December 2001

Research Capsules
Edited by Harrison Wein, Ph.D.

Small Genetic Change Makes Flu Virus Deadly
After Cocaine Use, Craving Gets Progressively Stronger
Chronic Lyme Disease Symptoms Not Helped by Three-Month Antibiotic Regimen

Small Genetic Change Makes Flu Virus Deadly

In 1918, the "Spanish flu" killed more than 20 million people around the world. It is the most severe outbreak of acute human disease in recorded history, yet scientists still don't understand why it was so virulent. Nor do scientists completely understand the virulence of more recent pandemics, such as the "Asian flu" of 1957 or the "Hong Kong flu" of 1968. To protect against such future outbreaks, scientists need to understand what can make certain strains of influenza, the virus that causes flu, kill so many people while other strains are relatively benign. A major contribution toward that understanding has been made by a research group supported by NIH's National Institute of Allergy and Infectious Diseases (NIAID).

In 1997, an influenza virus called H5N1 jumped directly from chickens into people in Hong Kong and killed six out of the 18 people it infected. Public health authorities there responded by killing more than 1 million chickens to prevent further spread of the virus. NIAID grantees at the University of Wisconsin-Madison obtained samples of both deadly and benign strains of the H5N1 virus, and used a technique called reverse genetics to manipulate genes from both to create genetically engineered influenza viruses. They tested these in laboratory mice and found that a small change in the genetic sequence of one of the virus's 10 genes (known as PB2) was key to one strain's virulence. Scientists believe that PB2 directs the production of an enzyme that helps force an infected cell's molecular machinery to make more viruses.

While the virulence of H5N1 in humans likely involves more than this small genetic change, this work is a significant advance toward understanding the molecular basis for influenza virulence. The virus constantly changes, and new strains emerge each year, thus requiring new vaccines each year. In order to prepare effective vaccines or design more effective antiviral drugs, it is critical to understand what makes some strains of the virus so deadly.

— a report from The NIH Word on Health, December 2001
Science 293(5536):1840-42

For more information on NIAID-supported influenza research, and background on the virus itself, visit Focus on the Flu on the NIAID Web site at http://www.niaid.nih.gov/newsroom/focuson/flu00.

After Cocaine Use, Craving Gets Progressively Stronger

Some people think that once a cocaine addict quits using the drug, they're past the hardest part. But new research shows that cocaine craving actually intensifies over time. Former addicts may become increasingly vulnerable to relapse in the months after drug use has stopped. This discovery has important implications for people trying to kick a cocaine addiction and those trying to help them.

To investigate cocaine craving, researchers at NIH's National Institute on Drug Abuse (NIDA) trained rats to press a lever to receive cocaine injections. Once the rats had learned to associate the lever with the cocaine, the cocaine was withdrawn. The animals were then tested after different intervals to see how many times they would push a lever when cocaine was not available. Those deprived of cocaine for a single day pressed the lever the least. Those deprived for 60 days, the longest time interval studied, pressed it the most.

These results agree with what doctors believe they have seen in humans but could not confirm experimentally: former addicts are more vulnerable to relapse to cocaine use well beyond the acute drug withdrawal phase.

"This phenomenon helps explain why addiction is a chronic, relapsing disease," says outgoing NIDA Director Dr. Alan I. Leshner. "Craving is a powerful force for cocaine addicts to resist, and the finding that it persists long after last drug use must be considered in tailoring treatment programs."

— a report from The NIH Word on Health, December 2001
Nature 412:141-142

NIDA has information about research into cocaine abuse and addiction at http://www.nida.nih.gov/DrugPages/Cocaine.html. You can also call the National Clearinghouse for Alcohol and Drug Information at 1-800-729-6686 for information.

Chronic Lyme Disease Symptoms
Not Helped by Three-Month Antibiotic Regimen

Long after a standard course of antibiotics is complete, some patients with Lyme disease still suffer from symptoms that include muscle or joint pain, difficulty concentrating, and profound fatigue. Many patients believe that longer courses of antibiotic therapy will help them, despite the risks of such long-term treatment. But the results of the first randomized, placebo-controlled, double-blind trials testing antibiotics in these patients found that a 90-day course of both intravenous and oral antibiotics was no better than placebo at improving these chronic symptoms.

A total of 129 volunteers enrolled in two studies, identical in design, funded by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Center for Research Resources (NCRR). One of the trials enrolled 78 chronic Lyme disease patients who tested positive for antibodies to the Lyme bacterium — a sure sign of previous infection. The other enrolled 51 people with no evidence of antibodies but with well-documented previous cases of Lyme disease. All had previously received at least one course of recommended antibiotics and no longer showed evidence of persistent infection with the Lyme agent in blood or cerebrospinal fluid samples. Despite the absence of the Lyme bacterium, however, all these people still suffered from persisting symptoms.

Volunteers in each study were assigned at random to receive either antibiotic treatment or an inactive placebo for 90 days. Another 90 days after the treatment ended, the patients were given a health-related quality-of-life questionnaire. During an interim review, however, an independent group of doctors and researchers in a data safety and monitoring board unanimously recommended that NIAID stop the treatments in both trials because the data showed no significant difference between the patients who received antibiotic treatment or placebo.

The researchers did find that the impact of Lyme disease on physical health was "substantial" — at least equal to the disability of patients with congestive heart failure and osteoarthritis, and greater than in patients with type 2 diabetes or a recent heart attack. It had an effect on mental health too. But treatments for 90 days with antibiotics that are known to kill the Lyme disease bacterium didn't improve the patients' symptoms any more than placebo. Unfortunately, despite many theories, the cause of these persisting symptoms still remains something of a mystery, and scientists continue to search for new, promising ways to treat chronic Lyme disease.

— a report from The NIH Word on Health, December 2001
New England Journal of Medicine 345(2):85-922

For more information on Lyme disease from NIAID, see Lyme Disease: The Facts, The Challenges at http://www.niaid.nih.gov/publications/lyme/default.htm.
For links to other Lyme disease information, go to http://medlineplus.nlm.nih.gov/medlineplus/lymedisease.html.