Fungal meningitis from contaminated drugs--clinical presentation

FUNGAL INFECTION, CONTAMINATED DRUG - USA (02)
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In this update:
[1] CDC clinical report
[2] 1st 4 cases in New Hampshire
[3] Additional case in Florida

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[1] CDC clinical report
Date: Fri 12 Oct 2012
Source: Morb Mortal Week Rep 2012; 61(early release): 1-4 [edited]
<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm61e1012a1.htm?s_cid=mm61e1012a1_w>


On 18 Sep 2012, the Tennessee Department of Health was alerted by a
clinician regarding a patient with culture-confirmed _Aspergillus
fumigatus_ meningitis diagnosed 46 days after epidural steroid
injection at a Tennessee ambulatory surgical center. By 27 Sep 2012,
the initial investigation, carried out by the Tennessee Department of
Health in collaboration with CDC [Centers for Disease Control and
Prevention] and the North Carolina Department of Health and Human
Services, had identified an additional 8 patients with clinically
diagnosed, culture-negative meningitis: 7 in Tennessee and one in
North Carolina. All 9 patients had received epidural steroid injection
with preservative-free methylprednisolone acetate solution (MPA)
compounded at New England Compounding Center (NECC) in Framingham,
Massachusetts. All 9 patients had received one or more injections from
3 lots of MPA (lot numbers 05212012@68; 06292012@26; and 08102012@51).
As of 10 Oct 2012, a multistate investigation led by CDC in
collaboration with state and local health departments and the FDA had
identified 137 cases and 12 deaths associated with this outbreak in 10
states. Active case-finding efforts and extensive investigation into
medications and medication lot numbers received by patients have
confirmed that, as of 10 Oct 2012, no cases were associated with other
lots of MPA, nor were any associated with other NECC products. This
report describes the ongoing investigation by CDC and state and local
health departments and includes important recommendations for
physicians and patients.

NECC was informed of the ongoing investigation on 25 Sep 2012 and
provided invoice information indicating that about 17 500 vials of MPA
(80 mg/mL) from these lots were packaged in 1mL, 2mL, and 5mL vials
and distributed to 75 facilities in 23 states. These lots of MPA were
used to treat both peripheral joint and back pain. On 26 Sep 2012,
NECC voluntarily recalled the 3 lots of MPA, followed by an expanded
voluntary recall of all lots of MPA and all lots of sterile products
intended for intrathecal injection on 3 Oct 2012. This was followed by
a voluntary recall of all remaining products on 6 Oct 2012.

Some patients received multiple injections with the 3 lots of MPA, and
some vials were unused. As of 10 Oct 2012, state and local health
departments had identified almost 14 000 persons potentially exposed
to medications from at least one of these lots. Active notification of
exposed persons was initiated by state health departments and CDC on
25 Sep 2012. Passive case finding was conducted by widely disseminated
notices of the potential contamination of the 3 MPA lots via Epi-X (a
CDC electronic public health notification system), through
professional societies and listservs, and the news media. As of 10 Oct
2012, state health departments had reported that about 90 per cent of
patients exposed to medication from one of the 3 lots of MPA recalled
on 26 Sep 2012 had been contacted at least once, by telephone,
voicemail, home visit, or registered mail.

As of 10 Oct 2012, 4 categories of cases in patients who received an
injection with MPA produced by NECC had been identified: 1) fungal
meningitis or nonbacterial and nonviral meningitis of subacute onset
following epidural injection on or after 21 May 2012; 2) basilar
stroke following epidural injection on or after 21 May 2012, in a
person from whom no cerebrospinal fluid (CSF) specimen was obtained;
3) spinal osteomyelitis or epidural abscess at the site of injection
following epidural or sacroiliac injection on or after 21 May 2012; 4)
septic arthritis or osteomyelitis of a peripheral joint (for example,
knee) diagnosed following injection of that joint on or after 21 May
2012. Clinical meningitis was defined as having one or more symptoms
(for example, headache, fever, stiff neck, or photophobia) and CSF
pleocytosis (more than 5 white blood cells per microL, adjusting for
presence of red blood cells), regardless of CSF protein and glucose
levels. Clinically diagnosed septic arthritis was defined as new or
worsening pain with presence of effusion or new or worsening
effusion.

