How the Outbreak Evolved

Early in the outbreak, patients had symptoms of meningitis for weeks before the diagnosis was made. Neutrophilia in cerebrospinal fluid was extreme in many cases, and complications, including basilar-artery stroke, were common. 1-3,10,11 The incubation period for patients who presented with meningitis was 1 to 4 weeks after injection. After notifying patients at risk and performing lumbar punctures as soon as even mild headache occurred, clinicians began to see patients who had milder clinical disease.

As the outbreak evolved, it became increasingly rare for a patient to present with meningitis. The manifestations of infection changed to those related to localized infection at the injection site. Early in the outbreak, a few patients had increasing back pain as the prominent symptom and were found to have an epidural abscess or diskitis or vertebral osteomyelitis at the site of injection. It is now clear that in some centers, epidural abscess or phlegmon, arachnoiditis, and diskitis or vertebral osteomyelitis became the major disease manifestations. Michigan had a disproportionate number of these cases, and the pain clinic in which most of these injections were administered had received lot number [email protected] from the NECC. Fewer patients had infection of peripheral joints or bursae from the implicated lots, but 33 infections in these sites have been documented to date, with most of the patients presenting with increasing pain several months after injection.

Spinal Tap, Joint Aspiration, or Imaging Studies

Exposed patients were alerted to tell their physician about any new-onset headache, neck stiffness, photophobia, fever, or strokelike symptoms. Because the symptoms of CNS fungal infection are often more subtle than those usually seen with bacterial meningitis, there was a very low threshold for performing lumbar puncture if any symptom suggesting possible CNS infection occurred. Even with headache as the only symptom, values for cerebrospinal fluid have been abnormal in some patients. The criterion for initiating therapy was suggested to be a white-cell count above that which is considered normal (i.e., >5 cells per cubic millimeter). White-cell counts in patients in this outbreak of fungal meningitis have ranged from 13 cells to 15,000 cells per cubic millimeter, almost always with a neutrophil predominance. Glucose and protein levels were not suggested as criteria for initiating therapy. Most important, it was suggested that empirical antifungal treatment be given as soon as pleocytosis is detected in the cerebrospinal fluid, without waiting for results of diagnostic studies.

Increasing back pain, pain that differed in quality from the chronic back pain for which a patient received an epidural injection, or development of the cauda equina syndrome alerted physicians to the possibility of an epidural abscess or phlegmon, arachnoiditis, or diskitis or vertebral osteomyelitis at the site of injection. Magnetic resonance imaging (MRI) of the spine was suggested in such patients. Early symptoms of these complications were often subtle, and localized infection occurred most often without meningitis. It was suggested that any fluid or tissue obtained by means of aspiration or at the time of surgery should be sent for culture and PCR studies for exserohilum. Some centers embarked on a program to perform MRI in all patients who received an injection from the highly contaminated lot. Reports followed that some of these patients who had only subtle symptoms of back pain were found to have an epidural abscess or phlegmon requiring surgical intervention.

It was suggested that patients who received an intraarticular injection should be alert for new pain, especially if it differed in quality from their original pain, or if they had erythema or swelling of a joint. In such cases, it was suggested that aspiration of synovial fluid should be performed immediately for diagnostic studies. Given the variability in what is considered to be a normal number of white cells in synovial fluid, no firm guidance has been given for the number of cells required to initiate therapy. It was suggested that clinical judgment, along with the symptoms and signs of joint disease before the injection, should be used to make therapeutic decisions. If there was any question of whether infection was present, arthroscopy to obtain synovial fluid and possibly synovial biopsy for culture and PCR studies should be performed as soon as possible.

Treatment as the Epidemic Evolved

Recommendations for the treatment of this rare infection were based on small case series, individual case reports, and personal experience. A large number of patients in this outbreak were older adults, many of whom had substantial coexisting illnesses that made therapeutic decisions challenging. Treatment recommendations evolved during the outbreak as clinicians gained more experience with managing these infections. It was suggested that given the paucity of data pertaining to treatment and the complexity of management, decisions about the treatment of patients with proven or suspected infection should be made with the input of an infectious diseases specialist.

Initial recommendations for therapy were to use high doses of both liposomal amphotericin B and voriconazole because the causative organism was not known and the index patient had been shown to have infection with A. fumigatus. As events moved forward, it quickly became evident that the primary pathogen was a black mold, and clinical experience had shown that an azole was the usual drug of choice for infection with such organisms. In addition, a large number of patients had serious toxic effects from the high doses of amphotericin B that were recommended. Thus, the therapeutic regimen was modified in favor of monotherapy with voriconazole, except for the sickest patients or those who had substantial side effects while receiving this agent, for whom amphotericin B could play a role.

Voriconazole was selected over posaconazole and itraconazole for several reasons. First and foremost, there was experience in the use of voriconazole for various mold infections. Both intravenous and oral formulations were available, and oral administration produced serum levels equivalent to those achieved by intravenous administration. Levels of the drug in cerebrospinal fluid are approximately 50% of serum levels,12 and levels both in cerebrospinal fluid and in serum are above the MIC for many dematiaceous molds. By comparison, neither posaconazole nor itraconazole achieves substantial levels in cerebrospinal fluid, and their oral absorption can be erratic.