As part of the Year in Review series, MedPage Today reporters are revisiting major news stories and following up with an analysis of the impact of the original report, as well as subsequent news on the topic. Here’s what’s happened with the fungal meningitis outbreak since we published our first report.
The fungal meningitis outbreak that made headlines in the fall was “unprecedented,” in the words of the of the clinicians at the eye of the storm.
What’s more, “we’re not out of the woods yet,” said Tom Chiller, MD, deputy director of the CDC’s mycotic diseases branch.
The outbreak was unprecedented for its size, for the spectrum of disease, for the clinical challenges that faced doctors, and for the way the pattern of illness has changed since the outbreak began, Chiller told MedPage Today.
It also has enormous implications for patients, their families, hospitals, and insurers, said Carol Kauffman, MD, a fungal infections expert at the University of Michigan in Ann Arbor, Mich.
“The extent and repercussions of this outbreak, in comparison to other smaller outbreaks, are really amazing,” Kauffman told MedPage Today. “The huge morbidity and, for some, mortality, is enormous.”
The outbreak, which has been linked to an injectable drug widely used to control chronic pain, has also seen the FDA under attack for not doing more to monitor so-called “compounding pharmacies.”
And the FDA has responded by saying it did not have clear authority to intervene, even though worries about the pharmacy in question, the New England Compounding Center (NECC) of Framingham, Mass., date back to at least 2002.
The agency is now asking for its authority to be clarified, although an organization representing compounding pharmacies has told lawmakers the FDA had all the power it needed, but just dropped the ball.
The bottom line from a public health standpoint is that as of Dec. 17, the CDC had recorded 620 cases of disease and 39 deaths. And more are likely, according to Chiller: “We’re still in the middle of this thing.”
Compounding Out of Bounds
The outbreak can be said to have started in the summer, when NECC made 17,675 vials of preservative-free methylprednisolone acetate, an injectable steroid, and shipped them to 76 healthcare facilities in 23 states.
That was problematic in itself: The company was licensed as a compounding pharmacy, meaning in principle it was allowed only to make up small quantities of specialized drugs, after getting a prescription from a doctor for an individual patient.
Instead, it was acting more like a large-scale drug manufacturer, and had been for some years, according to Massachusetts officials, which should have placed it under the FDA’s authority.
The manufacturing scale played a key role in what ensued: more than 13,000 people were exposed to the drug when they got injections – mainly into the spine – to control chronic pain.
They were also exposed to a fungal contaminant in the steroid vials, later found to be a black mold called Exserohilum rostratum, which only rarely causes human disease.
Oddly, the index case for the outbreak, reported to health authorities on Sept. 18, was a 56-year-old man in Nashville who had a case of meningitis apparently associated with the fungus Aspergillus fumigatus.
It is so far the only case in the outbreak in which A. fumigatus has been found, although a pathogen has not been definitively identified in all cases, largely because fungi are very hard to grow. And it has not been found in any of the unopened vials of the steroid.
Clinical Picture of the Outbreak
For the most part, the earliest cases presented with very severe symptoms, including stroke, Chiller said, and clinicians were initially grappling in the dark.
“When we started, early in the outbreak, we had some very sick people that died of strokes, some of which happened fast before we even knew what was going on,” he said.
But almost immediately the clinical picture of the outbreak began to change, largely because of the public health efforts of the CDC and state health authorities.
As events unfolded, details of the NECC customer list allowed health authorities to call thousands of pain patients and get them to hospitals for testing.
One effect of that, Chiller said, is that clinicians saw that unprecedented spectrum of disease – from the deadly symptoms seen commonly in the early days to milder illness that was only picked up because patients were called in for a spinal tap.
Would those patients with mild disease have gone on to become even more ill? No one really knows, but Chiller and his colleagues think they probably saved some lives.
A physician who was involved in combating a similar outbreak in 2002 credits the CDC with an impressive response to what he called a “national disaster.”
“I suspect there is nowhere in the world that an agency could respond so efficiently, rapidly, and accurately,” commented John Perfect, MD, of Duke University in Durham, N.C.
Indeed, if there is good news about the outbreak, it’s the CDC’s role, according to Kauffman.
