UT public health experts discover new information about diabetes' link to tuberculosis

16 oct 2008--New evidence discovered by researchers at The University of Texas School of Public Health Brownsville Regional Campus shows that patients with Type 2 diabetes may be at increased risk of contracting tuberculosis because of a compromised immune system, resulting in life-threatening lung infections that are more difficult to treat.
Blanca I. Restrepo, Ph.D., assistant professor of epidemiology; and Susan P. Fisher-Hoch, M.D., professor of epidemiology; and Joseph B. McCormick, M.D., regional dean, previously reported that Type 2 diabetes was the leading risk factor for tuberculosis (TB) in the United States/Mexico border area. Several other studies in Asia and elsewhere have confirmed this observation.
The UT School of Public Health team has now led three new studies that revealed key findings:
Type 2 diabetes, especially Type 2 diabetes involving chronic high blood sugar, is associated with altered immune response to TB, and this was particularly marked in patients with chronically high blood sugar.
Patients with diabetes and TB take longer to respond to anti-TB treatment.
Patients with active tuberculosis and Type 2 diabetes are more likely to have multi-drug resistant TB.
The World Health Organization estimates that 180 million people in the world have diabetes, and that number is expected to double by 2030. Also, according to the WHO, each person with active, untreated TB infects on average 10 to 15 people per year. "You do the math and it adds up to a major public health threat," McCormick said. "If you have Type 2 diabetes in an area with high rates of TB, your chances of getting TB goes up. In countries where a third of the population is infected with TB, this becomes a real issue."
In a recently published study in linical Infectious Diseases, researchers reported that the immune systems of patients with Type 2 diabetes and tuberculosis respond differently compared with patients with TB alone. "This immune impairment may be what makes patients with diabetes so susceptible to TB," said Fisher-Hoch, whose career as a scientist was recently honored with a Hall of Fame Award from Women In Technology International.
Restrepo and her colleagues found that innate and type 1 cytokine responses were significantly higher in patients with tuberculosis who had diabetes than in the control group of patients with TB and no diabetes. The effect was consistently and significantly more marked in diabetic patients with chronic hyperglycemia, or uncontrolled high blood sugar. Diabetes results in the body's ineffective use of insulin. If left uncontrolled, the chronic high sugar in the bloodstream can affect the critical immune system and damage the body's systems, especially the nerves, the retina of the eyes and blood vessels.
"These findings are the opposite of what we were expecting," Restrepo said. "These innate and type 1 cytokines are typically associated with TB protection, but in patients with diabetes, it appears the cytokines are not effective. Diabetics may have more advanced TB with more bacteria, and hence, more stimulation for secretion of type 1 cytokines."
The researchers wrote, "More detailed knowledge of the underlying mechanisms should focus on the effect of chronic hyperglycemia on the immune response to help in understanding the enhanced susceptibility of diabetic patients with tuberculosis."
In a second study, which was published in an October issue of the American Journal of Tropical Medicine and Hygiene, the researchers demonstrated that diabetic patients with TB were more likely to take longer to clear the TB bacterium during the first phase of treatment than TB patients who are not diabetic. Using data from 469 TB patients in south Texas, those with diabetes had a five-day delay in mycobacterial clearance within the first 60 days of treatment.
"Despite the goal of global eradication by the year 2050, in 2004, there were an estimated 8.9 million new cases of TB worldwide," the researchers wrote. "Our data showed that adult onset diabetes mellitus (also known as Type 2 diabetes) seems to interfere with sterilization of pulmonary TB by drug therapy. By 2030, it is estimated that 336 million of the world's population will have diabetes mellitus, many in TB-endemic countries. Diabetes on this scale may impact TB control. Prospective studies are needed to define more clearly the consequences for transmission among diabetes patients and the prevention and therapeutic measures that might be taken to lessen the effect."
A third study demonstrated that patients with diabetes were more at risk of developing multi-drug resistant tuberculosis. In an Epub abstract online in Scandinavian Journal of Infectious Diseases, researchers reported that almost 6 percent of patients living along the Texas-Mexico border had TB that was resistant to rifampin and isoniazid, common medications for tuberculosis. Of those with multi-drug resistant tuberculosis, 30 percent also had Type 2 diabetes. "It is possible that impaired immunity in Type 2 diabetes increases susceptibility to infection with resistant strains," the abstract states.
