public health authorities

have the resources to track down missing patients

quickly, a potentially difficult and labor-intensive

task, particularly for homeless or other difficultlocate patients, it may be less expensive and as

effective in some communities.
20 | The Continuing Challenge of Tuberculosis

OPTION 4. Require periodic TB skin testing, active

case finding (by chest x-ray) and preventive treatment

in Federal hospitals, prisons, and other facilities.

Epidemiological evidence indicates that hospitals, prisons, and other facilities housing people in

congregate settings may be appropriate targets for

TB prevention because institutions house many

individuals at high risk of progressing to active

disease. Identifying infected residents and workers at high risk of developing active TB, as well

as those who already have active TB, offers an

opportunity to prevent the potential spread of the

disease to others with whom the active cases have

close contact. Immigrants, currently screened for

active disease for legal entry into the United

States, are another high-risk group that the

Federal Government may wish to consider for

screening and preventive treatment if found to

have tuberculous infection.

Positive skin tests would help identify candidates for preventive treatment, although health

officials would have to consider the problem of

false negative among immunocompromised individuals with tuberculous infection. In addition, officials would need to consider the best way to use

chest x-ray technology in order to identify active

disease.

By requiring screening and preventive treatment programs in its own facilities, the Federal

Government would be setting a standard that

could encourage State and local authorities to

adopt voluntarily for their own congregate institutions. However, there are some potential drawbacks to a Federal policy. The Federal agencies

charged with administering each type of institution may not correctly identify groups at high

enough risk of active disease to warrant screening

and follow-up preventive treatment.

For example, many patients admitted to Veterans Administration or other Federal hospitals for

short periods of time may be at very low risk of

developing active TB if infected. In addition,

nonfederal institutions attempting to follow the

Federal Government’s lead might also establish

screening programs where they are likeIy to yield

little benefit. Workplace screening in low-risk

settings such as a factory are unlikely to have

much effect on the spread of much TB. Analysis

in this report suggests that research into the most

cost-effective ways of running screening and

preventive treatment programs may not be available to guide the implementation of this option.

Funding for screening and prevention in Federal institutions would presumably come from the

budgets of the agencies charged with administering them as do most current TB control efforts.

The Department of Veterans Affairs (U.S. DVA)

currently pays for TB control in its own hospitals,

the Bureau of Prisons in Federal prisons, and so

on. This decentralized administration of Federal

facilities raises the further problem of ensuring

compliance with a screening and prevention

requirement. Current Bureau of Prisons policy

already requires chest x-rays for new inmates and

tuberculin skin testing every 2 years, but no data

are available on the extent to which such testing

is actually carried out. Adoption of screening

requirements would require mechanisms to ensure they are carried out as well as sufficient

resources to ensure appropriate diagnostic folIowup and treatment; this includes not just

money, but trained personnel as well.

OPTION 5. Directly purchase anti-TB drugs and

distribute them to State and local authorities.

The rationale behind universal TB drug purchase is that the Federal Government, acting as a

single, large-volume buyer should get the needed

pharmaceuticals at a lower cost than can individual States or local health departments. The same

considerations could apply to universal purchase

of PPD skin testing kits.

The Federal Government already purchases

some childhood vaccines under contract at prices

substantially below retail. The CDC’S recent

survey of trends in anti-TB drug prices revealed

that the price paid for the same form and dose of

a drug can vary greatly from State to State. In

addition, if the Federal Government were to take
—-—— .

on the function of paying for all TB drugs, State

and local governments could use the money that

would have gone to pharmaceutical purchase for

other purposes.

CDC currently has the statutory authority to

take on this activity; it requires only the appropriations to do so. CDC estimates that in 1993, the

cost of purchasing all anti-TB drugs used at the

State and local levels would total $80 million.

This figure is included in the CDC’S estimates of

fully implementing its National Action Plan for

the elimination of TB.

However, this amount of money would cover

only the cost of the drugs themselves and does not

include the cost of administering the drug purchase program or distributing the pharmaceuticals. CDC currently has no estimates of the costs

of these functions. It is also not clear whether the

Federal Government would take on the function

of distributing the drugs to the States or whether

that function would continue to be done by the

drug suppliers. U.S. DVA currently purchases

drugs in bulk for use in its own hospitals, but does

so with a highly centralized distribution system,

thus minimizing the distribution costs borne by

the pharmaceutical suppliers. The willingness of

suppliers to give discounts for bulk purchasing

may be partially dependent on whether the

Federal Government took on responsibility for

distributing the drugs since the suppliers’ costs

would be lower.

CDC has not indicated the assumptions that

went into its $80 million estimate. Not only is it

not clear what prices the government would

expect to pay for each pharmaceutical, but also

CDC has not shown how improved case finding

might increase drug costs in subsequent years or

how decreases in TB rates would ultimately

decrease funds necessary to purchase drugs.

The final price negotiated for these drugs could

also depend on the number of manufacturers for

a drug. Some of the more expensive drugs are still

covered by patents and hence only have one

manufacturer. When manufacturers do not face

competition, they may not see an incentive to give

Chapter l-Summary and Policy Options | 21

significant discounts in order to sell their products. In other cases, there may be only one

manufacturer of a drug or its active ingredient

even though it is no longer covered by a patent

(121,152). These manufacturers may also be

reluctant to give significant discounts. Finally,

the pharmaceutical industry has suggested that

centralized purchase would provide an added

disincentive for firms to invest in research to

develop new drugs as discussed in option 8 below

(286).

OPTION 5a. Directly purchase anti-TB drugs with

State and local authorities reimbursing the Federal

Government.

This option would be identical to Option 5

except that the Federal Government would not

bear the $80 million estimated to be necessary for

the purchase of the pharmaceuticals themselves.

Instead, State and local governments would

continue to pay for drugs, but would reap any cost

savings the Federal Government can realize by

purchasing on their behalf. Such cost savings

might not be spread evenly among the States. The

CDC survey indicates that some States, presumably those purchasing large quantities of drugs,

already receive a discount through negotiated

contracts with drug suppliers. These States would

likely benefit less per unit of drug purchased than

would areas of the country paying higher retail

prices for their TB drugs.

OPTION 6. Increase support for international TB

control activities.

The American Lung Association, among others, advocates greater support of the World Health

Organization’s TB programs, greater CDC provision of its technical staff to international organizations, and selected nations, more support for TB

research in developing countries through ND-I,

and greater involvement of AID in tuberculosis

control as well as in bilateral programs with other

countries and through WHO (85). As noted in

chapter 7, the Federal Government supports each
22 I The Continuing Challenge of Tuberculosis

of these activities to a certain extent, although the

vast bulk of current and expected TB spending is

targeted to the United States.

If Congress decided to increase TB control

efforts in less developed countries, it could decide

to do so purely on humanitarian grounds. However, even if Congress sought only to protect this

nation’s health, controlling TB abroad could

lower TB incidence of the disease here given the

mobility of foreign born people to the United

States. Research oriented toward developing countries could also have benefits at home; for

example, a fast, definitive diagnostic test designed for developing countries that do not have

easy access to sophisticated clinical laboratories

could be of great use in many urban and rural

areas of the United States as well.

A potential danger of increasing United States

support of TB efforts abroad is that it might divert

resources from domestic TB control activities.

The Federal Government has already laid out an

ambitious domestic agenda to control TB for

which there may not be sufficient funds to fully

implement in the short-run. If money for expanded TB control efforts outside the United

States would come from appropriations that

would otherwise go to domestic public health and

research activities, Congress may need to weigh

the value of supporting efforts abroad against the

impact that money would have on the health of

people with TB at home.

Options That Affect the Research, Development,

and Availability of Technologies for Combating TB

OPTION 7. Make a concerted effort to develop health

services research relevant to the fight against tuberculosis and to disseminate research results to policyrnakers and health professionals.

Several areas of this report suggest that better

health services and economic research results

could help policymakers target TB control efforts

more efficiently. Through legislation or through

direction of U.S. DHHS, relevant agencies such

as the CDC, AHCPR, HCFA, NIH, and HRSA

could publicize TB health services research as a

priority in various types of extramural funding

programs. Several of these agencies have said

they intend to expand their efforts in this area.

Two sample questions suggested by OTA’S

analysis that might be answered by health services and health economics research are:

What are the effectiveness and cost-effectiveness of various forms of DOT and how do

these measures vary among different parts of

the country and different groups of patients?

What sources of income do TB patients have

and what impact do government benefits have

on the identification, treatment, and control of

TB such as through SS1, Aid to Families with

Dependent Children, housing programs, and

food stamps?

This option could include efforts to disseminate

to policymakers and health professionals the

results of both health services and clinic research

to improve the delivery of health services and to

ensure appropriate clinical treatment for TB.

One drawback of this such research is that it

could draw resources away from direct TB

control. Data on the effectiveness and costeffectiveness of treatment strategies such as DOT

are best gained through randomized clinical trials,

which are expensive. In addition, the size of such

studies increases as one wants to learn more about

differences in effectiveness among different sociodemographic groups or according to other

ways that differentiate TB patients. Policymakers

would also want to consider health services

research already being undertaken by State and

local governments and private groups such as

foundations to assess its quality and to avoid

duplication.

CDC’S estimates of funds necessary to implement its responsibilities under the 1992 National

Action Plan include funds for the health services

and health economics it hopes to carry out.

Estimates of funds needed for new health sources

research that other Federal agencies would support are not available.
Chapter l-Summary and Policy Options ! 23

OPTION 8. Fullyfund basic and clinical TB research

as outlined in the CDC’S 1992 National Action Plan to

Combat Multidrug-Resistant Tuberculosis and NIH’s

1993 Tuberculosis Research Opportunities.

CDC estimates that its research under the 1992

National Action Plan would cost $62 million in

the first year above fiscal year 1993 spending.

NIH estimates that new TB research would cost

$102 million over several years. These research

activities include not only basic research on the

TB organism and its behavior in the human body,

but also clinical investigations of new forms of

prophylaxis, diagnosis, and treatment; the experimental study of environmental infection control

technologies; and relevant human behavioral

research.

On the rate of funding increases, the same

considerations for policymakers described under

Option 1 apply here. The ability of the scientific

infrastructure to absorb funding for certain types

of TB research include a limited number of

researchers and clinicians trained to perform work

in this area and a limited number of biomedical

laboratories with sufficient containment facilities

to prevent accidental infection of laboratory staff

and others, On the other hand, some researchers

have suggested that increases in funding will

naturally lead to an increased capacity to do

research (152).

As with Option 1, clarification of funding

priorities for R&D activities would help Congress

and other policymakers understand better the

implications of partial or phased-in funding of the

CDC National Action Plan. NIH has provided

detailed priorities for research projects in its plan.

In addition, analysis in this report suggests

several areas of relatively high priority: development of faster and definitive diagnostic and drug

susceptibility testing techniques, development of

new anti-tuberculosis drugs, and the development

of easier-to-use dosage forms of the treatments,

such as combinations of commonly used drugs

and slowly released, implantable formulations,

and new research to bolster our understanding of

the TB bacilli and its manifestations in the human

body.

The area of drug development raises a few

additional issues for the Federal Government.

The FDA indicates that some drug companies

have been reluctant to develop a drug for both TB

and non-TB uses for fear that many physicians

would reserve the drug for TB treatment only

rather than using it for more common infections.

The companies fear that these implicit restrictions

of the drugs’ use would limit the revenue they

generate and their ability to recoup the manufacturers’ initial R&D costs. In addition, the pharmaceutical industry is concerned about disincentives

to engage in research should the Federal Government attempt to force discounts for TB drugs as

discussed in Option 5 (120).12

This situation suggests that there are important

constraints other than funding and resources in

making new therapies available. Congress, executive branch agencies, and groups outside of

government may wish to examine new ways to

encourage drug industry participation in TB drug

development beyond those that the FDA has

already tried. New ideas could run the gamut of

measures, from focusing public attention on the

need for new treatments, to clarifying the applicability of orphan drug subsidies to this area,13 and

to offering new, more direct financial incentives.

OPTION 9. Support the creation of additional regional ‘‘centers of excellence” for TB treatment and

research.

Several centers that specialize in the treatment

of drug-susceptible and more complicated cases

12 me FDA cites tie classes of drugs known as qunolones and macrolides as potential examples.

13 T. C.ncowage be development of new ~a~ents for conditions titfi~t fewer ~~ 2~,~ persons in@ United State% tie @hn

Drug Law (Public Law 97-414) provides incentives including a 7-year market exclusivity as well as grants and tax credits to support clinical

research. Currently, active TB fits the definition of an orphan condition.
24 I The Continuing Challenge of Tuberculosis

of TB already exist.14 One TB expert has suggested establishing a total of 6 to 12 centers

funded at a cost of about $5 million each per year

(29,30). In addition to treating difficult cases and

training TB clinicians and researchers who would

pursue future work on this disease, these centers

would provide an opportunity to study and

disseminate new technologies for the diagnosis

and treatment of TB. Not only would researchers

be able to study the technologies under relatively

controlled conditions, but also the centers could

train clinicians and technicians in their use.

The main question for policymakers is whether

establishing additional centers is the most efficient public policy to treat difficult patients, train

TB professionals, and bring together TB research

interests. Even if it were an efficient approach to

TB care, research, and training, it is not clear

whether 6 to 12 centers (or any other suggested

number) are commensurate with the threat posed

by TB. It is also not clear how sick patients would

be before they would have to be transferred to the

centers for treatment. Policymakers would want

to consider the number of patients in need of such

specialized services in deterrnining how many

centers the country needs. The existence of such

centers might encourage their use for some

patients that could be treated in institutions closer

to their homes. Furthermore, once the current

epidemic is brought under control, the country

might not need as many such centers.

Pollicymakers may want to understand better

whether there would be cost or other advantages

to treating patients in centers instead of other

institutions. They may also want to consider

whether existing institutions could be modified

for less than the cost of establishing a new center

to conduct biomedical TB research. Similarly, it

might be possible to train clinicians and other

professionals sufficiently in existing institutions

for less money.

Another issue that would need to be examined

is how centers would be reimbursed for the care

of patients from a separate jurisdiction if the cost

of such care would usually be borne by the health

department or Medicaid program where the patient currently usually lives. The centers would

also require trained personnel who may only be

available in sufficient numbers over time.

Options That Affect the Financial Security and

Financial Access to Housing and Health Care

Services for Persons with or at Risk of TB

OPTION 10. Expand the Federal Government’s definition of disability to include active TB as a disabling

condition for the purposes of Supplemental Security

Income and Disability Insurance benefits.

Underlying this proposal is the observation that

many people with active TB are in precarious

financial situations. Their poverty may interfere

with their ability to receive treatment and to

prevent transmission of the disease to others.

Many TB patients are homeless. For disabled

individuals without other sources of income, SSI

provides a very basic subsistence and categorical

eligibility for Medicaid health insurance. In the

case of substance abusers, many residential treatment programs have been successful in receiving

SSI to cover some of the costs of those patients in

treatment may last more than a year.

As described in Chapter 7, most individuals

with TB alone are not considered disabled because their condition does not prevent them from

working for a year or longer. Changing this rule

in order to make active TB patients eligible for

SSI would require congressional legislation to

amend the Social Security Act. In passing such

legislation, Congress would also need to decide

whether this exception applies only to the SS1

program or whether it would also apply to the DI

14 ~ese ~clude Natio~ Jewish Hospiti in Denver, Colorado, the University of Medicine and Dentistry of New Jersey in Newark, New

Jersey and Bellevue Hospital in New York City.
Chapter l-Summary and Policy Options | 25

program as well

same definition

disability.

A new law

since both currently rely on the

and processes for determining

would establish a significant

exception to one of the most basic tenets of

current disability policy. A major drawback of

this option is that it would use a disability

program to provide financial benefits to a group

of people who are not disabled according to the

way Congress has defined disability over the

history of the SS1 and DI programs. In adopting

this option, Congress could be opening a Pandora’s box of requests to use disability programs

as a means of providing income to other groups of

individuals who are not currently considered

disabled.

A proposal to revise the SSA’S disability

definition to include TB may reflect two other

problems perceived by proponents of this option:

1) a perceived lack of coordination of all public

benefits for which TB patients may currently be

eligible, and 2) a lack of resources to provide

housing for many TB patients in some areas of the

country,

To the extent these two perceived problems are

real, the Federal Government, along with State

and local authorities, may wish to consider other

options for coordination of relevant Federal

benefits for each case of active TB and directly to

consider other ways the Federal Government

could help alleviate TB patients’ need for housing. Dealing with these policy problems directly

may be preferable to setting a precedent of using

disability programs in ways they were not designed. Specific actions to provide housing are

not included in the CDC’S 1992 National Action

Plan.

One alternative action for policymakers that

would not require a change in statute would be to

educate patients and their caregivers to make sure

TB patients currently eligible for SS1 already

because of HIV, substance abuse, or protracted

TB treatment actually apply for the program.

OPTION 11. Provide States with the option to expand

categorical Medicaid coverage to persons without

other forms of health insurance who have tuberculous

infection or active TB.

Over the years, Congress has expanded categorical Medicaid eligibility, especially for certain

groups of women and children. Congress offers

States the option of extending eligibility to all

persons with tuberculous infection or active

disease with the usual mix of Federal and State

funds. The added cost of this option to State or

Federal Medicaid budgets is uncertain. For the

State government, the cost largely depends on the

prevalence of TB in the State. For the Federal

Government, it depends on how many and which

States decide to adopt the option. In addition, to

the extent that patients with TB have other

medical problems but were not previously covered by Medicaid, the costs of expanding Medicaid eligibility would be more than just those costs

associated with TB care.

This option would transfer some share of the

burden for TB services from public health department budgets to the Medicaid program at both the

Federal and State levels. The option would also

reinforce the trend toward the ‘‘privatization’ of

TB services (noted in chapter 6), shifting the

focus of TB control from public health activities

to individual, reimbursable health services. Another impact of this option would be to add to the

administrative costs of State Medicaid programs

in processing applications for eligibility and

claims reimbursement. Finally, as noted in chapter 6, financial access is not the only factor in

ensuring that patients receive and complete treatment; expanding Medicaid eligibility does not

guarantee that there will be enough trained

professionals to provide and supervise appropriate therapy.

OPTION 11a. Limit the option of expanding categorical Medicaid eligibility to those with active disease

only.

Although limiting Medicaid coverage to active

disease cases only would reduce the cost of this
26! The Continuing Challenge of Tuberculosis

option, it would also exclude from Medicaid

reimbursment any diagnostic services and preventive therapy for people with qtuberculous

infection (unless the infected patients were eligible for Medicaid through some other provision in

the Medicaid statutes).

OPTION 1 lb. Limit categorical Medicaid eligibility

to TB-related services only.

This option would also save money by limiting

the reimbursement to services related to TB only.

Under this option, Congress could cover all

people with tuberculous infection or limit coverage to those with active TB Only.15 This option

has the disadvantage of excluding treatments for

other conditions the individual may have, such as

HIV. Treatment for these other conditions not

only affects the individual’s overall health, but

can affect his or her ability to recover from TB

itself. However, some portion of patients with

both TB and other conditions like HIV would

qualify for full Medicaid eligibility through other

provisions in the Medicaid statutes.

15 me MS ~ew~ ~~ ~ its fii publis@ s~ges, Conqss adopt~ a version of this option (P.L.103-66) giving SUWS the OppOdty

to use Medicaid funds to pay for TB services only for low income individuals with either tuberculous infection or active disease who do not

othetwise qualify for Medicaid.
I Transmission of

Tuberculosis 2

T

uberculosis (TB) was once commonly called ‘consumption’ because of the wasting patients suffered. Its former

medical name ‘‘phthisis’ also referred to the progressive wasting or consumptive condition of patients with

the disease. Its current name refers instead to a histological

feature of the disease: the characteristic presence of nodular

lesions, or “tubercles,” in the early stages of the disease.

The infectious nature of TB and the agent responsible for its

transmission from person to person have been known for over a

hundred years: in 1882, the German scientist Robert Koch

identified a species of bacteria, Mycobacterium tuberculosis

(M./b. or tubercle bacilli), as the cause of TB (169),1 Despite this

single underlying cause, clinical manifestations of the disease

vary from person to person and the ways in which the body

controls the infection or allows it to progress to a destructive

disease state are still not adequately understood. Furthermore,

concurrent human immunodeficiency virus (HIV) infection

appears to impair some of the critical immune processes involved F*” ~ -. — —

in preventing tuberculous infection from progressing to disease,

~’”-- - @@

creating a somewhat different clinical course for individuals who

are dually infected. Infants and young children generally

manifest tuberculous infection and disease differently from

adults, but have many of the characteristics of TB in HIVinfected adults.

This chapter provides background information about TB

transmission and disease processes relevant to topics covered in

1 Other types of mycobticteria can cause tuberculosis in humans, but are not significant

contributors to the disease in the United States. Earlier this century, M. bovis, which

causes TB in cattle, was transmitted to human beings through unpasteurized milk and

respiratory exposure to infected cattle, but now accounts for less than 1 percent of human

TB cases in North America (347).

27
28 I The Continuing Challenge of Tuberculosis

other chapters of this report. The factors involved

in transmitting tuberculous infection and in developing active disease are summarized first,

followed by a brief description of the clinical

course of the disease in immunocompetent and

immunocompromised individuals and in children.

TRANSMISSION AND INFECTIVITY

TB has two general stages relevant to its

transmission and infectivity: tuberculous infection (sometimes also called “latent TB”) and

active tuberculosis. As used in this report and in

most of the medical literature, TB refers primarily

to the active disease. Although infection with

tubercle bacilli is necessary to develop TB, the

majority (90 percent) of immunocompetent adults

with tuberculous infection do not develop TB.

The only evidence of their infection may be a

positive tuberculin skin test (see chapter 4).

Children and immunocompromised individuals

with tuberculous infection carry a greater risk for

developing active TB (see below).

Individuals with tuberculous infection are asymp

tomatic and not contagious to others, whereas

individuals with active pulmonary disease may be

symptomatic and contagious—particularly if they

are untreated or inadequately treated and if the

disease is manifested in the lungs (or, rarely, in

the larynx). Regarding risk of transmission, the

critical difference between the two types is the

ability to expel (e.g., through coughing, singing,

speaking, or sneezing) airborne particles containing viable tubercle bacilli.

As airborne infections go, TB is not considered

the most contagious; certain airborne viral infections, such as measles and varicella (chicken

pox), are more readily transmitted (66,204).

However, because TB can be transmitted through

casual contact (breathing) and it can be debilitating or even fatal if untreated (or untreatable, as in

some cases of multidrug-resistant TB (MDRTB)), the public’s perception of the actual risk of

TB contagion has generally been magnified.

Health departments and TB centers report increased demand for tuberculin skin testing among

very low risk individuals or the ‘‘worried-well’

(129,243). A recent editorial in the Washington

Post described TB as a highly contagious, deadly

disease that ‘‘you can catch from the person next

to you in a movie theater or classroom” (49).

According to available data, both from decades

ago and the present, a single, casual contact with

an infectious person in a public place (such as a

subway or movie theater) is unlikely to lead to

tuberculous infection, although the risk is not

zero; there is a possibility, albeit remote, that

inhalation of just one infectious particle containing M.tb. could be enough to produce infection in

some cases (31). In practical terms, however,

much more than a single airborne bacillus is

needed to cause infection. A number of factors

(outlined below) occurring simultaneously are

considered critical in determining the likelihood

of transmitting tubercle bacilli, of developing the

infection, and of ultimately developing TB. Depending on the mix of factors in any given

situation, the risk may be significant or insignifi

cant (274).

Factors Influencing the Probability of

Acquiring Tuberculous Infection

Most of the factors that determine the risk of

acquiring tuberculous infection are environmental.

By contrast, the risk of developing active TB after

tuberculous infection is considered to be largely

an individual characteristic, determined by immunologic status and other physiologic factors

(described below). The main factors in determining whether the initial tuberculous infection is

likely to occur are listed below:

Probability of coming into contact with someone with infectious TB.

Closeness or intimacy of that contact.

Duration of contact.

Number of viable bacilli present in the air.

Susceptibility of the uninfected individual.
Chapter 2–Etiology and Transmission of Tuberculosis | 29

9 Environmental conditions (e.g., volume of

airspace, ventilation with outside air, relative

humidity, presence of sunlight).

Crowding, particularly in living quarters, increases both the probability of coming into

contact with an infectious individual if one is

present and the closeness of that contact (66).

Various types of institutional residences (e.g.,

nursing homes, hospitals, prisons, jails, and

homeless shelters) can provide circumstances

conducive to the transmission of TB. Health care

workers (HCWS) are necessarily at increased risk

of coming into contact with infectious patients.

Performance of certain cough-inducing medical

procedures, such as, bronchoscopy and administration of aerosolized pentamidine, on patients

with infectious TB can increase HCWS’ risk of

exposure to airborne tubercle bacilli (52).

Infection occurs at the point in time when an

infectious particle is inhaled. However, the likelihood of inhaling that particle is dependent on the

concentration of such particles in the air and the

length of time spent breathing that air; the greater

the exposure, the greater the likelihood that

infection will result. Frequent or prolonged exposure to an infectious source case (e.g., months) is

usually necessary for transmission to occur(11 3).

According to data derived in the mid-1980s, on

average, less than 30 percent of household

members become infected while living with an

infectious source case, but the risk is highly

variable (27,249). Under extraordinary circumstances (when the concentration of infectious

particles in the air is much higher than usual),

exposures as brief as 2 hours have reportedly led

to infection (8).

In any given situation, the infectiousness of the

source case determines whether any period of

exposure could result in transmission. Individuals

with untreated active pulmonary or laryngeal

TB,2

an advanced stage of disease, evidence of

tubercle bacilli in sputum samples, and who

cough frequently without covering the mouth are

considered to be prime sources of infection (180).

Those not posing a risk of infection to others

include individuals with tuberculous infection

(rather than active disease), individuals with

active TB who have been receiving adequate

treatment long enough to render them noninfectious, and individuals with extrapulmonary TB

without any lung or airway involvement. Adequate antimicrobial treatment can quickly reduce

and eventually eliminate the infectiousness of

individuals with drug-susceptible TB (160,253).

Although the exact period of time required for this

change varies from one patient to another and

cannot be predicted precisely, research suggests it

is about 6 months or longer (211). Patients with

drug-resistant TB can, in some cases, be treated

effectively, although the period of infectiousness

may be prolonged until an adequate combination

of appropriate drugs is determined. Those with

MDR-TB for whom available drugs are ineffective may remain persistently infectious to others.

There is no evidence that untreated MDR-TB

is more contagious than untreated drugsusceptible TB (291). However, because of delays in diagnosing resistance patterns and initiating adequate treatment, patients with MDR-TB

are more likely to remain infectious for longer

periods, thereby increasing their potential to

infect others (see chapter 5). In several recent

outbreaks of MDR-TB in hospitals, HCWS who

were exposed to undiagnosed, persistently infectious patients with MDR-TB were more likely to

have shown a tuberculin skin test conversion,

indicating recent tuberculous infection, than HCWS

without such exposure (350). There is also no

evidence that HIV-infected patients with pulmo-

~ Transmission of TB from patients with extrapulmonwy TB (TB in tissue other than the lung) is unusual but has been reported, e.g., through

manipulation of lesions or processing of lesions in the hospital or laboratory. Transmission of TB has been traced to patients with skin ulcers,

abscesses, or other open lesions containing large numbers of tubercle bacilli that may be released into the air during medical procedures such

as surgical draining or wound care (106,144,310).
30 I The Continuing Challenge of Tuberculosis

nary TB are more or less infectious than non-HlVinfected patients with pulmonary TB (50).

Little is known about specific host factors that

influence susceptibility to tuberculous infection.

At present, there is no firm evidence that HIVinfected individuals are more likely to acquire

tuberculous infection, although the frequency and

rapidity with which HIV-infected individuals

developed active TB in several recent outbreaks

raises the possibility of heightened susceptibility

in some populations with HIV (69,77). Individuals who are already infected with tubercle bacilli

are generally considered to be partially resistant

to further infection, but reinfection has been

documented (207).

The concentration of infectious particles in the

air also determines the likelihood of infection.

Normal indoor air currents keep such particles

(referred to as “droplet nuclei”) airborne for long

periods of time and disperse them throughout a

room or a building (7,252). Until they dehydrate

naturally, they remain infectious. These particles

remain suspended until they are removed or

diluted by ventilation or air filtration, or possibly

inactivated by ultraviolet (UV) irradiation (see

chapter 4). The use of these and other infection

control measures can reduce the risk of transmission in the presence of infectious individuals

(359).

Factors Influencing the Development of

Active TB After Infection

The risk of developing active TB is highest

shortly after tuberculous infection occurs and

declines thereafter. Accordingly, the risk of

disease is highest in the most recently infected

individuals, who can be identtifed through contact investigation. The observed incidence of TB

among those with positive tuberculin skin tests

differs widely among populations studied, for

reasons that are still unclear (66). Some evidence

also indicates that the risk of infection is higher

among those exposed to the most infectious cases

and those with the closest contact to such cases

(66).

Ninety percent of adults with tuberculous

infection do not develop active TB, apparently

due to the ability of their immune systems to hold

the infection in check. Impairment of immune

function (as in acquired immune deficiency

syndrome (AIDS), by treatment with glucocorticoid or immunosuppressive drugs, malnutrition,

various infections, or chronic conditions such as

asthma and emphysema) tips the balance in favor

of development of active TB among those with

tuberculous infection (278,378). Whereas only 3

to 5 percent of immunocompetent individuals

who acquire new tuberculous infection are

thought to develop active TB within the first year

after infection (97), the percent of HIV-infected

individuals who acquire new infection and go on

to develop active TB within the first year is

estimated to be far greater (77). In a recent report,

approximately one-third of the HIV-infected individuals sharing a residential facility who became

infected with tubercle bacilli developed TB within

120 days (69). Most cases of TB among HIVinfected individuals are believed, however, to

result from reactivation of latent tuberculous

infection, rather than progression of recently

acquired infection (278), although recent data

from New York City indicates that the latter is

increasing.

DEVELOPMENT OF TUBERCULOSIS AND

ITS CLINICAL MANIFESTATIONS

Active TB manifests in a variety of ways,

depending in part on the primary site of infection

in the body. Pulmonary TB is the most common

form of the disease, leading to cavity formation

and progressive destruction of lung tissue. Pathologic and inflammtory processes associated with

the disease produce weakness, fever, chest pain,

cough, and when a small blood vessel is eroded,

bloody sputum (31).
—.

Chapter 2–Etiology and Transmission of Tuberculosis I 31

TB, caused by an airborne bacillus, primarily affects the lungs. If untreated, it can destroy lung tissue and

spread to other parts of the body and to the outside air. Pictured above are x-rays of a slightly diseased lung (left)

and an extreme/y diseased lung (right).

The disease can affect other sites in the body

(“extrapuhnonary TB”), although only pulmonary and laryngeal TB are contagious through the

airborne route. Various forms of extrapulmonary

TB are more likely to occur in HIV-infected

individuals and in children. These disseminated

forms of the disease can result in the formation of

small miliary (seed-like) lesions or lifethreatening meningitis (inflammation of the membranes surrounding the brain and spinal cord).

Such dissemination begins in the lung, which is

the initial site of infection, and travels through the

bloodstream to other parts of the body or through

lymphatic to regional lymph nodes. Some organs

take up and allow the multiplication of bacilli

more readily than others, e.g., upper lung, kidneys, bone, and brain. Long-term damage can

result, even in cured cases of TB, including

impaired breathing due to lung damage, mental

impairment from meningitis, and spinal deformity and leg weakness due to vertebral involvement

(152),

Immune Responses to Tuberculous

Infection and Disease

The cellular immune system is believed to play

a central role in the development of TB in the

body. While some of the relevant immunologic

processes have been identifed, fundamental questions remain concerning the interplay and regulation of immunologic forces that both inhibit the

progress of the disease and actually contribute to

the destructive disease process itself (31,74).

Airborne particles containing tubefcle bacilli

that are inhaled (and that manage to reach the

lower parts of the lung) are initially engulfed by

macrophages (a type of scavenger cell) in the

alveoli (terminal air sacs in the lung). If the bacilli

are not destroyed by the alveolar macrophages,

the bacilli multiply, killing the cell and attracting

nonactivated macrophages from the bloodstream.

In these new macrophages, the bacilli multiply

logarithmically. Antigenic substances present within

or secreted by tubercle bacilli stimulate Tlymphocytes (CD4 cells) to produce chemical
— ..—

32 I The Continuing Challenge of Tuberculosis

substances (lymphokines), which activate these

new macrophages, enabling them to destroy or

inhibit the bacilli. The process by which macrophages are armed to destroy the bacilli they ingest

is called cell-mediated immunity (CMI) and

forms one part of the body’s immune response to

TB.

Another interrelated immune process that occurs in response to tuberculous infection is called

delayed-type hypersensitivity (DTH), an inflammatory response that destroys bacilli-laden inactivated macrophages. An overabundance of DTH

is blamed for most of tissue damage characteristic

of pulmonary tuberculosis: caseous necrosis (death

of tissues, leading to caseating granulomas and

liquefaction of solid caseous tissue, producing

cavities in the tissue) (71,72,73,74). Within the

liquefied caseum, tubercle bacilli multiply outside of the cells, reaching tremendous numbers.

Host resistance may be overwhelmed and the

bacilli may develop resistance to antimicrobial

drugs. Liquefaction and cavity formation allow

the disease to become contagious, because the

bacilli spread via the airways to other parts of the

body and to the outside air.

Clinical Course in HIV-Seropositive

Individuals

HIV-related immunodeficiency impairs both

parts (DTH and CMI) of the immunologic response to tuberculous infection, leaving individuals with HIV more vulnerable to the development

of clinical TB. Recent evidence suggests that TB

tends to occur early in the course of HIV infection

(321) often as the first overt manifestation of HIV

infection. Infection with (non-contagious) non

tuberculous mycobacteria, e.g., Mycobacterium

avium complex, occurs frequently in individuals

with AIDS, often leading to serious complications and earlier death. The surveillance definition of AIDS was recently expanded to include

TB as an AIDS-defining condition among those

with HIV infection (364).

The clinical course of TB in individuals with

AIDS is dramatically different from TB in immunocompetent adults. Pulmonary TB in individuals with AIDS resembles that of TB in infants.

The bacilli disseminate (via the bloodstream and

lymphatic), producing extrapulmonary lesions,

including tuberculous lymphadenitis or meningitis. Characteristic features of TB in individuals

with HIV infection include a high prevalence of

anergy to tuberculin skin testing (see chapter 4),

atypical x-ray presentation of the disease in the

lung, and frequency of extrapulmonary disease

(162).

Clinical Course in Children

Infants and young children also manifest TB

differently from immunocompetent adults, but

the specific reasons for this are not yet clearly

defined. Infants and young children can or are

more likely to develop severe, life-threatening TB

as an immediate complication of the primary

infection, without the long latent period common

in adults. They are more likely to develop

extrapulmonary forms of the disease, especially

lymphadenitis, osteotuberculosis, and meningitis

(25 1,301). Active TB in such children typically is

manifested by caseous lesions that do not liquefy

or cavitate, so they are less likely to transmit the

disease to others.
Epidemiology of

Tuberculosis 3

A

fter decades of steady decline in the number of new cases

each year, tuberculosis (TB) is now on the increase in the

United States. This turnabout has received considerable

attention in the news media, medical literature, and

public health sector. Reports of clusters of TB cases, particularly

the more dangerous multidrug-resistant (MDR-TB) forms occurring recently in several hospitals and prisons, have been

highlighted. These reports raise the specter of a serious,

accelerating public health problem with the potential to spread

regionally and nationally. For a disease that was widely

considered to have been headed toward elimination in this

country, the resurgence seems surprising and disturbing.

While many of the basic features of TB and its transmission are

the same as those described decades ago, there are new elements

that have changed the nature and magnitude of the problem. This

chapter reviews current epidemiologic features of TB in the

United States, including overall incidence, high-risk groups in

the population, rates of confection with human immunodeficiency virus (HIV), and the cases of MDR-TB. Although the

focus is on TB in the United States, some international data are

included for comparison. Various factors that may be responsible

for the recent changes in TB are discussed at the end of the

chapter.

OVERALL TRENDS IN TB INCIDENCE

In 1953, the U.S. Public Health Service began a nationwide

reporting system for TB, based on annual summaries of total TB

cases reported in each State. In 1979, the Centers for Disease

Control (CDC) began to phase in the “Report of a Verified Case

of Tuberculosis’ (RVCT) surveillance system, based on individ33
34 I The Continuing Challenge of Tuberculosis

Figure 3-l—Reported Tuberculosis Cases In the

United States, 1953-92

I1

II l,, ,,, ,,, ,,, ,,, ,, 1,

1953 1963 1973 1983 1992

SOURCE: Office of Technology Assessment, 1993, based on data

from U.S. Department of Health and Human Services, Public Health

Service, Centers for Disease Control and Prevention, 1992.

ual case reports from all 50 States, the District of

Columbia, and New York City (159).1 The system

was fully implemented in 1985. By using a

standardized case definition and collecting data

on individuals with TB (including age, sex, race,

ethnicity, and country of origin), the RVCT

system permitted a more detailed picture of TB

epidemiology in the United States than was

previously possible with aggregate data. In general, incidence rates based on case reports underestimate the true incidence of a disease, since

many factors can influence the likelihood that any

given case will actually be reported. It is unlikely

that changing the TB reporting requirements in

the RVCT system affected the overall ascertainment of cases, although it clearly produced more

information about each case reported. The increased number of cases reported since the

mid-1980s is much greater than could be accounted for by changes in the reporting system. In

fact, significant underreporting of TB may still be

occurring (28,250,307).

In 1953, there were 84,304 reported cases of

TB, equivalent to a case rate of 53.0/100,000

population (27). Over the next 31 years, incidence

declined steadily, with a few exceptions,2 to

22,255 new cases in 1984 (case rate of 9.4/

100,000 population) (233). The rate of decline

averaged about 6 percent per year between 1953

and 1974, and about 5 percent per year between

1975 and 1984 (159,249). By 1984, the incidence

of TB had declined 74 percent from its 1953 level

(see figure 3-l).