The event “highlights the ability of the CDC to respond quickly in tracking this outbreak and providing timely updates and recommendations for treatment to clinicians,” Kauffman said.
A Clinical Conundrum
The outbreak had clinical puzzles from the beginning. Why did some patients show up with serious cerebrospinal illness, but no focal infection where they got the steroid shot?
Equally puzzling, why did some patients, initially treated for meningitis, later develop a focal infection at the injection site?
And why has there been a third wave of disease in which patients only have the focal infection?
For those latter patients, Chiller noted, “the challenge is just identifying them.” While they had pain at the injection site, he said, it was hard for patients to tell whether the pain was any worse than the baseline pain that initially led them have the steroid injection.
In the absence of the continuing public health effort, they might not have sought treatment. Whether they would then have developed more serious illness remains uncertain.
There was also the question of treatment, which was developed on the fly in the first few days and weeks of the outbreak – usually a combination of the anti-fungal drugs voriconazole (Vfend) and liposomal amphotericin B.
Both drugs have been used for years, but one lesson of the outbreak was how little was actually known about that combination, according to Kauffman.
The outbreak “reinforces the fact that we do not have ideal antifungal agents,” she said. “The experience with giving amphotericin B and voriconazole to these patients has been eye-opening.”
There were “many, many adverse effects, some of which, in the case of AmB, we were prepared for, but many, in the case of voriconazole, were not expected or were much more common than realized previously,” she said.
The optimum duration of therapy – especially given the adverse effects – remains an unanswered question. So far, according to Chiller, all treated patients remain on therapy, although many have been discharged from hospital.
How long that will last is anybody’s guess, especially because the effect of treatment on the fungal infections involved is difficult to monitor. If no pathogen can be isolated, is it gone? Or is it still there but just refusing to grow in the lab, or possibly in a dormant state?
“If we had injected people with steroids and a bacteria, this thing would be over,” Chiller said. But fungi, which he called “challenging, interesting, and unpredictable” organisms, have the ability to “hang out and do nothing,” he added.
Then, after a long period of apparent dormancy, they can begin again to cause disease, Chiller said.
And that may be linked to another puzzle of the outbreak – why some people got sick and others did not.
“We understand the route of infection,” Chiller said. “What we don’t understand and have a good handle on is what happened after the injection.”
Infection Control, Appropriate Oversight
While the outbreak is likely to give mycologists interesting research for some time, the bottom line is that contamination of a product that was supposed to be sterile led to hundreds of cases of disease, 39 deaths, and immense suffering.
The FDA has been blamed for not cracking down on the company involved much earlier. The head of the Massachusetts pharmacy board, which is charged with regulating compounding pharmacies in the state, was fired. The company itself is shuttered.
“This disastrous outbreak need not have happened if standard infection control techniques and appropriate oversight had been in place and heeded,” Kauffman said.
Like many others, she believes the federal government should regulate compounding pharmacies, something that is now in the hands of the states.
Under fire from lawmakers, FDA Commissioner Margaret Hamburg, MD, has said her agency’s authority over compounding pharmacies is “limited, unclear, and contested.”
She has suggested a tiered approach under which “traditional” compounding pharmacies – which made up prescriptions for individual patients in limited numbers – would continue to be regulated by states.
But “nontraditional” pharmacies, which make up large quantities of a drug in anticipation of orders, should come under FDA authority, Hamburg has said.
The International Academy of Compounding Pharmacists countered that the FDA already has all the authority it needs. In a statement to a House of Representatives committee, David Miller, RPh, the organization’s executive vice-president, said the problem was that NECC was breaking state laws in a way that gave the FDA clear authority to intervene.
Current law, he said, “allows FDA oversight when a pharmacy is not operating in conformity with governing state laws, or akin to a drug manufacturer.”
Both Miller and others have characterized NECC as a rogue company that was not interesting in complying with the law.
“Unfortunately, NECC showed a blatant disregard for existing rules and regulations,” Miller said.
Inspections of the Framingham plant showed lapses in processes that seemed almost certain to lead eventually to problems, if only because potential contaminants were everywhere.
“We know that sort of contaminant is ubiquitous,” Chiller said. “You need to have a system in place to eliminate them.”