Infectious Disease Experts Mull Fungal Meningitis Outbreak

Daniel M. Keller, PhD

October 22, 2012

SAN DIEGO, California — Experts presented the latest information and recommendations related to the recent outbreak of fungal meningitis and septic arthritis in a special session here at ID Week 2012.

The outbreak has been attributed to the use of preservative-free methylprednisolone acetate (MPA) for injections produced by the New England Compounding Center (NECC), a compounding pharmacy.

Tom Chiller, MD, MPHTM, deputy chief of the Mycotic Diseases Branch of the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, gave a brief history of the rapidly evolving situation.

On September 18, the Tennessee Department of Health was contacted about a culture-confirmed case of Aspergillus fumigatus meningitis diagnosed 46 days after an epidural steroid injection.

Seven more cases turned up in Tennessee and North Carolina, all traced back to NECC, which had distributed approximately 3 lots consisting of 17,500 vials to 75 facilities in 23 states. NECC voluntarily recalled the 3 lots on September 26. However, other injectable products made by NECC might also be involved.

The MPA in question has been implicated in clinical syndromes of fungal meningitis and nonbacterial or nonviral meningitis of subacute onset, basilar stroke, spinal osteomyelitis or epidural abscess at the site of injection, and septic arthritis or osteomyelitis of a peripheral joint after injection. It is possible that the MPA was administered to 14,000 patients.

As of today, there have been 254 cases of central nervous system (CNS) disease and 3 cases of peripheral joint infections. There 20 deaths have all been associated with CNS disease.

Two thirds of the initial 70 cases were women, and median age was 68 years (range, 23 to 91 years). Most (91%) had meningitis, and 3% to 4% each had stroke without lumbar puncture, epidural abscess, or multiple findings. Many patients with meningitis had only a few mild symptoms but had cerebrospinal fluid (CSF) pleocytosis.

Atypical presentations of meningitis are possible. The Infectious Diseases Society of America (IDSA) recommends that clinicians consider performing a lumbar puncture if patients have mild symptoms and have received a steroid injection from an implicated lot of MPA.

A letter published online October 17 in the Annals of Internal Medicine described the autopsy results of a woman who died from the infection. They revealed angioinvasive fungal disease with a grossly necrotic brainstem, diffuse vasculitis, and hemorrhagic infarction of the brain and spinal cord.

The diagnosis of septic arthritis should involve synovial fluid testing and radiographic imaging, according to IDSA.

Causative Organisms

Most of the cases have been caused by Exserohilum rostratum, a brown–black environmental fungus found in soil and on grasses. Aspergillus fumigatus and Cladosporium have been isolated once each.

The median incubation period from injection to the onset of symptoms has been 15 days (range, 1 to 42 days), but much longer periods are possible, and the IDSA advised that physicians be vigilant in this regard.

Cultures of CSF have not often been positive. If cultures are negative, the IDSA recommends reserving CSF for polymerase chain reaction testing rather than galactomannan testing.

Treatment and follow-up are probably best handled by an infectious diseases physician, if available. The interim recommended treatment of CNS or paraspinal infection is voriconazole 6 mg/kg every 12 hours, with the possible addition of liposomal amphotericin B for severe infection or progressive disease.

However, panelist Thomas Patterson, MD, professor of medicine and chief of the division of infectious diseases at the University of Texas Health Science Center at San Antonio, warned that "we're talking about drugs that are potentially very toxic."

Panelist Carol Kauffman, MD, professor of internal medicine at the University of Michigan and chief of infectious diseases at the Veterans Affairs Medical Center in Ann Arbor, said that for stable patients with suspected septic arthritis, it might be reasonable to wait up to 72 hours to confirm a diagnosis before initiating empiric antifungal therapy.

The IDSA recommends voriconazole at a loading dose of 6 mg/kg every 12 hours for 2 doses, followed by 4 mg/kg every 12 hours for the duration of treatment.

Guidance on the subject of these fungal infections is available on the CDC Web site.

Dr. Chiller and Dr. Kauffman have disclosed no relevant financial relationships. Dr. Patterson reports financial relationships with Astellas, Merck, Pfizer, Toyoma, and Viamet.

Ann Intern Med. Published online October 17, 2012. Letter

ID Week 2012. Presented October 18, 2012.