11-ID-15
Committee: Infectious Disease
Title: Case Definitions for Non-notifiable Infections Caused by Free-living Amebae
(Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp.)
I.
Statement of the Problem
Free-living amebae infections can cause corneal keratitis, blindness or severe, neurologic
illnesses that commonly result in death. Although these infections are rare and not currently
nationally notifiable, creating standardized case definitions would facilitate more systematic
collection of clinical, epidemiologic, and laboratory data to assist in understanding the risk
factors for infection with free-living amebae and increase the potential for development of future
prevention recommendations.
II. Background and Justification
Infections caused by free-living amebae (Naegleria fowleri, Balamuthia mandrillaris, and
Acanthamoeba [keratitis and non-keratitis infections]) have been well documented worldwide.
These amebae can cause fatal or severe skin, eye, and neurologic infections (e.g., N. fowleri
causes primary amebic meningoencephalitis [PAM]; B. mandrillaris and several species of
Acanthamoeba cause granulomatous amebic encephalitis [GAE]; and Acanthamoeba can also
cause keratitis). Annually, during 2005–2008, 3–6 fatal N. fowleri infections occurred
underscoring that although these infections are rare, the outcomes are often severe and can
undermine the public’s confidence in certain public recreational activities (e.g., swimming in
fresh water lakes). A recent case in a Northern tier state (with no history of recent travel)
indicates these organisms might be more geographically widespread than previously thought.
Clusters of cases associated with organ transplantation occurred in 2009 and 2010, indicating the
potential for multiple persons being affected by one source case. Currently, no standardized case
definitions exist to facilitate collection of uniform clinical, epidemiologic, and laboratory data, or
to serve as a guide for state and local health agencies to use in characterizing such severe
illnesses.
III. Statement of the desired action(s) to be taken
1. Establish standard reporting and case classification for non-notifiable diseases caused by
N. fowleri, B. mandrillaris, and Acanthamoeba spp. (including keratitis) and recommend
that any State or Territory conducting surveillance for these conditions using standard
reporting and case classification.
2. CSTE recommends that State and Territories conducting surveillance according to these
methods consider reporting case information to CDC.
3. CSTE recommends that CDC publish data on disease caused by N. fowleri, B.
mandrillaris, and Acanthamoeba spp. (including keratitis) as appropriate.
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In addition, CSTE calls upon CDC to 1) work with the American Medical Association and other
partners to expand physician education regarding the diagnosis and treatment of PAM, GAE,
Acanthamoeba keratitis, and other free-living amebic infections, and 2) increase public education
about PAM, GAE, Acanthamoeba keratitis, and other free-living amebic syndromes to promote
prevention and early recognition.
IV. Goals of Surveillance
Although free-living amebae infections are non-notifiable diseases, the purpose of this statement
is to provide standardized case definitions to facilitate better understanding of these diseases and
identify potential prevention measures.
The goals of surveillance for free-living amebae infections are to monitor the geographic
distribution and temporal trends in disease, and to collect standardized epidemiologic and
clinical data to better characterize the illnesses to inform prevention measures.
V. Methods for Surveillance:
Surveillance for free-living amebae infections should use the following recommended sources of
data and the extent of coverage listed in Table V.
Table V. Recommended sources of data for case identification and extent of coverage for
ascertaining cases of free-living amebae infections.
Source of data for case identification
Clinician reporting
Laboratory reporting
Reporting by other entities (e.g., hospitals,
veterinarians, pharmacies)
Death certificates
Hospital discharge or outpatient records
Extracts from electronic medical records
Telephone survey
School-based survey
Other: media accounts
Coverage
Population-wide
Sentinel sites
X
X
X
X
X
X
VI. Criteria for case identification
A. Narrative: A description of suggested criteria that may be for case ascertainment of a
specific condition.
Voluntary reporting of all illness to public health authorities that meets any of the following
criteria:
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1. Any person with clinical signs and/or symptoms consistent with primary amebic
meningoencephalitis, granulomatous amebic encephalitis, or corneal keratitis who has a
positive laboratory test for N. fowleri, Acanthamoeba spp., or Balamuthia spp. These
tests may include any of the following:
a. Isolation of free-living amebae in culture from a clinical specimen
b. Detection of free-living amebae antigen or nucleic acid from a clinical specimen
2. Any person whose healthcare record or death certificate contains a diagnosis of primary
amebic meningoencephalitis, granulomatous amebic encephalitis, or Acanthamoeba
keratitis
3. Any person with ocular or neurologic manifestations consistent with free-living amebae
infection after having receiving an organ or transplanted tissue from a person confirmed
or suspected to have a free-living amebae infection
Table VI-B. Table of criteria to determine whether a case should be reported to public
health authorities.