McCormick, the senior author of all three papers, said these research findings shed new light on a long-known correlation between diabetes and tuberculosis. "It opens a door to doing something about it," said McCormick, the university's James H. Steele Professor. "We can educate physicians and offer more TB screenings. We have an opportunity to make sure patients are diagnosed correctly and that there is no delay in diagnosis."
Fisher-Hoch said the research could help diagnosis TB patients who previously would not be considered at risk for contracting the airborne, contagious disease. "The classic TB patient in this country is a younger male in an urban setting who may have alcohol and drug abuse problems and be HIV-infected," she said. "Our research shows older female patients who have never been in jail and have no history of alcohol and drug abuse or HIV infection are at risk of contracting TB if they have diabetes."
"I think we are illuminating a very important association between TB and diabetes that had pretty well been overlooked," Fisher-Hoch added. "The public health aspect is that we are trying to make sure we can prevent and treat these patients, and when they are TB-infected, treat them better."
Fisher-Hoch recommends that medical professionals screen patients for TB if they have diabetes and a chronic cough. She also recommends that patients with Type 2 diabetes take precautions. "If they are visiting an area where there is a lot TB, they need to be careful," she said. "TB spreads in crowded places with poor ventilation."

Potential new weapon against TB: free cell minutes

By JAY LINDSAY
15 june 2008--Researchers at MIT believe they've discovered a new weapon in the battle against tuberculosis: Free cell phone minutes.
For years, doctors have struggled to get some TB patients to take all their medication, which generally involves a six-month regimen of multiple drugs.
Now a student-led group at the Massachusetts Institute of Technology has developed a way to use cell phones to let patients test themselves. And if the tests show patients are following doctor's orders, they get rewarded with free minutes.
"We're piggybacking on one of the bigger rollouts of infrastructure out there, which is wireless technology and telecom technology," said Jose Gomez-Marquez, one of the project's leaders.
The system works like this: Patients test their urine using a strip that reveals a numeric code if it detects TB medicine. They then text message the code to their health care provider and get credit toward incentives such as free minutes.
The in-home tests also eliminate the need for health care workers to make several patient-monitoring visits a week, a routine that is often impractical in remote places, Gomez-Marquez said.
Mobile phones are good tools for the project because they are common in the developing world, where it's often cheaper to erect cell towers than miles of poles and wires, Gomez-Marquez said.
Dr. Mario Raviglione, director of a World Health Organization program to fight TB, called the MIT idea "creative." But he said personal visits must continue because systems that depend heavily on patient self-reporting have often failed.
"I would think it's a dangerous game to rely only on incentives," he said.
In 2006, the most recent year statistics are available, 9.2 million people worldwide were diagnosed with tuberculosis and 1.7 million died.
The disease can be cured with a steady regimen of drugs. But many patients start feeling better and stop taking the medicine too soon. Others abandon the drugs because of side effects such as nausea, fever and rashes.
If the drugs are taken only sporadically, the bacteria build up resistance. The WHO estimates that 5 to 10 percent of TB deaths are patients who stop taking medication properly.
The MIT group — which originally included five students — took on the TB problem in 2007 as part of the university's annual "IDEAS competition," which challenges participants to solve various world problems.
Under the TB treatment system used by the WHO, the relationship between the patient and health care worker can get adversarial, said Elizabeth Leshen, an MIT junior working on the project.
"We wanted to do something that takes the health care worker out of the supervisory role and puts him or her back into the patient care role," she said.
Cell minutes were chosen as an incentive because patients want them and phone companies are willing to give them out, said Gomez-Marquez, who added that other incentives and reporting methods can be tailored to different regions.
A small study of 20 patients in Nicaragua last year indicated the MIT system could work, and a larger study in Pakistan is planned for this summer. The team is trying to raise the $200,000 for a full-scale clinical trial.
The WHO's Raviglione said the MIT group's program could be an asset, particularly in developed countries, where people are more familiar with technology. But he said it must be combined with regular visits from health care workers or community leaders who can ensure patients take their medicine.