This longstanding downward trend began to

change in 1985. First, the decline in incidence

slowed to just 0.2 percent in 1985, and then

increased by 2.6 percent in 1986. Then, in 1987

and 1988 the decline in new cases resumed, but by

only 1.1 and 0.4 percent, respectively. Further

increases occurred in 1989 (4.7 percent), 1990

(the largest to date, 9.4 percent), 1991 (2.3

percent), and 1992 (1.5 percent) (334b). The

number of reported cases in 1991 was 26,283

(case rate of 10.4/100,000), and in 1992 it was

26,673 (10.5/100,000) (353,356). This 1992 case

total represented an 20 percent increase over

1985.

Averaged over the 6-yea period, these data

suggest a current upward trend of about 3 percent

per year in cases, compared with the previous 5 to

6 percent annual decrease observed before 1984.

Based on data indicating much sharper upturns in

case rates in certain areas (see discussion below),

it is possible that national rates may possibly

continue to rise 2 percent per year, or go even

higher, in the next decade.

DEMOGRAPHIC CHANGES IN TB

One of the most striking changes in TB

epidemiology in the United States in recent

decades has been a gradual shift in TB occurrence

1 Data from Puerto Rico and the Virgin Islands are also collected, but are not referred to in the data cited in this report.

z A l-year increase occurred in 1980 following a large influx of Indochinese refugees into the United States, and @lcial increases were

recorded in 1963 and 1975 due to changes in reporting criteri~
Chapter 3-The Changing Epidemiology of Tuberculosis 135

Figure 3-2—Rates of New Tuberculosis Cases in the United States, by State, 1991

of Columbla

Cases per

population

p 0 . 0

m 4 . 8

L__.J 9.5

14. 2

= 18. 9

Puerto RICO

100,000

- 4.7

- 9.4

- 14.1

- 18.8

SOURCE: Office of Technology Assessment, 1993, based on data from U.S. Department of Health and Human

Services, Public Health Service, Centers for Disease Control and Prevention, 1991.

from broader to narrower demographic populations (295), identified to some extent by geography, age, sex, race, ethnicity, and country of

origin, A description of these changing characteristics can reveal where and in whom TB is

occurring, It offers only limited information,

however, about the epidemiology of the disease,

since these characteristics are not causally related

to TB; at best, they may be only indirectly

associated with causal factors. Historically, TB

has been linked primarily with environmental

conditions that increase the likelihood of transmission, such as crowded, poorly ventilated

housing and working conditions. Current data,

described below, indicate that TB now occurs

disproportionately among individuals who lack

stable housing, abuse intravenous drugs or alcohol, become incarcerated, or are employed as

migrant farm workers. A common element in

these cases may also be environmental. The

increasing occurrence of TB among individuals

with HIV reflects a causal risk factor due to

immunosuppression, as well as lifestyle factors

such as drug abuse.

This section describes the current distribution

of TB among demographic groups and summarizes the available data on the prevalence of TB in

some high-risk populations. The epidemiologic

association between TB and HIV is discussed

later in the chapter.

Geographic Distribution

In 1991, more than half

cases came from five of

of the Nation’s new

the most populous

States--California, New York, Texas, Florida,

and Illinois (334). The highest TB case rates (the

number of cases per 100,000 population), however, are found not only in these States but also in

many smaller ones (see figure 3-2). New York
36 I The Continuing Challenge of Tuberculosis

State ranked highest with a case rate of 24.5.

Twelve other States recorded case rates above the

national average of 10.4 for the same year: in

descending order, Hawaii, California, Texas,

Georgia, Florida, New Jersey, Alaska, Arkansas,

Mississippi, Tennessee, South Carolina, and Alabama. The Southern region as a whole has long

been above the national average in TB case rates

(235). The lowest rates in 1991 were found in

New Hampshire, Wyoming, North Dakota, Idaho,

Nebraska, and Vermont (334).

Large urban areas as a group account for a

disproportionate number of TB cases. In 1991,

cities over 250,000 population accounted for 18

percent of the population, but more than 43

percent of new TB cases. About 14 percent of the

Nation’s cases came from New York City alone.

The other major urban centers accounted for a

much smaller percent of cases; Los Angeles, the

city with the second highest number of new cases,

accounted for about 4 percent of the Nation’s

cases, while Chicago, with the third highest, less

than 3 percent (334a).

The ranking of cities by TB case rate indicates

where TB is most concentrated. In 1991, the

highest case rates were noted in Atlanta (76.4),

Newark (71.8), New York City (50.3), Miami

(48.5), and San Francisco (46.0) (see figure 3-3)

(334a). Philadelphia and Chicago had relatively

fewer cases, given their population size.

Some of the cities with currently high TB case

rates have consistently had a high burden of TB

for many years, even while the U.S. average case

rates were declining. For example, figure 3-4

Figure 3-3-Highest and Lowest Rates of Active Tuberculosis in U.S. Cities of

250,000 or More, 1991

Atlanta,GA ~

7

’ ”

4

New York, NY 50.3

Miami FL~48 5

San Francisco, CA I 46

Oakland, CA 40.9

Houston, TX ‘

43.5

Tampa, F L

3 1 1

Los Angeles, CA ~ 30.6

Santa Ana, CA ‘ 30

U.S. AVERAGE 25.2

Minneapolis, MN -

I 7.1

Indianapolis, IN ~6. 9

Tulsa, OK 16.8

Albuquerque, NM ~ 5. 7

Wichita, KS ===J4.6

Virginia Beach, VA p 4. 3

Mesa, AZ =4. 1

St. Paul, MN m Highest rate

33. 3

Omaha, NE U.S. averag e

~ 3.3

Colorado Springs, CO x2.5 ~ Lowest rate

Toledo, OH ~ 1.8 I \ I 1

0 20 40 60 80 100

SOURCE: Office of Technology Assessment, 1993, based on data from U.S. Department of Health and Human Services, Pubtic Health

Service, Centers for Disease Control and Prevention, 1991.
Chapter 3-The Changing Epidemiology of Tuberculosis 137

Figure 3-4-U.S. Localities With Highest Tuberculosis Case Rates

Compared With U.S. National Rates, 1969-91

2 5 0

● Central Harlem, NY + Chicago, IL

I

t New York, NY A MiamiMlamt, FL

g 200

- United States %

Y

n

o

Q 150

~

oE

;

Q.

m

 100~“+

a) m

: 5(J

~ + -

0 1 1 I I

I

196070 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91

SOURCES: Office of Technology Assessment, 1993, based on data from Janice M. Burr, Medical Director of Tuberculosis Control Program, Dade

County Department of Health, Miami, FL, personal communication, 1993; John Kuharik, Director, Tuberculosis Program, Chicago Department of

Health, Chicago, IL, personal communication, 1993; K. Brudney and J. DobkM, “Resurgent Tuberculosis in New York City: Human Immunodeficiency

Virus, Homeles-sness, and the Decline of Tuberculosis Control Programs,” American Review of Respiratory Disease 144:745-749, 1991.

shows TB case rates in Central Harlem New York

City, (one of the areas of New York with the

highest case rates), Chicago, and Miami, along

with the national average rates since 1969 (45).

Although the downward trend in U.S. rates began

to change in the mid-1980s, case rates in New

York City began to rise in 1979, and in Miami and

Chicago, in the late 1980s; all three cities have

been dealing with case rates well above the

national average for many years. The exceptionally high rates of TB in Central Harlem all

through the 1970s and 1980s show that TB

remained endemic for decades even while the

disease was receding nationally, presumably moving toward elimination (128).

Race, Ethnicity, Age, and Sex

Historically, TB in the United States has been

most prevalent among ethnic and racial minorities

living in impoverished areas (245), and today this

trend still holds, In 1991, 71 percent of new cases

occurred in racial and ethnic minorities (see

figure 3-5). From 1985 to 1991, relatively large

increases in numbers of TB cases occurred among

Hispanic Americans (increasing 72 percent),

Americans of Asian or Pacific Islands origin

(increasing 32 percent), and black Americans

(increasing 26 percent). During the same period,

reports of cases decreased among non-Hispanic

white Americans 9 percent and among Native

Americans, 13 percent (293). Approximately

two-thirds of cases in 1991 were reported in

males, although the percent increase was slightly

higher for females than males (293).

TB cases and rates generally increase with age,

except among 5- to 14-year-olds, who have the

lowest case rate of all age groups (159). Since

1985, however cases increased in all age groups

except for those 65 or older. The largest increase

by far, however, occurred among the 25- to

44-year-olds, who now constitute 39 percent of all

cases (see figure 3-6) (293).

A comparison of the age distribution of cases

divided according to race and ethnicity (see figure
38 I The Continuing Challenge of Tuberculosis

Figure 3-5-Racial and Ethnic Distribution of

Tuberculosis Cases in the United States, 1991

I

Americans of

Asian or Pacific

Islander origin

r 12.7!40

mericans of

erican Indian

WZ2ZZ=’ or Alaskan origin

White Americans, 1 .39’0

non-Hispanic

29.30/o

SOURCE: Office of Technology Assessment, 1993, based on data

from U.S. Department of Health and Human Services, Public Health

Service, Centers for Disease Control and Prevention, 1991.

3-7) shows a dramatically different pattern among

whites compared to black Americans and Hispanic Americans. Among white Americans, the

majority of cases occur among elderly individuals, while among black and Hispanic Americans,

an increasing number of cases is occuring among

young adults in the 25- to 44-age-group. Minorities are disproportionately represented, particularly in this age group; of the 10,263 cases

reported in 1991 among 25- to 44-year-olds, 45

percent occurred among black Americans, 22

percent among Hispanic Americans, 19 percent

among white Americans, and 13 percent among

Americans of Asian or Pacific Islands origin

(293).

Children

Unlike cases among adults, TB among children

is evidence of recent transmission of the diseasesuggesting the presence of other individuals

(usually adults) with active, infectious TB in the

community (163,302,307). While transmission to

children could occur in group settings such as

family homes, schools, family day care homes, or

nursery schools, a large TB clinic in Houston

traced 80 percent of the cases to an infectious

adult contact in the child’s household (302). In

some areas of the country, immigration from

countries with high rates of TB may also account

for high rates of TB among children.

Nationally, new cases of TB in children declined an average of 6 percent annually from 1962

until 1987, but then began to rise in 1988. In 1991,

1,662 new cases were reported in children under

15 years of age, an increase of 32 percent over

1985; most of the increase occurred among

Hispanic American children, so that in 1991

Hispanic Americans accounted for nearly half of

all cases in children. Overall, 86 percent of cases

occurred in racial and ethnic minorities, compared with 80 percent in 1985 (302). Cases

declined, however, not only among white American children, but also among Americans of Asian

or Pacific Islands origin, American Indian, and

Alaskan Native children during this period (293).

Figure 3-6-Reported Tuberculosis Cases in the

United States by Age, 1985 and 1991

12,000

_ 1985 n 1991

10,000-

5

z 8,000- [

c

“=

(t-J ~ 4,000

c1

2,000

0 1- -r

0-4 5-14 15-24 25-44 45-64 65+

SOURCE: Office of Technology Assessment, 1993, based on data

from U.S. Department of Health and Human Services, Public Health

Service, Centers for Disease Control and Prevention, 1991.
Chapter 3-The Changing Epidemiology of Tuberculosis | 39

Individuals at high risk of TB in the United States

include elderly people and economica//ydisadvantaged people, especially those who are

members of racial and ethnic minority groups,

children, and those born in other countries.

Figure 3-7—U.S. Tuberculosis Cases Among Black and Hispanic Americans

Compared With Non-Hispanic White Americans, 1985, 1987, 1989 and 1990

2,000- Black and Hlspanlc Americans

1,800- / - \

I i

1,600- /

1,400 “ i

~ 1,200 Non-Hispanic White

Americans

800-

. . . . . . . . . .

.-*

600

.,. -- -<. ,

4

q,

- - - . .

. .

. . ~. \

/--- $<- +2s ~ \

.

.

200-

Ot , , , , ,

I

o 10 20 30 40 50 60 70 80 90 100

Age

— — 1990 1989 1987 -- “ -----1985

SOURCE: M.E. Villarino, L,J, Geiter, and P,M. Simone, ‘The Multidrug-Resistant Tuberculosis Challenge to Public

Health Efforts to Control Tuberculosis,” Public Health Reports 107(6):616-625, 1992.

In 1991, three States contributed almost 60 New Jersey and Arizona (293). High rates of TB

percent of the cases among children: California among immigrants such as in California and

(with 563 cases), Texas (with 219 cases), and increases in TB among parents of the 25 to 44 age

New York (with 198 cases). Large percent group may account for the observed increases

increases in recent years, however, occurred in among children.
40 I The Continuing Challenge of Tuberculosis

Elderly Individuals

In 1991, elderly individuals accounted for

nearly a quarter of all new TB cases; the case rate

among individuals 65 or older is currently the

highest of any age group (358). The vast majority

of these cases result from infection acquired

earlier in life when TB was more prevalent, with

the infection then progressing to active disease in

older age (31 1). Some evidence suggests, however, that some TB cases among the elderly

individuals result from recent infection or active

transmission (309,31 1). Residents of nursing

homes or other long-term care facilities maybe at

greater risk for TB than those living in single

family homes (312). Data from a CDC survey of

over 15,000 TB cases among elderly individuals

living in nursing homes compared with noncongregate sites between 1984 and 1985 showed an

annual case rate in nursing homes nearly twice as

high (358). A smaller, more intensive survey

among cases reported in Arkansas suggested an

even higher relative risk for nursing home residents (312).

High-Risk Populations

Immigrants and Refugees

As a group, U.S. residents born outside of the

United States tend to have higher rates of TB than

those born in this country (360). This trend

reflects the fact that TB is more prevalent in many

areas of the world, particularly regions of Asia,

Africa, and Latin America, than in the United

States (199,316). In 1991,27 percent of the 6,982

new cases were reported among the foreign-born;

this is increased from 22 percent in 1986 (293).

The vast majority of these cases were reported

in people of either Hispanic, Asian, or Pacific

Islands origin. Such cases made up sizable

proportions of all cases within each of these

ethnic groups: 55 percent of all Hispanic American cases and 89 percent of all cases among

Americans of Asian or Pacific Island origin were

reported as foreign-born in 1991 (293),

Residents of Homeless Shelters

Various surveys among selected clinics and

shelters serving homeless individuals indicate

that the prevalence of active TB may range from

2 to 7 percent (184,275,289). The prevalence is

likely to be highly variable, however, depending

on the site, population, and time period studied.

The proportion of TB patients who are also

homeless may be high. In New York City, 20

percent of new TB cases reported in 1991 were

also identified as homeless, based on a computerized matching of shelter addresses to TB cases in

the registry (57).

There are several factors that make homeless

individuals generally more vulnerable to development of active TB. The prevalence of tuberculous

infection among homeless individuals is reported

to be quite high-up to 50 percent in some studies

(16,184,285,289,342). Factors predisposing homeless individuals with TB infection to progress to

active disease include impaired immunity (due to

poor nutrition, poor health status overall, substance abuse, and/or HIV infection) and lack of

access to preventive treatment (184).

In addition, homeless shelters typically provide

ideal conditions for transmission of tuberculous

infection-large numbers of people in close

proximity, poor ventilation, the presence of undiagnosed or untreated infectious cases, and prolonged exposure due to lengthy stays particularly

in winter months (325). Studies have also shown

that previously infected residents may also become reinfected in the shelter and progress

rapidly to active disease (207). In recent years,

several outbreaks of TB disease in homeless

shelters have been reported (207,212,342,351).

Drug Users

Drug users are another population that overlaps

with several other identifiable groups at high risk

for TB, particularly the HIV-infected and homeless. Results of a recent study of MDR-TB in New

York City indicated that intravenous drug use was

an independent risk factor for the development of

MDR-TB in that population (107). A survey
Chapter GThe Changing Epidemiology of Tuberculosis | 41

conducted in the early 1970s of drug-dependent

individuals identified through New York City

drug addiction treatment centers and methadone

maintenance treatment programs showed a high

prevalence of TB in this population (246). A

recent report documented an outbreak of TB

among crack cocaine users in Contra Costa

County, California (349). In 283 cases of TB

reported during a 42-month period, 16 percent (44

individuals) were found to have occurred among

crack cocaine users. Fifteen of the 44 drug users

frequented one or more crack houses, environments that may facilitate active transmission of

TB. Crack use, which damages the lungs and

promotes coughing, can lead to increased active

transmission of TB among users in close quarters

and in poorly ventilated surroundings typical of

crack houses. No direct link of crack use in the

risk of infection was documented.

Prisoners and Inmates

The prevalence of TB in correctional institutions (including prisons, jails, and detention

centers) is related both to the prevalence of

tuberculous infection and HIV in the incarcerated

population and to conditions within the institutions favoring spread of tuberculous infection. On

both accounts, TB has become a significant and

increasing health problem within the correctional

system (23). These factors are an issue not only

for the correctional system itself (with its average

daily population of 1.2 million in 1990) (1 12), but

for the country as a whole, since inmates who

develop TB within the system carry it with them

into the community following release (308); in

addition, correctional staff who become infected

and develop active TB can, in turn, transmit the

disease to their family and other contacts in the

community (346).

Population groups at high risk for TB—

individuals who abuse drugs, who are HIVinfected, and who are homeless—are disproportionately represented in the connectional system

(112,346). In the New York State system, 26

percent of the women and 16 percent of the men

were also found to be HIV-infected in a recent

blinded serosurvey. Almost one-third of newly

admitted inmates in New York State reported

having been homeless just prior to incarceration,

and the majority of inmates had histories of

substance abuse (209).

TB may be at least three times more prevalent

among inmates and prisoners than in nonincarcerated adults (335). In the New York State, New

Jersey, and California correctional systems, for

example, the prevalence of TB in the mid- 1980s

was 6 to 11 times higher than in the general

population of those States (41,346). In New York

State, the incidence of TB began rising in the

early 1980s (before any confections with HIV

were identified) but accelerated its rise in 1986; it

increased four-fold from under 25 cases per

100,000 in the late 1970s to over 100 per 100,000

in 1986. Approximately one-half of the cases

between 1985 and 1986 were found to have HIV

infection, based on a study matching TB and

AIDS registries. Most TB cases were in minority

men between 30- and 49-years-old with histories

of intravenous drug use (41).

Since 1985, at least 11 outbreaks of TB have

occurred in correctional institutions in eight

States (346); the most recent one involved a

cluster of MDR-TB cases in which 13 inmates

and one correctional officer died of the disease.

The presence of inmates with active, infectious

disease in close proximity with large numbers of

highly susceptible individuals in poorly ventilated surroundings creates a scenario for rapid and

widespread infection (308). Frequent transfers of

prisoners within and between facilities may also

serve to broaden the scope of the problem.

Migrant Farm Workers

Evidence suggests that migrant farm workers,3

many of whom are immigrants from counties with

a high prevalence of TB, may also be at high risk

3 Migrant farm workers are defined as seasonal agricultural workers who move from area to area for jobs.
42 I The Continuing Challenge of Tuberculosis

for TB. A 1988 study of 543 migrant farm

workers in North Carolina found an overall

prevalence of active TB in 2 percent of workers

(0.47 percent in Hispanic American workers and

3.6 percent in black American workers), along

with high rates of TB infection (33 percent of

Hispanic Americans, 54 percent of black Americans, and 76 percent of Haitian immigrants) (55).

High rates of tuberculous infection have also been

noted in other migrant worker populations (2%,362).

Since there is no regular monitoring of this

population, the overall prevalence of TB in the

U.S. migrant farm worker population is unknown.

Data from the North Carolina study suggest

that TB in migrant farm workers maybe at least

partly an occupational problem, since those with

longer migrant work histories had greater risks of

TB. Lack of access to health services and

substandard working and housing conditions are

likely factors in this heightened risk. Characteristics of the migrant population also predispose

them to TB. A high percentage of workers, mostly

black Americans, are recruited from homeless

shelters, soup kitchens, and alcohol rehabilitation

centers. While immigrants (generally from Central America, Mexico, and Haiti) constitute a

large part of the migrant work force, the North

Carolina study found much higher rates of TB

disease among U.S.-born black workers compared with the foreign-born workers (55).

HIV AND AIDS: EPIDEMIOLOGIC

ASSOCIATION WITH TB

Reports in the mid-1980s were the first to

describe an association between TB and AIDS,

based on clinical studies of Haitian immigrants in

Florida (23 1) and intravenous drug users (IVDUS)

in New Jersey (319). In recent years, a significant

physiologic interaction between the two infections has become clear. This interaction is relevant not only to the medical care of individuals

confected with tubercle bacilli and HIV, but also

to the resurgence of TB in many areas.

Current evidence indicates that HIV-related

immunsuoppression impairs the body’s ability to

contain infection with tuberculous mycobacteria.

As a result, individuals infected with TB and HIV,

particularly those with advanced immunosuppression, are at high risk of progressing rapidly to

active TB disease; this is true whether they have

recently become infected with TB or previously

harbored the latent TB infection (69,77,81,278).

Rapid progression to active TB disease among

individuals with AIDS seems to be a more

dangerous course of TB, with death often occurring before treatment for TB begins or within the

first month of treatment (290). The estimated

annual risk of progression to active TB disease

among dually-infected individuals has been estimated to be as high as 8 percent per year (278),

compared with an average risk among HIVseronegative individuals of 10 percent per lifetime.

In addition, preliminary observations suggest

some individuals with HIV infection may be more

likely than a healthy individual to acquire the

initial TB infection after contact with someone

who has active, infectious TB (69). Heightened

susceptibility and prolonged periods of infectivity have been cited as potential factors in several

recent outbreaks of MDR-TB among HIVinfected individuals in congregate settings

(48,69,77,81,195).

An estimated 10 million people in the United

States are infected with tubercle bacilli (248) and

an estimated 1 million are infected with HIV. As

has been seen in some areas, the presence of HIV

can profoundly affect the incidence of TB,

particularly where populations with TB and HIV

overlap to a large extent (202,229,249,315).

According to a recent CDC analysis of trends in

reported cases of TB among U.S.-born individuals between 1985 and 1991, the largest increases

in numbers of TB cases were found in groups of

States with the highest incidence of AIDS (defined as 138 to 636/100,000 population); TB

incidence was found to have declined in States

with the lowest cumulative AIDS incidence (5 to
Chapter 3-The Changing Epidemiology of Tuberculosis 143

46/100,000), and remained at the same level in

those with an intermediate incidence of AIDS (48

to 97/100,000) (293). These data suggest that HIV

may be having a direct impact on TB, accounting

for at least some of the resurgence of TB in these

areas. Common factors, such as the occurrence of

both diseases in some of the same demographic

groups, may also be contributing to the observed

association, Inmates and IVDUS, for example, are

at higher risk for TB than the general population

because a greater proportion of individuals in

these groups have tuberculous infection and are

also at high risk for HIV infection; in addition,

noninfected inmates and IVDUS are also at high

risk for TB due to the potential for transmission

within correctional facilities, crack houses, and

other settings (23,355).

A recent analysis of U.S. death certificates filed

between 1980 and 1990 indicated an increase in

deaths due to TB in young adults, believed to be

associated with the AIDS epidemic. In 1990,

more than half of the deaths with TB in individuals 20- to 49-years-old occurred in those who also

had AIDS listed on their death certificates (39).

In developing countries, particularly in subSaharan Africa and Haiti where both AIDS and

TB are more prevalent than in the United States,

AIDS appears to be having a substantial impact

on TB. According to World Health Organization

(WHO) estimates, 4 million people worldwide are

dually infected with tubercle bacilli and HIV, the

majority of whom live in developing countries; as

many as two-thirds of TB patients in some

countries may be HIV-seropositive (236). Internationally, TB is one of the most common

opportunistic infections of AIDS and is the

AIDS-defining condition in about 30 percent of

cases (132). This could lead to a dramatic increase

in the number of deaths from TB over the next

decade in regions where TB and AIDS are

endemic (135,201).

The Prevalence of TB

Among Individuals With AIDS

Studies of individuals with AIDS in the United

States have consistently shown a higher prevalence of TB compared with the general population, even after adjustment for age, race, and sex

(67,232). Overall, 4.9 percent of AIDS cases

reported up to 1990 also appeared on TB registries, according to a CDC analysis of TB and

AIDS registries in 43 States and 11 localities

(293,344). Substantially higher prevalence rates

of TB among individuals with AIDS have recently been reported in certain populations: for

example, 26 percent of men with HIV infection

and 40 percent of men with AIDS or AIDS-related

complex living in a homeless shelter in New York

City and 13 percent of patients with AIDS in a

New York City hospital were found to have active

TB (177,325). The 1990 overall proportion of 4.9

percent increased from 4.0 percent 2 years earlier

(344).

Another indicator that the prevalence of TB

may be increasing among individuals with AIDS

is the disproportionate increase in the incidence of

extrapulmonary TB, which rose by 20 percent

nationwide, compared with pulmonary TB, which

rose by 3 percent, between 1984 and 1989.

Extrapulmonary TB is more often seen among

individuals with AIDS (see chapter 2) (27,218 ).4

M.tb. isolates may represent only 10 percent of

mycobacterial infections in patients with AIDS,

however. Infection with nontuberculous mycobacteria such as M.avium is very common among

AIDS patients; these infections occur in later

stages of AIDS (when CD4 cell counts are below

100/mm

3

), are untreatable, and may be lifethreatening.

4 According to CDC’S 1987 definition of AIDS, an HIV-infected individual with extrapulmonary TB would be reportable as AIDS (40).

In 1993, this definition was broadened to include, among other conditions, pulmonary TB as a defining condition of AIDS among HIV-infected

individuals with CD4+ lymphocyte counts waler 200 cells/rnm3 (365).
44 I The Continuing Challenge of Tuberculosis

MULTIDRUG-RESISTANT TUBERCULOSIS

Drug-resistant TB is not a new phenomenon,

but in recent years, the predominant types of

MDR-TB have changed, as has the overall

number of cases in the United States.

Three general categories of drug resistance

apply to TB, although, in practice, it is not always

possible to determine which one applies in any

given case: primary resistance, which is a naturally occurring biological phenomenon that rarely

results in resistance to more than one drug, but

also refers to a drug resistance in a patient not

known to have received prior treatment; acquired

resistance, which is a manmade problem caused

by inadequate or erratic treatment and can result

in resistance to one or more drugs in each case;

and transmitted resistance, which occurs in active

transmission to contacts from infectious cases

(e.g., in institutional settings) and results in

resistance to the same number and types of drugs

as in the source case (154).5

Until the past several years, TB experts generally assumed that most cases of MDR-TB were

acquired through inadequate or erratic treatment

in an individual case. Increasingly, however,

transmitted resistance is being implicated in

reported cases of MDR-TB (48). For example, in

New York City, a survey of all TB cases reported

during April 1991 suggested that most patients

with drug-resistant isolates had drug resistance

because they were initially infected with resistant

bacilli (107). Although both categories of resistance appear to be important at present, the actual

proportion of each in the U.S. population is

unknown. Genetic fingerprinting technology has

recently been used to track the spread of specific

strains of tubercle bacilli among infected individuals in an outbreak situation, thus providing

strong evidence of active transmission in certain

cases (69).

From a public health standpoint, the most

significant forms of drug-resistant TB are resistant to both isoniazid (INH) and rifampin (RF),

two of the most powerful anti-TB drugs. Such

cases of MDR-TB are generally far more difficult

and costly to treat than drug-sensitive TB, and can

be fatal despite the best available treatment (see

chapter 5 for further details).

The proportion of cases with drug-resistant TB

in the United States, Canada, and Europe has

traditionally been lower than in many other

countries. In many areas of Latin America, Asia,

and Africa, higher rates of TB overall, inadequate

TB control programs, uncontrolled dispensing of

drugs, and ineffective treatment delivery systems

all contribute to higher rates of drug-resistant TB

(156). On entry to the United States, immigrants

from these areas can harbor tuberculous infection

that may be drug-resistant.

Current national data on the incidence and

prevalence of drug-resistant TB in the United

States are unavailable because, until 1993, the TB

surveillance system did not collect information

on drug-susceptibility of reported cases (382).

Although some States or communities regularly

preform susceptibility testing on TB cases, others

test only on some individuals on an optional basis

(156). As of 1993, reports of each case of TB will

be required to include drug susceptibility data

(26). Since 1961, CDC conducted periodic national surveys of primary drug resistance, but

discontinued the practice in 1986, partly due to

evidence of stable or declining proportions of

patients with drug resistance but also due to

competing priorities for CDC resources. Several

large national surveys conducted over the past

few decades do offer some information on the

epidemiology of drug-resistant TB in the United

States.

S Although these definitions are accepted by most TB experts, the CDC uses a different scheme to distinguish among types of resistance.

The CDC classification uses the term ‘‘primary resistance” to refer to all TB not previously treated; this category combines “primary” and

“transmitted’ resistance as they are defined in the text. The CDC’S term “secondary resistance” is equivalent to “acquired resistance’ aS

defined in the text.
Chapter 3-The Changing Epidemiology of Tuberculosis! 45

Figure 3-8-Culture-Positive Cases of Tuberculosis Resistant to One or More Drugs, by Region, 1991

I

II

Ill

Iv

c

o

6 V

$

VI

Vll

Vlll

lx

x

D

P

t---l

4

0 30 60 90 120

Number of cases

REGION I

Connecticut

Maine

Massachusetts

New Hampshire

Rhode Island

REGION II

New Jersey

New York

Puerto Rico

Virgin Islands

REGION Ill

Delaware

District of Columbia

Maryland

Pennsylvania

Virginia

West Virginia

REGION IV

Alabama

Florida

Georgia

Kentucky

Mississippi

North Carolina

South Carolina

Tennessee

REGION V

Illinois

Michigan

Minnesota

Ohio

Wisconsin

REGION VI

Arkansas

Louisiana

New Mexico

Oklahoma

Texas

REGION Vll

Indiana

Kansas

Missouri

New England

REGION Vlll

Colorado

Montana

North Dakota

South Dakota

Utah

Wyoming

REGION IX

Arizona

California

Hawall

Nevada

REGION X

Alaska

Idaho

Oregon

Washington

SOURCE: Office of Technology Assessment, 1993, based on data from U.S. Department of Health and Human Services, Public Health Service,

Centers for Disease Control and Prevention, 1991.

The incidence of primary resistance to anti-TB

drugs remained under 3 percent horn the 1940s,

when antibiotics were fwst used to treat TB,

through the 1960s (82). An average rate of

primary resistance of 7.1 (range of 3.3 to 15.1

percent) was found in a national survey of over

7,500 patients tested in 19 city and State laboratories by CDC between 1975 and 1977, with higher

rates found among Asian and Hispanic American

patients than other racial and ethnic groups.

Another survey of 20 State and city labs involving

over 11,000 patients, conducted between 1975

and 1982, found a declining incidence of primary

resistance over the period of the study, with a 6.9

percent rate overall and variation by geography,

race, and ethnicity (172,338,340).

A higher average incidence of primary resistance to one or more drugs (9.0 percent) (with 0.5

percent resistant to two or more drugs during this

same period) was found in a 1982-86 survey

conducted by CDC, (based on 3,760 samples

fkom 31 health departments across the country

(51,297). Results showed a decreased rate of

primary resistance during the 4-year survey.

Because of different methods of sampling and

data collection, however, results of the 1975-82

survey and the 1982-86 survey are not comparable.

More recent and comprehensive data are available fi-om a nationwide CDC survey of drug

resistance among new TB cases reported during

the frost 3 months of 1991. This survey did not

include data on drug resistance in prevalent cases,

so it provides only a minimal estimate on the

number of drug-resistant cases in the United

States. Provisional analysis of these data show

that drug resistant TB is present in many areas of

the country (see figure 3-8); cases resistant to at
46 I The Continuing Challenge of Tuberculosis

least one drug were reported from 36 States and

to both INH and RIF from 13 States.

A total of 114 cases of TB in newly diagnosed

cases resistant to both INH and RIF were found,

with more than half of these reported from New

York City.6 Resistance to both INH and RIF was

3.5 percent, representing cases in which the two

best anti-TB drugs could not be given. Overall,

14.2 percent of the cases had resistance to at least

one drug (the majority to INH) (19,363).

Rates of drug-resistance among selected populations of TB patients have also been described

(54). A recent study of drug resistance among TB

cases reported in New York City gives an

indication of the magnitude of the problem in that

area. In a collaborative study with CDC, the New

York City Department of Health conducted a

systematic survey of TB cases to measure drug

resistance among all patients in New York City

who had a positive culture for TB during the

month of April 1991 (107). Overall, 33 percent of

cases were resistant to one or more drugs, and 19

percent were resistant to both INH and RIF.

Divided according to primary and acquired

resistance, the study found that among cases not

previously treated, 23 percent were resistant to

one or more drugs and 7 percent to both INH and

RIF; among those currently or previously treated,

44 percent were resistant to one or more drugs and

30 percent to both INH and RIF. The New York

City Department of Health reported that for the

entire year of 1991, a total of 366 new cases of TB

resistant to both INH and RIF were reported in

New York City-about 10 percent of all cases

that year (57). No other area of the country

currently has as high a level of MDR-TB. Further,

limited evidence suggests that the prevalence of

MDR-TB in New York is increasing. During a

recent 3-year period at a large hospital center in

Brooklyn, the prevalence of TB cases resistant to

two or more drugs increased from 12 percent (31

cases per 265 patients) to 18 percent (39 cases per

221 patients) (280).

Recent Outbreaks of MDR-TB in

Institutional Settings

Although community outbreaks of drugresistant TB (237,339) are not an entirely new

occurrence, a recent series of reports indicate that

such outbreaks have become more common,

larger in scope, and more dangerous.

Since 1990, CDC has investigated nine outbreaks of MDR-TB in the United States (370). At

least seven additional clusters of drug-resistant

TB, however, have been reported in 1990 and

1991 but not investigated by CDC (in Illinois,

Mississippi, New York, and Michigan). They

have occurred in several hospitals in New York

City and Miami; in New York State and New

Jersey; and in prison facilities in New York State

(see table 3-l). The total number of individuals

who developed active MDR-TB in these outbreaks had risen to 297 as of October 1992 (78).

Most, though not all, were HIV-seropositive. The

majority (79 to 89 percent) of the individuals

affected by these outbreaks have died from the

disease, including six health care workers and one

prison guard; the median interval between diagnosis and death was just 4 to 16 weeks (363).

Almost all cases were resistant to at least INH and

RIF, and some to as many as seven drugs (80). It

is not known whether the high rate of mortality

observed in these outbreaks applies to other

individuals with MDR-TB, whether or not they

are HIV-infected.

In these institutional settings, MDR-TB was

transmitted from patient to patient, from patient to

health care worker, from inmate to inmate, and

from inmate to prison staff. A number of common

factors have been investigated as possible causes

of the rapid transmission of the disease in these

different settings (80). The immediate factor in

6 Cases of TB resistant to both INH and I?IF: 51 from New York City, 9 from New Jersey, 7 from Florid% 6 from Californi% 5 from Texas,

3 from Alabama, 3 from Illinois, and 1 each from Hawaii, Arizona, Virginia, Washingto@ Georgia, and Pennsylvania (26).
Chapter 3-The Changing Epidemiology of Tuberculosis | 47

Table 3-1—Nosocomial HIV-Related Multidrug-Resistant Tuberculosis Outbreaks,

1988 to October 1992

Time Total Resistance

Facility Location period cases pattern a

Hospital A Miami 1988-91 65 INH, RIF (EMB, ETA)

Hospital B New York City 1989-91 51 INH, SM (RIF, EMB)

Hospital C New York City 1989-92 70 INH, RIF, SM (EMB, ETA, KM, RBT)

Hospital D New York City 1990-91 29 INH, RIF (EMB, ETA)

Hospital E New York State 1991 7 INH, RIF, SM (EMB, ETA, KM, RBT)

Hospital F New York City 1990-91 16 INH, RIF, SM (EMB, ETA, KM, RBT)

Hospital i New Jersey 1990-92 13 INH, RIF (EMB)

Hospital J New York City 1991-92 28 INH, RIF (SM, EMB, ETA, KM)

Prison systemb New York State 1990-92 42 INH, RIF (SM, EMB, ETA, KM, RBT)

Total casesb

297

KEY: EMB = Ethambutol; ETA- Ethionamide; HIV- human immunodificiency virus; INH _-Isoniazid; KM Kanamycin;

RBT - Rifabutin; RIF - Rifampin; SM - Streptomycin.

a All ~SeS are resistant to first group of drugs listed. Some cases are also resistant to the drugs listed within the

parentheses.

b 24 prison ~SeS are also counted with Hos@tal C.

SOURCE: Office of Technology Assessment, 1993, based on data from U.S. Department of Health and Human

Services, Public Health Service, Centers for Disease Control, 1992.

each case is the presence of individuals with

active, infectious TB in close proximity to others;

such patients remain infectious until at least

several weeks into appropriate therapy under the

best of circumstances, or, in untreatable cases,

remain infectious indefinitely. Furthermore, delayed diagnosis and delayed initiation of appropriate therapy in treatable cases increase the

chances of spreading the disease. For a number of

reasons, HIV-seropositive individuals with MDRTB maybe more difficult to diagnose. In addition,

drug susceptibility testing, which is necessary to

assure an appropriate treatment regimen, usually

takes several weeks to months to complete.

Heightened vulnerability to the rapid development of active TB among HIV-seropositive

individuals infected with tubercle bacilli also

contribute to these outbreaks,

Delayed implementation of infection control

measures, premature discontinuation of isolation,

delayed reporting of drug-resistance, and lack of

isolation facilities were major factors in the

spread of MDR-TB within these institutions.

Given the medical limitations cited above, infection control practices adequate to the task may be

essential to prevent further spread of the disease

in these circumstances (see chapter 5 for further

details). In at least one setting where an outbreak

occurred, the adoption of improved infection

control practices was believed to be largely

responsible for the absence of further cases of

transmitted MDR-TB (20).

FACTORS UNDERLYING THE TB

RESURGENCE IN THE UNITED STATES

Recent changes in the nature and magnitude of

TB involve a broad range of interrelated factors.

