The outbreak of fungal meningitis linked to contaminated steroid injections represents a forced march into unexplored medical territory.
Most fungal infections occur on the skin and are easily treated. Inhaling fungus-contaminated dust sometimes causes pneumonia in healthy people. Fungal infections in the brain, however, are almost always confined to people whose immunity has been suppressed by AIDS, cancer, burns or organ transplantation.
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What's underway now -- a new form of fungal meningitis in 281 otherwise healthy people -- is an event without precedent.
To date, 23 people have died. New cases appear every day; the count went up by 13 on Saturday. In all, 14,000 people in 23 states received injections around the spine or a joint with the anti-inflammatory drug methylprednisolone acetate from three contaminated lots distributed by a Massachusetts company.
"This kind of fungal meningitis has not been reported in the medical literature. There is not enough data to say whether it will be more or less responsive to treatment . We don't know what the outcomes generally are," said Benjamin Park, a physician in the fungal diseases branch of the Centers for Disease Control and Prevention.
"The truth of the matter is that we don't have any experience with this," said Arturo Casadevall, an expert on fungal infections and chairman of microbiology and immunology at Albert Einstein College of Medicine, in New York.
Fungal infections of the brain are as feared as they are rare. They come on slowly and are hard to diagnose. They require at least three months of therapy with often unpleasant drugs. Treatment failure is common. Survivors are often left with disabilities.
As events unfold, physicians and public health officials are keeping in mind a cluster of five cases of fungal meningitis linked to contaminated injections that occurred a decade ago. One person didn't become ill until 152 days after injection.
"That's obviously making us concerned about this outbreak," said Tom M. Chiller, a physician also with CDC's fungal diseases branch. "We want patients and providers to continue to be vigilant and on the lookout for symptoms months after the injections."
The infections are rare in part because most fungi don't grow at body temperature. Exserohilum rostratum, the organism responsible for all but a few of the current cases, is an exception. One of the reasons they are difficult to treat is that fungal cells are similar to human cells in many structures and enzymes that are targets for antimicrobial drugs.
"The last thing you would think of when you look at a fungus is, 'I have a lot in common with that organism,' " said Robert Cramer, a molecular mycologist at Dartmouth Medical School. "But we have many more genes and proteins in common with fungi than we do with bacteria. Animals and fungi are more closely related than animals and plants."
Some fungi are especially hard to kill because they produce melanin -- one of nature's strangest protective substances.
Melanin is best known as the pigment that darkens skin and protects it from the damaging effects of too much sunlight. Its usefulness was discovered via single-cell organisms. Fungal species that grow on leaves and grass (as Exserohilum rostratum does) make it for the same reason people do -- to protect against ultraviolet light.
In fact, melanin absorbs virtually all wavelengths (which is why it is black) and some ionizing radiation. Melanin inactivates "free radicals", which are highly reactive chemicals made by cells of the immune system and used as molecular hand grenades to punch holes in bacteria, viruses and other pathogens. Granules of melanin in the cell walls of fungi also absorb certain substances -- including many drugs -- preventing them from gaining access to the interior.
"Imagine putting activated charcoal on the outside -- it's kind of like that," said Casadevall.
As it turns out, a few antifungal drugs aren't stopped by melanin. One of them is voriconazole, which is being used to treat the meningitis patients.
How important melanin's role may be in the current infections isn't known. It's unlikely to be the whole story.
"I don't know anyone in our field who has studied this organism and its virulence," said Cramer, the Dartmouth researcher. "But we definitely cannot attribute what's going on just to the production of melanin."
Some of the meningitis patients have suffered strokes, especially in the back of the brain -- the first stop for organisms migrating up the spinal canal. The fungus invades blood vessels, which clot off and deprive brain tissue of oxygen and blood flow.
Cramer thinks that fungal cells may be able to detect oxygen "gradients" -- minute changes in concentration -- in the cerebrospinal fluid they are floating in. The cells then grow toward the source -- oxygen-rich capillaries -- like slow-moving sharks homing in on bleeding swimmer.
It's a hypothesis he's now exploring in his laboratory.