Thursday, February 21, 2013

Leprosy [Hansen's disease] ancient disease of mankind

"Can Leprosy Finally Be Eradicated?"

A new test and vaccine could stop a disease that has cursed humanity for millennia.


Laura Fisher Kaiser

February 20th, 2013


Inside the headquarters of the Infectious Disease Research Institute, senior scientist Malcolm Duthie dumps a pile of white plastic test cassettes onto a small round conference table. They are the size of flash drives and resemble pregnancy tests but contain a strip of paper infused with four leprosy proteins. I pick one up. “Is that blood?” I ask, pointing to a crimson smear inside a divot.

“Yes!” says Duthie. “With a single drop of blood, we’re now able to determine if someone has leprosy. ”

He snaps the cassette into a cradle hooked up to smartphone and taps the screen. Two thin blue lines appear, indicating that this particular patient, part of a clinical trial in the Philippines last year, tested positive. “And see those numbers? That gives us a rough quantitative idea of their bacterial burden.”
Steven Reed, founder and president of IDRI, is pacing around the institute’s Seattle office on this sunny day in January. He is waiting on a phone call from Brazil, where IDRI is preparing to roll out the first rapid diagnostic test to identify people who have leprosy—before they show symptoms.

Leprosy microbes ravage the body slowly and stealthily. Part of what has made early diagnosis difficult is that symptoms vary widely and may take up to 10 years before they become apparent. A recent study in mice shows that leprosy bacteria hijack adult Schwann cells, which normally produce a fatty coating that insulates neurons, and reprogram them into stem cells so they can infiltrate the body’s muscle and nervous systems. An infected person might show zero symptoms or only nebulous ones such as skin rashes, numb patches, and respiratory congestion. The disease is commonly misdiagnosed, and a person with leprosy may squander critical months, even years, getting useless treatments. By the time a clinician clues in, the patient may be disfigured, blind, maimed, or crippled.

Meanwhile, an infected person can unknowingly spread the germ far and wide. One sneeze can spew 100 million bacilli, which can survive for more than a month in the environment, long enough for other people to breathe them in. The organism can remain potent even when dried out, and it can infect someone through the nose or a break in the skin. Although scientists don’t completely understand the mode of transmission, they agree that early detection is crucial to getting ahead of the disease.

IDRI’s test has Reed and colleagues around the world buzzing with optimism that, finally, they “are confronting leprosy in a strong and smart way.”

A few days later, Reed flies to Rio de Janeiro to register the test through ANVISA, Brazil’s regulatory authority, just in time for World Leprosy Day, which fell on Jan. 27. The annual commemoration was started 60 years ago to raise awareness for a disease that at the time infected almost 10 million people a year, was fast outwitting sulfone drugs, and for which a vaccine seemed impossible because leprosy germs cannot be grown in a test tube.

Scientists still can’t cultivate Mycobacterium leprae in vitro. But IDRI has now created the first leprosy vaccine by zippering together four key proteins. When tested on mice, the vaccine reduced the amount and growth of leprosy bacteria in their systems. The researchers are working to produce the fusion protein on a large scale. Clinical trials for humans are scheduled to begin by the end of 2013.

Ideally, the vaccine can be used prophylactically to prevent people from contracting the disease, as well as therapeutically in active cases to thwart bacterial replication. But first you have to know where the cases are. That’s why a quick and easy test is crucial, and IDRI’s can diagnose leprosy in seconds without a microscope.

Besides confirming a diagnosis in patients who already exhibit clear signs, the test can identify hidden cases. Someone with a positive blood test would be a candidate for antibiotic treatment as well as the vaccine. Because long-term exposure to people who have leprosy is the biggest known risk factor for contracting the disease, people who live in close proximity to those who already have leprosy would be candidates for immunization.

The two tools together could finally free humans from the vicious cycle of a disease that has afflicted the population for at least 4,000 years. Leprosy was prevalent in medieval Europe and was considered a serious public health threat in the United States until the 1930s. Most of the cases today are in Asia, Africa, and Latin America. Although leprosy can be cured with a combination of powerful drugs, many people don’t realize they are susceptible until long after they’ve been infected and start exhibiting symptoms.

