JAMA Update on Fungal Meningitis Outbreak
Edward H. Livingston, MD
A recent outbreak of fungal meningitis cases has been followed by the US Centers for Disease Control and Prevention (CDC).1 Three lots of injectable steroids, derived from the New England Compounding Center (NECC), appear to be responsible for these cases. Although nearly all patients exposed to the contaminated steroid injection have been notified of their exposure, any patients who received an epidural or joint injection of steroids since May 21, 2012, should check with their physician regarding the risk for complications related to contaminated steroids.
Four clinical syndromes are associated with contaminated steroid injections: (1) subacute meningitis, (2) basilar stroke, (3) spinal osteomyelitis or epidural abscess, and (4) septic arthritis. Ninety-one percent of all cases attributable to the contaminated steroid material were meningitis. Because these disorders are caused by fungal contamination, they present very differently than their bacterial or viral counterparts. The disease onset is slow, and symptom development is more insidious.
The Rational Clinical Examination series in JAMA summarized the diagnostic approach for meningitis.2 In the Table, the typical meningitis presentation as summarized in the JAMA article is compared with fungal meningitis cases observed in the current outbreak and reported by the CDC.
| Table. Characteristics of Patients (N = 70) With Fungal Infections Following Epidural Steroid Injection of Methylprednisolone Acetate From New England Compounding Center—United States, 2012, Compared With Summary of Signs and Symptoms From Attia et al1 |
|
Characteristic
|
Attia et al,1 %
|
Current Fungal Cases Reported by CDC,3 %
|
Abbreviation: NR, not reported.
a Includes nuchal rigidity (alone for report by Attia et al), with Kernig and Brudzinski signs for current fungal cases.
|
|
Signs/Symptoms
|
|
Headache
|
50
|
81
|
|
Fever
|
85
|
34
|
|
Nausea
|
30
|
30
|
|
Photophobia
|
NR
|
10
|
|
Meningeal Signsa
|
70
|
14
|
|
Gait disturbance
|
NR
|
4
|
|
Falls
|
NR
|
11
|
|
Stroke
|
NR
|
17
|
Steroid injection fungal meningitis has an insidious onset, averaging about 15 days after the fungal exposure to develop. Signs and symptoms of meningitis are more subtle than those observed in bacterial or viral meningitis. As the Table shows, fevers are frequent with conventional meningitis, whereas headache is more prevalent with the current fungal disease.
Any patient who received epidural injections from the contaminated lots of steroids should be carefully observed. Any sign or symptom consistent with meningitis should result in a diagnostic lumbar puncture.2
The US Food and Drug Administration (FDA) issued an advisory on October 15, 2012,4 regarding fungal contamination of other NECC products. These include triamcinolone and cardioplegia solutions. Most of the prior cases were associated with injectable methylprednisolone. These additional concerns have led the FDA to advise physicians to closely monitor all patients who received any NECC product.
Although the first case report of fungal meningitis related to steroid injections was caused by Aspergillus fumigatus,5 most cases were caused by Exserohilum rostratum.6-8 Exserohilum is a pigmented plant fungus that usually does not cause human disease. As noted above, presentation of this unusual fungal meningitis differs from that for bacterial disease. The CDC and FDA frequently update their websites regarding the identification and treatment of steroid injection–associated meningitis as new information becomes available. It is recommended that physicians refer to these websites for the most current information regarding this unusual form of meningitis.
Four clinical syndromes are associated with contaminated steroid injections: (1) subacute meningitis, (2) basilar stroke, (3) spinal osteomyelitis or epidural abscess, and (4) septic arthritis. Ninety-one percent of all cases attributable to the contaminated steroid material were meningitis. Because these disorders are caused by fungal contamination, they present very differently than their bacterial or viral counterparts. The disease onset is slow, and symptom development is more insidious.
