Fungal meningitis and arthritis from epidural, paraspinal and intra-articular injections with contaminated corticosteroid. Early status.

Abstract & Commentary

By Stan Deresinski, MD, FACP, FIDSA, Clinical Professor of Medicine, Stanford University, Hospital Epidemiologist, Sequoia Hospital, Redwood City, CA

This article originally appeared in the November 2012 issue of Infectious Disease Alert. It was peer reviewed by Timothy Jenkins, MD. Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.

An investigation initiated after a clinician reported to the Tennessee Department of Health on Sept. 18, 2012, the case of a patient who developed meningitis due to Aspergillus fumigatus after having received an epidural corticosteroid injection at an ambulatory surgical center quickly identified a number of other suspect cases.1 By September 27, another 7 patients in Tennessee as well as one in North Carolina who developed meningitis after epidural or paraspinal steroid injection had been identified, but in each case cerebrospinal fluid (CSF) cultures were apparently negative. Each of the injections had utilized a preservative-free solution of methylprednisolone acetate from one of 3 lots that had been compounded from at the New England Compounding Center (NECC). As of October 17, a continuing multistate investigation found that the number of identified cases was approaching 300, with 47 of these having laboratory-confirmed fungal meningitis. By October 22, there were 23 deaths reported, 9 of them in Tennessee. Some presented with basilar stroke rather than with a meningitis syndrome. In addition, “septic” inflammatory arthritis has been reported in 3 patients who had received intra-articular injections of the implicated product.

NECC voluntarily recalled the implicated lots, approximately 17,500 vials of which had been distributed to 75 facilities in 23 states, on September 26 and by October 6th expanded the recall to include all NECC products manufactured since Jan. 1, 2012. A total of almost 14,000 individuals were identified as possibly having been exposed and up to 97% have been notified.

Cases have been categorized as follows (all require that onset followed receipt of an injection of NECC-compounded methylprednisolone acetate after May 21):

• Fungal meningitis or nonbacterial and nonviral meningitis of subacute onset.

• Basilar stroke following epidural injection in a person from whom no CSF specimen was obtained.

• Spinal osteomyelitis or epidural abscess at the site of injection following epidural or sacroiliac injection.

• Septic arthritis or osteomyelitis of a peripheral joint (e.g., knee).

As of October 10, 12 (9%) of 137 patients from 10 states for whom information was available had died. Sufficient additional data to allow categorization was available for 70 of the 137: 64 (91%) had meningitis, 2 (3%) had basilar stroke without CSF examination, 2 (3%) had an epidural abscess or osteomyelitis, and 2 (3%) had both meningitis and epidural abscess or osteomyelitis. These 70 patients ranged in age from 23 to 91 years and 69% were women. At presentation, 81% complained of headache, 34% were febrile, 30% complained of nausea, and 10% had photophobia; 11% reported having fallen. Physical findings indicative of meningeal irritation were identified in only 14% while subtle gait disturbances were noted in 4%. The median time from injection to onset of symptoms for 25 patients who received a single steroid injection was 16 days (range, 4-42 days).

CSF white blood cell counts ranged from 13-15,400/mm3 (median, 1299/mm3) with neutrophilic predominance. CSF glucose ranged from 11-121 mg/dl (median, 42 mg/dl) while the range of protein concentrations was 45-588 mg/dl (median, 129 mg/dl). Laboratory confirmation of fungal infection was achieved in 47 patients as of October 17. Only the index case was due to A. fumigatus. Cladosporium was identified in one case, while the remaining 45 infections were caused by Exserohilum rostratum. Exserohilum as well as other fungi have been recovered from vials in the implicated lots.

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.2 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.3 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.4

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 amphotericin MIC of Exserohilum is reported to be 0.125-2.0 mcg/ml while that of both itraconazole and voriconazole is 0.04-0.5 mcg/ml.5 The CDC has recommended initiation of treatment with voriconazole at 6 mg/kg every 12 hours.6 It is further recommended that this dose, which is generally only used as a loading dose, be continued in order to increase the likelihood of achievement of adequate concentrations in the CNS. The serum concentration should be monitored with a view toward maintaining serum trough concentrations of 2-5 mcg/ml. Higher levels may be associated with an increased risk of toxicity. They also recommend consideration of the use of liposomal amphotericin B (7.5 mg/kg/d) instead in patients who present with severe disease or who fail to respond to voriconazole. CDC recommends against the intrathecal administration of amphotericin B and state “there is currently no clear evidence for the use of adjuvant steroid therapy.”

CDC currently does not recommend antifungal prophylaxis for asymptomatic potentially exposed patients who received epidural injections but instead, monitoring for symptoms with consideration of performing lumbar puncture, via a site other than that at which the injection had been administered, if these occur. They do not recommend performance of lumbar puncture in asymptomatic individuals.

This is not the first outbreak of fungal infections associated with contamination of products prepared by a compounding pharmacy. John Perfect has reminded us of the lessons that should have been learned from an outbreak of 5 cases of Exophiala meningitis or arthritis related to the use of contaminated preservative-free methylprednisolone acetate prepared by a compounding pharmacy during which he was involved in the recognition and management of some of the patients.7,8 The incubation period was reportedly as long as 6 months in one patient. The patients were treated with voriconazole with 3 of 4 with meningitis and one with sacroiliitis surviving.

An outbreak of fungal endophthalmitis involving 33 cases in 7 states occurred in March-April 2012 as the result of contamination of ocular products from a compounding pharmacy.9 Thirteen cases were associated with use Brilliant Blue-G dye and 13 with use of triamcinolone acetate; the former infections were caused by Fusarium incarnatum-equiseti species complex and the latter by Bipolaris hawaiiensis.

As of October 19, 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 of parameningeal infection or peripheral joint 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. 10

References

1. Centers for Disease Control and Prevention (CDC). Multistate outbreak of fungal infection associated with injection of methylprednisolone acetate solution from a single compounding pharmacy - United States, 2012. MMWR 2012;61:839-842.

2. 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. http://www.mycology.adelaide.edu.au/Fungal_Descriptions/Hyphomycetes_(dematiaceous)/Exserohilum/

6. http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html

7. Perfect JR. Latrogenic fungal meningitis: tragedy repeated. Ann Intern Med 18 October 2012.

8. CDC. Exophiala infection from contaminated injectable steroids prepared by a compounding pharmacy--United States, July-November 2002. MMWR 2002; 13;51(49):1109-12

9. CDC. Notes from the field:Multistate outbreak of postprocedural fungal endophthalmitis associated with a single compounding pharmacy - United States, March-April 2012. MMWR 2012;61(17):310-1.

10. 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