“To stop leprosy in its tracks, you need to find the people who are harboring the infection and get them treated,” says Duthie. “I can’t tell you how hard it was to convince some of the doctors in leprosy clinics I’ve gone to who say, ‘Why do I need a test? I can recognize leprosy walking in the door.’ So I have to ask, ‘Why then for the last couple of years has this patient been treated for fungal infections, acne, and all sorts of things—even cancer!—before getting properly diagnosed?’ It’s mind boggling.”

One of the places the disease persists is Brazil, the country with the second-most endemic cases after India. The nonprofit IDRI has partnered with a Rio de Janeiro-based diagnostic manufacturer, OrangeLife, to keep down production costs and ensure that price is not a barrier to patients.

“You could say that it took $100 million to create a $1 test,”
Reed says. Not that leprosy, as one of the World Health Organization’s official neglected tropical diseases, has ever attracted those kinds of bucks. But because leprosy is a bacterial cousin of tuberculosis, one of the diseases targeted by the Gates Foundation, IDRI has been able to piggyback on an influx of research dollars in recent years. “We’ve been able to apply all we’ve learned in TB to leprosy,” Reed says. “Our profit is in terms of public health, not dollars.”

The test and vaccine come at a critical time for the disease, which has been on the wane thanks to massive public health campaigns to distribute free multidrug therapy. The WHO reports a 90 percent decrease in leprosy prevalence since 1991, but active leprosy cases and leprosy-related disabilities still affect more than 4 million people worldwide. For the past 10 years, the number of new cases reported each year has flatlined at 250,000.

Some experts say that number is too conservative, though, and comes from pressure from WHO and government officials to declare victory. “The easiest way to eradicate a disease is to stop reporting it,” says Duthie, his Scottish brogue tinged with exasperation. “I believe that the problem is as large as 1.5 million to 2 million cases.” Another reason experts believe the actual number of cases may be higher than WHO claims is that the age-old stigma of the disease, long considered a curse, deters people from seeking medical help. Patients who are cured but disfigured often remain ostracized, even from their own families.

Increasing rates of infection, particularly among children and in countries like India with fast-growing populations, have experts worried that, as Duthie puts it, there is a “large reservoir of infection that is ready to pop.”
And multidrug therapy is no panacea. The drugs cannot reverse nerve, muscle, and bone damage. Nor do the drugs confer lifelong immunity, even after a year of taking them—a regimen especially difficult in poor countries with fragmented health care systems. Side effects can be harsh, which leads some patients to slack off their meds and relapse.

The sulfone drug Dapsone was the drug of choice starting in 1947, but increasing resistance is what prompted the WHO to introduce the current regimen, combining Dapsone with two other drugs. Antibiotic resistance to the new drugs may just be a matter of time.

It’s an axiom of epidemiology that the closer you get to wiping out a disease—and, let’s face it, very few scourges have been eliminated from the planet—the harder it is to whack that last mole. That is all the more true with leprosy, as scientists are not sure exactly where it lurks or all the ways it is transmitted.

In 2008, Duthie and his team went to a “hyperendemic” village in remote southwest China and collected blood specimens from leprosy patients and seemingly healthy members of their households. They kept their eye on one girl who had a low antibody count, indicating that she had been exposed to leprosy—her grandfather, with whom she lived, had had a severe case—but she had no visible symptoms. Subsequent monitoring using IDRI’s test indicated that the bacilli in her blood were multiplying. By October 2009, her bacterial index had gone up precipitously, and she had developed suspicious lesions on her back. A clinical exam confirmed the diagnosis.

Duthie notes that the grandfather had died three years earlier, indicating that the disease had been propagating in the child for at least that long. The case showed that a diagnosis based on antibody response could have been made at least eight months earlier, before the onset of dramatic symptoms.

“When I see a 12-year-old girl who gets diagnosed and treated thanks to this test, knowing that even by age 13 she could have been disabled for life,” says Duthie, “I come back re-energized, knowing that is why I do what I do.”

Leprosy [Wikipedia]

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