Between 1985 and 1991, the number of reported cases in this country increased almost in lockstep with the rise in HIV, injection-drug use and homelessness. Other contributing factors include a deterioration in the health-care infrastructure, a 37-percent increase in cases among the foreign born, and, ironically, the treatment itself.
Although TB overall has been on the decline since 1991, multidrug-resistant strains of the disease are showing up in all 10 public health service regions of the country. The deadly "Strain W" TB, resistant to every combination of anti-TB drugs available today, was first identified in New York City four years ago. It has now surfaced in California, Colorado, Florida, New Jersey, Nevada, North Carolina, Ohio, Pennsylvania, South Carolina and Puerto Rico. Multidrug-resistant tuberculosis is clearly a serious public-health threat, especially in large cities.
It is clear that increased funding for TB research, more effective drugs, and wider application of advanced technologies are needed to permanently eliminate this disease. Two relatively new tools being used in TB studies are DNA identification (or genetic fingerprinting) and geographic information systems (GIS). The combined application of these technologies is opening new windows into the molecular character and mobility of TB, enabling health professionals to ask far more incisive questions about the nature of the disease than was possible just a decade ago.
Multidrug-Resistant Strains
"TB is literally a crapshoot," said Barry Kreiswirth, molecular biologist and director of the Public Health Research Institute (PHRI), Tuberculosis Center in New York City. "You don't know if the cab driver -- who drove you to work this morning and turned around and gave you your receipt and coughed on you -- had TB."
The emergence of these new strains of TB is partly due to the failure of patients to complete their anti-tubercular treatment, a strict regimen of often toxic multidrug injections every week for six months to a year or longer, depending on the strain they carry. Partial exposure to the drugs merely gives the bugs an opportunity to develop even greater resistance through genetic mutation. Some clinics in the Bronx section of New York estimate that more than
half of their patients fail to complete the treatment. Since the disease is
airborne and highly infectious, TB dropouts become accidental terrorists, infecting everyone in proximity.
However, incomplete treatments are not the only cause of genetic mutations in MTB, said Ernest Drucker, professor of epidemiology at the Albert Einstein College of Medicine in New York and director of the Community Health Division at Montefiore Medical Center. "After 30 years of using antibiotics on them, the bacilli began to develop resistance -- like the cockroach with insecticide."
Genetic Fingerprinting and GIS
Prior to the laboratory discovery of DNA identification by Alec Jeffreys at England's University of Leicester in 1984, identification of different strains of mycobacterium tuberculosis (MTB) involved growing cultures of the bacilli in a dish, observing bacilli response to different antibiotics and observing patient responses to treatment; if only one of two patients responded to a certain combination of antibiotics, doctors knew they were dealing with different strains.
Finding an effective combination of antibiotics for the patient with "strain X" took several weeks. Even then, there was no way to identify and catalog the different strains. Since Jeffreys' discovery, advances in genetic fingerprinting and sequencing now enable researchers to quickly identify different strains of MTB and the combination of drugs to which they respond.
Since TB is spread through the air, databases of genetic fingerprints and patient demographics can be used in a GIS to map outbreaks in terms of strain identity. Researchers can actually see the clustering of strain types in different areas; analyze the physical, geographic and demographic connections between patients; spot routes of transmission, possibly identify sources of outbreaks; and track the migration of strains to other areas -- capabilities not possible even a decade ago.
The New Jersey Study
Genetic fingerprinting and GIS are the core tools in a regional study by Kreiswirth, Drucker and Dr. Philip Alcabes, assistant professor of epidemiology at New York University's School of Medicine. The investigators hypothesized that TB -- unlike HIV -- is local, with extensive intra-community spread but with little dispersion from one urban area to another or across state lines. Their findings, if true, could lead to more effective controls over TB's spread.
The study began in 1996 with a comparative analysis of the relationship between outbreaks of TB in New York City and those in the neighboring communities of New Jersey. Thousands of New Jersey residents commute to work daily in the Big Apple. The investigators wanted to determine whether the outbreaks had the same or different strains. This question is one of many in a projected four-year study of all reported TB cases in New Jersey, which will be used to test the hypothesis.
Genetic Characterization
The questions are being applied to Kreiswirth's extensive archive of identified TB strains from patients in New York City and parts of New Jersey. It will take another two years to complete DNA identification of the strains from the entire state of New Jersey. The process at the Public Health Research Institute involves genotyping different strains and their drug-resistant characteristics through fingerprinting and sequencing. Following molecular analysis, the barcode-like fingerprints are stored and compared in a software program that can detect and retrieve identical or like patterns. The program can also determine whether two or more sequences -- character strings representing distinct DNA molecules of MTB -- share a common genetic ancestor, a factor that assists health professionals in tracking down sources of outbreaks. Identified strains are exposed to different compounds and analyzed for anti-tubercular activity and virulence factors. Reflecting on the scope of the project, Alcabes said, "This might be the first time anyone has had the ability to genetically fingerprint every case of TB from one large area."
Providing a Geographic Perspective
The GIS phase of the study is being conducted by Barbara Tempalski, a specialist in medical geography and doctoral candidate at the University of Washington. To develop a point database, Tempalski secured patient demographics -- addresses, occupation, race, age, income level, number of people in the household, etc. -- from the New Jersey Department of Health and Senior Services and matched the addresses against a TIGER street network file provided by the Environmental Protection Agency. Geocoded addresses were linked to the TB databases containing strain fingerprints and characterization. The combined data was used in Environmental Systems Research Institute's ArcInfo GIS, Version 7.0, to map the distribution of the disease. The graphics enabled researchers to analyze the distribution and geographic clustering of different strains and spot spatial relationships of patients.
Kreiswirth said the visual impact is immediate. "Actually seeing the physical relationship of the patients provides a perspective not possible with tabular data. The first dataset Barbara [Tempalski] produced made that point. Even though you may know the precise address of patients who are on the same block, what you don't realize, until you see it in two dimensions, is how certain neighborhoods back up to each other, how different blocks have a common intersection, and you don't realize that patients with completely different addresses are literally living behind each other. You can actually see how strain types are clustered in certain areas, suggesting that this may be where the transmissions took place."
Tentative Findings
Preliminary indications are that strains from outbreaks in New Jersey are different from those in New York City, just a few miles away. Alcabes stressed that this is only the first phase of a study that will analyze data on TB outbreaks throughout the state. "We haven't proved anything yet. What we have seen suggests that, even though the distance between these areas is very small, the occurrence of TB might actually be local. If true, there could be implications here for the control of TB. Then, again, maybe not. It's too soon to say, and there are many questions that remain to be answered.
"GIS will be fundamental to asking the questions as well as finding answers," added Alcabes. "We can't ask the questions very well unless we can geographically juxtapose cases of a particular strain of TB with, say, population density or with proximity to an urban area or with incomes, overcrowding, homelessness, etc. GIS gives us the power to look, not just at an area where an outbreak occurs, but at relationships between many, seemingly unrelated factors."
Outlook
Although TB overall has been declining in the United States during the last four years, the emergence of multidrug-resistant strains has become a threat to public health, enough to warrant an increase in spending by the Center for Disease Control (CDC) for TB programs, from $45 million in 1992 to $145 million in 1997. However, if the disease is to be eliminated, not just controlled -- a goal Dr. Ken Castro, CDC director of TB elimination, said is achievable -- the effort will require mobilization on a scale commensurate with that used to wipe out polio. That will undoubtedly require greater funding, new levels of research and wider applications of powerful tools, such as genetic fingerprinting and geographic information systems.
Bill McGarigle is a writer specializing in communication and information technology.
June Table of Contents