The recent outbreak of meningitis resulting from epidural steroid injections raises concerns about the safety of medications used in hospitals and ambulatory surgical centers. Physicians and patients should be aware of where medications originate when used in hospitals and outpatient clinics. Methylprednisolone, a steroid used for epidural injections for back pain, was obtained from a compounding pharmacy that was not following acceptable standards for preparing medications. As a result, injectable medications were contaminated by fungus that caused meningitis in a number of patients.
The company responsible for this outbreak was operating as a compounding pharmacy rather than as a manufacturer. Compounding pharmacies mix drugs in preparations customized for individual patients. This is done when the drug cannot be administered by commercially available preparations from drug manufacturers. Compounding pharmacies and manufacturers are regulated in very different ways. Compounding pharmacies, like all local pharmacies, are licensed by individual states and fall within state regulations for monitoring their operations. They should adhere to United States Pharmacopeia (USP) <795> (Pharmaceutical Compounding—Nonsterile Preparations) and <797> (Pharmaceutical Compounding—Sterile Preparations) standards. These standards provide sufficient protection for individual patients receiving medications custom made for them.
Drug manufacturers make, package, and distribute drugs in large quantities. They are regulated by the FDA. FDA regulations and standards are rigorous and designed to protect the public from large-scale exposure to defective or contaminated medications as occurred in the current meningitis outbreak. Compounding pharmacies can be registered by the FDA. When this occurs, the FDA monitors their activities as they would a drug manufacturer. Drug manufacturers are governed by rigorous FDA Good Manufacturing Practice (GMP) regulations that detail expectations for manufacturing processes, equipment, facilities, personnel, and associated considerations.
Hospitals and clinics obtain medications through their pharmacies. Depending on the organization, responsibility for purchasing pharmaceuticals and associated hospital supplies may be handled in different ways and with different levels of evaluation. Given recent events, it would be best to acquire medications from major, recognized drug manufacturers. If medications are obtained from compounding pharmacies processing large volumes of medications, these pharmacies should be FDA registered. In contrast, pharmaceutical manufacturers have a very rigorous supplier qualification program to evaluate their sources of drugs and excipients, packaging supplies, and other purchased materials.
When prescribing injectable medications or performing procedures in a hospital or clinic, physicians should ensure the medications used originate from a safe source. In hospitals, quality is governed by the medical executive committee. Physicians should work through this committee to ensure a hospital’s medication supply derives from safe sources.
About 14 000 people undergoing epidural injections for back pain were exposed to contaminated steroid, resulting in more than 400 cases of fungal meningitis. This outbreak highlights the importance of assessing risks of procedures, even if they are remote. Since complications are always possible following procedures, it is essential that interventions are only done for the appropriate indications. A recent Cochrane review9 of epidural injections for back pain highlighted the very limited evidence to support the use of this procedure. To date, very few properly controlled clinical trials investigated outcomes for these procedures. Given the limited evidence, it is generally recommended that these injections be used on a limited basis for patients with nerve pain caused by impingement or inflammation of spinal nerves. It is not appropriate to inject epidural steroids for back pain without nerve involvement. Pain relief can be expected only for a few weeks. These injections should not replace permanent solutions to nerve compression such as surgery. Patients should not have more than about 3 injections in the course of a year. Beyond those first few injections, no further benefit from these injections can be anticipated.
References
1. Attia J, Hatala R, Cook DJ, Wong JG. Does this adult patient have acute meningitis? JAMA. 1999;282(2):175-181. doi:10.1001/jama.282.2.175.
2. Straus SE, Thorpe KE, Holroyd-Leduc J. How do I perform a lumbar puncture and analyze the results to diagnose bacterial meningitis? JAMA. 2006;296(16):2012-2022. doi:10.1001/jama.296.16.2012.
3. Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy—United States, 2012. MMWR Morb Mortal Wkly Rep. 2012;61(early release):1-4. Published online October 12, 2012.