Before personal visits became routine in the 1990s, death rates from tuberculosis were estimated at 40 to 50 percent, according to the WHO. After officials began making visits as part of a broad strategy to fight TB, that figure dropped to 15 percent.
"Human contact is essential for people who have to take drugs for a long time," Raviglione said.

A Tangle of Conflicting Accounts in TB Patient’s Odyssey

As the Atlanta lawyer with a dangerous form of tuberculosis began treatment yesterday in Denver, the patient and government officials here and abroad provided sharply divergent accounts of his 12 days of world travel. The accounts seemed to agree only in the missed opportunities to head off what has become an international public health scandal.
The patient, Andrew Speaker, has said that public health officials in Fulton County, Ga., told him a trip would not be risky. But those officials said that he had been clearly warned of the dangers. In interviews, public health officials at the county, state and federal levels all said he should not have traveled and defended their handling of the case.
The finger-pointing extended to Canada, Greece and Italy, where officials said they had received no word of Mr. Speaker’s presence in their countries in time to take action. Italian officials said they were first informed unofficially of an American with a dangerous tuberculosis case while Mr. Speaker was still in Rome, but had to take the initiative in calling the Centers for Disease Control and Prevention in Atlanta to ask for details. That information did not come until after Mr. Speaker had left Italy.
The likelihood that Mr. Speaker might have infected other passengers is low, tuberculosis experts say, because the disease is not as contagious as illnesses like influenza. In any case, Mr. Speaker has not been coughing, and may not have enough TB bacteria in his sputum to spread the disease if he did, health officials said.
But the risk was still real, and the bizarre case calls into question preparations to deal with medical crises like influenza pandemics and even bioterror attacks.
In the sharpest contradiction in the accounts, Mr. Speaker said yesterday on “Good Morning America” that county health officials who met with him all but wished him bon voyage. Although they urged him not to travel to his wedding in Greece because of his tuberculosis, he recalled, they backed off under his father’s lawyerly prodding, saying, “Well, we have to say that to cover ourself, but he’s not a risk.”
Steven R. Katkowsky, director of the Fulton County Department of Health and Wellness, said in an interview that the county had little power to detain Mr. Speaker, but insisted that they could not have made their warning more clear. “We told him that if you travel, you’re putting people at risk,” Dr. Katkowsky said.
County officials said Mr. Speaker did change his travel plans after the meeting. But instead of canceling his reservations for a wedding and monthlong honeymoon, he moved up the departure date to May 12 from May 14 — too soon to get the follow-up letter from the county stating, “it is imperative that you are aware that you are traveling against medical advice.”
Dr. Katkowsky said, “We are talking about a person who both had the intent and the means to escape the jurisdiction.”
Lingering Questions
Meanwhile, some of the most intriguing questions still remain unresolved. Why would a well-informed person aware of medical concerns get on an airplane after receiving a diagnosis of a disease that could be fatal to others? Why would he flee from health authorities once the diagnosis became even more grave? How could the man’s father-in-law, an expert in tuberculosis at the C.D.C., accede to the trip?
Laney Wiggins, a passenger who sat near Mr. Speaker on the Air France Flight 385 from Atlanta to Paris has been tested for tuberculosis and said she expected to learn that she was not infected. But that was small comfort, Ms. Wiggins added. “How many other people can do this or will do this?” she asked. “It’s hard to think about what this means for the future of air travel.”
The story continued to unfold on Friday. In Denver, doctors treating Mr. Speaker said they had started him on medications, and that he would probably be treated for at least two years and may need surgery to remove the infected sixth of one of his lungs.
Dr. Gwen A. Huitt, who is treating Mr. Speaker at National Jewish Medical and Research Center, announced that tests there suggested that it was unlikely he had infected anyone on the flights. “It is our opinion that he is of low communicability,” Dr. Huitt said, as the C.D.C. had also said.
But low does not mean zero, and the basic rules of public health state clearly that people like Mr. Speaker should not fly. Guidelines issued last year by the World Health Organization say that patients with multidrug-resistant TB (a category that includes his type, XDR) “must not travel by public air transportation” until they have proved to be noninfectious.