As of 10 Oct 2012, 137 patients in 10 states had been identified who
met one or more of the 4 definitions, all of whom underwent injection
with one or more of the 3 lots of MPA from NECC. No cases associated
with other lots of MPA, or other NECC products, had been identified.
12 (9 per cent) of the 137 patients died. Preliminary data are
available on 70 (51 per cent) patients. Of these, 64 (91 per cent)
have meningitis. Of the 6 remaining patients, 2 (3 per cent) have
stroke without lumbar puncture, and 2 (3 per cent) have an epidural
abscess or osteomyelitis. Two patients (3 per cent) met more than one
case definition. Characteristics of the cases are shown in the table
below.

Median CSF white blood cell count was 1299/microL (range: 13-15 400)
with a neutrophilic predominance; median CSF glucose was 42 mg/dL
(range: 11-121), and median protein was 129 mg/dL (range: 45-588). As
of 10 Oct 2012, evidence of a fungal infection had been found in 26
(37 per cent) patients by culture, histopathology, or polymerase chain
reaction. The fungal species had been identified in 14 patients;
_Exserohilum spp_ was identified in 13, and _Aspergillus fumigatus_
was identified in one patient. Further specimen evaluation is ongoing
at CDC and state public health and local laboratories.

For the 61 patients with symptom onset date available, the earliest
date was 18 Aug 2012 (Figure [for figure, see original URL. - Mod.LL).
For the 48 patients with both injection date and symptom onset date
available for analysis, the median time from last steroid injection to
onset of symptoms was 15 days (range: 1-42). A total of 25 of the 48
patients received a single steroid injection; the median time from
injection to onset of symptoms for these patients was 16 days (range:
4-42).

[authors: Kainer M, Wiese AD, Benedict K, et al]

Editorial note
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Meningitis and parameningeal infections are extremely rare
complications of epidural injection, with few cases reported (1-3).
Most often, these infections are bacterial; rarely is a postepidural
injection meningitis case caused by fungi, and when present, fungal
infection is often diagnosed only after a patient fails to improve on
antibiotic therapy. Diagnosis of fungal meningitis, particularly in
cases caused by molds, is difficult because traditional diagnostic
methods such as culture have a low yield (4-6). Molecular methods such
as polymerase chain reaction have been useful for detection in some
cases but currently remain in use only as research tools.

The clinical presentation of fungal meningitis is often indolent, with
few patients displaying the classic meningeal signs of bacterial
meningitis. Early in this outbreak, many patients with meningitis had
only a few mild symptoms but had CSF pleocytosis. In addition, some of
these patients either presented with, or later developed, a stroke in
the posterior circulation (which supplies the cerebellum, midbrain,
and brainstem), a finding described in one prior case series of fungal
meningitis (6). Clinicians should be aware of the atypical
presentation of meningitis in this outbreak and should consider
performing lumbar puncture if patients have mild symptoms and have
received a steroid injection originating from one of the 3 implicated
lots of MPA. Early identification and treatment of patients with
fungal infections might reduce the risk for serious complications,
such as stroke or death. It is possible that the lower case-fatality
rate reported here compared with other case series might have resulted
from intensive patient notification and earlier diagnosis and therapy;
further investigation is needed.

Close follow-up of these patients is needed to understand important
clinical questions, such as the optimal medications, dosage, and
duration of treatment. To provide guidance on these important clinical
issues, CDC, in consultation with experts in the diagnosis and
treatment of fungal infections, has drafted interim treatment
guidelines for infections associated with this outbreak. Current
recommendations for treatment of central nervous system and
parameningeal infections include consultation with an infectious
disease physician and initiation of empiric antifungal therapy with
high dose voriconazole and liposomal amphotericin B. Treatment
duration is likely to be prolonged, on the order of months, and will
need to be tailored to individual patients. Routine use of adjuvant
steroids or intrathecal amphotericin B in treatment and postexposure
prophylaxis or screening of asymptomatic persons by lumbar puncture
currently are not recommended. These recommendations are subject to
change as more information becomes available.

As of 6 Oct 2012, all products manufactured since 1 Jan 2012 have been
recalled by NECC and should not be used. The FDA and Massachusetts
Board of Registration in Pharmacy investigation into the NECC facility
is ongoing and includes microbiologic testing of unopened vials of the
3 lots of MPA as well as additional NECC products. If not already
completed, providers should contact all patients exposed to any of the
3 lots of MPA recalled on 26 Sep 2012 to inquire about symptoms.
Patients who received epidural injection with medication from any of
the 3 lots of MPA 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 (for example,
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>.

