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Fungal meningitis outbreak affects over 700
In Context
Fungal meningitis outbreak affects over 700 Contaminated intrathecal methylprednisolone from a New England pharmacy has been linked to 51 deaths since last September, and the number of people affected continues to rise. Carrie Arnold investigates whether this outbreak is just the tip of the iceberg
www.thelancet.com/neurology Vol 12 May 2013
Epidemiologists traced the source of infection back to the injectable steroids produced by the Compounding Center, who voluntarily recalled three batches on September 26. These batches contained roughly 17 000 vials that were injected into about 14 000 patients. “When the New England Compounding Center did the recall and I saw how much had been distributed, I was really nervous,” Kainer said. “Then when we heard that North Carolina had a case and we found [the patients] had been given methylprednisolone acetate, I thought ‘Oh my God, this is going to be huge.’ I just knew it was going to be a horrendous outbreak, but I never expected it to be as bad as it is.” Inspectors from the US Food and Drug Administration (FDA) visited the Compounding Center after being notified of the outbreak. Their report showed areas near sterile mixers that were “visibly soiled with assorted debris,” and a leaky boiler that created an “environment susceptible to contaminant growth.” Shortly after this report, the pharmacy ceased production of all products. Officials of the Compounding Center refused to testify before Congress, but reportedly stated that incompetent janitors were to blame, rather than company practices or oversight of even the most basic hygiene measures. However the FDA noted that the pharmacy had had problems with sterility since 2006. A separate FDA investigation revealed that a quarter of the steroid vials had “a greenish black foreign matter” visible to the naked eye. When the FDA realised that the contamination issues extended far beyond a few batches of injectable steroid, they ordered the pharmacy to
cease production. The company filed for bankruptcy in December, 2012. However, for many patients, these investigations were too late. Often, patients did not receive medical attention until symptoms were already severe because no-one knew these people were at risk, noted Thomas Chiller, Associate Director for Epidemiological Science at the CDC. People went to their physicians or local emergency rooms complaining of fever, headache, stiff necks, and nausea. The non-specific nature of many of these symptoms meant that patients were often sent home with a prescription for painkillers or antibiotics and instructions to return if things got worse. And for many, things did get worse. The untreated fungal meningitis— caused by several types of fungi, including Exserohilum rostratum and Aspergillus fumigatus—resulted in systemic infections and strokes. A study by Kainer and colleagues in the New England Journal of Medicine showed that the most common causes of death for patients with fungal meningitis were either haemorrhagic or ischaemic stroke. Although Kainer
For the FDA inspection report on NECC see http://www.fda.gov/ downloads/AboutFDA/ CentersOffices/OfficeofGlobalReg ulatoryOperationsandPolicy/ORA/ ORAElectronicReadingRoom/ UCM325980.pdf For the NECC janitorial report to the Securities and Exchange Commission see http://www. sec.gov/Archives/edgar/data/ 717954/000128408413000005/ form10q-1q2013.htm For the CDC guidelines for clinicians see http://www.cdc. gov/hai/outbreaks/clinicians/ guidance_cns.html For the study by Kainer and colleagues see N Engl J Med 2012; 367: 2194–203
E Geuho/Science Photo Library
It seemed like an average Tuesday afternoon in mid-September to Marion Kainer, an epidemiologist at the Tennessee Department of Health, but an email about a strange case of meningitis from Vanderbilt University physician April Pettit in Nashville, Tennessee, changed that. The patient had all the signs of meningitis caused by a fungus. Fungal meningitis was practically unheard of in a nonimmunocompromised patient. Several weeks before the man became ill, he had received a spinal injection of steroids for chronic back pain. Kainer immediately telephoned Pettit to discuss the unusual finding. Unknown to Kainer, her follow-up sparked a nationwide investigation into an alarming number of fungal meningitis cases caused by injections of tainted steroids. As of March 25, 2013, 730 people had fallen ill and 51 had died, in an outbreak that has now extended across 20 US states. 2 days after she received Pettit’s email, Kainer had discovered two other patients from the same outpatient pain clinic who had also received epidural steroid injections and had been admitted to hospital with meningitis, although the cause had not been identified. The steroids used were all from the same batch of preservative-free solutions of methylprednisolone acetate from the same specialist pharmacy: the New England Compounding Center. Soon, other calls began to come in from Tennessee physicians who were seeing patients with fungal meningitis, all of whom attended the same pain clinic. 2 days later, on September 27, the Centers for Disease Control and Prevention (CDC) were notified of patients in North Carolina with similar symptoms to those of the Tennessee patients.