Though Mr. Speaker has said repeatedly that he believed he was not a risk to others because he was “smear negative” — that is, the bacterium did not show up in his sputum — studies show that 17 percent of tuberculosis cases are traced back to a source whose smear is negative.
In Atlanta, officials at the Centers for Disease Control and Prevention said they had reached 74 passengers out of 310 from the United States, including all 26 people who were in the rows closest to Mr. Speaker on the flight to Paris. The agency is focusing only on American citizens, said Julie L. Gerberding, the director of the centers; she said other nations should be contacting their own citizens. The passengers are being advised to have tuberculosis tests immediately, and to have follow-up tests in several weeks.
When asked why the health organization could not move more quickly and catch up with Mr. Speaker before he took more flights, Dr. Gerberding said in the press conference that much of the previous week’s activity had been spent debating issues concerning the laws and regulations that govern isolation and quarantine in the United States and internationally. The World Health Organization regulations, she said, are “wonderful statements of principles” that do not provide “operational details of things like who should pay to move a patient, or who should care for a patient.” She said, “I think a central question that we will be grappling with is, whose patient is it?”
For his part, Mr. Speaker apologized to his fellow passengers yesterday on “Good Morning America” on ABC. From his hospital room in Denver he said: “I don’t expect those people to ever forgive me. I just hope they understand that I truly never meant them any harm.”
He said that when he was contacted by a representative of the Centers for Disease Control in Rome, he was told that he could not fly home unless he chartered a plane — at a cost of $100,000 — and that he should check into a local hospital. “I felt very abandoned,” he said, emphasizing that he firmly believed he could not infect others. He said he feared he might end up “stuck in an Italian hospital indefinitely, where I could die.” But when pressed by the interviewer, Diane Sawyer, he said, “In hindsight, maybe it wasn’t the best decision.”
Missed Opportunities
In that, however, Mr. Speaker appeared to be in good company. At every step in the case, opportunities to head off what became an international public health emergency were lost because of restrictive regulations, poor communication and questionable judgment, those involved with the case said.
Though their accounts differ, the county health authorities and Mr. Speaker agree that the officials did not try to forcibly restrict Mr. Speaker’s movement. Dr. Katkowsky, the county official, said that the law presented “kind of a Catch-22” when it comes to restricting the activities of tuberculosis patients against their will. “A patient has to be noncompliant before you can intervene,” he said. “There’s no precedent for a court stepping in before a patient has proven himself to be non-compliant.”
It would have been an extraordinary step that, while not unheard of in tuberculosis cases, would evoke a centuries-old struggle to balance public health and individual liberty. The term “quarantine” comes from the Italian phrase “quaranta giorni,” or “40 days,” the amount of time Venetians isolated those coming into port in the plague years of the 14th century, said Robert Klitzman, a co-founder of the Columbia University Center for Bioethics and an associate professor of clinical psychiatry at the university’s College of Physicians and Surgeons.
The specter of tuberculosis, the disease called “consumption,” loomed large in the United States, and hospitals devoted to treating the condition sprung up in the American West for those seeking treatment; those who refused treatment, like Mary Mallon, who infected nearly 50 people with typhoid as a cook and domestic servant at the turn of the 20th century, were forced into isolation.
In this century, quarantine and isolation have become less important thanks to vaccines and antibiotics, and civil liberties issues have tended to come to the forefront. Dr. Klitzman said that these days, quarantine and forced medical isolation “have a uniformly bad name to the more liberally-minded people,” raising the notion of “the state violating individual autonomy.”
Mr. Speaker first received a diagnosis of tuberculosis in January after a chest X-ray to see if he had broken a rib in a fall. Yet it would be months before the matter became a priority of county health officials.
The day of the meeting with Mr. Speaker, May 10, the county health officials called the Georgia Division of Public Health, said Dena Smith, the state public health press secretary. That office made a call to the Centers for Disease Control. Ms. Smith said the call from the county left officials in her office with the impression that the problem was largely hypothetical. “They had no idea at that time that the patient was thinking about leaving the country,” she said. Her office did not receive word that Mr. Speaker had flown overseas until May 17, she said.