No one factor appears to be the predominant

cause of the resurgence. Medical factors (such as

HIV-related immunsuppression), social factors

(e.g., hopelessness and incarceration), and health

policy issues (such as reduced resources for TB
48 I The Continuing Challenge of Tuberculosis

control in general) (see chapter 7) have all

contributed to the problem in various ways (31).

One of the most basic and often overlooked

reasons for the resurgence is inadequate control of

the disease in some areas, even though its overall

incidence steadily declined in the general population (277). The maintenance of a reservoir of TB

permitted the larger resurgence to occur when

conditions favored its spread. Certain communities in New York City, such as Central Harlem,

are examples of areas where TB rates remained

consistently high in the 1960s and 1970s compared with regional and national rates. The

incidence of TB in Harlem began to rise in the late

1970s (before AIDS became prevalent and well

before national TB rates began to rise). The rise

was driven by a variety of factors, particularly

hopelessness, intravenous drug use, and the

decline of TB control programs (45). TB rates

began to increase more quickly in Harlem in the

mid- 1980s, as HIV became prevalent in the same

population (57).

Social and public policy issues figure prominently in the resurgence. Some of the most

intractable social problems are generally believed

to play a role, directly or indirectly, in furthering

the spread of TB, including, poverty, hopelessness, substance abuse, poor health status, language barriers, and crowded, substandard living

conditions. The AIDS epidemic in some of the

same populations provided the vechile for an

accelerated rate of increase in TB. Immigration of

individuals from certain countries has added to

the level of disease in some areas, and has been a

continuing source of TB, although it is not clear

whether immigration in recent years has contributed substantially more to TB than it has in the

past (31). Growing numbers of inmates in correctional institutions, of residents in homeless shelters, and of patients with AIDS in health care

facilities may also have contributed to rapid

increases in TB in some areas. It is likely that a

combination of many of these factors in the same

populations produced the most volatile situation

for TB.

Despite the multitude of social factors favoring

its spread, most of which are not new, most TB

cases are curable and preventable by traditional

public health and medical approaches (see chapters 4 and 5). The withdrawal of public resources

and the dismantling and defunding of community

control programs credited with the earlier decline

in the disease appear to have played a major role

in the resurgence (31,45,240). Although the

proportion of current cases that could have been

prevented by surveillance and treatment is not

known, the majority of them potentially could

have been prevented. Moreover, the emergence of

MDR-TB is a sensitive indicator of deficiencies

in the process of ensuring treatment until cure,

one of the main responsibilities of TB control

programs.
——

T

Strategies to

Prevent

Tuberculous

Infection and

Active Disease 4

here are many approaches to tuberculosis (TB) prevention, ranging from basic public health measures to

technologically complex interventions. In the broadest

sense, improvements in the standard of living, particularly less crowded housing and better health status overall,

probably contributed the most to reducing the incidence of TB

earlier this century and maintaining it since then at relatively low

levels in the United States compared with many other countries.

Over the past three decades, the development of effective

medical treatment for TB has drastically reduced the period of

infectivity in individuals with active disease and allowed for cure

in the majority of cases treated (see chapter 5). Public health

efforts to find cases of active TB, deliver curative treatment,

investigate possible contacts of infectious cases, test them for

infection, offer information about the disease, and deliver

preventive treatment have become efficient means to break the

chain of transmission (91). In hospitals, prisons, homeless

shelters, and other congregate settings where infectious patients

may be in close contact with others, infection control measures

of various types are used to protect the uninfected from

respiratory exposure to infectious individuals.

Once tuberculous infection occurs in an individual, measures

can also be taken to lessen the chance that active disease will

develop months or years later. Preventive treatment (after

infection) and bacillus Calmette-Guerin (BCG) vaccination

(before infection) are the two main approaches used to prevent

the active TB.

This chapter examines three of these approaches—infection

control measures to prevent transmission in institutional settings,

preventive treatment, and BCG vaccination. The recent resur49
50 I The Continuing Challenge of Tuberculosis

gence of TB, along with multidrug resistant-TB

(MDR-TB) transmission and confection with

human immunodeficiency virus (HIV), has

brought some of the old issues in TB prevention

to light and created new ones. Current issues and

problems, along with developments in progress to

improve each approach, are also summarized.

INFECTION CONTROL

In the past several years, a series of large

outbreaks of MDR-TB in hospitals, prisons and

other facilities have renewed concern about TB

transmission and prompted debate over the need

for and usefulness of various approaches to

prevent further spread of infection (20,101,223,

348,350,352a). Thus far, more than 250 individuals contracted MDR-TB in these outbreaks, the

majority of whom died within a few months of

diagnosis. In nearly all cases, the outbreak strain

was resistant to isoniazid (INH) and rifampin

(RIF), the two most effective anti-tuberculous

drugs. Some cases were resistant to seven drugs.

Sixteen health-care workers (HCWS) and one

prison guard also developed MDR-TB, seven of

whom have died. Eighty percent of the patients,

inmates, and staff who developed active disease

in these outbreaks were known to be HIVseropositive or otherwise immunocompromised

(e.g., resulting from radiation treatment for cancer) (80,382). Epidemiologic investigations confirmed that the cases were acquired by airborne

infection within the facilities.

At two of the hospitals, about a third of HCWS

exposed to patients with MDR-TB were found to

have been recently infected around the time of the

outbreaks. At another hospital, more than 50

previously uninfected HCWS tested positive for

tuberculous infection following exposure to hospitalized inmates with MDR-TB. Transmission of

MDR-TB infection to HCWS in the other hospitals could not be determined because of a lack of

comparative test results (324,382). While it is

impossible to exclude the possibility that some of

the HCWS may have acquired tuberculous infection outside of the hospital, it is assumed that

most of the HCWS infections occurrin g during

the outbreak periods resulted from exposure to

infectious patients without adequate infection

control measures in place.

It has been suggested that medical housestaff,

nurses, and other HCWS have recently experienced high rates of new TB infection (151), but

recent data on rates of tubercuIous infection

among HCWS have not yet been published.

Although tuberculous infection has long been

recognized as an occupational hazard for HCWS,

the magnitude of the risk of infection has not been

well characterized in recent years because routine

annual screening for tuberculous infection among

most HCWS has been discontinued in many areas

or is not collected systematically or is not

reported publicly. Several surveys have reported

higher rates of tuberculous infection among

physicians and hospital personnel than the general population, though not all cases of infection

could be identified as having been acquired

through occupational, rather than community,

exposure (15,109,234).

Some evidence indicates that HCWS in certain

job categories are at higher risk of infection than

other HCWS. A 1983 national survey comparing

TB infection rates among physician trainees

found that physicians training in pulmonary

medicine had a greater risk of infection than

similarly exposed physicians training in infectious disease (182). The higher risk was thought

to be due in large part to the pulmonary physicians’ likelihood of exposure to patients with

pulmonary TB and involvement with certain

invasive respiratory procedures (such as bronchoscopy and endotracheal incubation) that stimulate

the patient’s coughing reflex.

The Centers for Disease Control and Prevention (CDC) recommends that routine surveillance

of HCWS by tuberculin skin testing be conducted

to monitor for possible infection in health care

facilities (359). The particular vulnerabilities of

HIV-infected HCWS to occupational TB expo-
Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease | 51

sure has recently prompted CDC and others to

examine that issue (22,214).

Two features clearly distinguish the recent

outbreaks from those of the past: undiagnosed or

inadequately treated MDR-TB as a potent source

of infection, and heightened vulnerability of

immuocompromised individuals to rapid development of active TB. The fact that these outbreaks occurred in facilities in different regions of

the country suggests that the problem is not

specific to certain hospitals or local populations,

but is a broader issue affecting individuals with

HIV, HCWS, prison staff, and the community at

large. The potential exists for nosocomial (acquired within the hospital) transmission of TB in

many urban areas, given increasing numbers of

hospitalized, incarcerated, and homeless individuals with acquired immunodeficiency virus (AIDS),

rising rates of TB in these populations, and

inadequate infection control measures for preventing the spread of infection within the facilities (80,87). Transmission of drug-susceptible TB

may also be occurring, although it is less likely

that such clusters would be recognized since they

would be indistinguishable from most other cases

in the community.

Investigations of the outbreaks revealed a

common set of problems and deficiencies that

allowed the disease to spread unchecked (20,87,223).

Failure or delay in diagnosing TB in patients and

inmates was cited as a major factor, One reason

for this was the often unusual clinical and

radiographic presentation of TB in individuals

with AIDS, which may obscure or complicate the

diagnosis. Further, a “low index of suspicion”

for TB among HCWS unaccustomed to seeing

patients with the disease was cited for HCWS’

failure to order appropriate diagnostic tests upon

admission so that potentially infectious patients

could be isolated until they were determined to be

noninfectious. In addition, laboratory procedures

caused additional delays in obtaining diagnoses,

confirmation, and drug susceptibility results. In

one hospital, for example, a median of 15 weeks

elapsed between the time patients’ specimens

were obtained and the time results were available

due (223), in large part, to the slow growth rate of

the bacilli.

Failure to render MDR-TB patients noninfectious through adequate treatment was another

major factor in the outbreaks. In many cases,

prolonged periods of infectiousness occurred

despite treatment, either because the specific type

of resistance was not yet identified and ineffective

drugs were prescribed, or because the few remaining drugs available to treat patients with multiple

resistance were not effective. The latter undoubtedly applied to the cases in which resistance to

seven drugs was documented, but even in cases

resistant only to INH and RIF, successful outcomes are far more diffficult to obtain (see chapter

5). Treatment failure then led to the persistence of

symptoms (such as coughing), longer hospital

stays, and a greater risk of transmission of

infection to others.

Despite these serious problems, it is likely that

transmission of tuberculous infection within the

facilities could have been substantially reduced,

if not totally prevented, by better use of recommended infection control measures. Investigations of the outbreaks revealed a number of

common problems in applying and maintaining

infection control measures. In various ways,

respiratory isolation of infectious patients was

either not achieved (i.e., the facility was not

designed to handle infectious TB patients) or

isolation was not consistently maintained. For

example, ventilation systems permitted air from

the patients’ rooms to mix with surrounding areas

rather than providing negative pressure relative to

the corridors and other rooms. Often these systems recirculated the air within the facility rather

than exhausting it directly to the outside. Patients

who were in respiratory isolation sometimes left

their rooms to walk to bathrooms down the hall,

or their doors were left open to the corridors. Also

noted was an insufficient number of properly

equipped isolation rooms to accommodate the

number of patients with suspected or confirmed

TB. In some cases, isolation precautions were
52 | The Continuing Challenge of Tuberculosis

Box 4-A-Summary of Recommendations for Preventing the Transmission of

Tuberculosis in Healthcare Settings, 1992

Early identification and treatment of persons with active tuberculosis

● Maintain a high index of suspicion for TB to identify cases rapidly.

● promptly initiate effective multidrug anti-TB therapy based on clinical and drug-resistance surveillance

data.

Prevention of spread of infectious droplet nuclei by source control methods and by reduction of microbial

contamination of indoor air

● Initiate acid-fast bacilli (AFB) isolation precautions immediately for all patients who are suspected or

confirmed to have active TB and who maybe infectious. AFB isolation precautions include use of a private

room with negative pressure in relation to surrounding areas and a minimum of six air exchanges per hour.

Air from the room should be exhausted directly to the outside. Use of ultraviolet lamps and/or

high-efficiency particulate air filters to supplement ventilation maybe considered.

. Persons entering the APB isolation room should use disposable particulate respirators that fit snugly

around the face.

● Continue AFB isolation precautions until there is clinical evidence of reduced infectiousness (i.e., cough

has substantially decreased, and the number of organisms on sequential sputum smears is decreasing). If

drug resistance is suspected or confifirmed, continue AFB precautions until the sputum smear is negative

for APB.

. Use special precautions during cough-inducing procedures.

Surveillance for TB transmission

● Maintain surveillance for TB infection among health-care workers (HCWS) by routine, periodic tuberculin

skin testing. Recommend appropriate preventive therapy for HCWS when indicated.

● Maintain sirveillance for TB cases among patients and HCWS.

● Promptly initiate contact investigation procedures among HCWs, patients, and visitors exposed to an

untreated, or inefficiently treated, infectious TB patient for whom appropriate APB procedures are not in

place. Recommend appropriate therapy or preventive therapy for contacts with disease or TB infection

without current disease. Therapeutic regimens should be chosen based on the clinical history and local

drug-resistance surveillance data.

SOURCE: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention,

1992.

discontinued prematurely, while patients were Infection Control Measures

still infectious. For many years, the merits and drawbacks of

A number of specific circumstances further

increased the probability that infection would be

spread. Most notably, two commonly used procedures-pentamidine aerosol treatment for patients with AIDS and sputum induction to collect

samples for TB diagnosis-elicit forceful coughing, propelling infectious particles into the air

unless contained in specially-designed booths

(52). Both procedures have previously been

associated with increased transmission of tuberCU1OUS infection in health care facilities (345).

various infection control strategies have been

debated. CDC recently updated and expanded its

comprehensive guidelines for preventing transmission of tuberculous infection within hospitals

and other facilities (359). These guidelines (which

are now undergoing further revision) call for

stricter application of a broad range of strategies

(see box 4-A), some of which involve relatively

simple modifications of procedures, while others

involve the incorporation of sophisticated and

expensive technologies. It is believed that such
Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease | 53

Adequate ventilation and ultraviolet-B light can both

decrease the likelihood of acquiring TB infection.

Here an ultraviolet light (above) and an exhaust

fan (Ieft) have been added to some hospital rooms

housing patients with infectious TB to help control

the spread of the disease.

measures have not yet been widely adopted by

health care facilities (254).

CDC’S guidelines emphasized a ‘‘hierarchy of

controls, ’ emphasizing first the implementation

of source control and administrative measures to

reduce or eliminate the production of infectious

particles or confine them to the patient where they

originate<. g., rapid identification of infectious

patients, prompt initiation of treatment, respiratory isolation of infectious patients, and instructing patients to wear masks or cover their mouths

when they cough. These measures are generally

considered to comprise the first and most important line of defense against transmission of

tuberculous infection in institutional settings

(21).

Additional measures to be used after the

previous and administrative ones are in place

included environmental controls for eliminating

infectious particles after they have been released

into the air (such as redirecting air flow and

faltering or irradiating the air to remove infectious

particles). Adequate ventilation generally includes directional air flow into isolation rooms

from adjacent areas, air filtration, and direct

exhaust of air to the outside. A minimum of six air

exchanges per hour in isolation rooms is specified

in CDC’S guidelines. Such measures are not

necessarily easy to implement in modern facilities that are designed to recirculate air for energy

conservation or in older buildings with no central

air circulation. New devices are currently in

development to filter and recirculate air within

individual rooms, although their usefulness is far

from demonstrated (205).

Disinfection of air with ultraviolet (UV) light

sources has also been advocated (252). It is

known from experimental data that tubercle

bacilli are readily killed by UV-C irradiation

(ultraviolet radiation of a shorter wavelength than

UV-B present in sunlight), but data on efficacy in

killing airborne tubercle bacilli under actual use

conditions are lacking. Relevant variables include

the intensity of the radiation, duration of contact,

and humidity of the air. The minimum effective

dose is unknown. Special fixtures have been

developed for overhead installation but precise

recommendations for their design and installation

have not yet been developed. Such devices could

be particularly appropriate where adequate ventilation and air filtration are impossible to attain. At

present, a number of practical issues limit the

effectiveness and application of such lights under

different conditions; however, modifications are
54 I The Continuing Challenge of Tuberculosis

likely to be made to permit wider use. These lights

pose a potential risk for temporary but painful

photokeratitis (inflammation of the cornea of the

eye), which can result from exposure to highintensity W-C light (206), so care needs to be

taken to prevent direct exposure. The safety of

properly designed UV-C lights on patients and

HCWS under actual conditions has not been

studied systematically. Anecdotal reports point to

success with W systems in some high-risk

settings (151).

The final type of measure discussed in CDC’S

guidelines on infection control was personal

protection devices, such as particulate respirators.

Standard surgical face masks probably do not

protect adequately against TB infection because

they allow inhalation of airborne particles around

the outside of the mask, although there is no

evidence that they have failed to protect against

infection. Masks designed to fit tightly around the

nose and mouth (disposable particulate respirators) are believed to provide at least some

protection against tubercle bacilli, but again,

relevant data are lacking.

One of the most controversial aspects of

infection control concerns the use of ‘‘powered

air purification respirators’ (PAPRs), which are

powered, halfmask respirators equipped with

high-efficiency particulate falters. They are commonly used in industrial settings to protect

workers from toxic fumes and other substances.

The National Institute for Occupational Safety

and Health (NIOSH), an agency within CDC,

proposed in a recent report to the Occupational

Safety and Health Administration, that PAPRs be

used to protect high-risk HCWS from occupational exposure to tuberculous infection (371);

NIOSH is mandated by the Occupational Safety

and Health Act of 1970 to ‘‘formulate sciencebased assessments of risk and preventive recommendations, which, if implemented, would assure

that no worker develops illness as a consequence

of exposure at work. Many experts have argued

that such devices are unnecessary, uncomfortable, and impracticalin clinical situations (151,328).

To review the underlying data and practical

implications of this recommendation, CDC convened a group of experts in TB infection control,

biosafety, occupational safety and health, and

representatives of labor groups and other organizations. William L. Roper, CDC’S director, concluded from the meeting that current evidence

was inadequate to determine the effectiveness of

such respirators in protecting HCWS from nosocomial transmission and that their routine use in

health-care settings was not recommended (254).

There appear to be no clinical studies evaluating the efficacy of any of the various infection

control measures to exist in preventing transmission of tuberculous infection (or other airborne

infections). One reason for this is the difficulty of

studying effects of single interventions in a

clinical setting. Accordingly, precise judgments

cannot yet be made about the efficacy or costeffectiveness of the various measures. It is

believed, however, that combinations of measures taken to improve infection control were

responsible for the cessation of some of the

outbreaks (e.g., in a Miami hospital) (219), the

most important measure being rapid diagnosis

and isolation of infectious patients. Nevertheless,

data on the clinical efficacy, efficiency, and

feasibility of the various measures will be needed

in the long run to help guide these decisions.

In the short term, decisions about the necessity

and appropriateness of individual measures in a

given site will probably be determined largely by

the prevalence of TB in that resident population,

available resources, and the physical characteristics of each facility that influence the risk of

transmission and the applicability of different

interventions. Different combinations of interventions would be appropriate for different settings (see boxes 4-B through 4-D), e.g., acute care

hospitals, prisons, HIV clinics, and homeless

shelters. Infection control experts have recently

recommended that such decisions be based on an

individualized risk assessment for each local area,

rather than on a universal set of requirements for

both high- and low-prevalence areas (21).
60Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease 155

Box 4-B—Changes in Infection Control Measures at

Bellevue Hospital, New York City

Bellevue Hospital, one of New York City’s largest municipal hospitals, admits mom than 400 patients with

active TB per year to its 1,232-bed facility. To protect against transmission of tuberculous infection within the

hospital, extensive changes have recently been made in its infection control capabilities and procedures.

In addition to standard ventilation, which provides two fresh air exchanges per hour in each mom, Bellevue’s

isolation and bronchoscopy rooms each have a window exhaust fan that allows four additional air exchanges per

hour, with air expelled directly outside through a high-efficiency particulator air filter. This ventilation system

is designed to create negative air flow relative to the corridor.

Each room also has been fitted with an air filtration system that recirculates air (at the rate of eight room

volumes per hour) through a prefilter in tandem with a high-efficiency particulator air (HEPA) filter. This system

is designed both to trap and remove airborne tubercle bacilli and also to facilitate mixing of the air, which enhances

the bactericidal activity of ultraviolet lights.

The cost of these ventilation changes is estimated at $10,000 per isolation room.

Ultraviolet (W) light fixtures have also been installed in each respiratory isolation room and in some of the

common areas where patients with active TB are likely to be present, including waiting and examination areas,

bronchoscopy rooms, radiology areas, and chest clinics, Each isolation room has two 30-watt UV fixtures,

mounted on the wall above eye level to provide W light for up to 200 square feet of floor space.

All hospital staff entering respiratory isolation rooms are required to wear a dust-mist particulate respirator.

Health care workers performing certain high-risk procedures on patients with active TB, such as sputum induction,

aerosolized pentamidine administration, and endotracheal incubation and suctioning, are required to wear a

particulate respirator. Patients with active TB are required to wear masks only when outside of their isolation

rooms.

SOURCE: W. Rem, Director and Professor, Department of Medicine, Division of Pulmormy and Critical Care Medicine, New

York University Medical Center, New York NY, personal communication June 1993.

TUBERCULIN SKIN TESTING AND

PREVENTIVE TREATMENT

Since the 1950s, when the anti-TB drug isoniazid

(INH) was introduced and frost evaluated for

efficacy in treating active TB (see chapter 5), it

has also been possible to use this drug for the

treatment of tuberculous infection to prevent

subsequent development of the active disease. A

number of clinical trials aimed at evaluating the

efficacy of INH as a preventive treatment have

shown over 90 percent effectiveness afforded by

completion of 12 months of INH preventive

treatment (IFT) among individuals with tubercu10US infection caused by INH-susceptible bacilli

(64,113). Unless reinfection occurs later in life

(generally unlikely in most U.S. populations), the

benefits of IPT are presumed to be lifelong

(1 13,131). IPT would not be expected to benefit

individuals infected with INH-resistant tubercle

bacilli.

Not all individuals with tuberculous infection

are equally likely to develop active TB. Some

develop it within a year or two after infection,

while others harbor the infection for decades

before becoming sick; most never develop the

disease at all (249,300). The reasons for these

differences are largely unknown, although some

specific risk factors associated with a greater

likelihood of progression have been identified.

From a public health standpoint, the most important of these is HIV infection.

Public health efforts to prevent TB concentrate,

for practical and economic reasons, on screening

for tuberculous infection where it most likely is to

be found—in identifiable high-risk groups (see

tables 4-1 and 4-2). In total, an estimated 10 to 15

million individuals in the United States have
56 I The Continuing Challenge of Tuberculosis

Box 4-C-infection Control Measures at Cook County Hospital, Chicago

Cook County Hospital (CCH), a 950-bed municipal hospital on Chicago’s near-west side, was built in 1910.

Its physical plant is antiquated: 30-bed open wards still exist, heating is provided by radiators, and there is no 

conditioning. Each year, approximately one-quarter of Chicago’s newly diagnosed TB patients are diagnosed at

CCH (168 patients in 1991); over 300 with active T.B were admitted to CCH in 1990. A long-suspectedproblern

with occupational exposure to TB was recently documented in a study of tuverculin skin test conversions among

CCH staff physicians; purified protein derivative conversions after 1 year of clinical work at CCH were noted

among 46 percent of housestaff training in internal medicine, compared with 5 percent of other physician trainees

(in emergency medicine, family practice obstetrics/gynecology, pediatrics, and radiology).

To address the problem, CCH implemented infection control measures according to the Centers for Disease

Control and Prevention’s 1990 guidelines, with adjustment for the hospital’s physical plant, available resources,

and patient care and health-cam workers (HCWS) concerns. All 51 single rooms with bathrooms were outfitted

with fans that expel room air outside at a rate sufficient to provide 6 or more air changes per hour and negative

air flow relative to the halls, and with a ultraviolet light. Common areas of the hospital where occupational

exposure might occur, including the pulmonary function test laboratory and a labor and delivery room, were also

outfitted with fans and UV lights.

A triage protocol was developed for CCH’S emergency room and walk-in clinics to speed identilfication and

isolation of patients with known or suspected TB. Sputum induction booths were installed in the emergency room,

HIV clinic, and the admittin “ “ g ward. Emergency room laboratory personnel were trained and equipped to perform

sputum smear examinatiom on site to avoid sending specimens out to the microbiology laboratory for processing.

Admitting procedures were changed so that patients with active TB could be admitted directly to isolation rooms

without going through the common admitting ward.

Surgical masks were replaced with particulate respirator for all HCWS and visitors entering respiratory

isolation rooms. HCWS were given training sessions on nosocornial transmission of TB and measures to protect

themselves from infection. Two nurses were hired to serve as a roving employee health service team to offer

tuberculin skin testing to HCWS at their worksites within the hospital.

The total cost of ventilation changes, UV lights, particulate respirators, and additional personnel was

estimated at $350,000 in 1992, with ongoing annual costs of approximately $100,000. Since these infection

control measures have been implemented, tuberculin skin test conversions among CCH housestaffhave dropped

from 15 perwmt per year in 1991 to around 6 percent in 1992 and 1993. The tubenwlin skin testing program is

currently reaching about half of the hospital’s HCWS at risk for occupational exposure to ‘I’B.

SOURCE: City of Chicsgo, Department of Health “Tuberculosis Morbidity and Mortality Report. 1991,” Tuberculosis

Control Program City of Chicago, Chicago, IL, August 25, 1992; L. Cocchiarella “ . R. Muzaffar, "PPD “PPI)

Conversion Among Housestaffin a Public Hospital” (abstract) American Review of Respiratory Diseases 145(4): (Suppl) A102,

1992; Rebecca M. Wurtz Director, Section of Epidemiology, Department of Infectious Diseases, Cook County Hospital,

Chicago, IL, personal communication, June 1993.

tuberculous infection (357). However, the preva- born children (307). At present, only three States

lence of tuberculous infection in specitlc populations and geographic areas is unknown, since the

practice of regular screening among children and

adults was abandoned during the 1970s and

1980s. No national surveys of tuberculous infection have been conducted in the United States in

over 20 years. Recent small surveys of children in

certain urban areas, however, have shown high

rates of infection, particularly among foreign-

(Indiana, Missouri, and Kentucky) require reporting of tuberculin skin test results in children under

six (307).

The medical community and public health

officals in the United States have long advocated

the policy of selective use of IPT. Recent increases in the incidence of TB in communities

with high rates of HIV, along with evidence of

rapid progression to active TB among those with
—

Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease | 57

Box 4-D-infection Control Measures at the Rikers Island

Correctional System, New York City

The tuberculosis case rate in the New York City correctional system is close to 600 cases per 100,000

population-three times the highest case rate in the general population of New York City. Montefiore Medical

Center, a private not-for-profit hospital in the Bronx, in a tripartite agreement with the New York City Department

of Health and Correction, provides comprehensive health services to the 14,000 men and women incarcerated on

Rikers Island Correctional Complex. The Montefiore Rikers Island Health Servicea has worked closely with both

agencies over the past few years on the implementation of infection control measures in the jails to curb the

increase in TB. Currently, 125 individuals are being treated for active tuberculosis. The TB control program is

challenged by the high turnover of the population, the short average length of stay of 59 days (with half of new

admissions discharged from the system within a week), and the rapid transfer of inmates between different

facilities. The creation of a respiratory isolation area, the development of a computerized tracking system, and

the increasing ability of the Department of Correction to locate prisoners within the system have facilitated their

ability to treat patients on TB medications.

To complement a TB control system that includes systematic screening, diagnosis, treatment, and contact

tracing among inmates, Rikers Island has instituted a series of environmental changes in its facilities to help stop

the spread of the disease.

In May 1992, the Department of Correction in conjunction with the Department of Health, Montefiore Rikers

Island Health Services and other city agencies opened its first 42 isolation beds. There are 140 such respiratory

isolation beds. Tent structures erected for housing of inmates were retrofitted to achieve levels of respiratory

isolation that exceed all State, city, and CDC guidelines. Each room has approximately 10 to 12 air exchanges

per hour, vents air to the outside, and has an anteroom with positive pressure. The corridor has approximately 18

air exchanges per hour. An extensive computer system monitors any cessation of negative pressure or other

malfunction and makes appropriate adjustments or notifications.

All patients with suspected or confirmed TB are placed in respiratory isolation until TB is ruled out or until

they are no longer infectious and have been evaluated for placement in the general jail population.

The facility has medical and nursing personnel 24 hours a day. Mental health services are provided daily for

the many patients who also suffer from mental illness or who have mental health crises triggered by their isolation

or adverse side effects from their medications. An estimated 60 percent are dually diagnosed with HIV infection

and have complicated medical conditions. TB patients wear surgical masks when outside of their rooms; the more

confining particulate respiratory masks may impair their breathing.

Upon release from jail, all patients receiving treatment for TB receive an appointment card that lists their

medications, diagnosis, and the location of a community-based clinic that will provide directly obsexved therapy

(DOT) to ensure continuity of treatment. These clinics include the Department of Health Chest Clinics and private

providers who provide DOT through the State Medicaid program.

Due to the high prevalence of TB in connectional settings, all Montefiore employees receive a purified protein

derivative (PPD) skin test every 6 months. Employees working in high-risk areas receive a PPD skin test every

3 months. Rikers Island has developed a computerized tracking system that automatically generates lists of those

employees due for a skin test and documents the results of those tests, Rikers Island also provides education about

TB for non-clinical staff including the appropriate use of particulate respirator masks worn in the presence of

suspected or confirmed TB patients.

SOURCE: L. Richmond, Assistant to the Director, Montefiore Rikers Island Health Services, Montefiore Medical Center, The

University Hospital for the Albert Einstein College of Medicine, New York NY, personal communication,1993 .
58 I The Continuing Challenge of Tuberculosis

Table 4-l—Risk Factors for Tuberculous Infection

●

●

●

●

●

●

Close contact with infectious tuberculosis cases (e.g., in the

same household).

Immigration from areas of high TB prevalence (i.e., parts of

Asia, Africa, Latin America, and the Caribbean).

Low- income status (including homeless people and migrant

farm workers).

Racial or ethnic minority (including African American,

Hispanic r Native American).

Substance abuse (especially alcohol and intravenous drugs).

Residence in correctional institution, nursing home, mental

institution, or other long-term care facility.

SOURCES: A.B. Bloch, H.L. Rieder, G.D. Kelly, et al., “The Epiderniologyof Tuberculosis in the United States. Implications for Diagrmsis and

Treatment,” C/inics in Chest Medicine 10(3):297-313, 1989; U.S.

Department of Health and Human Services, Public Health Servke, U.S.

Centers for Disease Control and Prevention, “Screening for Tuberculosis and Tuberculous Infection in High-Risk Populations. Recommendations of the Advisory Committee for Elimination of Tuberculosis,”

Morbidity and Mortality Weekly Report 39( RR-8):1-12, 1990.

both HIV and tuberculous infection (278,290),

have prompted renewed calls for expanding the

use of PT. Even in many developing countries,

where IPT has never been feasible because of the

sheer number of people involved and the lack of

adequate resources to deliver treatment (387), the

escalating cost of treating the enormous number

of active cases expected in the near future now

makes IPT appear to be a relatively less expensive

option for controlling TB (76,202,203).

For several decades, it has been theoretically

possible to prevent the majority of new TB cases

in the United States with the available diagnostic

and preventive treatment methods. As TB has

receded from the general population and become

more concentrated among particular populations

defined by ethnicity, race, geography, and age

(see chapter 3), such targeted efforts at prevention

should have become more feasible (28). However, because of limited resources available to TB

control programs, controversies about adverse

effects of IPT, problems with access to medical

care, difficulties in ensuring completion of lengthy

treatment regimens, among other reasons, IPT has

not been widely applied, even in the high-risk

populations for which it is most highly recommended (2,17,1 15,381). According to national

data collected by CDC, fewer than half of all

individuals with tuberculous infection identified

by TB control programs through contact investigation receive an adequate course of preventive

treatment (11 1).

Notable efforts have recently been made in

some areas to overcome these obstacles, as in a

program to offer IPT under direct observation to

residents of a Seattle homeless shelter (208). In a

nationwide effort involving 25 sites, CDC recently funded a project to evaluate the feasibility

of onsite screening for tuberculous infection and

for provision of IPT for clients at drug-treatment

centers and inmates at Federal and State correctional facilities (355). Among the more than

38,000 individuals tested, 16 percent were found

to have tuberculous infection (13 percent of

drug-treatment clients and 25 percent of inmates);

66 percent of the infected drug-treatment clients,

compared with 94 percent of infected inmates,

subsequently completed IPT. Although the project showed that screening could be successfully

conducted at these sites, ensuring completion of

Table 4-2—Fiisk Factors for Progression from

Tuberculous Infection to Active TB

● Symptoms suggestive of TB.

● HIV infection.

. Previously untreated TB,

. Underweight (at least 10 percent below ideal body weight).

. Medical conditions known to increase the risk of TB once

infected (e.g., silicosis, diabetes mellitus, chronic renal

failure, gastrectomy, some forms of cancer, treatment with

immunosuppressive agents).

● Extremely young age.

SOURCES: A.B. Bloch, H.L. Rieder, G.D. Kelly, et al., “The Epidemiology of Tuberculosis in the United States. Implications for Diagnosis and

Treatment,” Clinics in Chest Medicine 10(3):297-313, 1989; U.S.

Department of Health and Human Services, Centers for Disease

Control, “Screening for Tuberculosis and Tuberculous Infection in

High-Risk Populations. Recommendations of the Advisory Committee

for Elimination of Tuberculosis,” Morbidity andA.forta/ity Week/y Report

39( RR-8):1-12, 1990.
Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease | 59

The TB skin test, in which a purified protein derivative is injected under the skin, produces a reaction like the

one on the right in about 95 percent of immunocompetent individuals infected with the bacilli that cause TB.

The test detects infection in a much small percentage of peep/e with HIV or other types of

immunosupression.

IPT still posed substantial difficulties in the

drug-treatment setting.

The following section briefly describes the

available methods for identifying individuals

with tuberculous infection and for preventing the

development of active TB.

Identifying Individuals with

Tuberculous Infection

At present, methods for directly detecting the

presence of tubercle bacilli in the body (see

chapter 5) are applicable only for those with

active TB, which normally creates a large number

of bacilli in the body. By contrast, latent tubercu10US infection creates much smaller populations

of bacilli in the body and is not directly detectable

with current microbiologic methods (isolating,

culturing, and identifying populations of organisms) or histologic methods (staining a sample

containing bacilli and visually identifying them

under the microscope).

The preferred means to identify individuals

with tuberculous infection is the tuberculin skin

test, developed in the 1890s and still in widespread use (268). As an indirect approach, the

tuberculin skin test is designed to show a type of

immune response (a delayed-type hypersensitiv-
60 I The Continuing Challenge of Tuberculosis

ity (DTH) response mediated by T-lymphocytes)

to tuberculin, proteins derived from a culture of

tubercle bacilli (see chapter 2). Normally, the

immune system of individuals infected with

tubercle bacilli will be sensitized to tuberculin

and will react (within 48 to 72 hours) to the test

substance, as shown by a small raised area

(usually greater than 10 mm) in the skin on the

arm where the tuberculin is given. Individuals

without previous exposure to tubercle bacilli

should show no reaction on the skin to the test

substance, unless they have had BCG vaccination

or have been infected with nontuberculous mycobacteria.

For various reasons, responses to the tuberculin

skin test are not ‘‘all or nothing’ small reactions

(5 to 10 mm) could mean infection in some and no

infection in others. The test results must be

interpreted in light of the individual’s risk for TB

infection, previous BCG vaccination, age, immunocompetence, and exposure to mycobacteria

other than tubercle bacilli, among other factors. A

complex system for interpreting the test result for

each individual based on risk factors, medical

history, and size of the skin reaction has been

developed (7,357).

In healthy individuals, the test has about 95

percent sensitivity and variable specificity (18,268).

In individuals who are infected with HIV or who

are acutely ill (with various viral infections, or,

ironically, acute or overwhelming TB), its sensitivity is consistently lower or nonexistent; the test

cannot be used in these circumstances to exclude

the possibility of tuberculous infection (18,361).

For practical purposes, negative results in individuals with late stage HIV me uninterpretable

(126,143,361). Unless the tuberculin skin test is

given early in the course of HIV infection,

detection of true infection is much less likely, and

thereby reduces the efficacy and usefulness of

preventive treatment. CDC recommends that

since HIV-infected individuals with tuberculous

infection are at such high risk for developing

active TB, IPT should be given to those with HIV

who show small skin test reactions of 5 mm or

more or to those who are anergic and who are at

high risk for tuberculous infection (344). Others

have argued for bypassing skin tests in HIVinfected individuals and offering IPT to all

individuals with AIDS where the prevalence of

tuberculous infection is high (165).

The accuracy of the tuberculin skin test also

varies with the prevalence of tuberculous infection in the population being tested. In high

prevalence groups (more than 25 percent infected), such as immigrants from high-prevalence

areas of Asia, Africa, or Latin America, and

recent, close contacts of active cases, tuberculin

screening is generally considered to be informative and reliable. For many other populations,

prevalence data are likely to be unavailable, so

unless an individual is known to have been

exposed to an infectious case or has other risk

factors, interpreting the results of tuberculin skin

tests is problematic. In very low-risk populations

(prevalence of tuberulous infection less than 1

percent), such as the general U.S. adult population or, in many areas of the country, children

entering school, the vast majority of positive

results are likely to be falsely positive (18).

Screening in these populations could lead to

unnecessary isolation, testing, and treatment based

on an erroneous presumption of TB. For that

reason, tuberculin skin testing in low-risk populations is generally discouraged.

Limitations of the current tuberculin skin test

may become increasingly apparent as screening is

expanded to include more individuals with HIV,

including homeless individuals, foreign-born individuals, and others. Improvements in the diagnostic capabilities for detecting infection are

clearly needed. Specifically, a test that can be read

without a long waiting period would be particularly useful in institutional settings where individuals may be difficult to locate several days later

(e.g., jails and homeless shelters). A test that

accurately and directly detects the infection and

identifies the drug resistance pattern of the bacilli

without depending on adequate immune re-
Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease | 61

sponses to the infection would be essential for use

in HIV-infected populations.

Isoniazid Preventive Treatment

The purpose of preventive treatment is to

eliminate the living tubercle bacilli in the body,

thereby reducing the risk of subsequent disease.

These bacilli may be growing slowly, intermittently, or not at all. A treatment regimen based on

the use of a single antibiotic drug for a long period

of time (6 to 12 months) is necessary to substantially reduce the risk of subsequent disease. The

chance of creating drug resistance in the process

is considered low, since there are so few bacilli to

begin with and only a remote chance that any

drug-resistant ones are present. In the absence of

disease, distinguishing infection with drugresistant bacilli from infection with drugsensitive bacilli is impossible with current diagnostic methods. Epidemiologic investigations

could suggest the likelihood of drug resistance,

and assist with the choice of drugs to be used in

preventive treatment (13).