Electron micrograph of a conidiophore of Aspergillus fumigatus
429
In Context
noted substantial variability in case presentation, most patients reported symptoms that were consistent with bacterial meningitis—ie, headache, stiff neck, nausea, and back pain. However, lumbar punctures did not reveal any bacteria, just elevated concentrations of white blood cells and glucose. By October 19, a joint effort between the CDC, state and local health departments, and physicians, had notified 99% of the nearly 14 000 potentially exposed to the tainted steroids. Kainer’s preliminary data analysis did not identify any major factors explaining why, of 14 000 patients exposed, less than 1000 had fallen ill. Instead, a person’s likelihood of becoming ill has been considered a result of natural variation in the amount of fungus injected, storage and injection practices, and the person’s own immune system. Michigan was the other state hit hard by the outbreak. David Vandenberg, a hospitalist at St Joseph Mercy Hospital in Ann Arbor, Michigan, was so overwhelmed with the need to screen potential victims that he established the Fungal Outbreak Clinic, the only one of its kind in the country. The demand for CT and MRI scans was so intense that the hospital set up tents in the parking lots to manage the number of people that needed testing. Since the clinic opened in October, 2012, 629 patients have been screned for symptoms of fungal meningitis and 183 of these have been treated for either meningitis or focal fungal infections. At one point in midNovember, more than 80 patients were admitted at St Joseph’s alone. “We found a number of minimally symptomatic individuals who had pretty significant infections,” Vandenberg said. “There’s a sense that, to some degree, this disease is a bit dormant. We wonder if it could express itself at a later date if a patient is put on immunosuppressants.” Whereas many of the first patients seen in the outbreak had severe, fulminant 430
fungal meningitis, the severity of cases has waned over time. After the first wave of extremely severe cases with relatively short incubation periods, physicians began seeing patients with less intense forms of meningitis. “Incubation periods for fungi vary widely and can extend for months,” Chiller said. “There is evidence that in a number of these people, there is a smoldering infection.” As the outbreak has progressed, accumulating evidence suggests that the infections might be multiphasic. New preliminary data from the CDC show that a substantial proportion of patients are now presenting with localised infections, including epidural abscess, phelgmon, arachnoiditis, or vertebral osteomyelitis. Detection of focal fungal infections before they become systemic in these patients is complicated because many of them are people treated for chronic pain. The steroid injections are usually given in a painful area, such as the spinal cord or joints. Because one of the first symptoms of focal infections is pain, patients easily confuse these symptoms with the normal ebb and flow of their usual chronic pain. This factor has only added to the already long incubation periods of fungal infections. Because fungal meningitis is so rare, the CDC had no established protocols in place to handle an outbreak. Immediately after the CDC was notified, Chiller contacted the Infectious Diseases Society of America to assemble a specialist team of mycologists, neurologists, and infectious disease experts to provide guidance about how to treat these patients. Preliminary guidelines have been published on the CDC website. Treatment of a fungal infection is a long and difficult process, usually involving a cocktail of several potentially toxic medications. For patients of the Fungal Outbreak Clinic, discharge from the hospital is only the start of months of appointments and ongoing care. Vandenberg said that,
initially, liver and cardiac functions are monitored weekly in patients. Appointments become less frequent as time progresses. Treatment of focal infections or uncomplicated fungal meningitis are expected to take at least 3–6 months. For patients with osteomyelitis, treatment could continue for up to 1 year. Doctors are trying to balance the need to kill the fungi, with the serious side-effects of antifungal medication. “We’re treating a disease that has never been described before. In a way, the closest thing that one could probably compare it to is the early days of HIV, when you just didn’t know how something was going to behave,” Kainer said. Cooperation between physicians and public health officials was crucial to manage the outbreak and limit the extent of those affected. Communication between local, state, and federal agencies will be ongoing to ensure proper patient management and learn how to better treat others who might develop fungal meningitis. The CDC has convened the Mycosis Study Group to follow-up this group of patients and establish what the longterm effects of these infections might be, and how long they might need to continue treatment to successfully eradicate the fungi from their bodies. The outbreak also emphasises the inherent dangers of epidural corticosteroid injections. With no existing guidance, physicians cannot really predict what will happen next, Chiller said. Most of the patients with severe, acute forms of illness have been identified, either through case presentation or active screening. What remains is to better understand the disease course, from fulminant meningitis to smaller, smoldering infections. “It’s been an unprecedented, challenging outbreak, both from a clinical and public health standpoint,” Chiller concluded.