When federal health officials tracked him down in Rome, they offered what Mr. Speaker said was a very poor set of options, and let him know that he would be placed on a no-fly list to restrict his movement, officials at the disease centers said yesterday.
Once again, Mr. Speaker changed his travel plans, moving up his departure date and slipping out of the country on a roundabout path that would take him to Prague and Montreal, where he rented a car to return to the United States.
The disease centers learned on May 22 that Mr. Speaker had XDR tuberculosis, but they did not immediately contact Italian health authorities or the World Health Organization, Italian officials said.
Instead, on May 23, C.D.C. officials contacted a doctor who had worked at the disease centers in the past, but is now working in Italy. Dr. Martin S. Cetron of the disease centers said the doctor worked with the Italian Health Ministry, but Italian officials said the doctor was not with their agency. On the same day, Italian officials said, this doctor contacted the Italian Health Ministry to let them know about a tuberculosis case and tell them the disease centers would be in touch.
On May 24, when the Italian Health Ministry still had not received anything, Dr. Maria Grazia Pompa, who leads Italy’s tuberculosis surveillance program, said she “contacted the C.D.C and said, ‘Weren’t you supposed to contact us?’ ”
Dr. Pompa added, “At that time, the disease centers confirmed that there was a case, but did not provide details.” Those came in an e-mail message to Dr. Pompa on the afternoon of May 25, a day after Mr. Speaker drove back into the United States from Canada. United States officials did not get word to Canadian authorities that Mr. Speaker was in their country until after he left, Dr. Gerberding said. She defended that, by saying: “We didn’t know where he was. For all we knew, he was anywhere in the world.”
Still, by the time Mr. Speaker made his way to the United States border, an alert had been attached to his passport that warned customs agents to detain him. But the guard waved him through — a matter that is now under investigation.
On Friday, Homeland Security officials promised to examine anew their systems for detaining sickened travelers, but they acknowledged that there would always be holes in the system.
“We don’t have doctors at all the borders,” said Dr. Jeff Runge, assistant secretary and chief medical officer of the Department of Homeland Security. Indeed, the Division of Global Migration and Quarantine at the disease centers has only about 80 medical officers who can staff only 20 of the nation’s 326 border crossings, Dr. Runge said.
“We will do the best we can with the people we have,” he said.
Security Concerns
Senator Charles E. Schumer, Democrat of New York, said the mistake at the border was a sign that the Customs and Border Protection bureau was stretched too thin, with just 4,000 agents along a northern border that is required by law to have 5,000.
“The agents of the Customs and Border Control bureau are our first line of defense,” Mr. Schumer said. “We cannot afford even one mistake in an incident such as this.”
Other lawmakers called for strong and clear legal authority to deal with public health emergencies. Senator Richard M. Burr, Republican of North Carolina, issued a statement on Friday calling for “strong state and local public health authorities, tools to rapidly detect and track disease, and robust investment in the development of medical countermeasures,” along with “improved coordination between health officials and law enforcement.”
Ultimately, however, the idea of an all-seeing public health and enforcement network that could spot and stop a traveling patient could raise worries of its own, said Michael Osterholm, an epidemiologist who directs the Center for Infectious Disease Research and Policy at the University of Minnesota. “Short of a military state where you have 24/7 surveillance on someone,” Dr. Osterholm said, “you have to count on the good will of the individual.”
He called this a fact of life in an open society, one that could lead to major problems in an outbreak of pandemic influenza, in which many people would probably be boarding planes knowing they were sick to get away from an epidemic. “They would say, ‘I want to make sure I get out,’ ” whatever the risk to others. In that kind of situation, he said, the public health system would inevitably be unable to keep up.
As they sorted through the incidents of the past weeks, officials at the disease centers were left with what might be the biggest question from the case: Is it possible that their tactics, by the time Mr. Speaker was in Rome, inadvertently spurred him to escape? This was, after all, a patient who had already flown away from one set of public health officials who had tried to ground him.
Tom Skinner, a spokesman for the centers, did not address that question directly, but said, “There are going to be many lessons learned from this whole particular incident.”