So far, INH is the only drug evaluated in human

studies for efficacy in preventing progression of

tuberculous infection. The American Thoracic

Society, medical section of the American Lung

Association, recommendations state that when

INH cannot be tolerated, or if infection with

INH-resistant bacilli is suspected, rifampin (RIF)

can be used for preventive treatment in high-risk

individuals (6,13). Data on the efficacy of RIF

and other antibiotics in preventing TB are currently lacking. Animal data suggest that shorter

regimens, e.g., 2 months of twice-weekly treatment, using RIF and pyrazinamide (PZA), are

good candidates for study (150), and several

clinical trials are in progress (e.g., in Haiti) (60).

A recent placebo-controlled trial conducted in

Hong Kong found that 3 months of RIF was as

effective as 6 months of INH in preventing the

onset of TB (138). It is not yet known whether

regimens consisting of RIF and PZA for 2

months’ duration will replace longer courses of

INH for preventive treatment (131). The effectiveness and costs of these new approaches have

not been examined in detail.

The efficacy of INH in preventing TB is well

established through a series of randomized controlled trials involving more than 125,000 subjects. Results indicate that IPT can reduce the risk

of active TB among adults with tuberculous

infection by as much as 90 percent in those who

complete a full course of treatment and by about

50 to 60 percent if those who don’t complete

treatment are included in the analysis (1 3,97, 148).

In children, the reduction in risk approaches 100

percent (142).

The efficacy of preventive treatment for TB in

HIV-infected individuals with tuberculous infection has not yet been reported from controlled

trials (although such trials are in progress in

Zambia (383) and elsewhere) (202). Preliminary

results from one of the trials suggest that a

12-month course of IPT can lead to a 89 percent

reduction in TB among HIV-infected individuals

compared with a placebo. In its 1989 report on TB

and HIV infection, CDC recommended that

HIV-infected individuals with tuberculous infection should be offered IPT for a 12-month period,

based on evidence of effectiveness in HIVnegative populations and observations of success

with curative treatment for active TB in HIVinfected patients (344). Subsequent observational

data supported the use of IPT in HIV-infected

patients (279). The National Institute of Allergy

and Infectious Diseases (NIAID) is currently

supporting two clinical trials to evaluate the

efficacy of IIT in HIV-infected individuals (96).

One of the main reasons to evaluate alternatives to INH in preventive treatment is to avoid

the risk of rare, though serious, adverse effects

from the use of INH (in individuals who are not

sick with TB and not infectious to others). The

major concern is with toxic effects on the liver

and potentially fatal hepatitis. Although the drug

is well tolerated in most cases, particularly in

children, between 2 to 3 percent of adults overage

50 develop liver inflammation (which can lead to
62 I The Continuing Challenge of Tuberculosis

Table 4-3-Criteria for Determining Need for Preventive Therapy for Persons with

Positive Tuberculin Reactions, by Category and Age Group

Age group (years)

Category <35 >35

With risk factora Treat at all ages if reaction to Treat at all ages if reaction to

5TU PPD 210 mm (or 25 mm 5TU PPD 210 mm (or 25 mm

and patient is recent contact, and patient is recent contact,

HIV-infected, or has radiographic HIV-Infected, radiographs radiographic

evidence of old TB). evidence of old TB).

No risk factor. High-incidence Treat if PPD >lOmm. Do not treat.

groupb

No risk factor. Low-incidence group Treat if PPD >15mnF. Do not treat.

a Risk factors include HIV infectlon, recent contact with infectious person, recent Skintf3St conversion, abnormal chest

radiograph, intravenous drug abuse, and certain medical risk factors (see text).

b l-figh-inCldence group include foreign-born persons, medicalty underserved IOVf-inCOnle population% and res~ents

of long-term care facilities.

C ~wer or higher cm points may be used for ~entifying positive re~tions, deperlding Ori the rdath prWah3nCe Of

Myobacterlum tubercukwis infection and nonspecific cross-reactivity in the population.

KEY: PPD - purified protein derivative; TU = tuberculin unit.

SOURCE: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and

Prevention, “The Use of Preventive Therapy for Tuberculous Infection in U.S. Recommendations of the Advisory

Committee for Elimination of Tuberculosis,” Lfortidifyandhfortah’ty /?etiew29(RR-8) :6-8, 1990.

hepatitis if the drug is not stopped as soon as

serum tests indicate the condition). A recent

review of available case reports of fatal hepatitis

possibly associated with INH indicates that such

cases seem to be decreasing infrequency since the

early 1970s (possibly because of more limited use

of IPT, but also because of better biochemical and

clinical monitoring of patients on IPT). However,

such cases are still occurring, especially among

African American and Hispanic women (294).

The postpartum period may be an especially

high-risk time. Factors that increase the risk of

INH-associated hepatitis may include alcohol or

drug abuse, previous hepatitis, or simultaneous

use of hepatotoxic drugs. The magnitude of the

risk, and the specific factors contributing to it, are

still largely unknown.

If IPT were harmless, there would be little

controversy about offering it to virtually anyone

with tuberculous infection would exist. Since it is

not, disputes over balancing the risks and benefits

in low-risk populations are difficult to resolve

(65). A series of decision analyses comparing the

risks of INH-induced hepatotoxicity with the

benefits of preventing TB in low-risk populations

have been published, with conflicting results

(102,164,220,256,292,320). CDC developed criteria for determining how the use of IFT could be

limited to minimize the risks of hepatoxicity and

benefit those at highest risk. These criteria

recommend avoiding use of IPT in low-risk

populations (see table 4-3). Until alternative

regimens with drugs posing fewer and less serious

side effects are available, IPT will likely be

limited to these high-risk groups.

BCG VACCINATION

Since the early 1950s, the World Health

Organization (WHO) has advocated widespread

vaccination with BCG as a preventive measure

against TB. At present, over 70 percent of

children worldwide are given BCG in infancy or

childhood (386). Recommendations for vaccination schedules differ widely among countries,

ranging from a single dose at birth (recommended

by the WHO Expanded Programme on Immunization) to a single dose at age 13 (United

Kingdom Policy) to repeated vaccinations through-
Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease 163

out childhood (as in many Eastern European

countries). BCG vaccination is compulsory in 64

countries and officially recommended in 118

others (58). As a result of these policies, BCG has

become the most widely used vaccine in the

world, with more than 3 billion doses administered over the past 40 years (98).

Despite its widespread acceptance and longstanding use, controversy persists concerning the

variation and lack of predictability in BCG’S

protective efficacy against TB in different populations. In part because of questions about its

efficacy and low expected utility in populations in

which the rate of transmission of TB is relatively

low, BCG vaccination has never been applied on

a national basis in the United States. As of 1988,

when CDC’S Immunization Practices Advisory

Committee and Advisory Committee for Elimination of TB last issued recommendations on BCG

use, a very circumscribed role for BCG vaccines

was specified (343), Reexamination of the policy,

along with renewed calls for development of an

improved vaccine, are likely in the near future as

CDC and others consider options for containing

the current spread of TB.

This section briefly summarizes BCG’S nature,

intended effects, efficacy and safety, overall

impact, and policy issues concerning its role in

TB control efforts in the United States. Because

of the enormity of the international literature on

this subject dating back to the 1920s, only a brief

overview is possible in the context of this report.

The Nature and Rationale for BCG Vaccines

BCG refers to several strains of Mycobacterium

bovis derived from the original strain, which was

produced about 70 years ago in France by Albert

Calmette and Camille Gue'rin at the Pasteur

Institute. Using a virulent strain of Mycobacterium

bovis, the bacillus that causes tuberculosis in

cattle and in humans. 1 Calrnette and Gu&-in

produced an attenuated bacterial isolate (a strain

of tubercle bacilli unable to cause TB). Their

product, consisting of a liquid preparation of live

bacilli, was first used as an anti-TB vaccine in

French subjects (infants born to mothers with

TB).

Literature describing this early work often

notes that the original culture of BCG bacteria

was never saved, i.e., no bacteriologically identical samples were made. Instead, the original

strain was distributed to several different laboratories around the world, where it was maintained

under different conditions, thereby leading to the

generation of bacteriologically distinct strains. As

a result, vaccines currently marketed as BCG

actually comprise a group of related vaccines with

differing characteristics, e.g., potency. This is one

of several issues complicating the interpretation

of clinical trials in which BCG was evaluated for

efficacy (see below).

One freeze-dried strain of BCG containing live

bacteria (referred to as Tice) is currently manufactured and sold in the United States, with Food and

Drug Administration approval for use in the

prevention of TB (and recently also in the

treatment of bladder cancer) ( 10). The Tice strain

is administered by multiple puncture only, not by

the intradermal method generally preferred for

BCG vaccination.

It is generally believed that BCG does not

prevent initial infection with tubercle bacilli.

Instead, BCG enhances the cellular immune

response to M,tb. (by mechanisms that are not

fully understood), thereby lowering the risk of

developing active disease. It also seems to reduce

multiplication of bacilli and dissemination of the

disease to various parts of the body, thereby

lowering the risk of extrapulmonary TB (305).

How HIV-related immunodeficiency affects BCG’S

initial or subsequent immunologic actions is not

clear, However, because a functional T-cell im1 Mj’cobacten”um bovis can cause TB in humans who have extensive contact with infected animals or who drink milk laden with tubercle

bacilli.
64 I The Continuing Challenge of Tuberculosis

-9

Figure 4-l Summmary of Estimates of the Efficacy of BCG Vaccines

Against Tuberculosis

VACCINE EFFICACY (~0)

) -500-300 -200 -100 0 20 40 60 70 80 90 t

I

1 t

I

t Haiti

I

I

* * British school childr~

I ●

I

* N. American Indians I

i

● . 4 USA (Chicago infant

i ~ Puerto Rico gen. po[

~ S. India (Madanapall

-

~

USA (Georgia, Alabz

S. India (Chlngleput)

t

I

I # USA (Illinols chlldrer I 4

I USA (Georgia chlldr[

I ● t- — -9-- Brazil (Sao Paulo) /

I g ?--- - -*- – - –4 Brazil (Belo Horizoni I

1--o -+

; Argentina (Buenos A

t t- -0 -+ Cameroun (Yaounde I

1

[

o~$ Canada (Manitoba In

r 4

I

Indonesia (Jakarta)

I + + +

Burma (Rangoon)

-

#

I Srl Lanka (Colombo)

i

~

Colombia (Call)

Argentina (Santa Fe)

t

i

I Togo (Lome) I

I ) *

I Thailand (Bangkok)

1

la)

)

)

es)

indains)

SOURCE: Reprinted with printed with permission from P.E.M/ fine, " The “The BCG Story: Lessons From the Past and Implications for

the Future,” Review of the Infectious Diseases 11 (Suppl. 2):S353-S359, 1989.

mune system is believed necessary for BCG to Efficacy and Safety of BCG Vaccination

work, it is not known whether the vaccine would Ten major randomized clinical trials and many

protect against TB in HIV-infected individuals

(103).

nonrandomized studies of BCG vaccination have

been conducted in various populations since the

Unfortunately, there is currently no reliable 1930s (summarized in figure 4-1). These trials are

immunologic measure of protective immunity to noteworthy not only for their size (only the Salk

TB following BCG administration, so it is diffl- polio vaccine trials involved more subjects), but

cult to monitor and evaluate its effects. Tubbercu- also for the duration of followup. The most recent

lin sensitivity (by skin testing) following BCG trial, begun in 1968, involved 115,000 subjects

(referred to as a BCG-induced DHT response) followed for 7.5 years in Chingleput, South India

does not correlate with protective immunity to TB (327).

(98).
.

Chapter 4-Strategies to Prevent Tuberculous Infection and Active Disease | 65

Despite the enormous international effort to

determine the protective efficacy of BCG (defined as the percent reductionin risk of TB among

BCG recipients, compared with similary exposed nonvaccinated subjects), the issue remains

unresolved; a strikingly broad range of protective

efficacy, from zero (or negative) to 80 percent,

was found (98,99). As a result, there are major

differences in expert opinion on the subject, and

a continuing controversy surrounding the analysis

of the data (59,98).

Why the vaccine worked well in some study

populations and failed in others is still not known

and may never be known. Various biological and

statistical factors accounting for the variability

have been proposed and debated, including:

variations among the strains of BCG used in the

studies;

confounding immunologic effects of widespread infection with other types of mycobacteria commonly found in soil and tap water

in some areas, some of which can induce a

similar immunologic effect against tubercle

bacilli as BCG;

regional differences in virulence of the tubercle

bacilli;

nutritional and genetic differences in the populations studied; and

methodologic differences in trial design (59,

98,99).

Some or all of these factors, or others not yet

identified, may have influenced the trial results,

producing observed differences in efficacy. Current efforts to conduct a meta-analysis of the data

may clarify some of these issues (198). Development of a reliable animal model to compare

potencies of the BCG strains currently available

may be necessary to select vaccines likely to be

potent in the human population and to avoid those

likely to be affected (63).

The data from these studies suggest that BCG

offers greater protection for children against

disseminated forms of TB (including a reduction

in incidence of TB meningitis and miliary TB that

ranges from 52 to 100 percent) than it offers

against pulmonary TB (58,134,343).

Side effects and adverse reactions to BCG

vaccination are rare in immunocompetent individuals (179,343). The increasing prevalence of

HIV in some populations, however, has raised

concern over the safety of BCG vaccination in

immunodeficient individuals since BCG is an

attenuated live vaccine and thereby poses potential risks of dissemination in immunodeficient

individuals (42,238). Case reports of serious

complications of BCG vaccination in HIVinfected infants (141,210) and adults with AIDS

(11,33,341) have been reported. CDC notes that

HIV-infected individuals may be at greater risk

for complications from BCG vaccine, but current

data are insufficient to determine the magnitude

of the risk and level of immunodefiency at

which the effect might manifest (343).

Impact of BCG Vaccination on the

Incidence of TB

Although BCG vaccination has long been

conducted in many parts of the world with the

intent of reducing the incidence of pulmonary TB

in the population, its impact on the control of

pulmonary TB is not easily discernible. The large

burden of TB in many countries over the years

suggests that even if BCG vaccination has reduced the incidence of TB (which some argue it

must have, given the billions of doses administered over the years and some potential for

benefit) (99), it is obviously not a sufficient

strategy to prevent the disease. The degree to

which it contributed to previous declines in TB

incidence (e.g., in Western Europe) may never be

known, given other contemporaneous factors,

such as socioeconomic improvements and increased availability of anti-TB drugs. Within the

next decade, the rising prevalence of HIV may

substantially reduce the impact of BCG vaccination,
66 I The Continuing Challenge of Tuberculosis

Most experts agree, however, that BCG may

reduce the incidence of the serious (and noncontagious) childhood forms of TB (TB) meningitis

and other disseminated forms of TB). In some

high-risk countries, BCG vaccination may provide good protection against these forms of the

disease, but it is not likely to prevent transmission

of pulmonary TB among young and older adults,

who are the main sources of infection to children

and other adults in the population. Ironically,

global BCG vaccination campaigns may have

actually contributed more to complacency about

TB over the years, with a corresponding decline

in interest in developing better methods of

prevention and treatment, than to TB eradication

itself (98).

BCG Vaccination Policy in the United States

BCG vaccination of children or adults has

never been carried out on a routine basis in the

United States. CDC cites two main reasons for

this policy-a low risk of tuberculous infection in

the general population, and the variable efficacy

of the vaccine (378). In its most recent policy

summary, however, CDC does recommend selected use of the vaccine in certain high-risk

infants and children such as those with negative

tuberculin skin tests who are in unavoidable and

close contact with infectious individuals and who

cannot be treated with INH preventive therapy, or

those who are continuously exposed to individuals with MDR-TB. CDC also recommends BCG

vaccination in:

66

. . . tuberculin-negative infants and children in

groups in which the rate of new infections

exceeds 1 percent per year and for whom the usual

treatment and control programs are not effective.

These groups include persons without regular

access to health care, those for whom health care

is culturally or socially unacceptable, and groups

who have demonstrated an inability to use

existing health care” (378).

It is not clear whether the rationale for this

recommendation is narrow (i.e., to prevent the

childhood disseminated forms of TB), or broad

(i.e., to offer a prevention, albeit uncertain for

those who are either unreachable or not covered

by current TB control efforts). Previous policy

statements issued by CDC and the American

Thoracic Society made similar recommendations

(6), although they were not limited to infants and

children, also specif@g ‘‘alcoholics, drug addicts, migrants, and refugees” as those without

regular access to health care for whom BCG

might be appropriate (170).

BCG vaccination may itself cause subsequent

reaction to tuberculin skin tests, thereby making

interpretation of the skin test more difficult in

some cases. Currently, no reliable method for

distinguishing between tuberculin skin test reactions caused by BCG and those caused by

tuberculous infection exists (378) but the reaction

due to BCG is believed to wane after 3 to 5 years

(307). In general, some judgments can be made on

the basis of the size of the tuberculin reaction

(with “sigtilcant” reactions more likely indicating true infection), the individual’s risk of infection, presence of BCG “scar,” and how long ago

BCG was given (291,378). Framed as a policy

choice between alternative strategies for TB

prevention, skin testing and preventive treatment

have long been favored in the United State over

mass BCG vaccination, even though efforts to

deliver preventive treatment have not been widely

implemented.

In its 1988 statement on BCG, CDC reversed

its 1979 recommendation for high-risk HCWS to

receive BCG vaccination, citing a lack of evidence for increased rates of infection or tuberculin skin test conversion among HCWS (343).

They opted instead for promoting greater use of

skin testing and preventive therapy and of hospital infection control measures.

Because of possible risks of adverse effects

horn BCG vaccination among individuals with

HIV, CDC did not recommend BCG vaccination

for anyone known or suspected to be infected with

HIV, except in selected populations where the

risk of TB is high (343). Further data on
Chapter 4--Strategies to Prevent Tuberculous Infection and Active Disease I 67

complications of BCG in HIV-infected individuals (most likely reported from developing countries) may help to clarify these issues for which

there is little experience in the United States. Data

on the efficacy of BCG in HIV-infected individuals are nonexistent. All previously mentioned

clinical trials were conducted prior to 1980.

Issues Concerning Future Use of

Vaccination Against TB

The current resurgence of TB in the United

States highlights the continuing need for a vaccine that is effective and safe, particularly for

individuals infected with HIV, who are at highest

risk for developing active TB. Those who are

tuberculin-negative and in close contact with

individuals who have active, infectious MDRTB, such as prison staff and inmates, HCWS and

patients, and homeless shelter staff and residents,

have the most to benefit from effective vaccination, along with HIV-seronegative individuals

who are at high risk for becoming infected with

HIV.

Until an improved vaccine is developed, an

expanded role for BCG vaccination in HIVseronegative (and ‘‘ asymptomat’ HIVseropositive) groups needs to be considered in

light of the risks, possible benefits to the affected

individuals, and potential drawbacks to infection

monitoring and preventive treatment efforts.

The need for new, improved vaccines against

TB was noted in CDC’S recent “National Action

Plan to Combat MDR-TB. ” Ideally, such a

vaccine would effectively prevent infection progressing to active TB and would not interfere with

interpretation of tuberculin skin testing (166). In

order to develop and test a new TB vaccine, a

number of unresolved issues in TB immunology

may need to be addressed, including: identification of immunogenic and virulence components

of the tubercle bacillus and which of these elicit

protective immune responses, characterization of

these immune responses, and development of

animal models for TB prevention that correlate

well with human responses (363,373). The possibility of deriving an effective vaccine against TB

using a genetically engineered recombinant BCG

vaccine containing antigen-encoding genes has

been explored in recent studies (3,313). NIAID is

currently funding several research efforts aimed

at developing a new TB vaccine (see chapter 7)

(104).
Diagnosis and

Treatment of

Active TB 5

F

or tuberculosis (TB), as for many other infectious

diseases, rapid and accurate diagnosis coupled with

delivery of effective treatment are the central elements of

medical and public health efforts to control the disease.

Recent shifts in the nature of TB—notably, the increasing

numbers of multidrug-resistant TB (MDR-TB) cases and the

particular vulnerability to TB of individuals infected with the

human immunodeficiency virus (HIV)---have heightened the

need for improved methods of diagnosis and for shorter, simpler

treatment regimens.

Diagnostic methods currently in use in many countries have

remained unchanged for decades; the need for improved methods

is acute, particularly in areas with a high prevalence of HIV. In

the United States, newer diagnostic methods have been adopted

in the past few years, but additional developments are needed to

respond adequately to the recent rise in TB and MDR-TB.

Deficiencies in the current diagnostic technology could seriously

hamper efforts to control the spread of TB among HIV-infected

populations in particular.

This chapter examines current needs and capabilities for

diagnosis of active, infectious TB, along with the rationale and

design of corresponding treatment regimens. The focus is

primarily on pulmonary TB, rather than the various forms of

extrapulmonary TB (TB in organs or tissues of the body other

than the lung), because pulmonary TB is the predominant form

and is the one responsible for transmission of the disease (see

chapter 2). Details concerning the diagnosis and treatment of

extrapulmona.ry TB can be found in several recent reviews

(75,217,227). Treatment of noncontagious tuberculous infection,

as distinct from active TB, and issues concerning skin testing for

infection are discussed in chapter 4.

69
70 I The Continuing Challenge of Tuberculosis

DIAGNOSIS OF TB AND RESISTANCE

TO ANTI-TB DRUGS

Rapid, accurate diagnosis of TB allows for

appropriate treatment to be initiated so that

patients can be rendered noninfectious, cured of

the disease, and prevented from relapsing at a

later date. By causing delays in initiating appropriate treatment, diagnostic delays and errors can

lead to the avoidable continuation and spread of

TB. In many ways, current problems in diagnosis

are no different from those of the past. It has long

been recognized that the available methods are far

from ideal, but their widespread acceptance

suggests that they are adequate inmost uncomplicated cases. Increasingly, however, the inadequacies of the current methods have become magnified in the face of rising drug-resistance and the

need to prevent rapid spread of the disease among

patients in congregate settings and among HIVinfected populations. Patients with HIV who

develop active TB may be at increased risk for

rapid death from TB if effective treatment is not

begun promptly (14,174).

At present, there is no single, definitive, quick

test for active TB. By necessity, diagnosis is

based on a combination of clinical acumen (aided

by an assessment of the patient’s risk for TB,

medical history, and clinical signs) and laboratory

and x-ray findings (70). Clinical symptoms of

active TB include a persistent cough, hemoptysis

(coughing up of blood), weight loss, fatigue, night

sweats, and fever (8).

The tuberculin skin test is the standard method

for screening asymptomatic individuals for tuberCU1OUS infection (and possibly disease) (see chapter 4). However, because of a high rate of false

negative reactions (and some false positives) in

both immunocompetent and irnmunocompromised

individuals with TB, the skin test is considered

inadequate for diagnosing active disease (8).

The classic initial laboratory method for presumptively diagnosing active TB is the sputum

smear. Samples of the patient’s sputum (phlegm)

are placed on a slide, stained with a dye for

acid-fast bacilli (AFB), and examined under a

light or fluorescent microscope (7,70). The sputum smear test is quick and inexpensive, but is

useful only when positive; negative smears cannot be used to rule out TB. The smear test does not

distinguish tubercle bacilli from other types of

(nontubetculous) mycobacteria, nocardia, or some

legionella and nor does it indicate the bacilli’s

susceptibility to anti-TB drugs. However, when

considered with other indicators, the smear test is

used to make a presumptive diagnosis (276).

When the test shows AFB, it also allows an

estimation of the number of bacilli present and

being excreted, an indicator of the patient’s

degree of infectiousness (7).

The major limitation of the sputum smear is its

inadequate sensitivity due in part to technicianvariability: only 50 to 80 percent of patients with

pulmonary TB may have positive sputum smears

(276). The detection rate among patients with

advanced stages of HIV-related immunosupression maybe even lower (70,174,236). Samples of

other respiratory secretions, biopsy body fluids,

gastrics washings, bone marrow aspirates, and

urine sediments for staining and smear examinaion would be needed to rule out false negative

results (8). In addition, false positives are an

increasing problem, due to the high prevalence of

nontuberculous mycobacterial infections in HIVinfected individuals.

Chest x-rays are also used to detect active TB.

Typical findings of TB in immunocompetent

adults include infiltrates in the upper lung areas

and cavitation. In TB patients with HIV, chest

x-ray findings are likely to be atypical (with more

middle and lower lung lobe involvement, no

cavitation, and hilar or mediastinal lymphadenopathy); in general, the more advanced the immunosuppression, the more atypical the radiographic signs of TB (215,236,242). Because of

this and the likelihood of false negative sputum

smears, diagnosis of TB in patients with HIV

involves even more uncertainties than in immunocompetent patients.
Chapter -Diagnosis and Treatment of Active TB | 71

Definitive diagnosis of TB has traditionally

been based on specific identification of the

causative organism, Mycobacterium tuberculosis, isolated from sputum, body fluids, or tissue

and cultured in the laboratory (8). Positive culture

examination is considered to be far more sensitive

and specific than sputum smears, but is also more

expensive and time-consuming (123,276). Typically, conventional culture tests require 3 to 6

weeks to generate results because of the organism’s slow growth rate. Culture methods provide confirmation of suspected TB cases, but, by

necessity, empiric treatment is usually begun

before such results are available.

Diagnosis of active TB in children poses

additional difficulties, since sputum smear and

culture tests often do not reveal the presence of

tubercle bacilli (which may be present, though in

smaller numbers than in an adult). It is also

difficult to distinguish tuberculous infection from

active TB in children. Various indirect means are

usually used to establish a presumptive diagnosis

of TB in a child, including epidemiologic information about the child’s exposure to an adult with

active TB, tuberculin skin test results, chest x-ray

findings, and physical examination for symptoms

consistent with TB even though the child may be

asymptomatic (302). Conflation of active TB

through culture examination is often more difficult in children because of the difficulty in

collecting sputum samples and because of the

even lower sensitivity of alternative fluids (such

as gastric washings) for bacteriologic confirmation of TB (306).

In recent years, many laboratories responsible

for processing TB specimens have incorporated

more efficient methods for culture examination.

An automated, radiometric method (known by its

trade name BACTEC TM), which detects growth

of M. tuberculosis in a selective medium containing radiometric palmitic acid by measuring radioactive carbon dioxide given off by the bacteria,

reduces the testing time to about 10 days (384).

Gene probes specific for M. tuberculosis can also

be used in conjunction with radiometric testing to

shorten the time needed to identify tubercle

bacilli. Another method, also producing faster

definitive results, is based on detecting microcolonies of the organism grown on solid media

and identifying them as M. tuberculosis b y

morphology (384).

Conventional methods for testing tubercle

bacilli’s drug susceptibility, using solid media

and indirect testing, typically take 8 to 12 weeks

to identify bacilli resistant to anti-TB drugs. The

newer radiometric techniques, along with direct

testing, which are also used to test for susceptibility to the five first-line drugs, take up to 3 weeks

(133). Conventional drug susceptibility testing

methods, taking several weeks longer, are used to

test for resistance to other drugs and to confirm

results of the radiometric studies (382).

Jacobs and colleagues recently reported a new

laboratory method for rapid determination of

drug-susceptibility (158). The technique is based

on a light-producing reaction catalyzed by the

firefly enzyme luciferase to distinguish drugresistant and drug-sensitive tubercle bacilli, and

can generate results in 2.3 days. It has not yet been

adapted for clinical use.

TB diagnosis based on deoxyribonucleic (DNA)

methods has recently been reported. At present,

the most fully developed of these methods is one

based on DNA amplification using the polymerase chain reaction (which allows the use of

uncultured clinical specimens) followed by gene

probes for DNA sequences specific for M. tuberculosis (44,281). Results can reportedly be obtained in 48 hours (89), although the testis not yet

available for routine clinical use. An alternative to

the use of radioactive isotopes in this method was

recently reported (322). Other approaches, such

as those based on immunoassay, are in developmental stages (70,122,188).

Delayed diagnosis was considered to be one of

the main factors contributing to several of the

recent nosocomial outbreaks of MDR-TB (discussed in chapters 3 and 4). Patients with TB who

remained infectious for prolonged periods transmitted the disease to other patients and health care
72 | The

workers

reasons

Continuing Challenge of Tuberculosis

(HCWS). There were several likely

for this, including HCWS’ failure to

suspect TB, unusual clinical features of TB in

these patient populations, and the lengthy period

of time required for laboratory identification,

confirmation, and reporting of drug-susceptibility

results (174). In addition, adequate infection

control precautions were either not taken or not

maintained, permitting infectious patients to remain in contact with patients and staff (see

chapter 4). In congregate settings, such as hospitals, prisons, nursing homes, and other sites, there

is a premium on rapid, accurate diagnosis to

reduce the risk of active transmission.

The increasing prevalence of MDR-TB creates

additional need for a rapid capability to identify

the resistance pattern in each case so that the

initial period of infectiousness can be shortened

by administration of appropriate drugs for treatment. Recent Centers for Disease Control and

Prevention (CDC) recommendations state that

during the initial period when specific drug

resistance information is not yet known, patients

should generally be treated initially with four

drugs (8,366). CDC lists patients more likely to

have drug-resistant TB as those:

from high-prevalence areas of the United States

or foreign countries; and

who have been in contact with other patients

already infected with MDR-TB, have cavitary

disease, or have been previously treated for TB

(382).

Inpatients with drug-susceptible TB or who are

TB resistant to a single drug, the four-drug

regimen should render him or her noninfectious

within a short period and offer the eventual

possibility of cure. The regimen may be inadequate, however, in patients with resistance to

three or more of the drugs. These MDR-TB

patients could remain infectious for prolonged

periods, posing a risk of transmitting the disease

to other patients, family, and institutional staff. In

New York City, where the incidence of MDR-TB

is the highest in the country, the prevalence of

resistance to both INH and RIF may be as high as

19 percent, according to a recent survey (107).

Delays in obtaining drug-susceptibility data create additional need for hospitals to implement

infection control precautions and isolation procedures to protect other patients and staff. Treatment of patients with MDR-TB must rely on the

more toxic and expensive second-line drugs

(discussed later) or newer drugs with in vitro

activity against tubercle bacilli.

TREATMENT OF ACTIVE TB

Fifty years ago, before antibiotics were available for use in treating TB, treatment involved

mainly improved nutrition, extended bed rest

(often in TB sanatoria or other specialized institutions) and on some forms of surgical intervention

to remove part of the lung (127). Mortality rates

averaged around 50 to 60 percent 5 years after

completion of treatment (200).

The introduction of antibiotic drug treatment in

the late 1940s and combined-drug regimens in the

1950s dramatically changed the outcome of TB

treatment. Rather than spending long periods of

time in sanatoria or hospitals, patients could be

treated on an outpatient basis with oral drugs that

quickly rendered them noninfectious. Hospitalization could be limited to patients who needed

diagnostic evaluation, developed complications,

or could not care for themselves (l). Surgical

intervention became unnecessary in most cases.

Generally, patients could be treated at home and

could return to outside activities soon after

treatment was initiated (178). Although it was not

the case for the initial single antibiotic (streptomycin) regimen, the multidrug regimens have

reduced mortality from TB to about 4 percent

(236).

Since the 1940s, the theory and practice of

antibiotic treatment for TB has undergone substantial change and refinement both in the combination of drugs used and in the overall duration of

treatment. Streptomycin (SM) was the first antibi-
Chapter 5-Diagnosis and Treatment of Active TB | 73

otic applied to TB, followed by isoniazid (INH),

p-aminosalicylic acid (PAS), and ethambutol

(EMB). The potential for effective treatment and

cure of TB was quickly apparent, but the long

duration of treatment required for cure (e.g., 18 to

24 months) suggested the need for better drugs.

The subsequent availability and use in the 1960s

and 1970s of two other drugs-rifampin (RIF)

and lower doses of pyrazinamide (PZA)--

permitted shorter regimens to be used.

During the past 20 years, no new drugs have

replaced or supplemented the five main first-line

drugs-INH, RIF, PZA, EMB, and SM. Numerous other drugs of lesser effectiveness and greater

toxicity have also been available as second-line

drugs. During this time, clinical research and

practice have focused on determining the optimal

use of the first-line drugs. These efforts have

resulted in revised combinations and durations of

treatment for enhancing effectiveness, reducing

toxicity, improving compliance, and reducing

costs. Current regimens call for more intensive

use of these drugs over shorter periods of time—

now 6 months, compared with the previous 18- to

24-month schedule of treatment. The 6-month

period appears to be the irreducible minimum for

the currently available drugs; further reductions

in treatment time will depend on the development

of new agents.

Clinical trials conducted internationally by the

British Medical Research Council (BMRC) and

the U.S. Public Health Service produced the

evidence for these changes in practice. The first

East African/BMRC study reported in 1977

demonstrated that treatment could be shortened

from 18 to 9 months by using RIF along with INH

and SM, while still producing cures in over 95

percent of patients (86). Subsequent BMRC

studies conducted in Hong Kong, Africa, and

Singapore helped to define alternative drug combinations, minimum durations of therapy, and

frequency of drug administration. As of the early

1980s, these trials showed that a regimen of PZA

added to the first 2 months of daily INH, RF, and

SM therapy could elicit cures in 99 percent of

patients, that 6 months was the minimum period

of time necessary for such cure rates, and that

intermittent therapy could be used without reducing effectiveness (154).

A recently reported randomized, multicenter

study conducted by CDC demonstrated the effectiveness of shorter combination regimens in U.S.

patients with TB (62). The study compared the

effectiveness and toxicity of a 6-month regimen

with the “standard” 9-months regimen among

1,451 newly diagnosed adults patients with pulmonary TB. The study did not include immunocompromised patients such as those with metastatic cancer or with HIV. Patients receiving the

6-month regimen were further randomized to

treatment consisting of individual antibiotics

taken together and treatment with RifaterTM

, a

single, combination capsule containing the same

three antibiotics. The 9-month regimen consisted

of INH and RIF given daily for 36 weeks; the

6-month regimen consisted of the same two drugs

given daily for 24 weeks, plus a third drug, PZA,

given daily for the first 8 weeks of therapy.

Patients randomized to the RifaterTMregimen

received all three drugs for the first 2 months,

followed by INH and RIF (RifamateTM combination tablets) during the remaining 4 months.

The study found the 6-month regimen of the

three drugs produced better results than the

standard two-drug, 9-month regimen. Among

patients on the 6-month regimen, about 95

percent had negative sputum cultures by 16 weeks

of therapy (compared with 90 percent of patients

on the 9-month regimen). Patients taking RifaterTM had even higher conversion rates than

patients on the original 6-month regimen. The

two groups had similar rates of relapse (about 3

percent) by 96 weeks after treatment and similar

rates of adverse drug reactions (about 7 percent),

although the 6-month regimen was associated

with a higher rate of nonhepatotoxic reactions

(primarily gastrointestinal upset and joint pain).

The efficacy of both regimens was very high—

over 96 percent of the patients were cured. An

important practical benefit to the shorter regimen
74 | The Continuing Challenge of Tuberculosis

During the 1920s, before the discovery of drugs to treat

tuberculosis, sanatoriums and other TB hospitals were

the centerpiece of treatment that focused on keeping

the patient hearty. Sanatoriums were phased out

during the 1950s and 1960s.

was that a higher proportion of patients successfully completed therapy.

Rationale for Antimicrobial Treatment of TB

Theoretically, the ultimate goal of treatment is

to rid the body of tubercle bacilli before irreversible physiologic damage occurs in the lung, but in

practice, the specific goals are to render the

patient noninfectious, prevent the emergence of

drug-resistant disease, and to allow cure without

subsequent relapse. Certain characteristics of

tubercle bacilli and their sites of infection in the

body are important in determining how this can be

accomplished. In general, tubercle bacilli replicate slowly and can remain dormant in the body

for many years. Under favorable physiologic

conditions for bacilli, they double in number

every 20 hours, but in unfavorable conditions,

they divide much less frequently or remain

dormant for prolonged periods. This characteristic accounts for the long periods of treatment

necessary to eradicate all dividing bacilli in the

body and for occasional relapses despite apparently effective treatment.

Current anti-TB drugs kill tubercle bacilli only

during periods of replication and activity. Conditions are most favorable for the bacilli’s active

metabolism in the open cavities of the lung, where

the largest bacterial population is likely to be in

an adult with pulmonary TB. In immuncopetent hosts, bacilli in closed caseous lesions and in

macrophages are relatively slow metabolizes and

replicate only intermittently.

A theoretical model for characterizing different

subpopulations of tubercle bacilli in the body and

for explaining the differential action of the major

antibacterial drugs has been proposed (192).

These four subpopulations are distinguished according to growth rates and sites of infection in

the body.

One group is the subpopulation of bacilli

responsible for the infectiousness of TB. It is

characterized by active metabolism, relatively

rapid growth rates, and large numbers of bacilli,

including drug-resistant ones. These bacilli are

usually found in the wall of lung cavitary lesions,

where conditions favorable for growth occur

(high oxygen and low acidity), and in the sputum.

Bacilli are also found in the sputum. They are

particularly vulnerable to the bactericidal action

of INH, which kills rapidly growing bacilli during

the frost few days of treatment.

A second group of tubercle bacilli is characterized by slower or intermittent growth in acidic

environments within cells (and possibly also

outside of cells where there is an inflammatory

response). There are probably fewer of these

types of bacilli in the body, but they may persist

despite short-term bactericidal treatment. They

can also cause subsequent relapses later. PZA is

believed to be most active in killing these bacilli.

A third group is believed to persist within cells

and either remain dormant for long periods or

undergo intermittent activity. These are thought

to be treated most effectively with RIF. A fourth

population of bacilli maybe largely dormant, not

affected by any of the antibiotic drugs, existing

within solid caseous lesions and probably inaccessible to host immune forces (216).

Tubercle bacilli can undergo mutation in genes

that confers resistance to the effects of anti-TB
Chapter 5-Diagnosis and Treatment Iof Active TB | 75

drugs. It is estimated that 1 in 100,000 to 1 in 100

million bacilli are initially resistant to any single

drug used against TB. These few bacilli can,

under certain conditions such as treatment with

only one drug or erratic drug taking, become the

predominant cell type in a bacterial population,

creating single- or multidrug-resistant TB. Treatment with an adequate combination of drugs can

prevent the emergence of a population dominated

by drug-resistant bacilli (75).

