Multistate Fungal Meningitis Outbreak — Guidance For Physicians

Lieberman, Jay M., MD
Medical Director and Laboratory Director
Focus Diagnostics
Medical Director for Infectious Diseases
Quest Diagnostics
Cypress, CA Also by this Author 

The Centers for Disease Control and Prevention (CDC) report that, as of October 22, there have been 304 cases of fungal meningitis and 23 deaths related to epidural injections of a contaminated steroid product.1

Dr. Jay M. Lieberman, Medical Director of Infectious Diseases, Focus Diagnostics, highlights what is known, and not known, about this tragic outbreak and reviews CDC guidelines for evaluating and treating patients.

Status

The CDC and FDA continue to investigate an outbreak of fungal meningitis (and other invasive fungal infections) in the United States. These cases are occurring among people who received an epidural injection of a steroid, methylprednisolone acetate, usually for back pain. Three lots of the product,produced by New England Compounding Company (NECC), appear to have been contaminated with fungus. 75 facilities in 23 states received the potentially contaminated medication and it is estimated approximately 14,000 patients had at least one injection.1

Map of States that Received Recalled Lots of Methylprednisolone Acetate from NECC1

The list of facilities that received recalled lots of methylprednisolone acetate from NECC is available at: http://www.cdc.gov/hai/outbreaks/meningitis-facilities-map.html

As of October 23, there have been 304 cases of fungal meningitis in 17 states, with 23 deaths.1

Cases and Deaths with Fungal Infections Linked to Steroid Injections1

State Case Count Deaths
Florida (FL) 19 3
Georgia (GA) 1 0
Idaho (ID) 1 0
Illinois (IL) 1 0
Indiana (IN) 40 2
Maryland (MD) 17 1
Michigan (MI) 68 5
Minnesota (MN) 7 0
New Hampshire (NH) 10 0
New Jersey (NJ) 17 0
New York (NY) 1 0
North Carolina (NC) 2 1
Ohio (OH) 11 0
Pennsylvania (PA) 1 0
Tennessee (TN) 70 9
Texas (TX) 1 0
Virginia (VA) 41 2
TOTALS 308* 23

*304 cases of fungal meningitis, stroke due to presumed fungal meningitis, or other central nervous system-related infection meeting the outbreak case definition, plus 4 peripheral joint infections (e.g., knee, hip, shoulder, elbow). No deaths have been associated with peripheral joint infections

Case counts by state are based on the state where the procedure was performed, not the state of residence

On October 15, the FDA reported that a patient had been identified with possible meningitis associated with epidural injection of an additional NECC injectable steroid product, triamcinolone acetonide. In addition, a transplant patient with Aspergillus fumigatus infection who had been administered NECC cardioplegic solution during surgery was reported.  Investigation of this patient is ongoing and it has not been confirmed that this infection was caused by the NECC product.2

As a result, the FDA indicated that“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.” Although no cases of infection have been reported in connection with any NECC-produced ophthalmic drug, the FDA believes this class of products could present potentially similar infection risks.2

Fungal Meningitis - Symptoms

Exserohilum rostratum, a black mold, has been confirmed to be the pathogen in the vast majority of cases in which the etiology has been determined (45 of 47 laboratory-confirmed cases). It is a plant pathogen that had previously only rarely caused human disease.  Two patients have had other fungi isolated – Aspergillus fumigatus in one and Cladosporium in the other.1

 “Clinically, people with fungal meningitis usually present differently than patients with classic bacterial meningitis caused by pneumococcus or meningococcus,” explains Dr. Lieberman. “The presentation can be more insidious: slower onset, with more subtle symptoms in the initial stages.” The CDC states that some infected patients have had “very mild symptoms that are only slightly worse than usual.”1

Patients with fungal meningitis can have classic symptoms of meningitis, such as headache, fever, stiff neck, and photophobia, but may present with other neurologic manifestations, such as subtle gait disturbances, a history of falls, or stroke-like symptoms, including slurred speech, and new onset of weakness or numbness. The most common presenting signs and symptoms among 70 patients in the current outbreak were headache (81%), fever (34%), and nausea (30%).3 For fatal cases, the most frequent cause of death has been stroke or a complication of stroke.4

Increasing back pain or pain that is qualitatively different from the usual chronic back pain may be the only symptom of an epidural abscess or bone or disc infection.5

The incubation period for most patients has been between 1 to 4 weeks after the injections, but some patients have become sick after just 4 or 5 days, while another patient presented at 6 weeks.4

