Meningitis outbreak: From one strange case to nationwide outbreak

January 12th, 2015

An alert medical epidemiologist ultimately lost the patient she was trying to save, but there is little doubt she prevented other deaths by sounding the first alarm on a multistate meningitis outbreak that continues to unfold.

April Pettit, MD, an infectious diseases specialist at Vanderbilt University School of Medicine, began looking for other risk factors after finding that a patient was not responding to empiric antibiotic treatment for meningitis. Lab tests and word from family members that the patient had previously received a steroid shot for back pain at an outpatient clinic prompted Pettit to contact public health officials on Sept. 18, 2012. That was the index case in an unfolding 18-state outbreak, which as of October 25th was up to 328 patients infected and 24 dead.

The index case was a man in his 50s who presented 4 weeks after lumbar epidural injections with an 8-day history of headache and neck pain.1 His CSF protein concentration was 147 mg/dl, glucose 31 mg/dl and white blood cell count of 2304 cells/mm3 (72% neutrophils). He failed empiric antibacterial therapy and subsequent MRI of the brain and spinal cord showed meningeal enhancement and ventriculitis and a <1 cm fluid collection at L4-L5. CSF parameters were worse and after some initial improvement he had neurological deterioration at which time a CSF culture was found to be growing Aspergillus fumigatus and he was given voriconazole as well as liposomal amphotericin B (which had been initiated on the previous day). Retrospective analysis found that galactomannan antigen testing was positive on all CSF samples. Repeat MRI demonstrated midbrain and cerebellar infarcts. He then developed intraventricular and subarachnoid hemorrhage with worsening hydrocephalus and died.

Lyons and colleagues have described the cases of exserohilum infection in detail.2 A 51-year-old woman presented one week after a cervical epidural injection with a new occipital headache. The following day she was admitted after she developed diplopia, vertigo, nausea, and ataxia. Brain MRI was initially normal but her neurological disease progressed over the next 3 days, repeat MRI showed a small focus of diffusion restriction in the pons. Lumbar puncture was performed. The opening pressure was 34 cm H2O, while the CSF glucose was 105 mg/dl, protein 153 mg/dl, and white blood cell count 850/mm3, with 84% being neutrophils; Gram stain and culture were negative. Despite administration of acyclovir, cefepime, vancomycin, doxycycline and methylprednisolone, she continued to deteriorate and required intubation and mechanical ventilation. Repeat MRI showed areas of restricted diffusion in the pons, midbrain and cerebellum as well as diffuse meningeal enhancement. A new CSF sample was negative for several viral pathogens by PCR testing and histoplasmal and cryptococcal antigens were not detected; bacterial culture was negative.

MRI of the brain showed worsening disease with brainstem infarction and ventriculomegaly, the patient continued to deteriorate and died on the 10th day, on which day Exserohilum was identified in CSF culture. Post-mortem histopathological examination of her infarcted necrotic brainstem demonstrated angioinvasive septate hyphae. Exserohilum is a dematiaceous (dark-pigmented) filamentous fungus whose ecological niche is soil and plants. Human infections have rarely been reported with most cases involving skin and subcutaneous tissue, sinuses, and cornea, although osteomyelitis and endocarditis have been reported, as has disseminated infection in a patient with aplastic anemia.3

Many of the identified infections have been culture negative and only demonstrated to be due to Exoserohilum by amplification of 18S rRNA (“pan-fungal PCR”) followed by sequencing. As a result, it is recommended that, in addition to fungal culture (as well as studies to rule out other causes), CSF be sent to CDC for PCR testing. Use of plant-based agar has been suggested as a means of improving recover of Exserohilum in culture. Tissue specimens should be examined histologically and samples may be preserved at -70°C for future analyses.

The CDC recommends that -- if not already completed -- providers should contact all patients exposed to any of the three lots of MPA recalled on September 26 to inquire about symptoms. Patients who received epidural injection with medication from any of the three implicated lots of methylprednisolone acetate and who have symptoms of meningitis or posterior circulation stroke should be referred for diagnostic lumbar puncture, if not contraindicated. Patients with signs or symptoms infection (e.g., increasing pain, redness, or swelling at the injection site) should be referred for diagnostic evaluation, which might include aspiration of fluid collections or joint aspiration.

Although available preliminary data demonstrate incubation periods ranging from 4 to 42 days, the maximum incubation period for this infection is not known; therefore, asymptomatic but exposed patients should remain vigilant for symptoms and seek medical attention should symptoms develop. More guidance for patients and clinicians, including interim treatment guidelines, is available at http://www.cdc.gov/hai/outbreaks/meningitis.html.

A summary statement providing additional interim information for the clinician has been published. 5

-- Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA, editor of Infectious Disease Alert

References

1. Pettit AC, Kropski JA, Castilho JL, et al. The index case for the fungal meningitis outbreak in the United States. N Engl J Med October 19, 2012 DOI: 10.1056/NEJMoa1212292

3. Lyons JL, Gireesh ED, Trivedi JB, et al. Fatal Exserohilum meningitis and central nervous system vasculitis after cervical epidural methylprednisolone injection. Ann Intern Med Epublished 17 October 2012.

4. Aquino VM, Norvell JM, Krisher K, et al. Fatal disseminated infection due to Exserohilum rostratum in a patient with aplastic anemia: case report and review. Clin Infect Dis 1995;20(1):176-178.

5. Kauffman CA, Pappas PG, Patterson TF. Fungal nfections associated with contaminated methylprednisolone injections – preliminary report. N Engl J Med October 19, 2012 DOI: 10.1056/NEJMra1212617