Current Treatment Regimens

Combinations of antibiotic drugs with overlapping functions are used in current treatment

regimens to attack the various distinct groups of

tubercle bacilli in the body (75). Anti-TB drugs

are generally classified as bactericidal (producing

rapid killing of bacilli) or sterilizing (killing the

last surviving, slowly metabolizing bacilli over

the long term). The major bactericidal drug is

INH, which is capable of producing a rapid

decrease in the number of living bacilli in the

sputum at the beginning of treatment and rapidly

reducing the bacillary load in the patient. RIF and

PZA are the most potent sterilizing drugs. Their

use allowed the overall duration of treatment to be

reduced to 6 months while minimizing relapse

rates after initially successful therapy (1 10,192).

INH and RIF (and to a lesser extent EMB and SM)

are considered the most effective drugs in preventing the emergence of drug-resistant bacilli.

Corresponding to the different roles of these

drugs, current regimens consist of two phases of

treatment: an initial intensive bactericidal phase

intended to eliminate quickly the bulk of tubercle

bacilli from most body sites, followed by a

longer-term sterilizing phase intended to eliminate the remaining bacilli. The initial regimen

involves the daily use of four drugs (INH, RIF,

PZA and EMB or SM). The total duration of

treatment is 6 months, although several variations

of this regimen (in terms of types of drugs and

frequency of administration) are also used (366).

In general, the various combinations of the

four-drug regimens yield cure rates of 98 percent

or more and relapse rates of less than 3 percent

(8).

These drugs are not without side effects, the

most serious of which is hepatitis (inflammation

of the liver) (380). Usually associated with INH,

but also with RIF and PZA, drug-related hepatitis

is more frequent among older patients, those with

preexisting liver disease, and those who abuse

alcohol (these are also risk factors for hepatitis

unrelated to INH, PZA, and RIF) (1 14). Other

common adverse reactions include: hypersensitivity reactions, along with gastrointestinal distress (caused by RIF), hyperuricemia (caused by

PZA), vertigo or hearing loss and nephrotoxicity

(caused by SM), and optic neuritis (caused by

EMB). However, the more serious and more

frequent adverse effects are generally associated

with use of the second-line drugs (178).

The patient’s improvement with treatment is

measured first by clinical improvement such as

loss of fever, reduction in coughing, increased

appetite, and weight gain. Reduction in numbers

of tubercle bacilli in the patient’s sputum also

indicates improvement. Failure of sputum culture

conversion or reappearance of viable bacilli in the

sputum following initial clearing may signal

treatment failure. Subsequent signs of treatment

failure include a worsening of clinical status and

progression of disease as detected on chest

radiography. Patients are usually monitored on a

monthly basis for adverse effects and treatment

response (178). Within 2 to 3 months of treatment, about 90 percent of patients with uncomplicated, pulmonary TB would have negative sputum cultures. Patients with drug-resistant TB may

show persistently positive sputum cultures. The

treatment of TB in children follows the same

principles as in adults, although diagnosing and

monitoring progress with treatment is more complex and necessitates the use of various indirect

indices (303).
76 I The Continuing Challenge of Tuberculosis

Treatment of TB in Individuals with AIDS

Current recommendations for treatment of TB

in patients with AIDS specify the same combination of antibiotics as for immunocompetent TB

patients (344,366,378).

In general, TB is treatable in individuals with

HIV. Although experience is limited, reports to

date suggest that HIV-infected patients, even

those with advanced stages of immunodeficiency,

can undergo rapid elimination of tubercle bacilli

from the sputum, clinical improvement, and low

rates of relapse following standard anti-TB treatment (232,290,321). Most documented cases of

treatment failure in patients with HIV have been

linked to incomplete treatment or poor absorption

of anti-TB drugs (117,290).

Nevertheless, several added complexities in

treating TB in patients with HIV exist. Coexisting

infections and other AIDS-associated disorders

require treatments that may interact with the

antibiotics used to treat TB. High rates of

toxicities and drug reactions, especially to RIP,

have been noted in TB patients with AIDS

(103,212,290). Many of the adverse reactions

were considered serious enough to drop RIP from

the regimen, making a cure of TB in these cases

much more difficult. For a variety of reasons,

toxicities from anti-TB drugs may be more

difficult to interpret in patients with AIDS and TB

(230).

Another complicating factor is that various

types of disseminated or extrapulmonary TB

appear to be more common among patients with

HIV (100,230). Some of these (particularly central nervous system TB) may pose more immediate risks and are more difficult to diagnose and

treat (212).

Completion of treatment, a critical factor in

treatment of all TB patients, may be even more

critical to successful outcomes in patients with

HIV. At the same time, some subgroups of

patients such as intravenous drug users with HIV

may be at higher risk for treatment failure.

Chapter 6 examines this issue in greater detail.

Finally, although patients with AIDS usually

respond to TB therapy, the optimal duration of

therapy to prevent relapse following treatment in

these patients is uncertain (212,230). Initial recommendations for longer courses of treatment

were based on case reports of several patients

found to have progressive disease despite adequate treatment (319) and on prior difficulties

with the treatment of other opportunistic infections. Recent reports of successful outcomes with

6-month regimens (290,321) cast doubt on the

necessity of prolonged treatment, but clinical

trials with long-term followup will be needed to

determine the efficacy of short-course treatment

in larger groups of HIV patients. In the meantime,

HIV-infected patients treated for TB probably

need frequent followup, including regular mycobacterial examinations, for life (230).

Treatment of Multidrug=Resistant TB

When SM was introduced in the late 1940s as

the first chemotherapeutic agent against TB, it

was administered singly. The first group of

patients treated with SM responded well initially,

but in a short time, relapsed with large numbers of

SM-resistant tubercle bacilli. SM had effectively

killed the susceptible bacilli but not the resistant

ones, which had been present in small numbers

from the outset by random mutation.

It was soon recognized that the use of a single

antimicrobial drug in treating TB would lead

predictably to the development of resistant disease, and that multiple drugs to which the bacilli

were susceptible would be necessary to prevent

the development of drug resistance. The use of

combination chemotherapy to treat TB has been

standard practice since the early 1950s, initially

with INH, SM, and PAS, next with INH, SM, and

EMB, then INH and RIF, and now with four drugs

until a patient’s drug susceptibility test results are

known (287,366,382).

Given the current prevalence of MDR-TB in

the United States, such a four-drug regimen is

estimated to be adequate for over 95 percent of
Chapter 5-Diagnosis and Treatment of Active ITB | 77

TB patients (25). The remaining 4 to 5 percent are

resistant to 2 or more drugs in the current

recommended regimens. Cases of resistance of up

to seven drugs have been documented in recent

outbreaks of MDR-TB in several New York City

hospitals and prisons (382). In addition, patients

with bacilli resistant to as many as 11 drugs have

recently been reported (1 18).

Failure to complete a full course of appropriate treatment is a major cause of MDR-TB.

Patients on combination-drug therapy who stop

taking all medications at the same time may

ultimately relapse, but with bacilli showing the

same-drug susceptibility pattern as before. The

recurrent disease in such cases would be treatable with the same combination of drugs. In

contrast, patients who take their medications

erratically or who stop taking only one or two of

the drugs while continuing the others may

relapse with TB resistant to one or several of the

medications (267). In these cases, treatment of

recurrent disease requires a different combination of drugs. The success of further treatment

depends, in part, on the effectiveness of the

remaining drugs that can be used. Patients who

remain inadequately treated may also be capable of transmitting MDR-TB to others.

Data derived from a number of clinical trials

conducted overseas by the BMRC suggest that

patients with bacilli resistant to either INH or SM

can be treated effectively with regimens initially

containing four drugs (resulting in 94 to 97

percent cure rates in 6-month regimens), since the

other 3 drugs would be usable (194). Resistance

to RIF, however, poses a greater risk of treatment

failure (194). Successful outcome of treatment is

even less likely if there is resistance to both INH

and RIF, the two most active anti-TB drugs

currently available. High treatment failure rates

and overall mortality among HIV-infected individuals with MDR-TB have recently been reported (100,1 18).

Drug regimens for MDR-TB are determined on

a case-by-case basis, beginning with information

derived from the patient’s medical history (e.g.,

i

I

I

Individuals with active, drug-susceptible TB, like this

one at Bellevue Hospital in New York City, are often

hospitalized during the initial period of their treatment

while they are still infectious. Patients with drugresistant TB may require longer hospitalizations.

prior drugs taken for TB) and drug-susceptibility

testing. Cases resistant to two or more of the

frost-line drugs would be treated with a combination of remaining first-line drugs, second-line

drugs (capreomycin, kanamycin, ehtionamide,

cycloserine, and p-aminosalicylic acid and amikacin), often for 18 to 24 months or longer after

conversion of sputum cultures.

A number of other drugs have been less

extensively studied for anti-TB activity, and are

not yet approved (because of insufficient data on

efficacy) for the treatment of TB-clofazimine,

quinolones (sparfloxacin and ofloxacin) (153).

Reliable data to judge the effectiveness of these

second-line drugs are lacking, but anecdotal

experience suggests that they are much less

effective and much more likely to lead to serious

toxic effects (287). Adjunctive surgery to remove

tissue (usually in the lung) heavily infected with

tubercle bacilli is sometimes used as a treatment

of last resort in patients with localized lung

disease for whom drug treatment is inadequate

(1 16). In general, treatment of MDR-TB requires

more complex interventions, longer hospitalization and more extensive laboratory monitoring.
78 I The Continuing Challenge of Tuberculosis

Beginning in 1990, widespread shortages of

certain anti-TB drugs occurred in the United

States (224,352). A number of contributing factors have been identified, including various problems within the generic drug industry, the reliance

on sole suppliers of a bulk drug (often outside the

United States), single U.S. manufacturers of the

finished drug product, a low demand for anti-TB

drugs overall, and low profit margins for drug

companies manufacturing these drugs (189). In

April 1992, CDC began to make PAS and SM

available through an investigational new drug

agreement with the Food and Drug Administration (FDA). FDA has worked with U.S. manufacturers to reestablish production and supplies of

the affected drugs. As discussed in chapter 7, the

FDA has also begun offering a variety of incentives to pharmaceutical companies to develop

new anti-TB drugs, such as granting orphan drug

status, conducting expedited review of applications, offering accelerated approval with the

development of surrogate markers (interim outcomes), and accepting foreign clinical data (225).

New Approaches to Treatment

The rising prevalence of MDR-TB and the

complexities of treating TB in patients with HIV

have heightened the need for new anti-TB drugs,

shorter regimens, and better methods of drug

delivery.

Combination tablets containing three of the

frost-line drugs such as RifaterTM, containing

INH, RIF, and PZA, have been developed (192),

but are not commercially available in the United

States. In 1993, a new drug application to permit

marketing of RifaterTM in the United States was

submitted to the FDA (119). RifamateT M

, a

combination tablet containin g INH and RIF, is

FDA-approved and available; 40 percent of RIF

prescribed in the United States is currently given

as RifamateTM (119). Some data are available on

the effectiveness of combination preparations

separately. In two BMRC studies, conflicting

results were obtained in clinical trials, but in the

recent study reported by Combs and colleagues,

Rifater TM was found to be effective, although it

was associated with a higher rate of adverse

effects (62). Incorporation of these combined

preparations into TB treatment, however, could

possibly increase the overall success rate and help

prevent the development of MDR-TB resulting

from erratic drug taking or inadequate prescribing. One disadvantage of the combined preparations is that the regimen cannot be selectively

modified to reduce adverse effects of component

drugs without switching to individual drugs or

discontinuing therapy altogether.

Intermittent therapy of equivalent effectiveness (twice or thrice weekly instead of daily

administration) in the sterilizing phase of treatment improves chances for supervision of outpatient therapy, for reducing overall costs of treatment, and lowering drug toxicities (61). Further

experimentation with even less frequent administration may depend on the use of drugs with

longer duration of effect in the body (such as

rifamycins). In this context, rifamycins are currently being studied in clinical trials in China

(192). An optimal anti-TB agent would be bactericidal for all populations of bacilli within a very

short period of time, orally administered or

injectable in a single dose, and free of toxicities.

Other drugs being investigated for this purpose

include fluroquinolones, rifamycin derivatives,

and phenazines (127).

Alternative methods of drug delivery have

been discussed but are not yet ready for clinical

evaluation. Some of these include implantable

devices containing drugs for slow release into the

bloodstream (similar in design to the NorplantTM

device for contraception), and the use of liposomes as carriers for drugs directly to specific

sites in the body. Immunotherapeutic approaches

are also under investigation.

compared with the use of the same drugs given
Chapter 5--Diagnosis and Treatment of Active TB |79

Table 5-l—Trends in Drug Costs for Treating Tuberculosis in a 165 lb (75 kg) Patient,

1986-92: An Uncomplicated Case Versus a Case Resistant to INH and RIFa

Uncomplicated case:

Drug Daily dose Duration 1986 cost 1990 cost 1992 cost

Isonizaid 300 mg

Rifampin 600 mg

Pyrazinamide 25 mg/kg

Average annual percentage increase

A case resistant to INH and RIF:

Drug Daily dose

180 days $ 5.04 $ 6.50 $ 8.50

180 days 106.20 159.30 165.30

60 days 98.00 160.00 179.20

$209.24 $325.80 $353.00

in cost, 1986-92: 9.10/0

Duration 1986 cost 1990 cost 1992 cost

Pyrazinamide 25 mglkg 540 days $ 882.00 $1,440.00 $1,613.00

Ethambutol 15 mgikg 540 days 690,00 1,246.00 1,610.00

Streptomycin 15 mg/kg 120 days 138.00 192.00 206.00

Ethionamide 20 mglkg 540 days 890.00 1,458.00 1,691.00

CiprofIoxacin 1500 mg 540 days NA 3,000.00 3,600.00

$2,600.00 $7,338.00 $8720.00’

Average annual percentage increase in cost, 1986-92 (without Ciprofloxacin): 12.OYO

● Add ofloxacin=$4,080 .00

Add amikacin=$27,648 .00

Add clofazimine=$71 .00

KEY: NA - not available; mg - milligram; kg - kilogram (of patient body weight).

a Treatment costs based on median prices given in table 5-2. Costs are for an entire recommended treatment cycle.

Estimates include drug costs only.

SOURCE: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and

Prevention, Division of Tuberculosis Elimination, 1993.

The Cost of Drugs for

Tuberculosis Treatment

The purchase of anti-TB drugs varies by

jurisdiction and can be done by State or local

health departments, or by other organizations.

The drugs’ prices can vary depending on manufacturer, the quantities purchased, and other terms

of the sale (190), In addition, not all States use all

the same drugs or dose forms. In response to price

concerns over anti-TB drugs, CDC recently

completed a survey of 14 jurisdictions (13 States

and Baltimore City) to gather data on the last

prices they paid for their pharmaceuticals in 1986,

1990, and 1992. Tables 5-1 and 5-2 present

CDC’S results. Table 5-1 gives estimates prepared

by CDC of the costs of two possible drug

regimens for a 165-pound (75-kg) adult: one for

uncomplicated TB, the other a TB case resistant

to INH and RIF. Table 5-2 presents data on

increases in individual dosage forms of most

first-line and second-line anti-tuberculosis drugs.1

Although prices paid by State and local health

departments vary and the precise number of drugs

required for treatment is different for each patient,

these estimates still give a sense of the resources

needed for drugs to treat a TB patient as well as

1 Some dosage forms were purchased by only a small subset of States. According to CDC, its discussions with some State and local

authorities revealed that part of the increase in prices is due to the growing unwillingness of manufacturers to enter into contracts with public

health authorities to supply drugs over time at a set, discounted price. Some of the range in prices is also due to the fact that some municipalities

purchase in bulk under contmc~ while others lack the volume to do so (190),
80 I The Continuing Challenge of Tuberculosis

Table 5-2—Trends in Tuberculosis Drug Prices: Results of U.S. Centers for

Disease Control and Prevention Survey

1992

number Percent

Drug form and States 1992 1992 1990 1986 increase

Drug package size ordering price range median price median price median price 1990-92

Isoniazid

Isoniazid

Isoniazid

Isoniazid

100 mg 100/bottle

300 mg 30/bottle

300 mg 100/bottte

Syrup 1 pint bottle

14

13

5

14

11

13

14

6

9

10

7

7

2

1

2

3

12

9

6

10

1

8

9

2

3

4

1

2

3

$1.00-3.00

1.07-2.71

1.64-3.65

6.25-12.86

27.36-31.89

33.30-40.00

26.10-59.04

65.49-75.12

280.00-359.28

19.73-30.25

97.66-103.75

730.00-925.54

1.75-1.84

1.84

4.95-6.95

34.46-49.00

56.97-118.24

16.25-21.07

.75-22 .60

89.99-115.50

175.50

108.13-236.85

117.30-350,11

5.40-9.60

5.10-18.50

15.88-154.15

51.02

.59-1 .00

.84-1 .70

$1.75

1,41

2.41

9.55

31.40

33.45

27.25

71.70

326.63

29.18

101.57

889.94

1.79

1.84

5.95

41.86

103.88

18.80

.98

108.85

175.50

225.27

195.57

7.50

11.80

136.25

51.02

.80

.95

$1.25

1.09

2.33

7.72

27.36

29.60

26.55

60.97

292.63

24.05

78.87

718.67

1.67

N/A

4.96

33.70

89.51

14,84

.75

86.10

N/A

94.12

180.89

N\A

17.06

N/A

31.20

N/A

.85

$ .85

.84

1,36

8.29

19.60

18.20

17.70

38.42

188.62

16.37

53.82

500.13

1.32

N/A

3.25

14.80

52.87

11.95

1.40

34.78

N/A

75.00

N/A

N/A

14.29

N/A

31.21

N/A

.67

40%40

29

3

24

15

13

3

18

12

21

29

24

7

N/A

20

24

16

27

31

26

N/A

133

8

N/A

N/A

N/A

64

N/A

12

Rifampin and

Isoniazid

Rifarnpin

Rifampin

Combo pack30 day

150 mg 30/bottie

300 mg 60/bottle

Pyrazinamide 500 mg 100/bottle

Pyrazinamide 500 mg 500/bottle

Ethambutol

Ethambutol

Ethambutol

100 mg 100/bottle

400 mg 100/bottle

400 mg 1000/bottie

Streptomycin

Streptomycin

Streptomycin

1 gm vial

2.5 gm vial

5.0 gm vial

Paraamino

salicydicacid

Ethionamide

500 mg 500/bottle

250 mg 100/bottle

Capreomycin 1 gm 10 ml

Kanamycin 1 gm 3 ml

Cycloserine 250 mg 40/bottle

CiprofIoxacin

Ciprofloxacin

CiprofIoxacin

250 mg 100/bottle

500 mng 100/bottle

750 mg 100/bottte

Clofazimine

Clofazimine

50 mg 100/bottle

100 mg IOO/bottle

Ofloxacin 400 mg 50/bottle

Amikacin 1 gm

25 mg 100/bottle

50 mg 100/bottle

Pyridoxine

Pyridoxine

KEY: gm = gram; mg - milligram; N/A- not applicable.

SOURCE: Office of Technology Assessment, 1993, based on data from U.S. Department of Health and Human Services, Public Health Services,

Centers for Disease Control and Prevention, 1993.

the upward trend in their prices (190). The costs between 1986 and 1992, a rate significantly

of the regimen for uncomplicated TB described in higher than inflation during these years.

table 5-1 rose an average over 9 percent per year
Delivery of

Treatment for

Tuberculosis 6

espite the high potential for cure with current anti-TB

treatment regimens, actual achievement of such cure in

practice is far less certain. The multidrug and long-term

nature of current treatment make the attainment of cure

an exercise in perseverance. As described in chapter 5, treatment

in uncomplicated cases typically involves taking 3 to 4 different

drugs together on a daily, twice-weekly, or thrice-weekly

schedule continuously for 6 months or morel

Furthermore, some of the drugs cause unpleasant side effects

or toxic reactions, so treatment also involves regular medical

monitoring and substitution of different drugs, if necessary, in

order to minimize adverse effects. Even though symptoms

usually abate early in treatment and infectiousness may be

quickly reduced, regular and complete administration of anti-TB

drugs is necessary for eventual cure, prevention of relapse, and

avoidance of drug-resistant disease. An adequate course of

treatment for drug-sensitive TB is generally an arduous task,

requiring a continual effort on the part of both patients and health

care workers over a long, uninterrupted period of time.

In a broader sense, the achievement of cure with current

treatment also depends on the quality and availability of local

treatment services-Complete case reporting, rapid and accurate

diagnosis, appropriate prescription and provision of treatment,

sustained followup of each case, and education of health

professionals and patients concerning the disease and its

treatment. Although efforts combining all of these activities are

needed to control the spread of TB, methods of treatment

1 In more complicated cases, such as those with resistance te two or more drugs,

treatment involves taking at least 4 different drugs a day for 12 to 24 months, or even

longer, in addition to more extensive medical care in a hospital or long-term care facility.

81
82 I The Continuing Challenge of Tuberculosis

delivery and followup that foster close supervision and support of each patient are particularly

important in the prevention and control of multidrugresistant TB (MDR-TB).

Various social problems, such as hopelessness, substance abuse, and poverty, increase the

difficulty of assuring that patients receive regular

and continuous treatment for TB in many areas of

the United States. For some patients, access to

other health services and social assistance, such

as treatment for substance abuse, provision of

stable housing, or mental health services, may

play a critical role in their ability to make use of

available TB treatment services and to adjust to a

long-term treatment schedule (83).

Patients with active TB who do not receive an

adequate course of treatment face the prospect of

a progressively deteriorating condition and a

substantial risk of dying from the disease within

a short period of time. Moreover, for the patient

family, coworkers, and community, consequences

of treatment failure include the risk of further

spread of tuberculous infection to others, producing more cases of active TB and MDR-TB.

Although drug-resistant tuberculous infection can

be transmitted from person to person, virtually all

strains of drug-resistant bacilli initially develop

from erratic or inappropriate treatment in individuals with drug-susceptible TB. Furthermore, coinfection with the human immunodeficiency virus

(HIV) shortens the time between tuberculous

infection and active TB, further heightening the

medical and public health significance of treatment failure.

Since the recent upturn in TB case rates, health

officials have begun reexamining various strategies for improving the delivery of care for TB

patients and for reducing the probability of

treatment failure. Recent increases in MDR-TB

cases, as in New York City (107), indicate that the

inadequacy and ineffectiveness of current treatment delivery services are relevant issues for

Federal and State policy makers to examine.

This chapter summarizes available data indicating the magnitude of the problem of treatment

failure, and then briefly reviews the literature

concerning factors involved in treatment failure.

The final section summarizes various types of

treatment delivery strategies that have been proposed to augment current services.

MAGNITUDE OF THE PROBLEM

Outcome data based on samples of U.S. TB

case reports suggest that approximately 75 percent of U.S. patients being treated for TB

complete treatment within a 12-month period and

that 80 percent take their medication on a

continuous basis (136). These aggregate data are

derived from annual program management reports submitted on a voluntary basis to the

Centers for Disease Control and Prevention

(CDC) by some State and local TB programs,

separately from the mandatory “Report of a

Verified Case of Tuberculosis” (RVCT) surveillance system (see chapter 3). Beginning in 1993,

the RVCT system will be expanded to include

reporting of data on treatment completion and

outcome in individual cases (363).

Before 1985, these data were reported as the

percentage of patients completing 12 continuous

months of treatment within a 24-month period.

Since 1985, the reporting criteria have been

changed (reflecting the use of shorter treatment

regimens) to completion of 6 continuous months

of treatment within a 12-month period. Before

this change in reporting criteria the average

percentage of patients completing treatment rose

steadily from 69 percent in 1970 to 89 percent in

1985 (333a). At the same time, the sample size

increased from 24 reporting areas in 1970 to 79

areas in 1985. Whether a real increase in the

average completion rate during this period occurred is not known. Increased ascertainment of

data could account for the change. Since 1985, the

average rate of completion has changed little,

varying between 74 and 78 percent, while the

number of reporting areas increased from 82 to 93

(333a).
Chapter 6-Delivery of Treatment for Tuberculosis | 83

As of 1991, 93 reporting areas (including

States, counties, and cities) were included in this

database, corresponding to about three-quarters

of all cases reported that year. No information is

available from the remaining one-quarter of cases

not reported in this system; to the extent that areas

with poor reporting capabilities may also have

deficiencies in other TB control services, the

reported data may underestimate the average U.S.

rate of treatment failure, Even if the data were

complete, however, a single national average rate

of treatment completion reveals only limited

information about the nature of the problem,

because of the wide variation in completion rates

among programs and regions. For example, in the

late 1980s, cities such as Chicago, New York, and

the District of Columbia reported completion

rates ranging from 54 to 60 percent, while Dallas,

San Francisco, and El Paso reported rates above

94 percent. Outcome data for patients in Los

Angeles were not reported at all, and are not

reflected in the national average data (31). The

specific reasons for these differences have not yet

been determined. According to the National TB

Action Plan, CDC plans to evaluate and compare

TB control programs with the highest and lowest

rates of treatment completion rates, in order to

identify aspects of service delivery that contribute

to successful outcomes of treatment (363).

Additional information about the extent of the

problem in different populations or regions is

available from various published reports on

groups of patients undergoing treatment for TB.

For example, in a multicenter clinical trial conducted by the Public Health Service (PHS) in 22

TB clinics around the country enrolling a total of

1,451 patients, only 61 percent of patients on a

6-month regimen and 51 percent of patients on a

9-month regimen completed their treatment for

TB. Patients participating in this trial were treated

under actual program conditions in effect in their

local area; in general, treatment was selfadministered (not directly supervised by program

staff), although some incentives and educational

interventions were offered (62).

In another paper, 80 TB patients treated between 1978 and 1982 in a hospital-based general

outpatient clinic were compared with 104 patients

treated between 1982 and 1987 in a hospitalbased outpatient clinic specializing in TB treatment (385). The latter was designed specifically

to improve followup of each case and maximize

patients’ abilities to stay on treatment.2 In this

setting, only 12 percent of patients completed

treatment in the general outpatient clinic, whereas

86 percent of patients in the specialized clinic

completed treatment.

The most widely cited report of treatment

failure describes a group of 224 consecutive

patients with TB admitted to Harlem Hospital in

New York City during the first 9 months of 1988

(45). Of the 178 patients who were discharged

while still on treatment, 89 percent were lost to

followup service and did not complete their

prescribed regimens. Forty-eight of these patients

were later readmitted to the hospital with active

TB; 40 were later discharged while still on

treatment again; at least 35 of these patients were

again lost to followup. Patients in this group who

were homeless or alcoholic were significantly

less likely than the other patients to complete

treatment in the outpatient setting. Although the

report states that patients discharged from the

hospital were given an appointment for followup

care at the hospital’s chest clinic, no other details

of their management at discharge or at that clinic

were given.

At present, there are no national data on rates

of cure, failure, or relapse among TB patients,

since there has been no system for collecting and

reporting such data to CDC. Some local programs

may collect such data, but do not generally make

the data available. Annual reports published by

the New York City Department of Health and the

z For example, they used nurse specialists to follow each patients’ progress, offering combination drug preparations, and provided money

for public transportation to the clinic.
84 I The Continuing Challenge of Tuberculosis

City of Chicago Department of Health, include

detailed information on the epidemiology of TB

in New York City and Chicago, respectively, but

no data on outcome of treatment (56,57). As of

1993, CDC’S expanded RCVT system will reportedly include such data.

FACTORS INVOLVED IN

TREATMENT OUTCOME

The medical and public health literature contains ample recognition of the difficulty of

achieving successful outcomes in patients with

TB using available long-term treatment regimens.

Some experts noted the problem as early as the

1950s when outpatient treatment using anti-TB

drugs first became available (105,266). Analysis

of the underlying causes appears uneven, however, with greater emphasis on patients’ behavioral and social characteristics and much less on

factors relating to the delivery of treatment

services (43,53,92, 124,3 17,326). The terms commonly used in the literature to refer to treatment

failure-noncompliance or nonadherence—

reflect a primary focus on the patient’s willingness to follow treatment instructions, generally

without specific consideration of whether such

treatment is actually available, feasible, appropriate, or affordable. With a few recent exceptions,

(cited below) there have been no critical assessments of TB control programs themselves regarding the provision of adequate resources, expertise,

and coordination for effective treatment delivery

available. Similarly, little systematic information

exists on successful TB control programs responsible for high rates of treatment completion.

Nevertheless, greater examination of past experience with TB control and the broader service

delivery issues will be needed to fully address the

problem of how to reduce rates of TB in the future

and, particularly, to avoid further generation of

MDR-TB. The issue of treatment failure has

immediate repercussions for patients with active

TB and their communities. It is most likely to be

the focus of future efforts to control the disease.

In particular, the ability of a program to effectively supervise treatment such as in directly

observed treatment (DOT) may depend, in part,

on the quality of its overall management and

organization (46).

Because of inadequacies in the information

base, it is not feasible in this chapter to review all

the relevant issues regarding treatment failure in

the same detail or to capture all of their important

specifics. However, it is possible to make some

preliminary comments about the nature of the

problem and about potential causes of treatment

failure, if only to provide a general framework for

subsequent study. Discussed below are a number

of overlapping and interrelated issues relevant to

treatment outcome, grouped into the following

general categories: availability and quality of TB

control services; prescription of optimal treatment regimens; and personal behavioral characteristics influencing completion of treatment. The

relative importance of each of the factors in the

overall problem cannot be assessed at present

with the available data.

Provision of TB Control Services

All States delegate overall responsibility for

controlling the spread of TB and other communiable diseases to State and local health agencies,

most of which, in turn, contract with local

hospitals and clinics to provide TB services.

Statutes enacted by State legislatures provide

both mandatory and discretionary authorities

concerning the conduct of TB control in each

State. Although the specific terms of these

authorities vary among States, common elements

include the ability to order medical examination

of individuals suspected of having active TB, to

deliver treatment, and, if necessary, use a range of

public health powers to impose such treatment or

to detain and isolate infectious individuals. A

recent analysis of State TB laws concluded that

the majority of such statutes are antiquated and

may be incompatible with current standards of

constitutional law and public health. Such laws
Chapter 6–Delivery of Treatment for Tuberculosis | 85

include many of those concerning the way in

which health officials determine whether an

individual poses a significant risk to the public’s

health, whether the individual has a right to a fair

hearing, and whether health officials should be

required to try less restrictive measures before

imposing more restrictive ones in order to impose

compulsory treatment (124). In general, these

statutes focus on specifying the circumstances in

which health officials can compel an infectious

individual to receive treatment, rather than specifying the public health requirements and objectives of a publicly funded TB control system.

There is little systematic information on how

State and local programs have carried out their

statutory authorities regarding TB control in

recent years. Preliminary results of a recent CDC

survey of TB control laws and regulations (conducted independently of the one cited above)

indicate that State programs differ in basic

approaches to TB control. CDC’S survey found

variations in services designed to assure that

patients are treated until cured and in services for

monitoring treatment (such as hospital discharge

planning) (336). CDC is currently drafting recommendations that States can use in improving their

TB control laws and regulations, in an effort to

enhance the quality and uniformity of TB control

services across the country,

Although States have broad public health

powers to order treatment and detention, if

deemed necessary, for patients with active TB,

they are not legally required to assure that patients

are treated until cured. Communicable disease

statutes generally limit the scope of that authority

to the point of ensuring that patients are rendered

noninfectious (which may well be temporary if

treatment is not continued until completion) (9).

Nevertheless, completion of treatment is one of

the primary goals of TB control, despite the

absence of a specific legal responsibility for it. In

practice, health departments and TB control

programs are responsible for a variety of TB

services (some of which are uniquely public

health activities), although not all programs

provide all of these services listed below:

surveillance (maintaining registries of clinical

information concerning cases and suspected

cases and conducting contact investigations to

locate additional cases);

containm ent (screening for tuberculous infection, diagnosis and treatment of active disease,

and preventive treatment);

purchasing supplies of anti-TB drugs;

education (professional, public, and patientoriented);

laboratory services for diagnosis and drug

susceptibility testing;

medical consultation for primary care providers

treating TB patients; and

followup services (e.g., supervising treatment

delivery, including rapid detection and response to evidence of treatment interruption or

failure), and coordinating social assistance,

substance abuse treatment, or housing services

for patients (92).

It is widely held, though infrequently documented, that public health services in the United

States have generally not kept pace with health

problems in recent years, resulting in part from

dwindling resources, lack of expertise, and outdated technologies (12,146). Similarly, serious

problems in TB control programs have been

noted, including a decline in public funding, lack

of access to outpatient TB treatment services and

supportive services (such as substance abuse

treatment, social assistance, mental health care,

and stable housing), and problems maintaining

follow up of patients entreatment (45,46,83,90,240).

In addition, numerous aspects of clinic management that present practical obstacles to care (such

as long waiting times, an inhospitable environment for personal care, and lack of flexible

service hours, etc.) have been discussed (92).

Thus far, the critiques reporting serious problems have focused on New York City’s TB

services; detailed accounts of such services else-
86 I The Continuing Challenge of Tuberculosis

where are absent from the literature, even though

similar types of problems are believed to exist in

other areas, both urban and rural. CDC’S two

recent major initiatives, the 1989 Strategic Plan

for the Elimination of TB and the 1992 National

Action Plan to Combat MDR-TB (see chapter 7)

were aimed, in part, at correcting common

deficiencies in State and local TB control services

(in addition to refocusing and reinvigorating

Federal involvement in TB control). The extent to

which States have addressed the issues locally, by

adopting their own plans to control TB and by

supporting high-quality services, are not well

documented. 3

Medical Care Practices

Practicing physicians play a direct role in the

outcome of treatment for TB patients in several

ways, the most obvious of which is the prescription of an optimal regimen of anti-TB drugs.

Related to this is the ability to diagnose the

disease promptly and accurately, and to report and

record susceptibility testing results. Patients’

immunosuppression (due to HIV or other conditions) increase the practical difficulties physicians face in diagnosing TB (see chapter 5).

Closure of many of the specialized facilities for

treating TB in the 1960s and 1970s has gradually

shifted the job of TB diagnosis and treatment to

primary care physicians, many of whom, even in

high TB prevalence areas, are unaccustomed to

seeing patients with active TB or MDR-TB. As a

result, physicians may be less likely to suspect

TB, to diagnose it quickly, and to prescribe the

most efficacious treatment regimens (or to refer to

others with greater expertise) (241). Practical

limitations of confirmatory testing to verify the

diagnosis may add to these difficulties (92). A

critical mistake physicians can make is to add a

single drug at a time to a failing regimen; patients

treated this way have been found to develop drug

resistance sequentially to each additional agent

(116,153,366).

A 1983 survey of patients who developed TB

again after a course of treatment documented

prescribing errors by physicians in the failure of

previous treatment. The survey, including 800

patients reported as having recurrent TB disease

in 23 health jurisdictions nationwide, found that

many of the patients were prescribed inadequate

or inappropriate treatment with regard to choice

of drugs, dosage, and/or duration for their original

episode of TB. In addition, the survey found

physicians in private practice were more likely to

make these mistakes than physicians in other

types of practices (such as health departments)

(173).

Additional data on the extent and nature of

prescribing errors in TB treatment recently became available from a CDC-sponsored survey of

1,772 physicians in public and private practice,

including both generalists and specialists (318).

Using a mailed questionnaire, the survey was

assigned to determine the extent of physician

awareness of CDC and American Thoracic Society guidelines on recommended treatment regimens and the extent that physicians would

prescribe efficacious treatment regimens as specified in those guidelines. preliminary results of the

survey suggested that only about 58 percent of the

physicians, when asked how they would treat a

hypothetical patient with active TB, specified one

of the recommended regimens. Specialists or

those with fewer years in practice were more

likely than generalists or those with more years in

practice to describe a recommended regimen.

Another way in which physicians can influence

the outcome of treatment is by assuming at least

partial responsibility for ensuring that patients

take the prescribed treatment continuously and

completely (155,265,266). In certain areas, responsibility for monitoring patients on treatment

is shared with, or completely delegated to, staff

3 ~Ou@ Sbte ~p~s and~~g applications, CDC Collects some of MS informatio~ and reports it in its quarterly publication for public

health departments, TB Notes, but has not published it for general review.)
Chapter 6-Delivery of Treatment for Tuberculosis | 87

from the local TB control program-nurse case

managers or outreach workers (92). In other areas,

there may be no standard procedure in place to

follow patients’ progress with treatment, a carryover from the privatization of TB care that

followed the closure of sanatoria and most

specialized TB clinics in the 1960s and 1970s and

their incorporation into general medical practice

(153).

Patient Behavior

In cases where an optimal combination of

anti-TB drugs is prescribed, available, and feasible for the patient to take for the entire period of

time, success of treatment ultimately hinges on

patients taking their medication according to

schedule. In practice, this also requires that the

patient regularly submit sputum samples (so that

progress with treatment can be measured) and that

the patient regularly picks up medication supplies

and keeps to a schedule of appointments with the

health care provider responsible for delivering

and monitoring the treatment. Aside from the

small proportion of patients who refuse treatment

under any circumstances or who are mentally or

psychologically unable to follow a course of

treatment, the bulk of the available evidence

suggests that most patients would complete

treatment if it were feasible to do so or if

encouraged to do so through progressively more

stringent measures (43, 149), as allowed by law to

protect the public health.

The medical literature pertaining to patients’

willingness and ability to follow an entire course

of TB treatment dates back to the 1950s, when it

was noted that many hospitalized patients who

were given their TB medication at the bedside

still did not actually take it and that only about

half of patients on outpatient treatment took their

medication (266,269). Since then, the issue of

patient noncompliance or nonadherence, as it is

generally referred to, has been extensively reviewed, most notably over the years by Sbarbaro

and in a recent comprehensive review by Sumartojo (266,317). These and other reviews of the

role of patient behavior in the success of TB

treatment suggest that the relevant context for

such behavior encompasses factors both within

and beyond a patient’s control.

