Centers for Disease Control and Prevention

CDC officials meet at the beginning of the outbreak of fungal meningitis, which has now killed 39 people and made more than 600 ill.

A single phone call from a North Carolina clinic gave a Centers for Disease Control and Prevention investigator the heads up she needed to realize that an outbreak of fungal meningitis, which has now killed 39 people and made 620 sick, was likely going to be a national emergency.

The CDC published its first account on Wednesday of how state and federal investigators have handled the outbreak, and the agency warns the trouble is still not over. The report, published in the New England Journal of Medicine, describes how doctors, public health officials and clinic workers raced to track down patients at risk from lots of contaminated pain medication.

Dr. Rachel Smith had only been working at the CDC’s  fungal diseases branch for a year and a half when the reports came in last September about a patient at a Tennessee pain clinic who had a very unusual type of meningitis, apparently caused by a fungus. Dr. April Pettit, an infectious disease expert at Vanderbilt University who treated the patient,  had notified the Tennessee Department of Health, which in turn notified CDC.

There was a chance the contamination was a local problem, perhaps from dirty needles at the one clinic.

“We were certainly worried this could be a bigger issue but wanted to do due diligence,” Smith told NBC News in a telephone interview.

They’d already figured out that steroid injections might have been the source of the contamination and started calling pain clinics that may also have bought drugs from the same source: the New England Compounding Center in Framingham, Mass.

They asked the clinics to keep an eye out for patients with symptoms of fungal meningitis, such as headache, fever and pain where they got the injection. At some places, including the North Carolina clinic, Smith had to navigate layers of receptionists and she left multiple voicemails and messages.

“I still remember getting this call back from North Carolina,” Smith said. “They called me like three or four times, trying to get through because they no idea what this woman had, and when I called and said, ‘Hey do you have anyone with these symptoms?’ they said ‘Oh my god. That is what this woman has.'”

The next day, CDC officials started calling and emailing all 50 states. “It was really that one patient who turned the whole thinking about this outbreak,” Smith said.

And what made the CDC extra vigilant about the first few cases was the fact that NECC, the source of the steroids, was a compounding pharmacy. “Compounding pharmacies and compounded products had been the source of other outbreaks. When we saw this drug had been compounded we were a little more worried about it,” Smith said.

Since then, the Food and Drug Administration has found several batches of drugs made by NECC were contaminated with several species of fungus and bacteria. Inspections showed the pharmacy, which has since been closed, was filthy. Congress is investigating how FDA and state regulators allowed the pharmacy to operate far beyond its license, and the FDA is proposing new ways to regulate these companies.

The CDC’s report says it’s essential to make sure that drugs distributed by compounding pharmacies are clean.

“This outbreak shows that we need to make sure that drugs that are used for sterile injections are safe and uncontaminated,” Smith says. “The public has trust in us as public health officials and in the health system as a whole to deliver safe health care.”

Quick action by the public health system likely saved lives, said Smith. In other outbreaks of fungal infections the death rate has been around 40 percent. In this one, although as many as 14,000 people may have been injected with contaminated products, only 6 percent of those who were infected have died.

Without the alerts and publicity, many people may never have known why they were sick. For some patients, the first sign that something was seriously wrong was a stroke. Most had only vague symptoms -- headache, sometimes a fever, and sometimes pain where they were injected.

“Anecdotal data collected during the first week of the outbreak indicated that many of the initial patients had mild-to-moderate symptoms that ordinarily would not have prompted urgent medical evaluation,” the CDC report reads.

“We are still seeing cases and it’s not over yet,” Smith cautioned.

Now, more people are turning up with localized infections such as abscesses at the point of injection. But these can become very serious as the fungus works its way into tissue and even bone, where it is very hard to eradicate using antifungal drugs. Victims will have to take the drugs for weeks or months, and the antifungal medications themselves can damage the liver or kidneys.

Related stories:

• FDA to Congress: Fungal meningitis could happen again
• We didn't have the power to stop NECC, regulators say
• Compounding pharmacies - heroes or outlaws?

Two more drugs have been implicated in the ongoing outbreak of fungal meningitis linked to contaminated pain injections, federal health officials said Monday.

Both come from the same pharmacy, New England Compounding Center, that distributed the steroids suspected of sickening at least 214 people and killing 15 of them, the Food and Drug Administration said in a statement. 