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm61e1012a1.htm?s_cid=mm61e1012a1_w#Tab1. Accessed October 17, 2012.
4. US Food and Drug Administration. FDA Statement on Fungal Meningitis Outbreak.
http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm. Accessed October 17, 2012.
5. Pettit AC, Kropski JA, Castilho JL, et al. The index case for the fungal meningitis outbreak in the United States [published online October 19, 2012]. N Engl J Med. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1212292. Accessed November 5, 2012.
6. Malani P. Infectious disease experts offer updated guidance on fungal meningitis cases. http://newsatjama.jama.com/2012/10/19/infectious-disease-experts-offer-updated-recommendations-on-fungal-meningitis-cases/. Posted October 19, 2012.
7. Kauffman CA, Pappas PG, Patterson TF. Fungal infections associated with contaminated methylprednisolone injections: preliminary report [published online October 19, 2012].
N Engl J Med.
http://www.nejm.org/doi/pdf/10.1056/NEJMra1212617. Accessed November 5, 2012.
8. Lyons JL, Gireesh ED, Trivedi JB, et al. Fatal Exserohilum meningitis and central nervous system vasculitis after cervical epidural methylprednisolone injection [published online October 17, 2012].
Ann Intern Med.
http://annals.org/article.aspx?articleid=1384432. Accessed November 6, 2012.
9. Staal JB, de Bie RA, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for subacute and chronic low back pain: an updated Cochrane review.
Spine (Phila Pa 1976). 2009;34(1):49-59.
http://www.ncbi.nlm.nih.gov/pubmed/19127161.
Three batches of a mixture containing steroids used to inject joints and backs for pain relief are contaminated with fungus. This can cause serious disease, including meningitis. Any patients who underwent an injection with these contaminated substances should contact their physician right away. At the time this update was written, 90% of all patients exposed to these fungi have been notified. If you were exposed and develop a headache, fever, or stiff neck, you should be seen by a physician as soon as possible.
Meningitis is the most serious disease caused by the fungus-contaminated steroids. The fungus-related disease presents differently than typical meningitis. Patients with the usual form of meningitis (bacterial or viral) get very ill quickly and usually develop fever, headache, and neck stiffness. Meningitis caused by fungus develops slowly, and patients may not develop all the classic signs and symptoms of meningitis. If a patient exposed to the fungus-containing steroids develops a headache, fever, or stiff neck, then a lumbar puncture (taking some fluid out of the spinal canal) should be performed to establish the diagnosis of fungal meningitis.
There are concerns that all products that came from the New England Compounding Center (NECC) may be contaminated with fungus. These include steroids used for spinal injections, some eyedrops, and solutions used to support the heart during cardiac bypass operations. Any medication packaged by the NECC company should not be used. Check with your physician if you are concerned that you may have been exposed to these products.
When undergoing procedures, patients should ask their physicians where medications that will be injected into them are obtained from. It is reasonable to expect that medications received were prepared using the most rigorous standards. See Knowing Medications Are Safe.
See also the following JAMA Patient Pages:
Meningitis. JAMA. 2007;297(1):122. doi:10.1001/jama.297.1.122.
Meningitis in children. JAMA. 1999;281(16):1560. doi:10-1001/pubs.JAMA-ISSN-0098-7484-281-16-jpg0428.
Lumbar puncture. JAMA. 2006;296(16):2050. doi:10.1001/jama.296.16.2050.
US Centers for Disease Control and Prevention. Multistate Fungal Meningitis Outbreak Investigation. http://www.cdc.gov/hai/outbreaks/meningitis.html.
The CDC has a free physician consultation service for fungal meningitis. It operates from 8:00 AM to 8:00 PM Monday through Friday (Eastern Time), except federal holidays: Call 1-800-CDC-INFO (1-800-232-4636).
US Food and Drug Administration. FDA Statement on Fungal Meningitis Outbreak. http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm.
Last updated: November 6, 2012