Patient Evaluation

The CDC coordinated active outreach to patients exposed to recalled lots of methylprednisolone acetate that have been implicated in the outbreak.Patients who have any symptoms have been instructed to see their clinician and be evaluated: “If patients have taken or used medications from New England Compounding Center, and they are worried that they are ill because of use of one of these products, they should seek medical attention.”1Clinicians are advised to have a “very low threshold for performing lumbar puncture” if patients have any symptoms suggesting central nervous system infection.5

The CDC guidelines recommend a thorough diagnostic work-up in an exposed patient with signs and symptoms of CNS infection or septic arthritis. An algorithm has been developed to guide clinicians, although the CDC emphasizes that these instructions are meant to supplement routine laboratory and microbiologic test deemed necessary by the clinical team. The CDC recommends that a lumbar puncture (LP) should be performed, if not contraindicated, on patients who received epidural injection with medication from the affected lots, and who have any symptoms of possible meningitis or basilar stroke.6

“Obviously the clinician should do any laboratory or microbiological evaluation that they think is indicated by the clinical presentation,” notes Dr. Lieberman. “But the bottom line is, when possible, they should get a large volume of cerebrospinal fluid (CSF) for evaluation. That CSF should be sent for routine studies, including gram stain and bacterial cultures, as well as cell count, glucose and protein. The priority after that is fungal culture, because that may be the only way to identify the offending pathogen if indeed there is meningitis.”

The CDC also requests that any remaining spinal fluid, ideally at least 1 mL, be sent to CDC for polymerase chain reaction(PCR), but only from patients who have abnormal CSF results (at least 5 WBC).6

There are currently no recommendations for a spinal tap or other evaluations on patients who received injections but are asymptomatic.6

Treatment

The CDC acknowledges that uncertainty concerning the possibility of other molds being involved in the outbreak, combined with the lack of data on Exserohilum meningitis, pose challenges to develop treatment recommendations. They recommend consultation with an infectious disease physician to assist with diagnosis, management, and follow–up.7

The current recommendation is to initiate treatment with voriconazole, preferably at a dose of 6 mg/kg every 12 hours, and to continue this dose, when possible, for the duration of treatment. Regular monitoring of serum voriconazole concentrations (e.g., weekly) is recommended, aiming for trough levels of 2-5 mcg/ml. Patients with more severe disease should be started on voriconazole IV.7

Providers are advised to consider adding liposomal amphotericin B to the voriconazole regimen in patients who present with severe disease, and in patients who do not improve or who experience clinical deterioration on voriconazole monotherapy. Liposomal amphotericin B should be given at a dose of 7.5 mg/kg IV daily.7

The duration of therapy has not yet been defined, but will be prolonged, probably at least 3 months.5

An Uncertain Situation

Dr. Lieberman stresses that the situation is fluid and recommendations will evolve as more data accumulate.

“There are a lot of things that we don’t yet know,” he continues. “We don’t know the risk posed by any individual injection, the sensitivity of our diagnostic tests, or the optimal treatment, including duration of therapy. So, we are all going to have to learn as we go along.”

As the outbreak continues to evolve, the CDC urges clinicians to aggressively seek a diagnosis in suspected cases and to check the CDC's website each day for changes in recommendations as the investigation unfolds.4

References

  1. Multistate Meningitis Outbreak Investigation. Centers for Disease Control and Prevention
    http://www.cdc.gov/hai/outbreaks/meningitis.html. Accessed 10/23/12
  2. FDA Statement on Fungal Meningitis Outbreak: Additional Patient Notification Advised. October 15, 2012. http://www.fda.gov/Drugs/DrugSafety/ucm322734.htm Accessed 10/16/12
  3. CDC. Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy — United States, 2012. Morbid Mortal Weekly Rep October 12, 2012;61 (Early release) http://www.cdc.gov/mmwr/preview/mmwrhtml/mm61e1012a1.htm?s_cid=mm61e1012a1_w
  4. Meningitis outbreak poses questions for experts, clinicians.Center for Infectious Disease Research & Policy, Academic Health Center, University of Minnesota
    http://www.cidrap.umn.edu/cidrap/content/other/news/oct1012fungal3br.html
  5. Kauffman CA et al. Fungal infections associated with contaminated methylprednisolone injections – preliminary report. N. Engl J Med 2012; October 19 http://www.nejm.org/doi/full/10.1056/NEJMra1212617
  6. Multistate Meningitis Outbreak Investigation. Instructions for Clinicians Regarding Diagnostic Testing and Specimen Shipping for Central Nervous System and Parameningeal Infections
    http://www.cdc.gov/hai/outbreaks/clinicians/instructions_testingandsubmission.html
    Accessed 10/22/12
  7. Multistate Meningitis Outbreak Investigation. Clinical Guidance
    http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html
    Accessed 10/22/12