One is a steroid called triamcinolone acetonide and another is a product used during heart surgery. While the FDA hasn’t confirmed that the two products are to blame, it’s issued a warning.

“A patient with possible meningitis potentially associated with epidural injection of an additional NECC product, triamcinolone acetonide, has been identified through active surveillance and reported to FDA,” the agency said in a statement.

“Triamcinolone acetonide is a type of steroid injectable product made by NECC. The cases of meningitis identified to date have been associated with methylprednisolone acetate, another similar steroid injectable product.” Both can be injected into the spine. The FDA didn't specify what the triamcinolone was being used for in this case. Methylprednisolone was being used to treat pain.

Until now, just three lots of methylprednisolone made by NECC had been suspected – but as many as 14,000 patients were treated with steroid from those three batches.

“In addition, two transplant patients with Aspergillus fumigatus infection who were administered NECC cardioplegic solution during surgery have been reported,” the FDA added. “Cardioplegic solution is used to induce cardiac muscle paralysis during open heart surgery to prevent injury to the heart.”

The agency said it is still investigating. “FDA has not confirmed that these three infections were, in fact, caused by an NECC product,” it said.

“At this point in FDA’s investigation, the sterility of any injectable drugs, including ophthalmic drugs that are injectable or used in conjunction with eye surgery, and cardioplegic solutions produced by NECC are of significant concern, and out of an abundance of caution, patients who received these products should be alerted to the potential risk of infection,” FDA added.

“At this time, no cases of infection have been reported in connection with any NECC-produced ophthalmic drug that is injectable or used in conjunction with eye surgery, but FDA believes this class of products could present potentially similar risks of infection.”

The FDA has warned NECC about eye drugs before. In 2006 it issued a long and detailed warning letter to the pharmacy, saying it was going far beyond its licensed authority in packaging and compounding drugs.

It took a special interest in the company’s repackaging of Avastin, a cancer drug. Avastin stops tumors from growing by starving them of blood supply. It can also help treat a common form of blindness called wet macular degeneration using the same mechanism.

Centers for Disease Control and Prevention

Aspergillus (left) and Exserohilum (right), the two molds linked with the ongoing outbreak of fungal meningitis.

The drug’s maker, Roche, has a different formulation of Avastin that is packaged specifically to be injected into the eye. This drug, called Lucentis, costs as much as $2,000 per dose, compared to $150 a pop for Avastin when reformulated by a compounding  pharmacist. NECC was taking Avastin and making an injectable version. The dose needed to treat the eye is much lower than the dose needed for treating colon and other cancers.

“FDA is particularly concerned about the manipulation of sterile products when a sterile container is opened or otherwise entered to conduct manipulations,” the agency said in its 2006 warning letter to NECC. “The moment a sterile container is opened and manipulated, a quality standard (sterility) is destroyed and previous studies supporting the standard are compromised and are no longer valid. We are especially concerned with the potential microbial contamination associated with splitting Avastin - a single-use, preservative-free, vial -- into multiple doses.”

Microbes that get into such an injection could damage vision or even blind patients. “The absence of control over storage, and delays before use after repackaging, only exacerbate these concerns,” the FDA said. It also warned NECC about other eye drugs it was preparing, and the latest notice appears to reflect those concerns.

Meningitis is an inflammation of the membrane surrounding the brain and spinal cord. Symptoms include fever, headache, stiff neck, nausea and vomiting and sensitivity to light. 

The Centers for Disease Control and Prevention updated its count of people affected by the outbreak. CDC says 214 people in 15 states have been infected. Most have meningitis, but two have infections apparently caused by steroid injections in the joints, including the ankle.

CDC also updated its guidance to doctors treating patients affected by the outbreak. Only patients who show clear signs of infection should be treated, the CDC says. At least two patients don’t have meningitis, but have evidence of infection from a steroid injection into a joint, including a patient in Michigan who was injected in the ankle.

Patients will likely have to undergo months of treatment with two antifungal drugs, voriconazole and amphotericin B. “Adequate duration of antifungal treatment is unknown, but patients likely will require prolonged therapy tailored by the clinical response to treatment,” CDC said.

But patients who have symptoms such as headache but who don’t show signs of inflammation should not get antifungal drugs, but should instead be watched carefully, the CDC advised. The two antifungal drugs can cause serious side effects, including kidney damage.