Carrie Arnold www.thelancet.com/neurology Vol 12 May 2013
Fungal meningitis outbreak affects over 700 Contaminated intrathecal methylprednisolone from a New England pharmacy has been linked to 51 deaths since last September, and the number of people affected continues to rise. Carrie Arnold investigates whether this outbreak is just the tip of the iceberg
www.thelancet.com/neurology Vol 12 May 2013
Epidemiologists traced the source of infection back to the injectable steroids produced by the Compounding Center, who voluntarily recalled three batches on September 26. These batches contained roughly 17 000 vials that were injected into about 14 000 patients. “When the New England Compounding Center did the recall and I saw how much had been distributed, I was really nervous,” Kainer said. “Then when we heard that North Carolina had a case and we found [the patients] had been given methylprednisolone acetate, I thought ‘Oh my God, this is going to be huge.’ I just knew it was going to be a horrendous outbreak, but I never expected it to be as bad as it is.” Inspectors from the US Food and Drug Administration (FDA) visited the Compounding Center after being notified of the outbreak. Their report showed areas near sterile mixers that were “visibly soiled with assorted debris,” and a leaky boiler that created an “environment susceptible to contaminant growth.” Shortly after this report, the pharmacy ceased production of all products. Officials of the Compounding Center refused to testify before Congress, but reportedly stated that incompetent janitors were to blame, rather than company practices or oversight of even the most basic hygiene measures. However the FDA noted that the pharmacy had had problems with sterility since 2006. A separate FDA investigation revealed that a quarter of the steroid vials had “a greenish black foreign matter” visible to the naked eye. When the FDA realised that the contamination issues extended far beyond a few batches of injectable steroid, they ordered the pharmacy to
cease production. The company filed for bankruptcy in December, 2012. However, for many patients, these investigations were too late. Often, patients did not receive medical attention until symptoms were already severe because no-one knew these people were at risk, noted Thomas Chiller, Associate Director for Epidemiological Science at the CDC. People went to their physicians or local emergency rooms complaining of fever, headache, stiff necks, and nausea. The non-specific nature of many of these symptoms meant that patients were often sent home with a prescription for painkillers or antibiotics and instructions to return if things got worse. And for many, things did get worse. The untreated fungal meningitis— caused by several types of fungi, including Exserohilum rostratum and Aspergillus fumigatus—resulted in systemic infections and strokes. A study by Kainer and colleagues in the New England Journal of Medicine showed that the most common causes of death for patients with fungal meningitis were either haemorrhagic or ischaemic stroke. Although Kainer
For the FDA inspection report on NECC see http://www.fda.gov/ downloads/AboutFDA/ CentersOffices/OfficeofGlobalReg ulatoryOperationsandPolicy/ORA/ ORAElectronicReadingRoom/ UCM325980.pdf For the NECC janitorial report to the Securities and Exchange Commission see http://www. sec.gov/Archives/edgar/data/ 717954/000128408413000005/ form10q-1q2013.htm For the CDC guidelines for clinicians see http://www.cdc. gov/hai/outbreaks/clinicians/ guidance_cns.html For the study by Kainer and colleagues see N Engl J Med 2012; 367: 2194–203
E Geuho/Science Photo Library
It seemed like an average Tuesday afternoon in mid-September to Marion Kainer, an epidemiologist at the Tennessee Department of Health, but an email about a strange case of meningitis from Vanderbilt University physician April Pettit in Nashville, Tennessee, changed that. The patient had all the signs of meningitis caused by a fungus. Fungal meningitis was practically unheard of in a nonimmunocompromised patient. Several weeks before the man became ill, he had received a spinal injection of steroids for chronic back pain. Kainer immediately telephoned Pettit to discuss the unusual finding. Unknown to Kainer, her follow-up sparked a nationwide investigation into an alarming number of fungal meningitis cases caused by injections of tainted steroids. As of March 25, 2013, 730 people had fallen ill and 51 had died, in an outbreak that has now extended across 20 US states. 2 days after she received Pettit’s email, Kainer had discovered two other patients from the same outpatient pain clinic who had also received epidural steroid injections and had been admitted to hospital with meningitis, although the cause had not been identified. The steroids used were all from the same batch of preservative-free solutions of methylprednisolone acetate from the same specialist pharmacy: the New England Compounding Center. Soon, other calls began to come in from Tennessee physicians who were seeing patients with fungal meningitis, all of whom attended the same pain clinic. 2 days later, on September 27, the Centers for Disease Control and Prevention (CDC) were notified of patients in North Carolina with similar symptoms to those of the Tennessee patients.