References
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1. Cooper AB, Sharpe MD. Bacterial meningitis and cauda equina
syndrome after epidural steroid injections. Can J Anaesth 1996;43(5 pt
1): 471-474.
2. Snarr J. Risk, benefits and complications of epidural steroid
injections: a case report. AANA J 2007;75: 183-188.
3. Kolbe AB, McKinney AM, Kendi AT, Misselt D. Aspergillus meningitis
and discitis from low-back procedures in an immunocompetent patient.
Acta Radiol 2007;48: 687-689.
4. Verweij PE, Brinkman K, Kremer HP, Kullberg BJ, Meis JF.
Aspergillus meningitis: diagnosis by non-culture-based microbiological
methods and management. J Clin Microbiol 1999;37: 1186-1189.
5. Viscoli C, Machetti M, Gazzola P, et al. Aspergillus galactomannan
antigen in the cerebrospinal fluid of bone marrow transplant
recipients with probable cerebral aspergillosis. J Clin Microbiol
2002;40: 1496-1499.
6. Rodrigo N, Perera KN, Ranwala R, Jayasinghe S, Warnakulasuriya A,
Hapuarachchi S. Aspergillus meningitis following spinal anaesthesia
for caesarean section in Colombo, Sri Lanka. Int J Obstet Anesth
2007;16: 256-260.

Characteristics of patients (n=70) with fungal infections following
epidural steroid injection of methylprednisolone acetate from New
England Compounding Center -- United States, 2012

Median age (yrs) (range)
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68 (23-91)

Sex
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Male 22 (31 per cent)
Female 48 (69 per cent)

Case definition met
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Meningitis 64 (91 per cent)
Stroke without lumbar puncture 2 (3 per cent)
Epidural abscess 2 (3 per cent)
Multiple 2 (4 per cent)

Median incubation period (days from last injection) (range)
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15 (1-42)

Signs/symptoms
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Headache 57 (81 per cent)
Fever 24 (34 per cent)
Nausea 21 (30 per cent)
Photophobia 7 (10 per cent)
Meningeal signs 10 (14 per cent)
Gait disturbance 3 (4 per cent)
Falls 8 (11 per cent)
Stroke 12 (17 per cent)

Fungi identified by culture, PCR or histopathology (n=26)
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_Exserohilum spp_ 13 (50 per cent)
_Aspergillus spp_ 1 (6 per cent)

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[2] 1st 4 cases in New Hampshire
Date; Sat 13 Oct 2012
Source: Keene Sentinel [edited]
<http://www.sentinelsource.com/news/local/cases-of-fungal-meningitis-found-in-new-hampshire/article_a13c6c9c-1575-11e2-8250-001a4bcf887a.html>


The national outbreak of fungal meningitis has finally hit the Granite
State. The NH Department of Health and Human Services announced 4
cases in New Hampshire on Sat 13 Oct 2012 associated with steroid
medication produced by New England Compounding Center of Framingham,
MA.

The cases under investigation include 3 males and a female, all
between 40 and 60 years of age. No locations were given.

In New Hampshire, the medication believed to be related to this
outbreak was only distributed to Pain Care LLC's Somersworth,
Merrimack, and Newington locations. Pain Care has identified 741
patients who may have been exposed to the recalled product.

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[3] Additional case in Florida
Date: Sat 13 Oct 2012
Source: Associated Press [edited]
<http://www.cbs12.com/template/inews_wire/wires.regional.fl/2d4b3a8a-www.cbs12.com.shtml>


Florida now has 10 confirmed cases of fungal meningitis. The Florida
Department of Health confirmed on Saturday [13 Oct 2012] that Escambia
County has its case of fungal meningitis associated with contaminated
steroid injections from the New England Compounding Center. A 47 year
old man who received treatment from Pain Consultants of West Florida
in Pensacola was injected with one of the tainted shots.

Six facilities in Florida have received and used the contaminated
injections. Florida surgeon general and secretary of health Dr John
Armstrong says they do not anticipate "more patients will be affected"
as the investigation continues.

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[The moderator apologizes for not picking up the MMWR report for 24
hours. This report provides important information regarding the
clinical presentation of the cases of this frightening outbreak.
Additional reports from 13 Oct 2012 add 5 more cases to the mix,
crossing the 200 barrier to 203. - Mod.LL