Federal officials recognized the doctors may be besieged and offered them a break. “We ask you to use your clinical judgment in deciding which patients are at risk and contact those patients in whatever communications mode you prefer, whether it is email, phone or letter. Face-to-face communication with patients is not necessary,” the FDA said.

Related stories:

The brothers-in-law at the heart of the fungal meningitis investigation

Fungal meningitis worries man who got suspect shots

Fungal meningitis outbreak has doc thinking about where they get drugs

Regulators say they had no clear power to stop outbreak

CDC

CDC officials, including Dr. John Jernigan, center, discuss the ongoing outbreak of fungal meningitis in the U.S.

A few more people have been diagnosed with a rare form of fungal meningitis linked to contaminated back pain injections, federal health officials said Friday.

A case was reported in Texas, bringing the total number of patients diagnosed to 185, with 14 deaths, the Centers for Disease Control and Prevention reported. Overall, patients have been diagnosed in 12 states.

The CDC and the Food and Drug Administration are working to confirm the source of the contamination, which is traced to three lots of steroid injections made at a Framingham, Massachusetts pharmacy. All of the drugs made at the pharmacy, the New England Compounding Center, have been recalled.

The CDC suggests more cases will turn up. The two molds that have been found in patients grow slowly and can cause very subtle symptoms, at least at first.

“Patients need to remain vigilant for onset of symptoms because fungal infections can be slow to develop. Typically in this outbreak, symptoms have appeared 1 to 4 weeks following injection, but it’s important to know that longer and shorter periods of time between injection and onset of symptoms have been reported,” the CDC said in a statement on its website.

Many of the patients who have died suffered strokes, so doctors may have to go back and check records to see if patients who received the steroid injections died of strokes that may not have been linked to the treatment.

CDC

Two types of fungi have been detected in the ongoing outbreak of meningitis related to contaminated steroid injections. Exserohilum, left, and Aspergillus, right, have been detected in patients.

All of the patients who have been confirmed with the infection got injections in the neck or spine of a steroid called methylprednisolone. There is also one patient in Michigan with an infection in the ankle, and it's not clear yet if he has a fungal infection, the CDC says.

The meningitis cannot be passed to anyone else. Patients who are diagnosed must undergo weeks of infusion with two antifungal drugs.

NECC and a sister company, Ameridose, have closed for the time being.  Dr. Madeleine Biondolillo, director of the Massachusetts health department's Bureau of Health Care Safety and Quality, said NECC had broken the rules "This organization chose to apparently violate the licensing regulations under which they were allowed to operate," Biondolillo told reporters in a telephone briefing Thursday.

She and an FDA official said state and federal agencies needed more guidance on how to regulate such pharmacies, which have morphed from small operations licensed to mix drugs on a case-by-case basis to large scale manufacturers.

Reuters reported late on Friday that NECC had cut its work force by at least half, laying off 40 or so workers."The events of the past two weeks are a great tragedy, and the thoughts and prayers of all those connected to New England Compounding Center continue to be with the individuals and families affected," the company said in a statement. "As a result of these events, on Thursday and Friday of this week NECC informed employees of a workforce reduction at the company - a necessary step under the current circumstances."

Related stories:

Compounding pharmacies - heroes or outlaws? 

Fungal meningitis worries man who got suspect shots

ERs the front line in fungal meningitis case

Health officials are working to track down everyone who may have been treated with an injection for lower back pain that is linked to an outbreak of rare fungal meningitis.  So far, 35 people have been diagnosed with the infection in six states and five of them have died.

At least 75 clinics in 23 states received batches of the steroid drug from a Massachusetts compounding pharmacy and have been told to notify all affected patients, health officials said.

"Unfortunately, despite the current recall, we expect to see additional cases as this investigation unfolds. However, it is possible if patients are identified soon and started on appropriate antifungal therapy some of the unfortunate consequences may be averted," Dr. Benjamin Park of the U.S. Centers for Disease Control and Prevention told reporters in a telephone briefing.

Food and Drug Administration officials warned health care workers not to use any drugs from the New England Compounding Center in Framingham, Mass., which has voluntarily ceased distribution of all of its products.

The 35 cases include 25 people in Tennessee, one in North Carolina, two in Florida, three in Virginia, two in Maryland, and in Indiana, the CDC reported. Three of the deaths were in Tennessee, one in Virginia and one in Maryland.