Electron micrograph of a conidiophore of Aspergillus fumigatus
429
In Context
noted substantial variability in case presentation, most patients reported symptoms that were consistent with bacterial meningitis—ie, headache, stiff neck, nausea, and back pain. However, lumbar punctures did not reveal any bacteria, just elevated concentrations of white blood cells and glucose. By October 19, a joint effort between the CDC, state and local health departments, and physicians, had notified 99% of the nearly 14 000 potentially exposed to the tainted steroids. Kainer’s preliminary data analysis did not identify any major factors explaining why, of 14 000 patients exposed, less than 1000 had fallen ill. Instead, a person’s likelihood of becoming ill has been considered a result of natural variation in the amount of fungus injected, storage and injection practices, and the person’s own immune system. Michigan was the other state hit hard by the outbreak. David Vandenberg, a hospitalist at St Joseph Mercy Hospital in Ann Arbor, Michigan, was so overwhelmed with the need to screen potential victims that he established the Fungal Outbreak Clinic, the only one of its kind in the country. The demand for CT and MRI scans was so intense that the hospital set up tents in the parking lots to manage the number of people that needed testing. Since the clinic opened in October, 2012, 629 patients have been screned for symptoms of fungal meningitis and 183 of these have been treated for either meningitis or focal fungal infections. At one point in midNovember, more than 80 patients were admitted at St Joseph’s alone. “We found a number of minimally symptomatic individuals who had pretty significant infections,” Vandenberg said. “There’s a sense that, to some degree, this disease is a bit dormant. We wonder if it could express itself at a later date if a patient is put on immunosuppressants.” Whereas many of the first patients seen in the outbreak had severe, fulminant 430
fungal meningitis, the severity of cases has waned over time. After the first wave of extremely severe cases with relatively short incubation periods, physicians began seeing patients with less intense forms of meningitis. “Incubation periods for fungi vary widely and can extend for months,” Chiller said. “There is evidence that in a number of these people, there is a smoldering infection.” As the outbreak has progressed, accumulating evidence suggests that the infections might be multiphasic. New preliminary data from the CDC show that a substantial proportion of patients are now presenting with localised infections, including epidural abscess, phelgmon, arachnoiditis, or vertebral osteomyelitis. Detection of focal fungal infections before they become systemic in these patients is complicated because many of them are people treated for chronic pain. The steroid injections are usually given in a painful area, such as the spinal cord or joints. Because one of the first symptoms of focal infections is pain, patients easily confuse these symptoms with the normal ebb and flow of their usual chronic pain. This factor has only added to the already long incubation periods of fungal infections. Because fungal meningitis is so rare, the CDC had no established protocols in place to handle an outbreak. Immediately after the CDC was notified, Chiller contacted the Infectious Diseases Society of America to assemble a specialist team of mycologists, neurologists, and infectious disease experts to provide guidance about how to treat these patients. Preliminary guidelines have been published on the CDC website. Treatment of a fungal infection is a long and difficult process, usually involving a cocktail of several potentially toxic medications. For patients of the Fungal Outbreak Clinic, discharge from the hospital is only the start of months of appointments and ongoing care. Vandenberg said that,
initially, liver and cardiac functions are monitored weekly in patients. Appointments become less frequent as time progresses. Treatment of focal infections or uncomplicated fungal meningitis are expected to take at least 3–6 months. For patients with osteomyelitis, treatment could continue for up to 1 year. Doctors are trying to balance the need to kill the fungi, with the serious side-effects of antifungal medication. “We’re treating a disease that has never been described before. In a way, the closest thing that one could probably compare it to is the early days of HIV, when you just didn’t know how something was going to behave,” Kainer said. Cooperation between physicians and public health officials was crucial to manage the outbreak and limit the extent of those affected. Communication between local, state, and federal agencies will be ongoing to ensure proper patient management and learn how to better treat others who might develop fungal meningitis. The CDC has convened the Mycosis Study Group to follow-up this group of patients and establish what the longterm effects of these infections might be, and how long they might need to continue treatment to successfully eradicate the fungi from their bodies. The outbreak also emphasises the inherent dangers of epidural corticosteroid injections. With no existing guidance, physicians cannot really predict what will happen next, Chiller said. Most of the patients with severe, acute forms of illness have been identified, either through case presentation or active screening. What remains is to better understand the disease course, from fulminant meningitis to smaller, smoldering infections. “It’s been an unprecedented, challenging outbreak, both from a clinical and public health standpoint,” Chiller concluded.
Carrie Arnold www.thelancet.com/neurology Vol 12 May 2013