In some cases, a variety of social, economic,

and cultural factors, such as homelessness, substance abuse, financial barriers to medical care or

general poverty in general, and unfamiliarity with

or distrust of Western medical care, may be very

relevant to patients’ behavior toward TB treatment (95,263,317). In other cases, none of the

above may apply. Etkind and colleagues cite

examples of a physician at a local teaching

hospital in Massachusetts who would not complete his own treatment regimen and of a working

corporate executive who had active TB for 4 years

and developed MDR-TB as a result of erratic

drug-taking (94). One expert noted that the

majority of newly diagnosed cases of TB occur

among ‘‘just plain folks” i.e., individuals with no

apparent social or behavioral characteristic(s) that

would suggest that he or she is likely to take the

medication emetically or not at all (149).

Not surprisingly, researchers have been unable

to identify a set of patient characteristics that

would permit reliable predictions of patients who

will complete treatment with little or no encouragement and those who will fail treatment even

with extraordinary amounts of assistance (317).

To some extent, this naturally complex behavior

may be difficult to simplify to a set of predictive

traits. Given the nature of the treatment regimen,

it may be reasonable to assume that many, if not

most, patients could encounter difficulties staying

the course, but that those with major problems,

such as hopelessness or mental illness, would be

more likely to fail treatment without special

assistance or residential care (94,271). The most

difficult practical issue in this regard concerns the

majority of patients without such major problems

whose behavior toward the treatment regimen

cannot be reliably predicted.
88 I The Continuing Challenge of Tuberculosis

AVAILABLE STRATEGIES FOR

IMPROVING TREATMENT DELlVERY

As discussed above, the outcome of TB treatment may be determined by a number of interrelated factors concerning the organization and

quality of services, the prescription of an optimal

regimen, and the behavior of patients. Accordingly, strategies to improve the chances of cure

following treatment may need to involve several

types of changes in treatment delivery. Although

these changes can be guided by Federal recommendations such as those developed by CDC’S

Advisory Council for the Elimination of Tuberculosis), the actual decisions about the nature and

extent of such changes in treatment delivery will

be made by State and local health officials, based

in part on available resources and expertise, social

and cultural characteristics of the patient population, and available medical services.

Current methods of treatment delivery in the

United States can be characterized as heterogeneous, encompassing self-administered (unsupervised) treatment, various degrees of supervision,

and even involuntary commitment with compulsory treatment. During the past several decades,

self-administered treatment has generally been

the norm. Treatment is delivered in many different types of sites, including general outpatient

clinics, chest clinics, correctional facilities, private medical practices, hospitals, and long-term

care facilities (92).

A number of strategies for improving treatment

delivery are currently being considered and debated among health officials, community groups,

and policy makers. Many of these are already

being used to some extent in some areas. These

strategies include:

greater use of combination medications, such

as RifamateTM (INH and RIF) or a three-drug

combination, RifaterTM (INH, RIF, and PZA),

which is expected to be commercially available

in the United States in 1993.

greater use of intermittent regimens, rather than

daily regimens, which make direct observation

of treatment feasible on a wider scale.

greater use of DOT, either in a treatment

facility or in the community, conducted by

health care workers or outreach workers.

greater attention to followup of each case, by

public health nurses or outreach workers,

involving planning for continuation of treatment and referral to other health and social

services after patient discharge such as treatment for substance abuse, HIV treatment,

stable housing, mental health services.

use of incentives, as appropriate, including

provision of money, bus tokens, food, or

individually determined ‘ ‘gifts’ to encourage

sustained participation in treatment.

administrative changes in clinic operations,

such as reduced waiting times, appointment

reminders, followup of missed appointments,

weekend hours.

use of residential or long-term treatment facilities, as necessary.

improved professional training for TB diagnosis and treatment.

educational programs for patients and the

community at large.

An adequate public health approach for improving the delivery of TB treatment would likely

involve some or all of these strategies, and

perhaps others as well, depending on local needs

and conditions. In the long run, the ability of TB

control programs to implement these strategies

will depend on consistent funding provided by the

State or Federal Government and the quality of

each program’s organization, management, and

expertise. Inevitably in some areas, strategies

designed to assist patients in completing TB

treatment will also address problems such as

acquired immunodeficiency virus (AIDS), substance abuse, homelessness, and mental illness.

A central issue in improving outcomes of TB

treatment concerns the degree to which supervision by HCWS is necessary to bring about higher
Chapter 6-Delivery of Treatment for Tuberculosis | 89

rates of treatment completion. Much of the recent

policy debate about TB control at national and

local levels has focused on this issue. Although

supervised treatment was recommended by experts long ago, and has been used extensively in

other countries for many years, it has been used to

only a limited extent in the United States (193,

266,273). CDC estimated that in 1991, approximately 17 percent of TB patients (approximately

4,400) were receiving treatment under direct

observation. Two-thirds of this was paid for by

CDC cooperative agreement funds employing

213 outreach workers (370). In 1991, $8.5 million

was awarded through 46 TB cooperative agreements to 34 States, the District of Columbia,

Puerto Rico, Guam, and nine major U.S. cities. In

New York City, approximately 500 patients are

currently receiving directly observed treatment

regimens, and this number is expected to double

by the end of 1993 (130). Only three States’

statutes (Maine, Michigan, and Minnesota) explicitly provide for DOT as a routine service

(124).

CDC defines DOT as observation of the patient

by a health care provider or another responsible

person (who has frequent contact with the patient,

such as family members, social workers, or

clergy) as the patient ingests anti-TB medications

(366). Some programs limit DOT to health care

facilities, which require that the patient visit the

facility 2 or 3 times a week. In other areas,

workers go out into the community, meeting

patients at their residence or at another site (366).

DOT can rarely be offered by private physicians

without assistance from the local health department because private practices generally do not

employ staff to perform this function (43).

Although simple in concept, DOT is a laborintensive effort in practice, requiring skill, diligence, and perseverance on the part of outreach

workers (43,266). Furthermore, in some populations, its effectiveness may depend on the simultaneous use of other interventions, such as provision of methadone treatment and on the use of

field workers familiar with the practical issues of

working with individuals with AIDS and those

who use intravenous drugs (68).

Expert groups have recently recommended

more widespread use of DOT for most patients

with TB, particularly those with resistance to one

or more of the first-line drugs (157,366). CDC

recommended that all patients be considered for

DOT, but that local decisions regarding the

expanded use of DOT should be based on

completion rates for each area. A report by the

United Hospital Fund, which focused on TB

control issues in New York City, went further by

recommending mandatory DOT for all patients;

this would remain in effect until there was

convincing evidence mounted in each case showing treatment was longer needed (83).

Critics argue that requiring all patients’ treatment be directly observed is ‘‘wasteful, inefficient, and gratuitously annoying’ and “undercuts the legitimate desire to individualize treatment

and to use the least restrictive and intrusive public

health interventions” (9). Moreover, it is argued

that other interventions, such as effective discharge planning and provision of stable housing,

can also increase completion rates without DOT,

although close followup of patients’ progress

would be needed to judge when DOT would

become necessary (9). Others hold that universal,

mandatory DOT would be a violation of individual liberty and would create undue burden on

those who can complete treatment without it;

accordingly, it is argued, DOT should be imposed

only after an administrative or judicial hearing in

each case to determine whether the patient has not

taken treatment or is at high risk of taking

treatment erratically or not at all (83).

Several programs have described high completion rates among patients treated under direct

observation (92). In Denver, where DOT has been

used for many years for patients on intermittent

regimens, more than 90 percent of patients

complete treatment (61). Even higher rates were

reported in South Carolina, where the health

department routinely uses a variety of strategies,

including DOT (and even court-ordered DOT,
90 I The Continuing Challenge of Tuberculosis

when necessary) (354). There are also several

examples in the literature on programs in which

patients who have previously failed treatment

were successfully treated under direct observation (187,272). Recent data on results of DOT in

Mississippi suggests that TB case rates leveled

off and then, after DOT was expanded to include

over 90 percent of cases on treatment, began to

decline (139). Some populations may be difficult

to reach even through DOT: a recent report cited

data indicating that among individuals using

crack cocaine, DOT alone was not particularly

successful in increasing treatment completion

rates (349),

While these descriptive studies suggest that

DOT may work under certain circumstances and

not in others, the effectiveness of DOT compared

with other strategies or among broader populations has not yet been examined in prospective,

controlled studies. The cost-effectiveness of DOT

compared with other strategies is similarly unknown. Comparisons between the cost of treating

a patient under DOT versus the cost of treating a

patient with MDR-TB are not relevant for public

policy discussions since not all patients treated

without DOT develop MDR-TB and not all

patients on DOT are assured of cure (157). A

more complete assessment of costs and outcomes

is needed to generate useful information.

In general, improvement in delivery of TB

treatment will require the availability of several

different treatment strategies that can be applied

according to local needs and customs, levels of

community involvement, and amounts of public

health resources. As a public health strategy,

unsupervised treatment appears to be an inadequate approach to control TB and to prevent

MDR-TB, even though some patients may succeed without supervision. More active involvement by public health workers in each patient’s

course of treatment would appear necessary in

many areas, along with improved educational

efforts for physicians concerning the prescription

of optimal TB treatment. The adoption of a

comprehensive system of services and support

may be a valuable objective for many programs.

As described by Sumarjo, such a comprehensive system would include: teams of HCWS

responsible for continuity of care, careful case

management and followup, clinical TB services

that are accessible and acceptable to patients,

social assistance provided to patients who need it,

and supervision of treatment (317). Ongoing

evaluation of effectiveness of treatment will be

needed to make judgments about long-term changes

in the delivery of TB treatment.
Federal

P

rimary responsibility for designing

tuberculosis (TB) control services in

rests not with Federal officials, but

health departments and local health

Involvement in

I

Tuberculosis

Control

and Research 7

and carrying out

the United States

with State public

authorities. Governed by State laws that specify overall responsibilities regarding

TB and the use of public health powers intended to prevent

further transmission of the disease (124), State public health

departments provide and coordinate a range of services. To

varying degrees, these services generally include: surveillance;

laboratory services, treatment, and followup; contact investigation; education; and consultation (93).

Private health care providers and a variety of organized groups

(e.g., patient advocacy groups, public and professional groups,

voluntary organizations, and community-based organizations)

are also closely involved in these activities. In practice,

individual TB control programs differ substantially from place to

place, according to available resources, quality of the program

management, available expertise, local prevalence of the disease,

and characteristics of the affected population.

In the United States, the Federal Government is responsible for

developing a national plan to control TB and for assisting in

various ways to implement it. Although the Federal Government

has long held responsibilities in regard to TB control (see box

7-A), the resurgence of TB has recently prompted Federal

agencies and departments to expand their involvement, particularly in guidance and oversight of prevention and treatment

activities, support of research and development, and assuring the

availability of anti-TB drugs. In addition, the increasing size of w

the patient population has implications for reimbursement of TB

services through government-sponsored health insurance programs like Medicaid and Medicare.

91
92 I The Continuing Challenge of Tuberculosis

Box 7-A—The History of Tuberculosis Prevention and Control

Within the U.S. Public Health Service

From the late 1800s to the 1940s, the primary method of tuberculosis (TB) control was the isolation of

infected individuals in special sanatoriums until death or until the disease went into remission. In the early part

of this century, TB control was largely a voluntary grass-roots movement at the State and local level. Local health

departments set up TB programs at the urging of the Society for the Prevention of Tuberculosis, which had been

established in 1904. With the advent of antibiotics in the 1940s, effective treatment for TB became possible. The

U.S. Public Health Service’s (PHS) Bureau of State Services became involved in the evaluation of

anti-tuberculosis drugs such as streptomycin, para-amino salicyclic acid, and isoniazid both in the United States

and Europe. During the 1940s and 1950s, TB treatment still involved along stay in a sanatorium with additional

treatment and lifelong followup after discharge.

In 1944 Congress passed the Public Health Service Act, which established the Division of Tuberculsosis

Control within PHS and authorized grants to States for tuberculosis control. By the end of World War II, PHS

had organized TB support teams available to population centers with more than 100,000 residents to augment the

supply of x-ray and case finding staff. By 1953, these teams had examined about 20 million people in 20 cities.

Better living conditions and the availability of drugs to treat TB led to a decrease in the numberof new cases found

by the support teams. This decrease along with rising costs and growingconcearn about exposure tox-rays led PHS

to discontinue the program.

As it became obvious by the 1960s that long-term isolation of patients with active disease was not necessary

to protect the patient and the community, PHS began to recommend that States close their sanatoriums and treat

patients mainly on an outpatient basis. Although this change represented significant potential savings to State and

local governments, the closing of sanatoriums also placed new demands on local health departments to conduct

followup of TB patients. In the early 1960s, health department case registures carried 75,000 to 100,OOOTB patients

requiring outpatient followup services. In addition, health departments also had to identify, test, and possibly treat

an average of five individuals that each case of active TB may have infected. These new demands on local health

departments necessitated assistance from PHS.

In 1959, TB experts met in Harriman, New York to take stock of the Nation’s TB control efforts and to

develop standards for evaluating control programs. This meeting came to be known as the Arden House

This chapter focuses on the current involve- current initiatives and programs concerning TB

ment of the Federal Government in public health and the approximate funding allocated for them.

efforts to control TB, research and development

of new technologies for diagnosis and treatment

of TB, regulation of TB treatment interventions,

health services research, and reimbursement for

TB services. The discussion is based mainly on

information obtained by the Office of Technology

Assessment (OTA) from each agency, institute,

or organization. OTA received information that

contained varying degrees of detail and synthesis

regarding each group’s involvement in TB -

related work. Rather than attempting to provide a

detailed account or evaluation of all Federal

activities directly or indirectly related to TB, the

discussion that follows highlights the major

The discussion provides recent spending information for the few agencies able to distinguish TB

money from other funds.

PUBLIC HEALTH ACTIVITIES

The Centers for Disease Control and

Prevention

The lead agency for TB control operations

within the Federal Government is the Centers for

Disease Control and Prevention (CDC). In fiscal

year 1993 CDC’S budget for TB control activities

totaled approximately $79 million: $34.3 million

in project grants to State and local health departments in support of prevention and control
Chapter 7–Federal Involvement in Tuberculosis Control and Research! 93

Conference. The group recommended eradication of TB mainly through drug treatment. A set of 11 secondary

recommendations focused on making treatment feasible and efficient, led to the current approach to TB prevention

and control-to treat active disease in order to cure the patient and prevent further spread of infection in order

to prevent the development of active disease.

On November 1, 1960, the Tuberculosis Branch of the PHS’s Bureau of State Services was organizationally

transferred to the then Communicable Disease Center (CDC), In 1960, the Branch also initiated Federal TB project

grants to State and local governments in response to the Surgeon General’s Task Force on Tuberculosis. Funding

for these grants reached a peak of $20 million in 1968. In addition to providing funds, the CDC’S TB missions

have been to provide national leadership in the development and implementation of effective strategies to interrupt

the transmission of TB and ultimately eliminate the disease. CDC has established policies and guidelines for TB

control programs in conjunction with American Thoracic Society. A important function of CDC has been to gather

data on the disease to define the overall tuberculosis problem and examine more specific issues. CDC has provided

consultative visits by headquarters staff to local programs and in some areas direct long-term assignments of CDC

staff have been made to assist in program implementation. In addition, the agency provides training courses for

TB workers.

During the late 1960s, categorical TB project grants were phased out in favor of General Public Health

Formula Grants under section 314(d)of the Public Health Service Act (Ch. 373,58 Stat. 682). Because these new

grants did not require that State and local governments use any of the funds for TB control, many health

departments redistributed the funds to other purposes.

Uniform nationwide reporting of active TB cases to CDC began in 1953. For the next three decades, the

United States saw a decline in active TB cases, from 84,304 reported in 1953 to a low of 22,255 cases in 1984.

After 1985, however, the number of new cases began to increase again to 26,673 in 1992. Despite the overall

increasing morbidity, in much of the country, TB had retreated into well-defined segments of the population (see

chapter 3). Against this background and as a result of the occurrence of outbreaks of drug-resistant TB, CDC

coordinated the 1988 ‘‘Strategic Plan for the Elimination of Tuberculosis in the United States’ and the 1992

‘‘National Action Plan to Combat Multidrug-Resistant Tuberculosis” described in chapter 7.

SOURCE: C. Bozzi, Assistant to the Director for Tuberculosis Coordination, Division of TB EliminationCenters for Disease

Control and Prevention Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA, personal

communication 1993.

services (including directly observed therapy 330). Table 7-1 gives a breakdown of CDC TB

(DOT) and educational activities); $39.2 million

in emergency funds appropriated separately by

Congress for TB control programs in six States

and seven cities most heavily affected by TB; and

$5.2 million for TB program operations at CDC,

In addition to the $79 million designated for TB,

$25.4 million designated for human immunodeficiency virus (HIV) activities were used for

HIV-related TB activities (e.g., investigation of

MDR-TB outbreaks and related issues; expansion

of screening and prevention demonstration projects in drug treatment centers, correctional facilities, and other sites; and expansion of demonstration projects for the treatment and prevention of

TB in HIV-infected or at-risk populations) (255,

spending in fiscal year 1993 according to the use

to which the funds are put.

The total expenditure for fiscal year 1993

greatly exceeded previous years’ budgets (see

figure 7-l). For fiscal year 1994, the President

requested that Congress appropriate $129 million

for TB control at the U.S. Department of Health

and Human Services (U.S. DHHS); the $50

million increase over 1993 is intended to support

State programs in directly observed therapy and

screening in high-risk populations, and to improve TB diagnosis, surveillance, prevention, and

education (332).

The American Lung Association (ALA), a

voluntary, national organization originally founded
94 I The Continuing Challenge of Tuberculosis

Table 7-I —U.S. Centers for Disease Control and Prevention Spending for

Tuberculosis by Function, Fiscal Year 1993

Dollars Percent

($ millions) of budget

Community-based control programs (screening, treatment, prevention,

infection control)

Outreach and service linkage (implementation of directly observed therapy)

Research and demonstration

Surveillance, epidemiology and data systems

Laboratory services

Public education and information

Professional competence assurance (training for service providers,

physicians, researchers, and laboratory personnel)

Leadership and administration (technical assistance to improve

management of State and locai TB control programs)

Community protection/regulatory programs

Total

$36. 9

36,7

9.8

7.0

4.8

4.4

2.2

2.2

NA

$104.0

350/0

35

9

7

5

4

2

2

NA

100?40’

NA - not available.

a Coment percentages do not add up to 100 percent due to rounding error.

SOURCE: Office of Technology Assessment, 1993, based on data from C. Bozzi, Assistant to the Director for

Tuberculosis Coordination, Division of Tuberculosis Elimination, Pubiic Health Service, Centers for Disease Controi

and Prevention, U.S. Department of Health and Human Services, Atlanta, GA, personal communication, Juiy 9, 1993.

in 1904 to coordinate public and private TB

control campaigns (262), recently recommended

that CDC’S budget for TB control be increased to

$380 million in fiscal year 1994, stating that

additional funds are needed to support DOT,

training and educational activities, surveillance

and epidemiologic studies, and evaluation of

current programs (244).

ALA also recommended that continued funding to the States through CDC’S project grants be

contingent on the adoption of an adequate State

TB elimination plan (244). Other experts have

suggested additional uses for CDC’S TB funds,

including direct support of clinical services (as in

New York City chest clinics of the 1970s) and the

facilities in which they are housed, regional

‘‘centers of excellence’ specializing in the care

of patients with TB, long-term care facilities and

subsidized housing for TB patients, and bulk

purchasing of anti-TB drugs and infection control

supplies (130).

The CDC’S Division of TB Elimination had its

organizational beginnings in the 1940s. Box 7-A

gives a history of U.S. Public Health Service

(PHS) involvement in TB control. Federal TB

activities and funding were drastically scaled

back in the late 1960s as TB was perceived to be

under control, but were restarted in the early

1980s (240). In the mid- 1980s, following indications that TB was no longer in decline and that a

resurgence in cases was likely, CDC developed a

comprehensive plan for TB control, entitled “A

Strategic Plan for the Elimination of ‘Tuberculosis

in the United States. The plan was adopted in

1988, endorsed by then U.S. DHHS Secretary

Louis Sullivan, and set as a national goal the

elimination of TB by the year 2010 (i.e., reducing

its incidence to less than one in a million).
—. .

Chapter 7–Federal Involvement in Tuberculosis Control and Research | 95

Figure 7-l—Tuberculosis Funding, U.S. Centers for Disease Control and Prevention,

Fiscal Years 1960-93

120

c

1960 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 9293

a Fiscaly years 1972 through 1982 categorical grants ceased. Funds to States were in block grants nOt specific fOr TB.

b Fiscal year 1992 includes $26 million in HIV funds used for HIV-related TB activities.

c Flscal year 1993 icludes $25 million in HIV funds used for HIV-related TB actiVities.

SOURCE: Office of Technology Assessment, 1993, based on data from the Department of Health and Human

Services, Public Health Service, Centers for Disease Control and Prevention.

The plan also set a target of 3.5 cases per

100,000 population by the year 2000 as an interim

goal. To achieve this, the plan emphasized three

concurrent efforts: more intensive use of existing

prevention and control methods; the development

and evaluation of new diagnostic, treatment, and

prevention technologies; and the rapid transfer of

knowledge, skills, and new technologies into

clinical and public health practice (270,367).

Shortly thereafter, CDC, together with the

American Thoracic Society and representatives

from 22 national organizations, coordinated the

National Tuberculosis Training Initiative, an

educational effort geared toward medical and

allied health professionals. The initiative’s purpose was to make medical and public health

professionals aware of the Strategic Plan, to

improve the quality of care for individuals with

tuberculous infection and active disease, and to

improve medical education regarding TB (239).

Through this effort, U.S. DHHS published the

‘‘Core Curriculum on Tuberculosis,” summarizing current information on TB and TB control

(378).

In 1992, following the recent worsening of the

problem as indicated by the series of MDR-TB

outbreaks, CDC released another national plan

designed to complement and enhance the Strategic Plan: the “National Action Plan to Combat

Multidrug-Resistant Tuberculosis” (363). The

Action Plan was developed by a task force

assembled by CDC, composed of representatives

from a number of Federal agencies, and consultants from various other public health groups. The

task force’s main focus was to define ways of

intervening rapidly to prevent further transmission and generation of drug-resistant TB, as part

of its ongoing efforts to control TB in general.

The Action Plan identified a series of objectives

in TB control and laid out a detailed plan of

implementation involving an array of Government agencies and professional organizations

with ongoing responsibilities in TB control and

research. In general, the Action Plan defined a

process to bring the current outbreaks under
96 I The Continuing Challenge of Tuberculosis

Box 7-B—A Summary of the U.S. Centers for Disease Control and

Prevention’s Muitidrug-Resistant Tuberculosis Action Plan

In response to the emergence of MDR-TB, a Federal task force was convened in December 1991 to develop

a national action plan to combat the problem. The plan identifies a number of objectives to be undertaken at the

national level. The objectives [as described by CDC staff in a recent article] are summarized [here]

Epidemiology and Surveillance-To better define the magnitude and nature of MDR-TB, national

surveillance will be expanded to capture information on the incidence of drug-resesiatant TB. Epidemiologic studies

will be used to identify where MDR-TB is being spread, what activities are associated with increases or decree

in transmission, and which preventive strategies are effective in community and in institutional settings. The

impact of HIV infection on recent trends in TB disease and infection, including MDR-TB, will be assessed.

Laboratory Diagnosis-To improve the rapidity, sensitivity, and reliability of diagnostic methods for

MDR-TB, widespread changes and improvements need to be implemented in clinical and public health

laboratories. These changes include the use of the most sensitive and rapid laboratory diagnostic methods

available, including the use of a primary susceptibility test panel of five chugs (INH, RIP, PZA, etharnbutol, and

streptomycin). New equipment, training courses, and information systems will be used in laboratories to achieve

these objectives.

Patient Management-Activities need to be implemented to prevent patients with drug-susceptible TB from

developing drug-resistant disease and to manage patients optimally who have developed drug-resistant disease. To

achieve these goals, effective initial anti-tuberculosis therapy regimens and implementation of DOT [directly

observed treatment] for all TB patients who would benefit from it regardless of their ability to pay for these services,

will be promoted. Options for the long-tam hospitalization of drug-resistant TB patients, when needed, will be

explored. Efforts to facilitate access to diagnosis and treatment will be directed to those at high risk for both TB

and nonadherence to therapy, such as persons who are homeless, mobile populations of migrant farm workers,

refugees and immigrants from areas with a high prevalence of TB, and persons with substance abuse problems.

Screening and Preventive Therapy—To distinguish persons who are infected or at risk of developing

MDR-TB to help prevent them from developing clinically active TB, widespread dissemination and

control, to prevent new ones, and to resume a single year, CDC supplied OTA with its

progress toward elimination of TB (see box 7-B

summarizing key points of the MDR Action Plan).

CDC estimates that full implementation of

those parts of the Action Plan for which it has

responsibility would require $380 million in

annual spending (1993 dollars) above the $104

million spent in fiscal year 1993. Estimates from

other agencies are not available, but CDC has

begun collecting such information following

OTA’S queries.

In an effort to help OTA assess CDC’S priorities in implementing its part of the Action Plan

should Congress not fully fund the Action Plan in

estimates of how it would allocate funding

increases of $50 million, $95 million, and the full

$380 million above fiscal year 1993 levels. CDC

gave these funding breakdowns according to the

same categories presented in table 7-1. CDC’S

projections indicate that for these three potential

funding levels, the proportion of funds allocated

to each spending category would be essentially

the same as that for actual fiscal year 1993

funding; partial or full funding would not change

CDC’S relative priorities among these funding

categories (38). No information on priorities within

each spending category was available to OTA1

1 CDC has also identiled 215 individual steps necessmy to implement the Action Pla~ assigning each a priority score of “1“ (highest

priority), “2”, or “3” (lowest priority) (369). The vast majority of implantation steps were given a priority of “1“ (76 percent) with most

of the rest (23 percent) given the middle score of “2.” Although these priorities underscore the sense of urgeney of the Federal interagency

group that prepared the Action PlarL they do not indicate how CDC and other agencies would proceed if funding did not permit full

implementation of all steps identifkd as high priority.
Chapter 7–Federal Involvement in Tuberculosis Control and Research! 97

implementation of recently published guidelines on management of persons exposed to MDR-TB will be

promoted. Screening and preventive therapy (directly observed when necessary) among populations at risk for

both TB and nonadherence to therapy will be implemented.

Infection and Outbreak Control-Given the circumstances of recent MDR-TB outbreaks in hospital and

correctional institutions, the risk of transmission of MDR-TB to patients, workers, and others in institutional

settings needs to be minimized. Implementation of current guidelines for reducing this risk is of the highest

priority. Adequate screening and monitoring for TB infection among workers in settings where there is a

substantial risk of TB transmission will be ensured.

Outbreaks represent a challenge to public health authorities in controlling TB. Various officials and

organizations will collaborate to enhance the control of outbreaks of MDR-TB.

Program Evaluation—TB control programs need to be evaluated for effectiveness in managing patients and

preventing the development of MDR-TB. Local epidemiologic data will be used for assessing the adequacy of

the TB control programs.

Information Dissemination, Training, and Education-To disseminate information about MDR-~ and

its prevention and control, high-risk populations, such as persons working in drug treatment centers, homeless

shelters, HIV clinics, and correctional and other institutions with close living quarters, and their clients; refugees;

and immigrants will be identified to be educated about TB. A system for the professional education of those

involved in the prevention, control, diagnosis, and treatment of TB will be developed.

Research—Research is needed to identify better methods to combat MDR-TB. Increased knowledge of the

basic genetics and biology of M. tuberculosis is necessary to understanding better the pathogenesis, immune

response, and mechanisms of drug resistance of TB, so that improved diagnostic assays, drugs, and vaccines can

be developed. A research subcommittee of the Public Health Service’s National MDR-TB Task Force was

recently formed to coordinate current and future TB research efforts among participating Federal agencies.

SOURCE: Excerpt from M.E. Villarino, L.J. Geiter, and P.M. Simone, “Multi-DrugResistant Tuberculosis Challenge to Public

Health efforts to Control Tuberculosis,” Public Health Reports 107(6):623-624, 1992.

As part of its current TB control efforts, the conducted a risk assessment on the use of

CDC has also encouraged the formation of State personal respiratory protection in preventing

and local TB elimination advisory committees.

By the end of 1992, such committees have been

formed in 28 areas resulting in TB elimination

plans for 10 States and 4 cities (370).

In the past several years, the National Institute

for Occupational Safety and Health (NIOSH), an

agency within CDC, has conducted studies on

occupational risks from respiratory exposures to

TB, including health hazard evaluations in hospitals, health clinics, correctional facilities, laboratories, drug treatment centers, homeless shelters,

and other sites. Also planned is surveillance for

TB in workers; development of methods for

detecting and measuring airborne particles containing tubercle bacilli; and evaluation of compliance with standard infection control guidelines in

occupational settings (34,368). NIOSH recently

transmission of TB in health care facilities (371)

(see chapter 4). It has also recently begun

additional research on the effectiveness of infection control interventions, including ventilation

systems, ultraviolet light, and respirator efficiency (24).

Occupational Health and Safety

Administration

The U.S. Department of Labor’s Occupational

Health and Safety Administration (OHSA) has

regulatory and enforcement responsibilities for

workplace health and safety. OHSA’s recent

TB-related activities include the issuance of

guidelines to compliance safety and health officers on conducting inspections following a worker’s
98 I The Continuing Challenge of Tuberculosis

complaint of TB exposure in the workplace,

outreach and training for labor, industry, academia, and professional groups, and 20 workplace

inspections in response to employee complaints.

OSHA is also a lead agency in implementing

several steps in the National Action Plan to

Combat MDR-TB (108). OSHA’S budget for

TB-specific activities was approximately $330,000

in fiscal year 1992 and $339,000 in fiscal year

1993 (36).

U.S. Departments of Justice and State

Because Federal law bars immigration of

individuals with communicable diseases, including active TB, while they are infectious (8 USC

1182, 1224, 1226), the U.S. Departments of

Justice and State also play roles in TB control.

Consular officers in U.S. embassies abroad require applicants for immigration visas to undergo

chest x-rays and sputum smears (if the chest x-ray

is abnormal). Those found to have active TB can

usually proceed to the United States once treatment has rendered them noninfectious. At the port

of entry, the U.S. Department of Justice’s Immigration and Naturalization Service (INS) notifies

a CDC quarantine officer who in turn informs

State or local health officials in the area the

immigrant plans to reside. Consular officers in

U.S. embassies abroad can require medical examinations of applicants for non immigrant visas as

well.

The INS funds detention facilities for individuals found to be in the United States illegally while

they await immigration hearings or deportation.

At nine of the facilities that the INS runs itself,2

the PHS Office of Refugee Health provides

tuberculin skin tests upon inmates’ arrivals with

followup diagnosis, treatment of active and latent

cases, and notification of relevant State and local

health departments for those released in the

United States (181). As of July 1, 1993, there were

5,658 persons under INS detention its own and

contract facilities (47).

U.S. Department of Veterans Affairs

Through its nationwide system of hospitals,

nursing homes, and outpatient clinics, the U.S.

Department of Veterans Affairs (U.S. DVA) is

responsible for a broad range of TB control

services for veterans and their families. In general, the issues faced by these facilities regarding

treatment and prevention of TB and the VA’s

responses to them parallel those outside the VA.

A recent survey found patients with drugsusceptible or drug-resistant TB, some of whom

are also HIV-infected, in each of the four U.S.

DVA regions of the country (258). In 1992, a

cluster of MDR-TB cases was found at one VA

medical center, which led to a review by infection

control officials of current infection control

practices and compliance with existing U.S. DVA

guidelines and CDC recommendations for health

care facilities (259).

The U.S. DVA reorganized its longstanding

infection control program in 1990 under the

direction of its Central Office Medical Service,

which then issued revised hospital-based infection control guidelines based on recommendations from a number of expert groups. The

Medical Service conducts annual infection control surveys, organizes an advisory group on

infection control matters within the U.S. DVA,

and participates in CDC’S national task force on

MDR-TB (257). It also coordinates with State

health departments in providing TB treatment

services, reporting of cases of TB, investigating

contacts of cases, and other activities (379). There

is no separate budget within the U.S. DVA for TB

activities.

2 Some illegal immigrants are detained in facilities run by State governments, lod governments, or private firms under contract for the

INS. Information on TB services provided to these detainees was not available.
Chapter 7–Federal Involvement in Tuberculosis Control and Research 99

Indian Health Service

The Indian Health Service (IHS) works with

State and local health departments to coordinate

TB control services for American Indians and

Alaska Natives (AI/AN). These services are

delivered either through IHS facilities or State

health departments. No IHS funds are designated

specifically for TB services on a regular basis;

however, IHS does provide TB services for

special situations as needed (161).

In 1991, 345 cases of TB in individuals

self-identified as AI/AN across 33 States were

reported to CDC; 86 percent of these cases

occurred in children under the age of 5. At least

one cluster of TB cases has recently been reported

among AI/AN populations—among the Choctaw

tribe in Mississippi. In that case, Choctaw representatives requested and received a one-time

appropriation of $165,000 from the IHS to

upgrade their TB control program. Since 1992,

the Mississippi Board of Choctaw has assumed

responsibility for developing and implementing

its own TB control plan, although the State health

department still supplies technical assistance to

the tribe (161).

Federal Bureau of Prisons

The Health Services Division of the Federal

Bureau of Prisons sets policy concerning TB

control within Federal prisons nationwide. As of

June 1993, this agency was responsible for just

over 78,000 inmates in 71 institutions as well as

another 6,000 individuals in less restrictive community-based facilities (186). There is no specific

budget for TB services. Beginning in 1990, their

policy specified that each prison must maintain a

TB control program designed to identify infectious cases, isolate them, and begin effective

treatment in accord with CDC guidelines. The

basic components of the plan include: chest x-ray,

medical history, and physical examination of al l

incoming inmates; tuberculin skin testing every 2

years; HIV testing for all inmates suspected or

known to have active TB; reevaluation of all TB

cases at regular intervals; and provisions for all

cases that cannot be treated adequately at a given

prison site (185,346).

Despite these guidelines, however, experts

suggested to OTA that many Federal correctional

facilities may not fully comply with these guidelines due to a lack of resources or for other reasons

(247,323). OTA found no evidence to determine

the extent of compliance with the CDC guidelines

among Federal correctional institutions (4,247).

US. Agency for International Development

Since being foreign-born is a risk factor for TB

in the United States, attempts to control the

disease elsewhere in the world may affect the

extent of TB here. The U.S. Agency for International Development (U.S. AID), charged with

administering the United States’ foreign aid to

less developed countries, supports TB services

and research through several of its health-related

programs. TB-related spending has grown in

recent years and in 1992 included allocations of:

$7 million for bacillus Calmette-Gue'rin (BCG)

vaccination of children through the Child

Survival program;

about $850,000 for TB research and analysis,

including support for the research and development of a rapid, simple test to diagnose TB

appropriate for developing countries; and

about $500,000 for TB control programs.

Spending for TB control activities includes spending for centrally-administered programs as well

as activities carried out by the U.S. Agency for

International Development’s field missions ranging from direct funding of national TB control

programs to funding screening programs carried

out by nongovernmental organizations. The agency

HIV/AIDS programs also provide funding to the

World Health Organization’s Global Program on

AIDS that carries out some TB activities related

to the problem of dual infection with HIV and TB

(196,197).
100 I The Continuing Challenge of Tuberculosis

Health Resources and Services

Administration

The Health Resources and Services Administration (HRSA) is an agency of the Public Health

Service responsible for supporting health services

to disadvantaged and undeserved populations as

well as improving the education, supply, and

distribution of health professionals nationwide.

Much of its activities are carried out in cooperation with State and local health departments and

private organizations. Although the agency has

had no TB-specific budget to-date, the President’s budget for fiscal year 1994 includes a $40

million request for such funds. In addition, many

of its existing programs support TB activities.

HRSA’S Bureau of Primary Health Care (BPHC)

funds 800 clinics and other grantees who provide

primary care including TB screening, diagnostic

follow-up, and DOT for individuals at risk of

contracting the disease. This includes grantees

who receive funding through the Ryan White

Comprehensive AIDS Resources Emergency Act

(Public Law 101-381). BPHC also currently

supports the development of TB educational

materials and conferences for health care providers as well as the participation of its primary care

programs in clinical trials for those dually infected with HIV and TB. HRSA’S Hansen Disease Center in Camille, Louisiana conducts TB

drug development research with funds from the

CDC and the National Institutes of Health (NIH).

In fiscal year 1993, support from CDC and NIH

for work at Carville totaled $450,000 with an

expected $900,000 for fiscal year 1994 (264).

RESEARCH AND DEVELOPMENT

Although most of the current TB-related research and development is conducted with funds

from the NIH, a number of other DHHS offices

are also involved. For example, one of the

functions of the National Vaccine program Office

(NVPO), which reports to the Assistant Secretary

for Health (U.S. DHHS), is to coordinate research

carried out through NIH, CDC, the Food and Drug

Administration (FDA), and through the U.S.

Department of Defense (U.S. DOD), and the

Agency for International Development (U.S.

AID) on the development and evaluation of

vaccines against various diseases (333), including

TB. NVPO designated $1.3 million in fiscal year

1992 to support a number of research proposals

focusing on the development of effective vaccines for the prevention of TB in immunocompetent and immunocompromised individuals (166).

In fiscal year 1993, CDC supported an estimated

$9.8 million in TB research and demonstrations

that included basic scientific inquiry, behavioral

research, new diagnostic tools, infection control,

and clinical research into vaccines and treatment

(38). The FDA maintains its own research program to aid in the development and evaluation of

drugs and other technologies that is charged with

regulating. 3 The Substance Abuse and Mental

Health Services Administration (SAMHSA) supports some research relevant to the delivery of TB

services.