"Infected patients have presented approximately one to four weeks following their injection with a variety of symptoms including fever, new or worsening headache, nausea and our new symptoms consistent with a stroke," Park said. "Some of these patients symptoms were very mild in nature. Cerebrospinal fluid obtained from these patients has shown findings consistent with meningitis. It is important to note that this type of meningitis is not transmissible from person-to-person."

Health officials are asking anyone who had a spinal injection for pain and who has symptoms such as a headache, stiff neck, dizziness or trouble walking to see a doctor right away.

The drug is question is called methylprednisone and is used mostly to treat older patients for lower back pain.  Tennessee officials were the first to notice the unusual cases of meningitis, and discovered that the patients involved had all been treated at three specialty clinics. All had recieved direct injections of the steroid into their spines for pain. Women who received epidural infusions for childbirth are not in danger, the officials said.

Health officials have isolated aspergillus from five patients, CDC officials said. In addition, FDA officials detected fungal contamination in an unopened vial of methylprednisolone from one of three lots of 80-milligram injection doses recalled by the New England Compounding Center. 

"Looking under microscopic examination, it was identified as a fungal contaminant. For the sake of time, because we -- everything is unraveling and unfolding very quickly, we have not been able to further microbial testing of additional vials and what is necessary. So, right now, we can only say that it is a foreign material," FDA's Dr. Ilisa Bernstein said.

Everything the pharmacy made is being checked. Berstein said it's not clear how many potentially contaminated vials of steroid were distributed. "But if they are licensed in 50 states, there is a possibility that it could be elsewhere, not just this product, but as well as other products that they have made," she said.

Meningitis is an inflammation of the spinal cord, usually caused by bacteria or viruses. It can be very serious and is marked by a headache, fever, often a stiff neck and balance problems. Fungi and parasites can also cause this inflammation and in this case the common mold aspergillus is suspected.

Aspergillus is tricky to treat. It’s an infection that patients with damaged immune systems can get – notably cancer patients and those with HIV infection. It’s often found in the lungs because the mold – found in dead leaves and elsewhere -- can be breathed in. An antifungal drug called voriconazole can treat the infection but the health officials said in this case they want to be sure before they try it. The side effects from the antifungal treatment can be severe and include kidney and liver damage.

"Currently, we think that this type of meningitis is quite severe as we have been describing here. The antifungal treatment for this is intravenous antifungal treatment and requires initial hospitalization. But the duration of antifungal therapy could be prolonged possibly on the order of months," Park said.

Related links:

• Outbreak points to pharmacy problems
• Parents of killed toddler settle tainted wipes lawsuit
• Calif. lab worker died after handling rare meningitis strain

Getty Images stock

New research suggests that asthma patients can skip daily doses and just use their inhalers as needed.

Just about everyone with asthma knows the drill. Take a daily snort of a prescription inhaler filled with a steroid that helps fight inflammation, to prevent trouble. Not everyone actually does this, but patients with mild, persistent asthma know they are supposed to.

A study published on Tuesday questions this common wisdom, and offers the potential for millions of adults to be freed of having to take daily medication, not to mention the savings to patients, their employers, health insurance companies and the government. Caveat: The findings don't apply to kids with asthma.

"Daily treatment with an inhaled corticosteroid has long been believed to be the best treatment for mild persistent asthma, but it is not followed by the majority of patients,'' said Dr. Homer Boushey of the University of California San Francisco, who worked on the study. Boushey also helped the National Institutes of Health set guidelines for managing asthma.

"People don't seem to like taking this type of treatment every day -- just a third of the inhaler prescriptions are renewed even once,'' Boushey said. "So we wondered what would happen if people with mild asthma already well controlled by daily treatment with an inhaled corticosteroid instead took a puff only when they used their rescue medication -- usually albuterol -- for relief of symptoms.''

The researchers at 10 different universities studied 342 adults with moderate, persistent asthma. It was a small number of patients but an intense study, because the researchers assigned the volunteers to one of three different treatments: Being checked by a doctor and having the inhaler adjusted as needed every six weeks; getting checked and having the inhaler dose adjusted based on a measurement of exhaled nitric oxide, which tells doctors how much inflammation there is in the airways; or allowing patients to adjust their own inhaler use based on symptoms and taking one puff of their inhaled corticosteroid for every puff of albuterol.

