Jörg Ruhe, MD MPH
Dr. Ruhe is Editorial Board member of the journal; Division of Infectious Diseases Beth Israel Medical Center, and Assistant Professor of Medicine Albert Einstein College of Medicine.
There has been a recent outbreak of fungal meningitis in the United States related to injections of contaminated steroid solutions, used for the treatment of peripheral joint and back pain. The first patient was reported to the Tennessee Department of Health on September 18, 2012 with a diagnosis of culture-confirmed Aspergillus fumigatus meningitis 46 days after an epidural steroid injection in a Tennessee ambulatory surgical center. As of October 22, 294 cases of central nervous infections and 3 patients with peripheral joint infections were reported from 16 states. 23 (8%) of these patients have so far died. Investigations by the CDC, state and local health departments have related all currently known cases to the injection of preservative-free methylprednisolone acetate solution from 3 lots which were distributed by the New England Compounding Center (NECC) in Framingham, Massachusetts. By September 26, all three lots were recalled by NECC, followed by an additional recall of all other company products soon after that. An estimated 14,000 persons have received injections with medication from at least one of these three lots in 23 states. Thus far it appears that the steroid solutions became contaminated due to poor quality control during compounding at NECC - which has been shut down - and the FDA is examining whether other of their products may have been similarly affected.
Patients have so far presented with 4 distinguishable clinical scenarios:
1. A fungal meningitis of subacute onset;
2. Basilar stroke (in persons from whom no lumbar puncture was performed);
3. Spinal osteomyelitis or epidural abscess; and
4. Septic arthritis or osteomyelitis of a peripheral joint (1).
All patients must have received epidural or peripheral steroid injections, respectively, on or after May 21, 2012. Meningitis is defined by pleocytosis of the spinal fluid (ie, >5 white cells per μl) in the presence of compatible clinical symptoms.
A recent analysis of 70 patients who met one or more of the 4 above listed definitions found that 91% had meningitis, 3% had a stroke, and 3% had an epidural abscess or osteomyelitis. The most common clinical symptom was headache (81%), followed by fever (34%), nausea (30%), and photophobia (10%). Acute clinical symptoms frequently seen with bacterial meningitis such as neck stiffness, a positive Brudzinski or Kernig’s sign were uncommon. Examination of the CSF revealed a wide range of white cell counts (13-15,400/μl), but showed a median WBC count of 1,299/μl with a neutrophil predominance; the median CSF glucose was 42 mg/dl and the median protein was 129 mg/dl (range: 45-588 mg/dl). Thus, CSF findings may appear quite similar to these seen with bacterial meningitis; however, the clinical course of fungal meningitis is more subacute and indolent.
At this point, 3 fungal species have been identified from clinical specimens by culture, polymerase chain reaction, and/or histopathology; 2 of them, Aspergillus fumigatus in the index patient, and Cladosporium from another clinical specimen, were only seen in isolated cases. From the vast majority of cases with a known etiology, Exserohilum rostratum has been identified. E. rostratum is a dark-walled mold that causes slowly progressing subcutaneous infections (“phaeohyphomycosis”), but also serious infections such as brain abscesses.
Currently recommended empiric therapy, in addition to antibacterial therapy until a pathogen is identified, for patients with suspected fungal meningitis and abnormal CSF findings consists of high-dose voriconazole 6mg/kg every 12 hours. Voriconazole serum concentrations should be monitored at least weekly. The addition of liposomal amphotericin B can be considered for specific patients such as those who present with severe disease. In confirmed cases of fungal meningitis, duration of therapy needs to be individualized based on the patient’s clinical response. Voriconazole is also recommended for the empiric treatment of patients with suspected fungal septic arthritis. Additional arthroscopic joint lavage and/or debridement may be indicated in these patients; synovial fluid or tissue should be sent for fungal culture, histopathological examination, and molecular testing prior to the initiation of antifungal therapy; standard tests for bacterial infection and crystal-induced disease should also be performed.
As per CDC recommendations, physicians who may have administered potentially contaminated methylprednisolone acetate injections between May 21, 2012 and the product recall date on September 26, 2012, should first confirm the manufacturer and lot number of the administered solution. Patients who had received steroid injections from one of these lots should immediately be contacted and questioned about any symptoms of meningitis or other focal infections as outlined above. Based on the experience from a previous fungal meningitis outbreak caused by contaminated steroid injections, patients should be observed for at least 6 months for the occurrence of disease symptoms. All patients with symptoms of meningitis should be referred for a diagnostic lumbar puncture - even if symptoms are only mild. If possible, the lumbar puncture needle should be inserted at a site different from the previous steroid injection. In contrast, a lumbar puncture or antifungal prophylaxis are not recommended for asymptomatic patients. However, close clinical monitoring for the occurrence of any new symptoms is important. An infectious diseases physician should be consulted to assist with the diagnosis, management, and follow-up of patients with positive clinical and/or laboratory findings. Suspected cases should be reported to the local state health department.
1. Morbidity and Mortality Weekly Report (MMWR). Multistate Outbreak of Fungal Infection Associated with Injection of Methylprednisolone Acetate Solution from a Single Compounding Pharmacy—United States, 2012. 2012;61(41);839-842.
2. Centers for Disease Control and Prevention. Meningitis Outbreak Multistate Fungal Meningitis Outbreak Investigation. http://www.cdc.gov/hai/outbreaks/meningitis-map.html; last accessed on October 22 2012.
3. Aquino VM, Norvell JM, Krisher K, Mustafa MM. Fatal disseminated infection due to Exserohilum rostratum in a patient with aplastic anemia: case report and review. Clin Infect Dis. 1995;20:176-178.
4.Centers for Disease Control and Prevention. Interim Treatment Guidance for Central Nervous System and Parameningeal Infections Associated with Injection of Contaminated Steroid Products. http://www.cdc.gov/hai/outbreaks/clinicians/guidance_cns.html; last accessed on October 22 2012.
5.Centers for Disease Control and Prevention. Interim Treatment Guidance for Osteoarticular Infections Associated With Injection of Contaminated Steroid Products. http://www.cdc.gov/hai/outbreaks/clinicians/interim_treatment_options_septic_arthritis.html; last accessed on October 22 2012.
6. Centers for Disease Control and Prevention. Update: Multistate Outbreak of Meningitis and Stroke Associated with Potentially Contaminated Steroid Medication. http://emergency.cdc.gov/HAN/han00328.asp; last accessed on October 22 2012.
7. Kauffman CA, Pappas PG, Patterson TF. Fungal infections associated with contaminated methylprednisolone injections — Preliminary report. N Engl J Med. 2012 Oct 19. [Epub ahead of print]
8.Centers for Disease Control and Prevention. What Should Physicians Be Doing? http://www.cdc.gov/hai/outbreaks/clinicians/what-physicians-should-be-doing.html; last accessed on October 22 2012.