National Institutes of Health

Funding for TB research at NIH has increased

substantially in recent years: it went from approximately $300,000 in fiscal year 1985 to $4.3

million in fiscal year 1991, to $15.3 million in

fiscal year 1992, to $35.9 million in fiscal year

1993 (37,260). The 1992 budget includes $5.5

million designated for HIV research that was

directed to HIV-related TB research; the 1993

budget includes $14.1 million in such HIV money

as well as another $4.8 million in one-time funds

transferred by the NIH director from her discretionary budget (261).4 An additional $10.5 mil3 The FDA’s regulatory responsibilities are described later in this chapter.

q Hrv funding relevant to TB is counted in NIH’s estimates of both its TB funding and its HIV/AIDS Spending.
—

Chapter 7–Federal Involvement in Tuberculosis Control and Research I 101

lion was requested in the President’s proposed

fiscal year 1994 budget for TB research at NIH

(332). NIH’s TB research agenda covers a broad

array of strategies (374):

Basic research on the molecular biology of

tubercle bacilli and immunologic responses to

tuberculous infection considered essential for

the development of improved treatments, vaccines, and diagnostic methods;

Studies on the epidemiology and natural history of TB;

Development of tools to diagnose tuberculous

infection and active disease, and to determine

drug susceptibility;

New treatments for drug-susceptible and drugresistant TB and new delivery methods for

these drugs;

Evaluation of ways to improve patient compliance with treatment;

Clinical trials of preventive treatment in HIVinfected, purified protein derivative-positive

individuals;

Development of new vaccines to prevent TB;

Training of new TB researchers (e.g., in career

development awards) and improvements in

medical education regarding TB;

Educational efforts geared toward health care

workers, patients, and the general public concerning prevention of TB.

In addition, NIH is spending $2.3 million to

convert one of its buildings into a specialized

laboratory facility for researchers to conduct safe

experiments using drug-resistant strains of tubercle bacilli. As part of its requested increase in

fiscal year 1994, NIH (through the National

Institute for Allergy and Infectious Diseases,

(NIAID)) plans to fund one or more “TB

Prevention and Control Research Units, ’ multidisciplinary research centers with expertise and

activities in epidemiology, basic science, and

clinical interventions (260).

Seventeen of the relatively independent institutes and centers that constitute IWH report

Aerial view of the NIH campus in Bethesda, Maryland.

Seventeen of the institutes and centers that constitute

NIH support TB-related research and development,

although the bulk of this work is funded by the National

Institute for Allergy and Infectious Disease.

ongoing TB research or training; NIAID receives

the bulk of NIH’s budget for TB (57 percent in

fiscal year 1993) (376). Among the other 16

institutes and centers involved in TB research and

training, those with the largest efforts are the

National Center for Research Resources (NCRR),

the National Heart, Lung, and Blood Institute

(NHLBI), the National Institute for Environmental Health Sciences, the National Institute on

Drug Abuse (NIDA), the National Institute of

Mental Health (NIMH), the National Center for

Nursing Research (NCNR), and the National

Institute for General Medical Sciences (NIGMS)

(137,167,228,288,314,372,375)).

NIAID participated in the development of TB

research strategies for the PHS National Action

Plan. The agency estimates that funding for just

those Action Plan activities that fall within

NIAID’s purview would cost $45.6 million in

fiscal year 1994, $20.6 million above NIAID’s

estimated fiscal year 1993 spending for TB and

$10.1 million more than the President’s requested

increase in TB funding for fiscal year 1994 for all

of NIH. In spring 1993, an NIH Executive

Committee on Tuberculosis Research identified

and prioritized new TB research opportunities for
102 I The Continuing Challenge of Tuberculosis

all of NIH; complete funding of this research

agenda would cost of $102 million above fiscal

year 1993 funding.5

REGULATION OF TECHNOLOGIES

In its role as regulator of medical drugs and

devices, the FDA is responsible for ensuring the

safety and effectiveness of the drugs, devices, and

diagnostic agents to prevent, detect, and treat TB

including BCG and other vaccines, and tuberculin

skin tests. Although the agency has no budget

specifically for TB-related activities, the FDA’s

role in TB control in recent years has focused on:

alleviating the shortage of some anti-TB drugs;

expediting the approval process for new drugs

(e.g., by evaluating their effectiveness with

surrogate measures such as early conversion to

a negative sputum smear instead of cure rates

following the full course of treatment.)

developing guidelines for assessing the safety

and efficacy of new diagnostic devices for rapid

detection of TB (e.g. tests using polymerase

chain reaction (PCR) technology) as well as

devices used to help prevent the spread of M.tb.

(e.g. germicidal lamps).

Prompted by reports in early 1991 of shortages

of some anti-TB drugs and their ingredients, the

FDA established a TB task force to examine

factors contributing to the problem and to find

ways of reestablishing stable supplies. For an

interim period, a limited supply of streptomycin

(SM) and para-aminosalicylic acid (PAS) was

made available through CDC under an investigational new drug agreement for patients with

MDR-TB. The FDA is currently working with

pharmaceutical manufacturers to resolve problems in the manufacture and sale of anti-TB drugs

in the United States and is now attempting to

monitor supplies. The agency is also working

with companies to encourage the development of

implantable forms of anti-TB drugs and combination formulations (121). As mentioned earlier in

this chapter, the FDA’s regulatory role is complemented by a research program coordinated with

the CDC and NIH to aid in the development and

evaluation of new diagnostic tools, therapies, and

vaccines (226).

HEALTH SERVICES RESEARCH

The U.S. DHH's Agency for Health Care

Policy and Research (AHCPR) shares responsibility for funding research on the effectiveness,

appropriateness, and cost of TB health care

services and their delivery with CDC and some

institutes at NIH. Although most of AHCPR’s

work is conducted through extramural research

grants, it also conducts intramural research and

facilitates the development, periodic review, and

updating of clinical practice guidelines by panels

of experts from outside the Federal government.

The agency has had several activities to-date

related to TB:

Supporting the development of guidelines that

will include recommendations on screening

and prophylactic therapy for TB among HIVinfected people (32);

Sponsoring educational workshops, such as a

seminar for State judges on HIV/AIDS and TB

to help them in their adjudication of cases that

involve these diseases. Future workshops may

be conducted for State legislators, other elected

officials, and their staff (221,222);

Funding ongoing research efforts on HIV/

AIDS with an emphasis on studying comorbidities including TB; and

Working with CDC to develop estimates of

costs associated with TB (32).

Research at CDC, especially within its Division of TB Elimination, is increasingly focused

on studies of the costs and effectiveness of

treatment and other programs related to the

control of TB. CDC’S increased efforts in this area

5 This figure includes support for research projects that last for more than 1 year.
Chapter 7–Federal Involvement in Tuberculosis Control and Research! 103

are the result of its expertise in TB and its close

involvement with the State and local health

departments that run TB control programs (191).

NIH’s research portfolio also contains work

relevant to the provision of effective TB health

services, particularly behavioral research focusing on treatment compliance (314,375).

HOUSING

The U.S. Department of Housing and Urban

Development has no programs specifically targeted to tuberculosis or people with tuberculosis.

However, for a short period of time, it did send a

representative to the meetings of the CDCcoordinated National MDR-TB Task Force ( 145).

REIMBURSEMENT FOR TB SERVICES

Disability Programs Administered by the

Social Security Administration

The Social Security Administration administers two programs that provide income to disabled

individuals. The Social Security Disability Insurance (DI) program pays benefits to disabled

individuals who have paid social security taxes

and have achieved “insured status” as defined by

law. Benefits depend on the amount of taxes paid

over a person’s career. DI beneficiaries become

eligible for Medicare after receiving DI payments

for 2 years. The Supplemental Security Income

(SS1) program pays benefits to disabled individuals with low-income. SS1 pays a standard amount

to all beneficiaries and does not require that

individuals have paid social security taxes, SS1

recipients also become eligible for Medicaid.

Both SS1 and DI use the same definition of

disability-”an inability to engage in any substantial gainful activity by reason of any physical

or mental impairment which can be expected to

result in death or which has lasted or can be

expected to last for a continuous period of not less

than 12 months” (42 USC Sec 423(d)(l)(A) for

DI and Sec 1382(a)(3)(A) for SS1). SSA evaluates

disability applications in a sequential process to

establish that the individual is not engaged in

substantial, gainful activity due to an impairment

that is listed among SSA’S medical impairments

or that is at least as severe as a listed impairment.

Applicants who do not meet this criteria can also

be found to be disabled if they are unable, for at

least a year, to do their previous type of work or

other generally available work appropriate for

their ages, educations, and previous work experiences (88,331).

SS1 or DI is not available for most TB patients

without other disabling conditions because of the

statutory requirement that the patient’s impairment last for at least twelve months. As described

in earlier chapters, individuals with active, drugsusceptible TB and no other complicating conditions are usually infectious for only the frost few

weeks of treatment and are likely to be able to

work afterwards. Patients with drug-resistant

strains may be unable to work for a longer period

of time, but their impairment may not necessarily

be terminal or expected to last at least a year.6

The most likely mechanism for a person with

TB to qualify for DI or SS1 is to have an another

disabling condition, especially HIV. A diagnosis

of TB in a person with HIV is considered

disabling in itself according to the listing of

impairments (Amendments to 20 CFR 404 et seq.

published in 58 FR 36055, July 2, 1993). There is

a separate listing for substance abuse that may

also lead to disability benefits for some individuals with active TB (377).

The Role of Federal Health

Insurance Programs

Although TB control falls largely to public

health officials, the provision of medical services

to individuals is a significant component of the

G For those 773 patien~ whose disease does last at least 12 months, the SSA’S listings of medical imp*entS do mirm tit tie~ Pu~o~

infections arc considered disabling (377).
104 I The Continuing Challenge of Tuberculosis

Figure 7-2—Hospital Admissions With a Diagnosis

of Tuberculosis in 16 States’ by Payer, 1990

Self pay/

no charge

1 1%

Other

government

programs

20%0

Little, if any, systematic research has been

done on the role of health insurance in financing

care for TB Patients. However, indirect evidence A

suggests a significant Federal role, especially

through Medicaid. A 1990 breakdown of all

hospital admissions with tuberculosis as a diagnosis, in 16 States, according to payer (figure 7-2)

shows that Medicaid was the single most likely

payer (36 percent) with private health insurance

paying for just 16 percent of admissions.7 In total,

government pays for almost three-quarters of TB

hospitalizations in these States. Although not

representative of the entire country, the States

examined do include several with the highest

burdens of tuberculosis, notably New York and

California (see chapter 3). Figure 7-3 shows that

in New York State, Medicaid actually pays for a

majority of TB hospitalizations (57 percent).

Given that being poor and lacking access to

regular health care are risk factors for TB (see

chapter 3), the prominence of Medicaid, a program for low-income individuals and families, is

not surprising.

What types of TB patients and services are

covered under Medicare and Medicaid, the two

major insurance

The remainder

question.8

MEDICAID9

programs with Federal funding?

of this chapter addresses this

Medicaid is funded jointly by the Federal and

State governments and administered at the State

level. By Federal mandate, it provides health

insurance to certain groups of low-income individuals and families including all aged, blind, and

disabled recipients of SS1, mothers and children

7 As a comparison for hospitalizations for all diagnoses nationwide in 1991, Medicaid was the expected payer only 13 pereent of the time

with private health insurance covering 38 percent of admissions. These data are from the 1991 National Hospital Discharge Survey (175).

6 The Federal Government also provides direct care to qualified veterans and active military persomel in its own health care facilities as

well as health insurance to civilian dependents of active militruy personnel through the Civilian Health and Medical Program of the Uniformed

Services program. These programs may provide or pay for its beneikiaries with tuberculosis, rdthough Medieare and Medicaid represent the

major Federal contribution in health services reimbursement.

g While this report was in its find publishing stages, Congress adopted legislation giving States the option to use Medicaid funds to pay

for TB services only for low-income individuals with either tuberculous infection or active disease who do not otherwise qualify for Medicaid

(Public hW 103-66).
Chapter 7–Federal Involvement in Tuberculosis Control and Research I 105

who receive Aid to Families with Dependent

Children (AFDC), and other categories of poor

women and children. States also have the option

of covering ‘medically needy’ individuals whose

high medical bills, in effect, make them poor or

almost poor.

The Federal Government also requires that all

categorically-eligible Medicaid beneficiaries (AFDC

and SS1 recipients) and some medically needy

beneficiaries receive a minimum set of benefits

that would cover inpatient, outpatient, laboratory,

and other services. States are required to assure

the availability of transportation to and from

medical services and have the option of adding a

variety of supplemental services to the minimum

package. States receive matching Federal funds

for the optional coverage they decide to provide

as part of Medicaid (284,329).

While almost all inpatient, short-stay care

associated with TB for Medicaid-eligible individuals would qualify for Medicaid reimbursement,

concern over the eligibility of some long-term

care and outpatient facilities providing TB services and a desire for flexibility in reimbursing

various types of DOT has led the Health Care

Financing Administration (HCFA), the Federal

agency charged with administering the Federal

Government’s regulation of Medicaid, to issue

three pieces of correspondence to help guide the

States (389).

In July 1992, New York State filed an amendent to their “State Medicaid plan” explicitly

discussing the funding of DOT for Medicaideligible patients, the only State to have made such

a change to its Medicaid program. The amendment establishes three reimbursement rates for

DOT services designed to give flexibility in the

provision and supervision of TB treatment; the

reimbursement rate depends on the setting that

care is provided and the amount of effort necessary to ensure completion of treatment. Reimbursement can include the cost of food vouchers,

transportation tokens, and other incentives given

Figure 7-3-New York State Hospital Admissions

With a Diagnosis of Tuberculosis, by Payer, 1990

Medicaid

57%

Private

health

Insurers

13Y0

Self pay/

no charge

1070

Medicare government

1 1% programs

80/0

SOURCE: Office of Technology Assessment, 1993, based on data

derived from state hospital discharge abstracts covering 100 percent of

acute short-stay hospitals and U.S. Department of Veterans Affairs

hospitals. Data prepared by Codman Research Group, Inc., Lebanon,

New Hampshire.

by health care providers to encourage compliance

(168,282,283,284). As of April 1993, 22 health

care institutions in New York City have agreed to

provide Medicaid-reimbursed DOT with a total

enrollment of approximately 250 patients. The

State expects the first year of the program to cost

Medicaid $5.8 million in combined State and

Federal funds (284,390).

HCFA estimates that $75 million in Medicaid

finds went for the care of patients with tuberculosis in 1991. This estimate comprises $45 million

in Federal funds and $30 million in State funds

(391).

MEDICARE

Medicare provides health insurance to individuals over age 65 who have had the appropriate

taxes deducted from their paychecks during their

careers and to individuals who have received DI

disability benefits for at least 24 months (see

section on disability).l0 Both HIV, which can lead

10 Medic~e ~SO covers individuals receiving dialysis treatment for end-stage reti dkSSe.
106 I The Continuing Challenge of Tuberculosis

to disability, and old age are also risk factors for

TB as discussed in chapter 3. HCFA estimates

that in 1991,$65 million in Medicare funds went

for the treatment of TB (391).

Medicare consists of two types of insurance

coverage. Part A covers short-term hospital stays

after patients pay a deductible for each hospitalization. Hospitals are reimbursed under the diagnosis related group (DRG) system with a set

amount for each hospital stay regardless of

length. The actual reimbursement is based on the

average historical cost of treating all patients with

the same primary diagnosis. Part B covers outpatient services provided under a doctor’s supervision in an office or ambulatory clinic in return for

a monthly premium. Patients also pay an annual

deductible and 20 percent of allowable charges.11

Allowable charges are set by the Federal government.

For TB patients covered by Medicare, inpatient

services provided in short-stay hospital and ambulatory services provided in an office or clinic

under a doctor’s supervision (most care provided

while diagnosing active TB and treating it during

its most acute phases) are almost all likely to be

reimbursable. Most uncertainties about coverage

center around DOT and the provision of care in

specialized facilities. Although Medicare does

contain some limited home health care benefits,

the provision of DOT in the home would not be

among them.

12 Similary, Medicare pays for

limited long-term care and skilled nursing services in certain types of federally approved facilities. To date, neither HCFA nor its regional

contractors, usually private insurance companies

that actually administer Medicare for the Federal

Government, have undertaken any special efforts

concerning Medicare coverage of TB services

(389).

I I A majofi~ of elderly Medicare beneficiaries carry pfivate health insurance designed to provide benefits not covered under Medicare and

to help pay Medicare’s deductibles and copayments (5).

12 Arec~t~~ce of Tectiology Assessment report provides much more detail about current Medicare home health benefits (U.S. Con@ss,

OTAj Home Drug Infusion Therapy Under Medicare, OTA-H-509, Washington DC: U.S. Government Printing Office, May 1992).
Appendix A:

Acknowledgments

OTA wishes to thank The Continuing Challenge of Tuberculosis workshop participants, contractors, and the

individuals and organizations listed below for their assistance over the course of this study. These individuals and

organizations do not necessarily approve, disapprove, or endorse this report. OTA assumes full responsibility for

the report and the accuracy of its content.

Margaret Anderson

Professional Affairs

American Public Health Association

Washington, DC

Bascom Anthony

Division of Bacterial Products

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

John Bass, Jr.

Division of Pulmonary and

Critical Care Medicine

College of Medicine

University of South Alabama

Mobile, AL

Enn Y. Benin

Infectious Disease Service

Montefiore Medical Center

New York, NY

Phil Bierbaum

National Institute for Occupational

Safety and Health

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Cincinnati, OH

Joel A. Block

Department of Internal Medicine

Rush-Presbyterian-St. Luke’s

Medical Center

Rush University

Chicago, IL

Elizabeth Bolyard

Hospital Infections Program

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Lynn Bosco

Agency for Health Care Policy and

Research

U.S. Department of Health and

Human Services

Rockville, MD

c armine Bozzi

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Michael J. Brennan

Laboratory of Mycobacteria

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

107
108 I The Continuing Challenge of Tuberculosis

Don Brown

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Ruth Brown

Medical Technology Assessment

and Policy Research Center

Battelle

Washington, DC

Jacalyn Bryan

Governmental Affairs Committee

Association for Practitioners in

Infection Control

Fairfax Station, VA

Janice E. Burr

lbberculosis Control

Dade County Department of

Health

Miami, FL

Linda A. Chiarello

Infection Control and Occupational

Health Unit, AIDS Institute

Department of Health

State of New York

Albany, NY

Codman Research Group, Inc.

Lebanon, NH

Mitchell Cohen

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

David Cohn

Disease Control Services

Denver Department of Health and

Hospitals

Denver, CO

Frank Collins

Office of Vaccine Research and

Review

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

George W. Comstock

Department of Epidemiology

School of Hygiene& Public

Health

Johns Hopkins University

Baltimore, MD

Arthur Dannenberg, Jr.

Division of Occupational Health

School of Hygiene and Public

Health

Johns Hopkins University

Baltimore, MD

Thomas Daniel

Center for International Health

School of Medicine

Case Western Reserve University

Cleveland, OH

Katherine DeVinny

Division of Clinical Research

National Institute on Drug Abuse

National Institutes of Health

U.S. Department of Health and

Human Services

Rockville, MD

George DiFerdinando, Jr.

Tuberculosis Control and Refugee

Health Programs

Department of Health

State of New York

Albany, NY

Samuel Dooley

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Fran Du Melle

American Lung Association

Washington, DC

Barry Eigen

Office of Disability

Social Security Administration

U.S. Department of Health and

Human Services

Baltimore, MD

John Foulds

Tuberculosis Program

National Institutes of Health

U.S. Department of Health and

Human Services

Bethesda, MD

Thomas R. Frieden

Bureau of llberculosis Control

Department of Health

City of New York

New York, NY

Jeffrey Glassroth

School of Medicine

Northwestern University

Chicago, IL

Marian Goble

National Jewish Center for

Immunology and Respiratory

Medicine

Denver, CO
Mark J. Goldberger

Division of Antiviral Drug

Products

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

Sharon Hansen

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

Robert C. Hastings

Hansen’s Disease Center

Lxmisiana State University

Baton Rouge, LA

Alan Hinman

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Philip Hopewell

Chest Service

San Francisco General Hospital

San Francisco, CA

Robert L. Hotchkiss

Tuberculosis Program

Mississippi Department of Health

Jackson, MS

Michael Iseman

Clinical Mycobacteriology

Service

National Jewish Center for

Immunology and Respiratory

Medicine

Denver, CO

—

Appendix A–Acknowledgments | 109

Robert R. Jacobson

Hansen’s Disease Center

U.S. Department of Health and

Human Services

Carville, LA

Patrick Johannes

Indian Health Service

Health Resources Services

Administration

U.S. Department of Health and

Human Services

Albuquerque, NM

Margarite Johnson

Robert Wood Johnson Foundation

Princeton, NJ

William Jordan, Jr.

National Vaccine Program

U.S. Department of Health and

Human Services

Rockville, MD

Ruth Kasloff

Special Projects

Communications Department

American Lung Association

New York NY

Jim Kelly

Infection Control and Employee

Health

Siskin Hospital

Chattanooga, TN

Ruth Kirschstein

National Institute of General

Medicine

National Institutes of Medicine

U.S. Department of Health and

Human Services

Bethesda, MD

Susan J. Klein

Division of Epidemiology

Department of Health

State of New York

Albany, NY

Arata Kochi

Tuberculosis Programme

World Health Organization

Geneva, Switzerland

John Kuharik

Tuberculosis Program

Chicago Department of Health

Chicago, IL

June Lunney

Acute and Chronic Illness Branch

National Center for Nursing

Research

National Institutes of Health

U.S. Department of Health and

Human Services

Bethesda, MD

Jerry M. Mallick

Museum Specialist

Photographic Archives

National Gallery of Art

Washington, DC

Diane Maple

Media Relations

American Lung Association

Washington, DC

Linda McDonald

Association for Practitioners in

Infection Control

Fairfax Station, VA

Jeffrey Mecaskey

program in TropicaI Disease

Research

Edna McConnell Clark Foundation

New York, NY
110 I The Continuing Challenge of Tuberculosis

Bess Miller

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Dennis Mitchison

Department of Bacteriology

Royal Postgraduate Medical

School

London, England

Robert Moran

National AIDS program Office

U.S. Department of Health and

Human Services

Washington, DC

Sheldon Morris

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

Ed Nardell

State Laboratory Institute

Massachusetts Department of

Public Health

Jamaica Plain, MA

Charles Nolan

Tuberculosis Control program

Seattle-King County Department

of Public Health

Seattle, WA

Richard O’Brien

Tuberculosis Programme

World Health organization

Geneva, Switzerland

Cynthia Palmer

Medical Technology Assessment

and Policy Research Center

Battelle

Washington, DC

Mary Pendergast

Office of the Commissioner

Food and Drug Administration

U.S. Department of Health and

Human Services

Rockville, MD

Gina Pugliese

Infection Control and & Evironmental

Safety

American Hospital Association

Chicago, IL

Lynn Richmond

Montefiore Rikers Island Health

Services

Montefiore Medical Center

The University Hospital for the

Albert Einstein College of

Medicine

New York NY

William Rom

Department of Medicine

Division of Pulmonary and

Critical Care Medicine

New York University Medical

Center

New York NY

Gary A. Roselle

Infectious Diseases

Medical Service-Central Office

U.S. Department of Veteran

Affairs

Cincinnati, OH

Zeda Rosenberg

Office of the Director

National Institute of Allergy and

Infectious Diseases

National Institutes of Health

U.S. Department of Health and

Human Services

Bethesda, MD

John Sbarbaro

Division of General Internal

Medicine

Health Sciences Center

University of Colorado

Denver, CO

John Seggerson

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Teresa Seitz

Division of Surveillance

National Institute for Occupational

Safety and Health

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Cincinnati, OH

Stephen Shaw

Health Care Financing Administration

U.S. Department of Health and

Human Services

New York, NY

John Siegfried

Medical 

Pharmaceutical Manufacturers

Association

Washington, DC
Appendix A–Acknowledgments ! 111

Elaine Sloand

Office of the Director

National Heart Lung, and Blood

Institute

National Institutes of Health

U.S. Department of Health and

Human Services

Bethesda, MD

Peter Small

Howard Hughes Medical Institute

Stanford, CA

Dixie E. Snider, Jr,

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

William Stead

Tuberculosis Program

Arkansas Department of Public

Health

Little Rock, AR

Ellen Stover

Office on AIDS

National Institute of Mental Health

National Institutes of Health

U.S. Department of Health and

Human Services

Rockville, MD

Esther Sumartojo

Division of Tuberculosis

Elimination

National Center for Prevention

Services

Centers for Disease Control and

Prevention

U.S. Department of Health and

Human Services

Atlanta, GA

Bruce Tempest

Internal Medicine

Gallup Indian Medical Center

Indian Health Service

Health Resources and Services

Administration

U.S. Department of Health and

Human Services

Gallup, NM

Kim Marie Thorbum

American Correctional Health

Service Association

Honolulu, HI

Alan I. Trachtenberg

Science Policy and Analysis

Branch

National Institute on Drug Abuse

National Institutes of Health

U.S. Department of Health and

Human Services

Rockville, MD

Laurel Wiegand

Department of Medicine, Pulmonary

Care and Critical Care

Medicine

College of Medicine

Penn State University

Hershey, PA

Diana Weil

Tuberculosis Programme

World Health Organization

Geneva, Switzerland

Rebecca M. Wurtz

Department of Epidemiology

Cook County Hospital

Chicago, IL

Gerald Zelinger

Medicaid Bureau

Health Cam Financing Administration

U.S. Department of Health and

Human Services

Baltimore, MD
Appendix B:

Abbreviations

and

Glossary

Abbreviations

ACET

AFB

AFDC

AHCPR

AI/AN

AIDS

ALA

BCG

BMRC

BPHC

CDC

CMI

DI

DNA

DRG

DTH

DOT

EMB

FDA

GAO

HEPA

HCFA

HCWS

HIV

HRSA

Advisory Council for the Elimination of

Tuberculosis

acid-fast bacilli

Aid to Families with Dependent Children

program

Agency for Health Care Policy and

Research (PHS)

American Indian or Alaskan Native

acquired immunodeficiency syndrome

American Lung Association

bacillus Calmette-Gue'rin (vaccine)

British Medical Research Council

Bureau of Primary Health Care (HRSA)

Centers for Disease Control and

Prevention (PHS)

cell-mediated immunity

Disability Insurance program (SSA)

deoxyribonucleic acid

Diagnosis Related Group system

delayed-type hypersensitivity

directly observed therapy

ethambutol

Food and Drug Administration (PHS)

General Accounting Office (U.S.

Congress)

high efficiency particulator air (filter)

Health Care Financing Administration (-U.S.

DHHS)

health care workers

human immunodeficiency virus

Health Resources and Services

Administration (PHS)

II-Is

INH

INS

IPT

IUATLD

IVDUS

M.avium

M.bovis

MDR-TB

M.tb.

NCNR

NCRR

NHLBI

NIAID

NIDA

NIGMS

NIH

NIMH

NIOSH

NVPO

OSHA

OTA

Indian Health Service (PHS)

isoniazid

Immigration and Naturalization Service

(U.S. Department of Justice)

isoniazid preventive therapy

International Union Against Tuberculosis

and Other Lung Diseases

intravenous drug users

Mycobacterium avium

Mycobacterium bovis

multidrug-resistant tuberculosis

Mycobacten”um tuberculosis

National Center for Nursing Research

National Center for Research Resources

National Heart, Lung, and Blood Institute

National Institute of Allergy and

Infectious Diseases (NH)

National Institute on Drug Abuse (NIH)

National Institute of General Medical

Sciences (ND-I)

National Institutes of Health (PHS)

National Institute of Mental Health (NIH)

National Institute for Occupational Safety

and Health (CDC)

National Vaccine Program Office (U.S.

DHHS)

Occupational Health and Safety

Administration (U.S. Department of Labor)

Office of Technology Assessment (U.S.

Congress)

112
Appendix B–Abbreviations and Glossary I 113

PA PUS

PAS

PCR

PHS

PPD

PZA

R&D

RIF

RVCT

SAMHSA

SM

SSA

SSI

TB

U.S. AID

U.S. DHHS

powered air purification respirators

para-amino salicyclic acid

polymerase chain reaction

Public Health Service (U.S. DHHS)

purified protein derivative

pyrazinamide

research and development

rifampin

‘‘Report of a Verified Case of Tuberculosis” surveillance system (CDC)

Substance Abuse and Mental Health

Services Administration (PHS)

streptomycin

Social Security Administration (U.S. DHHS)

Supplemental Security Income Program

(SSA)

tuberculosis

Agency for International Development

(U.S. International Development Cooperation Agency)

U.S. Department of Health and Human

Services

U.S. Department of Veterans Affairs

ultraviolet light

ultraviolet-B light

ultraviolet-C light

World Health Organization

Terms

Acid -fast bacilli: Organisms that retain certain stains

even after being washed with acid alcohol. Most are

mycobacteria. When seen on a stained smear of

sputum or other clinical specimen, a diagnosis of

tuberculosis should be considered.

Acquired resistance: This term refers to the humanmade condition of patients who are unresponsive to

one or more of the primary drugs used to treat TB

as a result of prior inadequate or erratic treatment.

In the CDC’S classification of drug resistance, this

is referred to as secondary resistance. Compare

Primary resistance, Multidrug-resistant tuberculosis, Secondary resistance, Transmitted resistance.

Active tuberculosis: The latter of the two general

stages in the progression of TB. Individuals with

active TB can be symptomatic and contagiousparticularly if they are untreated or inadequately

treated. Active TB can affect many organs or

tissues; the lungs, however, are the most common

site of infection. The disease can be transmitted

during the active stage by persons expelling airborne particles containing tubercle bacilli through

coughing, singing, speaking, or sneezing. Symptoms vary with the organ or body system involved,

but generally include weakness, fever, chest pain,

coughing, and when a small blood vessel is eroded,

bloody sputum. See Tubercle bacillus, Tuberculosis.

Aid to Families with Dependent Children program:

A program, established by the Social Security Act

of 1935, providing cash payments to needy children

(and their caretakers) who lack support because at

least one parent is dead, disabled, continually

absent from the home, or unemployed, Eligible

families must meet income and resource criteria

specified by the relevant State.

AIDS (acquired immunodeficiency syndrome): A

disease caused by HIV and characterized by a

deficiency of the immune system. The primary

defect in AIDS is an acquired, persistent, quantitative functional depression within the T4 subset of

lymphocytes. This depression often leads to infections caused by microorganisms that usually do not

produce infections in individuals with normal

immunity. HIV infection can be transmitted from

one infected individual to another by means that

include the sharing of a contaminated intravenous

needle and engaging in unprotected sexual intercourse (i.e., intercourse without the use of condoms).

Alveoli: Terminal air sacs in the lung.

Anergy: The inability to mount an immune response

to one or several skin-test antigens as a result of

immunosuppression due to disease (e.g., HIV) or

immunosuppressive drugs. Anergic individuals infected with the TB bacilli may falsely test negative

with the PPD skin test.

Antimicrobial drug: Pharmaceutical agent used to

kill or inhibit the growth of microorganisms in

humans, See First-line drugs, Second-line drugs.

Attenuated live vaccine: A preparation of weakened

bacteria or viruses, fractions thereof, or synthesized

antigens identical or similar to those found in the

disease-causing organisms, that is administered to

produce or increase immunity to a particular

disease. In this report, attenuated live vaccine is

used in reference to BCG vaccine.
114 I The Continuing Challenge of Tuberculosis

BCG (bacillus Calmette-Guerin) vaccine: A family

of related vaccines, originally derived from an

attenuated strain of M.bovis, believed to enhance

the human immune system’s response to infection

and prevent the multiplication and dissemination of

bacilli to various parts of the body. The efficacy of

vaccine is still under debate. CDC recommends its

use in the United States be restricted to selected

high-risk populations among children.

Case rate: This term refers to the number of cases of

active TB diagnosed in a given year per 100,000

population.

Caseous necrosis: The characteristic lesion of TB, it

appears grossly as gray-white areas that resemble

cheese.

Cavitation: The formation of hollow spaces (cavities)

in the lungs.

CD4 cells: See T-lymphocytes.

Centers for Disease Control and Prevention: The

Federal agency, established in 1973 within the

Public Service of then U.S. Department of Health,

Education, and Welfare (now U.S. Department of

Health and Human Services), charged with the

primarily responsibility for providing funding and

other resources, leadership, and coordination to the

Nation’s tuberculosis control and prevention efforts. Prior to 1973, CDC existed as the Communicable Disease Centers.

Compliance: Refers to the completion by patients of

all aspects of the treatment regimen as prescribed by

the medical provider. Other terms, such as “adherence, ’ are sometimes used.

Contact tracing: The procedure of tracing persons

who have been in contact with a patient suffering

from tuberculosis or other infectious diseases, with

the object of discovering the source of infection and

preventing its spread.

Delayed-type hypersensitivity: An immune process

that occurs in response to tuberculous infection that

destroys bacilli-laden inactivated macrophages. An

overabundance of DTH causes most of the tissue

damage characteristic of pulmonary tuberculosis.

Diagnosis: Identification of a disease or condition by

a scientific evaluation of a patient’s physical signs,

symptoms, medical history, laboratory tests, and

procedures.

Directly observed treatment: A complianceenhancing strategy in which each dose of medication is observed by a healthcare worker or other

responsible person. In this report, also referred to as

directly observed therapy.

Disability: In this report, disability refers to the

condition that qualifies certain patients with TB for

benefits administered by programs of the U.S.

Social Security Administration. The agency defines

disability as an inability to engage in any substantial

gainful activity by reason of any physical or mental

impairment which can be expected to result in death

or which has lasted or can be expected to last for a

continuous period of not less than 12 months.

Disability Insurance program: See Social Security

Disability Insurance program.

Disposable particulate respirator: A face mask that

is designed to fit snugly and to filter out particles

under the supervision of a health care worker or

other responsible person.

Droplet nuclei: Microscopic particles (1 to 5 microns

in diameter) produced by coughing, sneezing, or

talking that carry tubercle bacilli and remain

airborne by normal air currents in a room.

Drug-resistant tuberculosis: Tuberculosis caused by

tubercle bacilli that have mutated to render them

unresponsive to anti-TB drugs. Compare Acquired

resistance, Multidrug-resistant tuberculosis, Primary resistance, Secondary resistance, and Transmitted resistance.

Drug-susceptible tuberculosis: Tuberculosis caused

by tubercle bacilli that are sensitive to anti-TB

drugs.

Efficacy: The probability of benefit to individuals in

a defined population from a health care technology

applied for a given health problem under ideal

conditions.

Epidemiology: The scientific study of the distribution

and occurrence of human diseases and health

conditions, and their determinants.

Extrapulmonary tuberculosis: Tuberculosis in any

part of the body other than the lungs, See laryngeal

TB, miliary TB, osteotuberculosis, and TB meningitis.

First-line drugs: The five primary drugs-isoniazid,

rifampin, pyrazinarnide, ethambutol, and streptomycin-used to treat tuberculosis. Current treatment regimens for uncomplicated cases usually

involves taking these drugs in two phases. Compare

Second-line drugs.
Appendix B–Abbreviations and Glossary | 115

Glucocorticoid drug: Pharmaceutical agent used to

suppress the immune system to treat allergic or

inflammatory diseases.

Granuloma: A nodular inflammatory lesion usually

small or granular, firm, persistent, and containing

compact grouped large white blood cells that ingest

microbes.

HEPA (high efficiency particulate air) filter: Specialized filter that is capable of removing nearly all

particles greater than 0.3 microns in diameter. May

be of assistance in environmental control of tuberculosis transmission. Requires expertise in installation and maintenance.

Hepatitis: Diseases characterized primarily by inflammation of the liver. In this report, it refers to the

most serious adverse effect of isoniazid, one of the

drugs commonly used to treat tuberculosis.

High-risk populations: Certain demographic groups

who are at a greater risk than the general U.S. public

to contract a particular disease. In the case of TB,

these groups include individuals who are economically disadvantaged; co-infected with HIV; foreign

born; members of a racial or ethnic minority group;

substance abusers; homeless; migrant farm workers; incarcerated; very young or advanced in age.

Histological: Pertaining to the study of anatomy that

deals with the minute structure, composition, and

function of the tissues; also called microscopical

anatomy.

HIV (human immunodeficiency virus): The pathogen that causes AIDS.

HIV-seronegative: Refers to individuals who produce

a negative reaction to tests that detect HIV antibodies as an indicator of HIV infection.

HIV-seropositive: Refers to individuals who produce

a positive reaction to HIV antibody tests showing

antibodies to HIV indicating infection with HIV.

Immunocompetent: Individuals that are capable of

producing normal or adequate immune responses.

Immunocompromised: A term used to describe

individuals who have a diminished or impaired

immune response as a result of diseases (such as

cancer or AIDS), malnutrition, or prior medical

treatment involving immunosuppressive drugs or

irradiation.

Immunodeficiency: A deficiency of immune response or a disorder characterized by deficiency of

immune response; classified as antibody (B cell),

cellular (T cell), combined deficiency, or pagocytic

dysfunction disorders, Cellular immunodeficiencies are marked by recurrent infections with lowgrade or opportunistic pathogens, by graft-versushost reactions following blood transfusions, and by

severe disease following immunization with live

vaccines.

Immunosuppression: Refers to the suppression of

natural human immune responses by infection as

caused by disease, malnutrition, or prior medical

treatment involving drugs or irradiation.

Immunosuppressive drugs: Pharmaceutical agents

that suppress natural human immune responses to

prevent the rejection of grafts or organ transplants.

Immunotherapy: The treatment of disease by the

administration to the patient of antibody raised in

another individual or another species (passive

immunotherapy) or by immunizing the patient with

antigens appropriate to the disease (active immunotherapy).

Incidence: The frequency of new occurrences of

disease within a defined time interval. The incidence rate is the number of new cases of specified

disease divided by the number of people in a

population over a specified period of time, usually

1 year.

Incident cases: New cases of a disease within a

defined time interval.

INH (isoniazid) preventive therapy: The treatment

of tuberculous infection with the antibacterial drug

isoniazid to prevent progression of tuberculous

infection to active disease.

Laryngeal tuberculosis: Tuberculosis of the larynx.

Latent tuberculosis: See Tuberculous infection.

Lesion: Any abnormal discontinuity of tissue or loss

of function. A wound, injury, or one of the

individual points or patches of a multifocal disease.

