323 infected in meningitis outbreak as experts study fungal culprit

In a growing fungal meningitis outbreak, 323 Americans have been infected, the Centers for Disease Control and Prevention announced Thursday. Twenty-four people have died.

Yesterday, the agency had reported 312 cases of fungal meningitis, including 24 deaths, in patients who received contaminated epidural steroid injections made by the New England Compounding Center, mostly for back pain.

The CDC also notes five peripheral joint infections from patients who received injections in joints such as the knee, hip, shoulder or elbow, for a total of 328 cases tied to the outbreak (up from 317 yesterday).

The Food and Drug Administration confirmed the same fungus found in at least 40 people sickened with fungal meningitis was also discovered in more than 50 unopened vials from one of the recalled lots of preservative-free methylprednisolone acetate injections from the New England Compounding Center. About 97 percent of the 14,000 patients who received injections from the implicated lots of steroids have been contacted for follow-up, according to the CDC.

A preliminary investigation of the NECC's Framingham, Mass., facility found dirty floor mats, a leaky boiler and black fungus specks in steroid vials, among complaints. State officials also said their investigation found drugs were sent out before test results on their sterility could be returned. They also said the company operated as a drug manufacturer by producing drugs for broader use, rather than filling specific prescriptions like its license allowed. The state has moved to revoke the company's license given its investigation.

The black mold creeping into the spines of hundreds of Americans who got the tainted shots marks uncharted territory for doctors, because this particular fungus has never been found to cause meningitis. The main culprit is a fungus called Exserohilum rostratum, which is commonly found in dirt and grasses. Only 33 human infections with Exserohilum rostratum have previously had been reported, and they are mostly eye or skin infections in people with weak immune systems, said Dr. Arturo Casadevall, a fungal disease specialist at New York's Albert Einstein College of Medicine.

Fungal infections don't get a lot of attention, but they afflict millions around the world, said David Perlin of the University of Medicine and Dentistry of New Jersey. Most are skin infections like athlete's foot, but fungi also can cause pneumonia, sinusitis and other problems.

Serious infections tend to strike people with immune systems weakened because of cancer, AIDS or other problems. Fungus-caused meningitis in particular is extremely rare -- especially in otherwise healthy people like in this outbreak -- and it is "very bad news," said Dr. Carol Kauffman, a professor of infectious diseases at University of Michigan in Ann Arbor, Mich. She has advised the CDC and co-authored advice in the New England Journal of Medicine on how to handle the complex medication used in treatment.

While the more common bacterial and viral forms of meningitis tend to strike quickly with obvious symptoms, fungal meningitis grows very slowly and is hard to diagnose. Few anti-fungal drugs are absorbed into the central nervous system, limiting treatment options. Plus, human cells and fungal cells have a lot of similarities, making it hard to attack the fungus without side effects, Kauffman explained.

Also, the Exserohilum rostratum fungus' brown-black color signals an armor that -- along with being injected near the spine -- allows this mold sneak past the immune defenses of otherwise healthy people, Casadevall said.

"What we're dealing with here is fundamentally different from a typical fungal infection," he said. "This is a bug that most of us don't know much about."

Here's how scientists think it's sneaking into the well-guarded spinal cord and brain of a healthy person:

-The steroid injected near the spine reduces inflammation, one of the immune system's defenses against contamination.

-The mold grows quietly until enough accumulates for it to burrow a tiny hole, or abscess, into the lining of the spinal canal, said Dr. William Schaffner of Vanderbilt University. Reaching the spinal fluid inside offers a direct pathway to the brain.

-The fungus' color signals how intractable it is. Brown-black molds produce melanin, the same chemical that helps human skin tan. It guards against the sun's mold-killing ultraviolet rays - and inside people, it fends off both antifungal drugs and other immune-system attacks, Casadevall said.

The good news: Black mold is treatable with a drug named voriconazole, with far fewer side effects than the older treatment initially recommended when the outbreak began. Kauffman cautioned doctors to carefully monitor patients because differences in metabolism can make levels surge in the bloodstream, causing hallucinations, confusion, nausea and occasionally liver damage. On the flip side, their bodies may process the drug too quickly to battle the fungus. Plus, voriconazole can interact badly with a list of other common medications.

Other bad news? It is incredibly hard to diagnose and kill, and requires at least three months of a treatment that can cause hallucinations. There is no good way to predict survival, when it's safe to stop treating or exactly how to monitor those who fear the fungus may be festering silently in their bodies.

"I don't think there is a precedent for this kind of thing," said Dr. Arjun Srinivasan of the Centers for Disease Control and Prevention.

Doctors are beginning to detail in medical journals the first deaths in this outbreak, and the grim autopsy findings make clear that treating early is crucial, before the fungus becomes entrenched. In one case, a woman died after the fungus pierced blood vessels in her brain, leading to severe damage.

People getting treated earlier "seem to be doing OK," with fewer of the strokes that characterized the outbreak's beginning, Kauffman said,

It's not clear how long to treat but at least three months is advised, Kauffman said. It begins with intravenous infusions that are hard to administer outside of a hospital. Then once the patient is stable enough, pills can be used.

People who got contaminated steroid shots have been told to be on guard for months for meningitis symptoms. But the CDC said Wednesday that the biggest risk for getting sick seems to be within 42 days of receiving one of the implicated back injections.

With the tainted shots recalled in late September, that means the period of greatest risk is nearing an end. It should help doctors bombarded with calls from worried patients determine who most needs a spinal tap to look for the very earliest signs of infection. Still, public health officials recall a 2002 meningitis cluster linked to steroid injections contaminated with a different fungus; one of those victims got sick 152 days after the shot.

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