In this case, the patients all got beclomethasone, a corticosteroid sold under a variety of brand names such as Qvar, Beconase, Beclovent or Vanceril. Other drugs in this category include fluticasone, sold under the brand name Flovent; budesonide, sold under the Pulmicort brand; mometasone or Asmanex and ciclesonide or Alvesco.

These drugs control the inflammation that can swell up airways, making it harder to breathe.

None of the groups fared any better or worse than the others. On average, they had the same number of flare-ups and symptoms, the researchers report in this week’s issue of the Journal of the American Medical Association.

“Asking patients to take their inhaled steroids only when they had symptoms was just as effective as having them take it every day and just as effective as having them take it using very sophisticated monitoring of inflammatory mediators in the airway,” Dr. William Calhoun of the University of Texas Medical Branch, who also worked on the study, said in a video commentary.  “So the simple question ‘how are you doing and are you having symptoms’ is just as good as sophisticated methods of adjusting corticosteroids.”

"This approach allows personalization of treatment and is easy for patients. Also, it could hypothetically result in saving $2 billion a year in medication costs,'' Boushey added.

About 25 million Americans, or 8 percent of the population, have asthma, according to the U.S. Centers for Disease Control and Prevention. It’s more than an annoyance. CDC says asthma killed 3,447 people in 2007. It costs the country about $3,300 per patient, for a total bill of $50 billion in 2007.

More than half of children and a third of adults who had an asthma attack missed school or work because of it in 2008.

In a commentary, Dr. George O'Connor of Boston University and Dr. Joan Reibman of New York University said it would save a lot of patients the inconvenience of having to take a drug daily if the results bear out in more study. But they said it's too early to change the guidelines just yet. "There is no compelling rationale to alter the current approach to inhaled corticosteroid dosing for mild or mild to moderate persistent asthma," they wrote.

Related stories:

• Asthma drug may stunt kids' growth permanently
• Magic bullet drug cuts severe asthma attacks in half
• High pollen counts send asthma patients to ERs

Does Tylenol worsen asthma?

An inhaled drug commonly used to treat children with asthma cuts about half an inch off their height permanently, researchers reported on Monday.

But the good news is that the stunting effect doesn’t get worse over time, the researchers report in the New England Journal of Medicine. They said doctors can work with parents to reduce the dose of the drug as much as possible to minimize the effects.

The drug is called budesonide and is marketed under several brand names, including Rhinocort and Pulmicort. It is very effective at controlling serious asthma, which affects an estimated 6 million U.S. children and millions more adults. So the researchers don't recommend taking kids off the drug if they need it.

A big study done more than a decade ago showed the drug was safe and very effective but doctors noted at the time that the kids in the study were about half an inch shorter if they got budesonide instead of other asthma treatments. The new study, presented at the European Respiratory Society Annual Congress in Vienna, Austria, shows the effect may be permanent.

“This was surprising because in previous studies, we found that the slower growth would be temporary, not affecting adult height,” said Dr. Robert Strunk of Washington University in St. Louis, who worked on the study.

“It clarifies that they do not eventually catch up as they age or fall further behind their peers,” added Dr. Gary Gibbons, director of the National Heart, Lung and Blood Institute.

The original study included more than 1,000 children aged 5 to 12 who got either budesonide, a non-steroid drug called nedocromil, or a placebo or sham treatment. William Kelly of the University of New Mexico and colleagues tracked down 943 of the original children, now adults. The children who got budesonide were still, on average, just about half an inch shorter.

In the original study, kids got a dose of 400 micrograms. Studies since have shown doctors can cut this dose in half and still control asthma, although kids who get even this lower dose are still just under half an inch shorter than children getting different treatments.

“This suggests that finding the minimum dose required to control each child’s asthma could help mitigate any potential effects on height,” Kelly said in a statement.

“If a child is not growing as they should, we may reduce their steroid dose,” agreed Strunk. “But we think that the half-inch of lowered adult height must be balanced against the well-established benefit of inhaled corticosteroids in controlling persistent asthma. We will use the lowest effective dose to control symptoms to minimize concerns about effects on adult height.”

Related links:

Watson gets approval for generic asthma drug

Dogs help prevent childhood asthma

Getting your kids asthma meds in school