Liquefaction: A disease-related process of solid

tissues decomposing into liquid.

Lymphadenitis: See Tuberculous lymphadenitis.

Microphage: A large and versatile immune cell found

in many tissues of the body that has an important

role in host defense mechanisms by ingesting

microbes, including bacteria, viruses, fungi, and

other foreign particles,

Medicaid: A government medical assistance program

that pays for medical expenses for the poor and

certain other classes of uninsured people, estab-
116 I The Continuing Challenge of Tuberculosis

lished by the Title XIX of the Social Security Act

of 1965. Each State administers its own program

Medicaid is funded by both the State and Federal

Governments.

Medicare: A federally administered health insurance

program covering the cost of services for people 65

years of age or older, receiving Social Security

Disability Insurance payments for at least 2 years,

or with end-stage renal disease. Medicare consists

of two separate but coordinated programs—

hospital insurance (Part A) and supplementary

medical insurance (Part B). Health insurance protection is available to qualified persons without

regard to income.

Meningitis: See Tuberculosis meningitis.

Miliary tuberculosis: Tuberculosis of various body

organs and tissues resulting from millet-like (miliary) lesions or life-threatening meningitis that have

been transported through the bloodstream from the

initial site of infection (usually the lungs). See

Active TB, Latent TB, Mycobacterium TB, Tuber-

 bacillus, Tuberculosis, Tuberulous infection.

Multidrug-resistant tuberculosis: Tuberculosis that

occurs in persons who are unresponsive to two or

more of the anti-TB drugs used to treat the disease,

particularly the two most powerful ones—isoniazid

and rifampin. See Acquired resistance, Primary

resistance, Transmitted resistance.

Mycobacterium: The name of the bacterial family that

causes TB and other infectious diseases in humans

and animals. In this report, only three members of

this category are discussed-Mycobacterium aviurn,

Mycobacterium bovis, and Mycobacterium tuberculosis.

Mycobacterium avium: A non-tuberculous mycobacterial

infection that occurs frequently in individuals with

AIDS and can lead to serious complications and

death.

Mycobacterium tuberculosis: The bacteria that causes

tuberculosis in humans. See A4ycobacterium, 11.E

berculosis.

National Action Plan to Combat MDR-TB: In 1992,

following the recent worsening of the TB problem

as indicated by the series of MDR-TB outbreaks, a

national plan was released by CDC to enhance the

Federal Government’s 1988 strategic plan, “National Action Plan to Combat Multidrug-Resistant

~berculosis. The Action Plan identified a detailed plan to control drug-susceptible TB and

MDR-TB implementation involving an array of

Government agencies and professional organizations. See box 7-B for a summary of key points of

the Action Plan.

Orphan drug: A drug product discovered and developed for the treatment of a rare disease or a drug

product not expected to produce enough revenue to

cover its R&D or manufacturing and distribution

costs.

Osteotuberculosis: Tuberculosis of the bone.

Polymerase chain reaction: A laboratory process

through which repeated cycling of the reaction

reproduces a specific region of DNA, yielding

millions of copies from the original. The process

has been adapted for the rapid detection of TB,

although such tests remain expensive and require

significant expertise to use.

Powered air purification respirators: Powered,

halfmask respirators equipped with high-efficiency

particulate filters that are specialized filters capable

of removing nearly all particles from the air. These

devices have been used as environmental control

measure by health care workers to control the

transmission of TB.

Prevalence: In epidemiology, the number of cases of

diseases, infected persons, or persons with disabilities or some other condition, present at a particular

time and in relation to the size of the population.

Also called ‘prevalence rate. ’ Compare Incidence.

Prevalent cases: Total number of cases of a disease

present in a defined population at a particular time.

Prevention: The averting of disease, traditionally

characterized as primary, secondary, and tertiary

prevention. primary prevention aims at avoiding

disease altogether. Secondary prevention strategies

detect disease in its early stages of development,

with the hope of improving outcome. Tertiary

prevention attempts to arrest further deterioration in

individuals who already suffer from a disease.

Primary resistance: This term refers to a naturally

occurring biological phenomenon in patients who

are unresponsive to the common drugs used to treat

the tuberculosis but are not known to have received

prior treatment. Also called transmitted resistance

in this report. In CDC’S classification, primary

resistance also refers to infection by a TB organism

already drug resistant. Compare Acquired resis-
Appendix B–Abbreviations and Glossary | 117

tance, Multidrug-resistant tuberculosis, Secondary

resistance, Transmitted resistance,

Pulmonary tuberculosis: Tuberculosis of the lungs,

the most common form of the disease.

Report of a Verified Case of Tuberculosis: The

individual TB case report sent by State and local

health authorities to CDC that allows uniform

collection and analysis of data on TB cases in the

United States.

Research and development: In this report, research

and development refers to Federal funding of the

activities to detect, prevent, and control the TB

problem in the United States, including basic

scientific inquiry, behavioral research, health services research, development of new or improved

diagnostic tools, infection control, and clinical

research into vaccines and treatment.

Resistance: See Drug-resistant tuberculosis.

Second-line drugs: Drugs used to treat TB when a

patient is unresponsive to treatment with first-line

drugs. The second-line drugs include amikacin,

capreomycin, cycloserine, ethionamide, kanamycin, and p-arninosalicyclic acid. Compare First-line

drugs.

Secondary resistance: See Acquired resistance.

Sensitivity: One measure of the validity (or accuracy)

of a diagnostic or screening test: the percentage of

all those who actually have the condition being

tested who are correctly identified as positive by the

test. Operationally, it is the number of true positive

test results divided by the number of patients that

actually have the disease (true positives divided by

the sum of true positives plus false negatives).

Compare Specificity.

Social Security Disability Insurance program: A

Federal social insurance program for workers who

have contributed to the social security retirement

program and become disabled before retirement

age, Beneficiaries receive monthly cash payments.

Specificity: One measure of the validity (or accuracy)

of a diagnostic or screening test: the percentage of

all those who do not have the condition being tested

who are correctly identified as negative by the test.

Operationally, it is the number of true test negatives

(all those with a negative test result who actually do

not have the condition being tested for) divided by

the sum of true negatives plus false positives (i.e.,

all those who do not have the condition). Compare

Sensitivity.

Sputum smear-positive: Sputum that is positive for

AFB when stained and viewed under a microscope,

Individuals with TB who are sputum smear-positive

for AFB are considered more infectious than those

with smear-negative sputum.

Supplemental Security Income: A Federal income

support program for low-income disabled, aged,

and blind persons. Eligibility for the monthly cash

payments is based on the individual’s current status

without regard to previous work or contributions to

a trust fund. Some States supplement the Federal

benefit.

Surveillance: Constant observation of an area to

determine the level of disease activity. In this

report, surveillance refers to public health activities

that include maintaining registries of clinical information concerning cases and suspected cases and

conducting contact investigations to locate additional cases.

T-lymphocytes: Specialized white blood cells involved in the body’s immune response. Blymphocytes originate in the bone marrow and

when stimulated by an antigen produce circulating

antibodies (Immoral immunity). T-lymphocytes are

produced in the bone marrow and mature in the

thymus gland and engage in a type of defense that

does not depend directly on antibody attack (cellmediated immunity).

Transmitted resistance: This term refers to TB drug

resistance that occurs when a strain of TB already

resistant to one or more anti-TB drugs is transmitted

to a new case (e.g., in institutional settings) and

results in resistance to the same number and types

of drugs as in the source case. Compare Acquired

resistance, Multidrug-resistant tuberculosis, Primary resistance, Secondary resistance.

Tubercle bacillus: A bacillus (bacteria) causing

tuberculosis; usually refers to Mycobacterium tuberculosis, the principal cause of human tuberculosis.

Tuberculin skin test: A method for demonstrating

infection with mycobacterium tuberculosis in which

antigenic material from M.tb. cultures is introduced

into the skin, either intradermally or percutaneously.
118 I The Continuing Challenge of Tuberculosis

Tuberculosis: A treatable infectious disease caused by

some species of Mycobacteria. Individuals can

contract TB when exposed to airborne particles

containing tubercle bacilli through inhalation (i.e.,

coughing, singing, speaking, or sneezing). TB has

two general stages: tuberculous infection (latent

tuberculosis) and active tuberculosis. The first stage

is asymptotic and not contagious to others, whereas

active TB is symptomatic and contagious—

particularly if untreated or inadequately treated. See

Active TB, Latent TB, Mycobacterium TB, Tubercle bacillus, Tuberculous infection. See also Extrapulmonary TB, Pulmonary TB, Laryngeal TB,

Miliary TB, and TB meningitis.

Tuberculosis meningitis: Tuberculosis of the membranes surrounding the brain and spinal cord.

Tuberculous infection: Condition in which living

tubercle bacilli are present in an individual, without

producing clinically active disease. Infected individuals usually have a positive tuberculin skin test,

but not symptoms related to the infection, and are

not infectious. TB infection is necessary to develop

active TB disease. Also known as latent tuberculosis.

Tuberculous lymphadenitis: Tuberculosis of the

lymph nodes.

Ultraviolet radiation: A form of invisible electromagnetic radiation having a shorter wavelength

than that of the violet end of the spectrum and

longer than that of x-rays. In this report, ultraviolet

radiation refers to an infection control method using

ultraviolet light sources to kill bacteria. These lights

can be part of ceiling or wall fixtures or found

within air ducts of recirculating ventilation systems.
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U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Approaches to Improving Adherence to Antituberculosis Therapy, ” Morbidity and Mortality Weekly Report

42:74-75, 81 1993.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, ‘Tuberculosis Prevention in Drug-Treatment Centers and Correctional Facilities—Selected U.S. Sites, 1990-

1991,’ Morbidity and Mortality Weekly Report

42(11 ):210.213, 1993.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Tuberculosis Morbidity-United States,” Morbidity artd Mortality Weekly Report 42(18):363, 1993.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, ‘‘Screening for Tuberculosis and Tuberculous Infection in High-Risk

Populations. Recommendations of the Advisory Committee for Elimination of Tuberculosis , Morbidity and Mortality Weekly Report

39( RR-8): 1-12, 1990.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Prevention and Control of ~berculosis in Facilities Providing

I.mng-Term Care to the Elderly. Recommendations of the Advisory Committee for the Elimination of Tuberculosis,” Morbidity and Mortality Weekly Report 39(RR-1O):7-2O, 1990.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Guidelines for Preventing the Transmission of Tuberculosis in

360.

361.

362.

363.

364.

365.

Health-Care Settings, With Special Focus on

HIV-Related Issues,’ Morbidity and Mortality

Weekly Report 39(R.R-17):1-29, 1990.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “llberculosis Among

Foreign-Born Persons Entering the United

States. Recommendations of the Advisory Council for the Elimination of ‘Ibberculosis, ’ MorbidityandMortaliQ WeeklyReport 39(RR-18):l21, 1990.

U.S. Department of Health and Human Services, Public Health Semice, Centers for Disease

Control and Prevention, “Purified Protein Derivative (PPD)-’lbberculin Anergy and HIV

Infection: Guidelines for Anergy Testing and

Management of Anergic Persons at Risk of

‘lhberculosis,’ Morbidity andMortality Weekly

Report 40(RR-5):27-33, 1991.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Prevention and Control of ‘lhberctdosis in Migrant Farm Workers.

Recommendations of the Advisory Council for

the Elimination of ‘Ihberculosis,” Morbidity

and Mortality Weekly Report 41(RR-1O):1-14,

1992.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, ‘National Action Plan

to Combat Multidrug-Resistant Ihberculosis, ’

Morbidity and Mortality Weekly Report 41(RR11), 1992.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Revised Classification System for HIV Infection and Expanded

Surveillance Case Definition for AIDS Among

Adolescents and Adults, ’ Morbidity and Mortality Weekly Report 41(RR-17):1-19, 1992.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Projections of the

Number of Persons Diagnosed With AIDS and

the Number of Immunosuppressed HIVInfected Persons,” Morbidity and Mortality

Weekly Report 41(RR-18):1-29, 1992.
138 I The Continuing Challenge of Tuberculosis

366.

367.

368.

369.

370.

371.

372.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “Initial Therapy for

lhberculosis in the Era of Multidrug Resistance. Recommendations of the Advisory Council for the Elimination of llberculosis, ’ Morbidi~andMortality Weekly Report 42(RR-7): 1-

8, 1993,

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, “A Strategic Plan for

the Elimination of Tuberculosis in the United

States,” Morbidi~ and Mortali~ Weekly Report 38(S-3):1-25, 1989.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control, Advisory Council for the Elimination

of lhberculosis, minutes, Atlanta, GA, Sept.

24-25, 1992.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, Interagency l_bberculosis Working Groups, “Proposed Steps for

Implementing the National Action Plan to

Combat Multidrug-Resistant Tuberculosis,’ U.S.

Department of Health and Human Services,

unpublished report, Sept. 24, 1992.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, National Center for

Prevention Services, Program Briefing, 1992:

Tuberculosis Elimination, U.S. Department of

Health and Human Services, Atlanta, GA,

unpublished report, Mar. 9, 1993.

U.S. Department of Health and Human Services, Public Health Service, Centers for Disease

Control and Prevention, National Institute for

Occupational Safety and Health, “Recommended Guidelines for Person Respiratory

Protection of Workers in Health-Care Facilities

Potentially Exposed to ‘Ihberculosis,” U.S.

Department of Health and Human Services,

Washington, DC, Sept. 14, 1992.

U.S. Department of Health and Human Services, Public Health Service, National Institutes

of Health, National Center for Nursing Research, “’Ihberculosis: Prevention and Adher373.

374.

375.

376.

377.

378.

379.

ence Interventions, ” No. RFA: NR-93-004,

NIH Guide 22(11), March 19, 1993.

U.S. Department of Health and Human Services, Public Health Service, National Institutes

of Health, National Institute of Allergy and

Infectious Diseases, “Research on ‘Ihberculosis,” paper prepared by the Office of Communications, National Institute of Allergy and

Infectious Diseases, National Institutes of

Health, Public Health Service, U.S. Department

of Health and Human Services, Bethesda, MD,

November 1992.

U.S. Department of Health and Human Services, Public Health Service, National Institutes

of Health, National Institute for Allergy and

Infectious Diseases, “Research Agenda for

llberculosis,’ background monograph prepared by the Office of Communications, National Institute for Allergy and Infectious Diseases, Bethesda, MD, June 1993.

U.S. Department of Health and Human Services, Public Health Service, National Institutes

of Health, National Institute on Drug Abuse,

“The Spread of ‘Ibberculosis Among Drug

Users,” Program Announcement No. PA-93-

44, January 1993.

U.S. Department of Health and Human Services, Public Health Service, National Institutes

of Health, Office of Science Policy and kgislation, table showing NIH budgets for tuberculosis in fiscal years 1991, 1992, and 1993, Feb.

19, 1993.

U.S. Department of Health and Human Services, Social Security Administration, Disability

Evaluation Under Social Security, SSA Publication No. 64-039 (Washington, DC: U.S.

Government Printing Office, May 1992).

U.S. Department of Health and Human Services

and the American Thoracic Society, Core

Curriculum on Tuberculosis, National Tuberculosis Training Initiative, 2nd Edition (Atlanta, GA: U.S. Department of Health and

Human Services, April 1991).

U.S. Department of Veterans Affairs, Veterans

Health Administration, “TB Control Responsibilities of VA Facilities,” VA Directive No,

10-92-063, Washington, DC, June 4, 1992.
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380. Van Scoy, R. E,, and Wilkowske, C. J., “Antituberculous Agents,” Mayo Clinic Proceedings

67:179-187, 1992.

381. Venne~A., “Contact Investigation and Isoniazid

Chemoprophylaxis in New York City, 1979-

1987, ” New York State Journal of Medicine

92(2):185-188, 1992.

382, Villarino, M. E., Geiter, L. J., and Simone, P. M.,

“The Multidrug-Resistant lbberculosis Challenge to Public Health Efforts to Control

Tuberculosis,” Public Health Repofls 107(6):616-

625, 1992.

383, Wadhawan, D., Hira, S,, Hwansa, N., et aI.,

“Preventive llberculosis Chemotherapy Whh

1son&id Among Persons Infected With Human

Immunodeficiency Virus,” (Abstract No. WB

2261 :247) presented at ‘VII International Conference on AIDS,” Florence, Italy, 1991.

384. Welch, D. F., Guruswamy, A. P,, Shaw, C.W,, et

al., ‘ ‘Implications of Multi-Drug Resistant

Tuberculosis for Clinical Laboratories, ” as

cited in J.L. Cox, ‘‘Coalition Reacts to Surge of

Drug-Resistant TB,’ American Society of Microbiology Ne~’s 58: 135-139, 1992.

385. Werhane, M. J., Snukst-TorbecLG., and Schraufnagel, D. E., ‘‘The Tuberculosis Clinic,” Chest

96(4):815-818, 1989.

386. World Health Organization, “Expanded Prograrnme on Immunization Information Systems,” WHO/EPI/GEN/89 (Geneva, Switzerland: World Health Organization, 1989).

387. World Health Organization, “Preventive lhberculosis Chemotherapy Among Persons Infected With Human Immunodeficiency Virus,’

WHO~B/AIDS/90.l (Genva, Switzerland:

World Health Organization, 1990).

388. World Health Organization, “Tuberculosis Prograrnme and Global Programrne on AIDS,”

WHOflB/92.166 (Geneva, Switzerland: World

Health Organization, 1992).

389. Zelinger, G., Medical Advisor, Medicaid Bureau, Health Care Financing Administration,

U.S. Department of Health and Human Services, Baltimore, MD, personal communication,

Mar. 30, 1993.

390. Zelinger, G., Medical Advisor, Medicaid Bureau, Health Care Financing Administration,

U.S. Department of Health and Human Services, Baltimore, MD, personal communication,

Apr. 5, 1993.

391. Zelinger, G., Medical Advisor, Medicaid Bureau, Health Care Financing Administration,

U.S. Department of Health and Human Services, Baltimore, MD, personal communication,

June 25, 1993.
Index

Acid fast bacilli, 8, 70

Active TB

description, 3

diagnosis, 8,70-72

drug-susceptibility determination, 8-9,71-72

immune responses, 31-32

incidence trends, 34

infectiousness, 29

manifestation, 30

positive tuberculin skin tests and, 30

risk factors, 30, 58

treatment, 72-80

Advisory Council for the Elimination of ‘llberculosis,

88

African Americans. See Black Americans

Age factors. See Elderly individuals; Immunocompetent adults; Infants and young children; Race,

ethnicity, age, and sex

Agency for Health Care Policy and Research, 102-103

AHCPR. See Agency for Health Care Policy and

Research

Aid to Families with Dependent Children, 105

AIDS. See also HIV infection

association between TB and AIDS among IVDUS,

42

BCG vaccination and, 65

clinical and radiographic presentation of TB and, 51

clinical course of TB, 32

epidemiologic association with TB, 5-6,4243,48

IPT and, 60

treatment of active TB and, 76

WHO program, 99

ALA. See American Lung Association

Alaska Natives

case rate, 99

child case rate, 38, 99

American Indians. See Native Americans

American Lung Association

DOT recommendation, 19

support for international TB control activities, 21-22

TB control budget recommendations, 93-94

American Thoracic Society

B(X3 vaccination recommendations, 66-67

INH preventive treatment recommendations, 61

National Tuberculosis Training Initiative, 95

treatment regimen guidelines, 86

Americans of Asian or Pacific Islands origin

case rates, 4, 37

child case rate, 38

Am.ikacin, 77

Antimicrobial treatment. See also INH preventive

treatment; specific hugs by nume

infectiousness and, 29

mechanism of action, 74-75

Bacillus Calmette-Gu&in vaccination. See BCG

vaccination

BACECY”, 8,71

BCG vaccination

CDC recommendations, 63

efficacy trials, 8, 64-65

impact on TB incidence, 65-66

mechanisms of action, 63

safety factors, 65

141
142 I The Continuing Challenge of Tuberculosis

Tice strain, 63

U.S. pOfiCy, 8,66-67

WHO recommendations, 7-8,62-63

Bellevue Hospital, NY

infection control measures, 55

Black Americans

case rates, 4, 5, 37

BMRC. See British Medical Research Council

British Medical Research Council

treatment studies, 73, 77, 78

Capreomycin, 10,77

Case rates. See Epidemiology

Casual contact

tuberculous infection and, 3, 28

CDC. See Centers for Disease Control and Prevention

Cell-mediated immunity, 32

Centers for Disease Control and Prevention

Advisory Council for the Elimination of

‘Ihberculosis, 88

AIDS incidence and TB, 42-43

BCG vaccination recommendations, 63,66-67

costs and effectiveness of treatment, 102-103

directly observed treatment, 12, 89

drug costs, 10, 11,20,79-80

drug shortages, 78

failure to implement TB control

recommendations, 2

formation of State and local TB elimination

advisory committees, 97

funding increase allocation, 96

infection control guidelines, 6-7, 52-54

INH preventive treatment, 58,61,62

institutional screening for TB, 58

MDR-TB surveys, 6,4446

National Action Plan to Combat MultidrugResistant llberculosis, 14,22,23,67, 83, 86,

95-97,98

National TB Action Plan, 83

National Tuberculosis Training Initiative, 95

prescribing practices of physicians in private

practice, 86

RV~ surveillance system, 33-34, 82,84

skin testing for health care workers, 50

spending for TB, by function, 94

Strategic Plan for the Elimination of ‘Ibberculosis in

the United States, 12, 86, 94-95

TB control budget, 12, 13, 14,92-94

TB control law survey, 85

treatment regimen guidelines, 86

treatment regimen studies, 73-74

Centers of excellence for patients with TB, 23-24,94

Chest x-rays, 8,20,70

Chicago

Cook County Hospital infection control measures,

56

epidemiology of TB report, 84

Children. See Infants and young children

Cities. See also Chicago; New York City

direct Federal intervention, 18-19

TB case rates, 35-37

Clofazimine, 77

CMI. See Cell-mediated immunity

Completion of treatment

consequences of treatment failure, 82

directly observed treatment and, 89-90

HIV-infected individuals, 76,77

INH preventive treatment, 58-59

MDR-TB and, 77

outcome data, 10, 82-84

patient behavior and, 10-11, 87

Cook County Hospital, Chicago

infection control measures, 56

Core Curriculum on lbberculosis, 95

Correctional institutions. See also Prisoners and

inmates

Federal prison system, 99

MDR-TB outbreaks, 6,41

prevalence of TB, 40

Cough-inducing medical procedures

health care worker exposure and, 50

infectiousness factor, 29, 52

Crack cocaine use

TB and, 41

Culture examination methods of diagnosis, 8,71

Cycloserine, 10,77

Delayed-type hypersensitivity, 32,59-60

Delivery of treatment. See also Completion

of treatment; Treatment of active TB

outcome data, 82-84

social factors, 82, 87

strategies for improvement, 88-90

treatment outcome factors, 84-87

Demographic changes

geographic distribution, 4, 35-37
Index I 143

high-risk populations, 5,40-42

race, ethnicity, age, and sex, 4-5, 37-zIO

shift to narrower populations, 34-35

Developing countries

AIDS impact on TB, 43

IPT use, 58

MDR-TB and, 44

TB control policy option, 22

DI. See Social Security Disability Insurance

Diagnosis of active TB

basis for, 8, 70

chest x-rays, 8, 70

culture examination, 8, 71

delayed diagnosis and MDR-TB outbreaks, 8,71-72

deoxyribonucleic acid method, 9,71

necessity for rapid diagnosis, 8, 70, 72

sputum smear, 8, 70

Directly observed treatment, 12,22, 88-90,93, 105,

106

policy option, 19

Disability insurance, See Social Security Disability

Insurance

DNA. See TB diagnosis and, 9,71

DOT. See Directly observed treatment

Droplet nuclei, 30

Drug shortages, 78

Drug-susceptibility testing, 8-9,71-72

Drug users, See Intravenous drug users

DTH. See Delayed-type hypersensitivity

Elderly individuals

case rate, 4, 40, 41

hepatitis side effect to treatment, 75

Epidemiology

case rates by locality, 4, 35-37

case rates by race, ethnicity, age, and sex, 3740

case rates for high-risk populations, 4042

demographic changes, 4-6,3442

HIV and AIDS, 42-44

incidence trends, 33-34

multidrug-resistant TB, 44-47

resurgence factors, 1, 47-48

Ethambutol, 9,73,75,76,79, 80

Ethionamide, 10,77

Ethnicity. See Race, ethnicity, age, and sex

Etiology of tuberculosis, 27

Extrapulmonary TB

AIDS and, 43

description, 3, 31

HIV infection and, 76

FDA. See Food and Drug Administration

Federal Bureau of Prisons

TB control activities, 12-14,20,99

Federal Government involvement in TB control. See

also specific agencies and programs by name

health services research, 102-103

housing, 103

public health activities, 92-100

regulation of technologies, 15, 102

reimbursement for TB services, 103-106

research and development, 14-15, 100-102

Federal health insurance programs

Medicaid, 15-16,25-26, 104-105

Medicare, 15-16, 106

Fluoroquinolones, 78

Food and Drug Administration

BCG vaccination approval, 63

drug development, 23

drug shortages, 10,78

new drug approval, 78

T’B control activities, 102

Foreign-born individuals. See Immigrants and

refugees

Gender factors. See Race, ethnicity, age, and sex

Gene probes, 71

Geographic distribution

case rates, 35-37

Hansen Disease Center, Carville, LA, 100

HCFA. See Health Care Financing Administration

HCWS. See Health care workers

Health Care Financing Administration

Medicaid regulation, 16, 105

Medicare funding, 106

Health care workers. See aZso Primary care physicians

annual screening, 50

BCG vaccination recommendations, 66

directly observed treatment and, 12, 88-89,90

HIV-infected, 50-51

job-specific infection rates, 50

MDR-TB exposure, 50

MDR-TB infectiousness and, 29

National Tuberculosis Training Initiative and, 95

powered air purification respirators and, 54
144 I The Continuing Challenge of Tuberculosis

risk of tuberculous infection, 3, 29

Health Resources and Services Administration

TB control activities, 14, 100

Hepatitis

drug side effect, 75

INH preventive treatment and, 61-62

High-risk populations, 40=42, See also speczjic groups

by name

Hispanic Americans

case rates, 4-5, 37

child case rate, 38

History of TB, 2-3,27

HIV infection. See also AIDS

active TB, development of, 30

BCG vaccination and, 6344,65,66-67

chest x-rays findings and, 70

clinical course of TB, 27, 32

completion of TB treatment and, 76, 77

DTH and CMI impairment, 32

epidemiologic association with TB, 5-6,4243

extrapulmonary TB and, 31

infectiousness and, 29-30

INH preventive treatment and, 56,58,61

MDR-TB and, 42

nontuberculous mycobacterial infections an~ 70

risk factor for TB, 55

TB manifestation, 32

tuberculin skin testing and, 60

Homeless individuals

case rate, 5,40, 48

IPT for, 58

Hospitals

MDR-TB outbreaks, 6,46,50

Medicare reimbursement, 106

VA hospital infection control guidelines, 98

HRSA. See Health Resources and Services

Administration

IRS. See Indian Health Service

Immigrants and refugees

case rate, 5, 40, 48

child case rate, 39

INS TB scrtxming activities, 98

MDR-TB and, 44

tuberculin skin testing, 60

Immigration and Naturalwa “ tion Service

TB control activities, 14,98

Immune responses

description, 31-32

development of active TB and, 30

Immunocompetent adults

chest x-rays findings of TB, 70

development of active TB, 30

Irnplantable devices for TB treatment, 10,78, 102

Incidence trends, 33-34

Indian Health Service

TB control activities, 14,99

Infants and young children

acquiring active TB after tuberculous infection, 28

BCG vaccination, 8,66

case rates, 5, 38-39, 99

clinical course of TB, 27, 32

diagnosis of active TB, 71

prevalence of TB, 56

treatment of active TB, 75

Infection control

CDC guidelines, 6-7,52-54

combining interventions, 54

MDR-TB outbreaks, 50-52,72

personal protection devices, 54

respiratory isolation, 51, 53

W radiation, 53-54

ventilation systems, 51, 53

veterans hospital guidelines, 98

Infectiousness

concentration of infectious particles in the air, 30

factors, 3

MDR-TB, 29

tuberculous infection, 29

INH. See Isoniazid

INH preventive treatment. See also Isoniazid;

Treatment of active TB

adverse effects, 61-62

completion problems, 58-59

efficacy in TB prevention, 7, 55, 61

policy option, 20

purpose, 61

selective use policy, 56, 58-59

Inmates. See Prisoners and inmates

INS. See Immigration and Naturalization Service

Institutional settings. See aZso Correctional

institutions; Hospitals; Nursing homes

MDR-TB outbreaks, 6,46,50-52

Intravenous drug users

association between TB and AIDS, 42

case rate, 5, 40
Index I 145

HIV infection and, 43

Isoniazid, 9,73-80. See also INH preventive treatment

MDR-TB and, 44

side effects, 7

IVDUS. See Intravenous drug users

Kanarnycin, 10, 77

Koch, Robert, 2, 27

Laryngeal TB, 29,31

Latent TB. See Tbberculous infection

Lmng-term care facilities

TB risk, 40

Lxmisiana

Hansen Disease Center, 100

MDR-TB. See Multidrug-resistant TB

Medicaid

eligibility and benefits for TB patients, 104-105

policy options, 25-26

reimbursement for DOT, 105

.Medicare, 106

Migrant farm workers

case rate, 5, 41-42

Mortality rates

AIDS and, 43

before antibiotic treatment, 72

MDR-TB outbreaks in institutions, 46

Multidrug-resistant TB

categories of resistance, 44

completion of treatment and, 77

correctional institution outbreak, 6, 41

delayed diagnosis and, 71-72

epidemiolo~, 44-47

infectiousness, 29

institutional outbreaks, 6, 41, 46-47, 50-52

intravenous drug use and, 40

risk factors, 72

second-line drugs, 77

transmission, 44, 46-47

treatment, 76-78

A4ycobacteriurn avium

AIDS patients and, 43

M)cobacterium bovis. See BCG vaccination

A4ycobacteriurn tuberculosis, 2, 27

subpopulation characteristics, 74-75

National Action Plan to Combat Multidrug-Resistant

Tuberculosis, 14,23,67, 86, 95-97, 98, 101

National Center for Nursing Research, 101

National Center for Research Resources, 101

National Heart, Lung, and Blood Institute, 101

National Institute for Environmental

Health Sciences, 101

National Institute for General Medical Sciences, 101

National Institute for Occupational Safety and Health

occupational risks from respiratory exposures to

TB, 97

powered air purification respirators, 7, 54

National Institute of Allergy and Infectious Diseases

IPT efficacy trials, 61

TB research activities, 101

vaccine development efforts, 67

National Institute of Mental Health, 101

National Institute on Drug Abuse, 101

National Institutes of Health

TB Prevention and Control Research Units, 101

TB research, 100-102, 103

National TB Action Plan, 83

National Tuberculosis Training Initiative, 95

National Vaccine Program Office

TB research, 100

Native Americans

case rates, 37, 99

child case rate, 38, 99

New York City

Bellevue Hospital infection control measures, 55

case rate, 4, 35-36, 48

homeless population cases, 5,40

intravenous drug use and MDR-TB association,

40-41

MDR-TB case rate, 6,46

MDR-TB incidence, 72

MDR-TB transmission, 44

Rikers Island Correctional System infection control

measures, 57

TB among HIV-infected persons, 30

TB control services, 85-86

treatment completion trials, 83-84

New York State

Medicaid funding for DOT, 105

prison sjstem prevalence, 41

NIAID, See National Institute of Allergy

and Infectious Diseases
146 I The Continuing Challenge of Tuberculosis

NIOSH. See National Institute for Occupational Safety

and Health

Non-Hispanic white Americans

case rates, 37

child case rate, 38

Nonadherence. See Completion of treatment

Noncompliance. See Completion of treatment

Nontuberculous mycobacteria. See aZso Mycobacterium

avium

AIDS patients and, 43

sputum smear and, 70

North Carolina

migrant farm worker survey, 42

Nursing homes

TB risk, 40

Occupational Health and Safety Administration

responsibilities, 97

TB-related activities, 14,97-98

OSHA. See Occupational Health and Safety

Administration

P~Rs. See Powered air purification respirators

Para-aminosalicylic acid, 10,73,76,77,78,

79,80, 102

Particulate respirators, 7,54

PAS. See Para-aminosalicylic acid

Personal protection devices

infection control measure, 54

Phenazines, 78

PHS. See U.S. Public Health Service

Physicians. See Primary care physicians

Policy options

categories, 16

description, 16-26

financial issues, 24-26

public health infrastructure, 16-22

research and development, 22-24

Polymerase chain reaction, 9, 71

Powered air purification respirators, 7,54

Prevention strategies

BCG vaccination, 62-67

infection control, 50-54

INH preventive treatment, 55,56,58-59,61-62

tuberculin skin testing, 55-56, 59-61

Primwy care physicians

National Tuberculosis Training Initiative and, 95

patient monitoring, 11-12, 86-87

prescribing errors, 86

Prisoners and inmates. See also Correctional

institutions

case rate, 5, 41, 48

MDR-TB outbreaks, 6,46

Pulmonary TB

BCG vaccination efficacy, 66

description, 3, 30

Pyrazinamide

active TB treatment, 9, 73-80

efficacy in TB prevention, 61

FZA. See Pyrazinamide

Quinolones, 77

Race, ethnicity, age, and sex

case rates, 4-5, 37-40

Refugees. See Immigrants and refugees

Reimbursement for TB services

Federal health insurance programs, 103-106

Social Security programs, 103

Report of a Verified Case of Tuberculosis, 33-34,

82, 84

Research and development

National Institutes of Health, 14, 100-102

National Vaccine Program Office, 100

Substance Abuse and Mental Health Services

Administration, 14, 100

Respirato~ isolation, 51, 53

RIF. See Rifampin

Rifamate TM, 10,73,78,79, 80, 88

Rifampin

active TB treatment, 9, 73-80

efficacy in TB prevention, 61

MDR-TB and, 44

Rifamycin, 78

RifaterTM, 10,73,78,79,80, 88

Rikers Island, NY, Correctional System

infection control measures, 57

RV~, See Report of a Verified Case of ‘Ibberculosis

Ryan White Comprehensive AIDS Resources

Emergency Act, 100

Screening tests. See lkberculin skin testing

Sex. See Race, ethnicity, age, and sex

Skin testing. See Tuberculin skin testing

SM. See Streptomycin

Social Security Disability Insurance, 15,24, 103
Index I 147

Sputum smear, 8,70

SS1, See Supplemental Security Income program

State and local TB control programs

outpatient medical care, 104

State TB laws, 11, 84-85

TB elimination advisory committees, 9 7

universal purchase of anti-TB drugs, 20, 21

Strategic Plan for the Elimination of Tuberculosis in

the United States, 12, 86, 94-95

Streptomycin, 9,72-73,75,76,78,79, 80, 102

Substance Abuse and Mental Health Services

Administration

TB research, 14, 100

Supplemental Security Income program, 15,24, 103

Surgical intervention, 10,72,77

TB control services

description, 85

program problems, 85

State TB laws, 84-85

TB Prevention and Control Research Units, 101

Tice strain of BCG vaccine, 63

Transmission

active tuberculosis, 30

MDR-TB, 44,46-47

stages of TB, 28

tuberculous infection, 28-30

Treatment failure. See Completion of treatment

Treatment of active TB

alternative methods of drug delivery, 10, 78

antimicrobial treatment rationale, 74-75

bactericidal phase, 9, 75

combined-drug regimens, 9, 72-74, 75, 76-77, 78

completion of treatment, 10, 11, 58-59, 76, 77,

82-84, 89_90

current regimens, 9, 73, 75

drug costs, 10, 11,79-80

drug shortages, 10, 78

duration, 9-10, 73,75,76,77

first-line drugs, 9,73

implantable devices, 10, 78, 102

individuals with AIDS and, 76

introduction of antibiotic treatment, 9, 72-73

multidmg-resistant TB, 9-10, 76-78

new approaches, 10, 78

second-line drugs, 10, 73, 77, 79, 80

sterilizing phase, 9, 75

surgical intervention, 10, 72, 77

Treatment outcome factors

clinic management, 85

data, 82-84

medical care practices, 86-87

patient behavior, 87

TB control services and, 84-86

Tbbercle bacilli. See Mycobacterium tuberculosis

Tuberculin skin testing

accuracy, 7, 30, 60

description, 3

false negative reading, 70

false positive reading, 60

high-risk groups, 55-56

limitations, 60-61

mechanism, 59-60

policy option, 20

positive reading, 30

result interpretation, 60

“worried well’ persons and, 28

lbberculous infection

description, 3

host factors, 30

probability of acquiring active TB and, 28

risk factors, 28-30, 58

transmission, 28

Ultraviolet radiation

inactivation of droplet nuclei, 30

infection control measure, 7, 53-54

United Hospital Fund

directly observed treatment recommendation, 89

U.S. Agency for International Development

TB control budget, 14,99

U.S. AID. See U.S. Agency for International

Development

U.S. Department of Health and Human Services. See

also specific agencies and programs by name

Agency for Health Care Policy and Research,

102-103

Core Curriculum on Tuberculosis, 95

TB control budget, 14,93

U.S. Department of Housing and Urban Development,

103

U.S. Department of Justice

TB control activities, 14, 98

U.S. Department of Veterans Affairs

purchaseoof drugs in bulk, 21

TB control activities, 14, 20, 98
148 I The Continuing Challenge of Tuberculosis

TB screening, 20

U.S. DHHS. See U.S. Department of Health and

Human Services

U.S. DVA. See U.S. Department of Veterans Affairs

U.S. Public Health Service. See also specljic agencies

and programs by name

history of TB prevention and control, 92-93,94

National Action Plan, 101

reporting system for TB, 34, 33

treatment completion trials, 83

UV radiation. See Ultraviolet radiation

Ventilation systems, 51, 53

Washington Post editorial, 28

WHO. See World Health Organization

World Health Organization

AIDS impact on T13 in developing countries, 43

BCG vaccination recommendations, 62-63

Global Program on AIDS funding from

U.S. AID, 99