Criterion
Reporting
Clinical Evidence
Primary amebic meningoencephalitis
O
Granulomatous amebic encephalitis
O
Acanthamoeba corneal keratitis
O
A person whose healthcare record contains a diagnosis of
S
primary amebic meningoencephalitis, granulomatous amebic
encephalitis, or Acanthamoeba keratitis
A person whose death certificate contains a diagnosis of
S
primary amebic meningoencephalitis, granulomatous amebic
encephalitis, or Acanthamoeba keratitis
Laboratory Evidence
Isolation of N. fowleri, Acanthamoeba spp., or Balamuthia
O
spp. in culture from clinical specimen
Detection of N. fowleri, Acanthamoeba spp., or Balamuthia
O
spp. antigen or nucleic acid from clinical specimen
Epidemiological Evidence
Any person with ocular or neurologic manifestations
S
consistent with free-living amebae infection after having
receiving an organ or transplanted tissue from a person
confirmed or suspected to have a free-living amebae
infection
Notes:
S = This criterion alone is Sufficient to report a case.
N = All “N” criteria in the same column are Necessary to report a case.
O = At least one of these “O” (Optional) criteria in each category (e.g., clinical evidence and
laboratory evidence) in the same column—in conjunction with all “N” criteria in the same
column—is required to report a case.
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C. Disease-specific data elements
Disease-specific data elements to be included in the initial report are listed below.
Basic demographics (e.g. age, sex, race, ethnicity, state of residence)
Clinical Information
 Date of onset
 Reported symptoms of illness
 Recorded diagnoses
 Hospitalization
 Outcome
 Concurrent or pre-existing conditions (to include any recent trauma or
immunosuppressing conditions)
 Medication and treatment
 Results of biopsies and cerebrospinal fluid studies (if applicable)
Epidemiological Risk Factors
 Recreational or occupational water exposure in past 10 days (including type of water
venue, location, and date[s] of exposure)
 Description of water-related activities (e.g., head submersion, diving, rough horseplay,
water skiing, use of water slides, swings or other equipment at recreational water venue)
or other outdoor activities (e.g., landscaping, gardening)
 Environmental conditions during period of water exposure if available (e.g., ambient air
temperature, water temperature, water turbidity, presence of aquatic vegetation at
recreational water venue, source of water)
 Travel in past 10 days
 Contact lens use (for corneal keratitis)
 Recent ill contacts
 Illness among coparticipants at recreational water venue
 Drinking untreated water
 Receipt of organs or tissues from persons having confirmed or suspected free-living
amebae infection
Laboratory Information
 Method(s) of laboratory testing (culture, PCR, antigen)
 Type of antigen testing
 Molecular characterization of organism (if available)
VII. Case Definition for Case Classification
A. Narrative: Description of criteria to determine how a case should be classified.
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1) Naegleria fowleri Causing Primary Amebic Meningoencephalitis (PAM)
Clinical description
N. fowleri is a free-living ameboflagellate that invades the brain and meninges via the nasal
mucosa and olfactory nerve to cause acute, fulminant hemorrhagic meningoencephalitis (primary
amebic meningoencephalitis – PAM), primarily in healthy children and young adults with a
recent history of exposure to warm fresh water. Initial signs and symptoms of PAM begin 1 to 14
days after infection and include sudden onset of headache, fever, nausea, vomiting, and stiff neck
accompanied by positive Kernig’s and Brudzinski’s signs. In some cases, abnormalities in taste
or smell, nasal obstruction and nasal discharge might be seen. Other symptoms might include
photophobia, mental-state abnormalities, lethargy, dizziness, loss of balance, other visual
disturbances, hallucinations, delirium, seizures, and coma. After the onset of symptoms, the
disease progresses rapidly and usually results in death within 3 to 7 days. Although a variety of
treatments have been shown to be active against amebae in vitro and have been used to treat
infected persons, most infections have still been fatal.
Laboratory-confirmed N. fowleri infection is defined as the detection of N. fowleri
1) Organisms in CSF, biopsy, or tissue specimens, or
2) Nucleic acid (e.g,. polymerase chain reaction) in CSF, biopsy, or tissue specimens, or
3) Antigen (e.g., direct fluorescent antibody) in CSF, biopsy, or tissue specimens.
Case classification
Confirmed: a clinically compatible illness that is laboratory confirmed.*
* When available, molecular characterization should be documented (e.g., genotype).
Comment
N. fowleri might cause clinically similar illness to bacterial meningitis, particularly in its early
stages. Definitive diagnosis by a reference laboratory might be required. Unlike Balamuthia
mandrillaris and Acanthamoeba spp., Naegleria fowleri is commonly found in CSF.
2) Balamuthia mandrillaris Disease
Clinical description
B. mandrillaris is an opportunistic free-living ameba that can invade the brain through the blood,
probably from a primary infection in the skin (from ulcers or dermatitis), sinuses, or via organ
transplantation. The incubation period is not well-characterized but has been observed to range
from 2 weeks to months or possibly years. Once in the brain, the amebae can cause
meningoencephalitis and/or granulomatous amebic encephalitis (GAE). B. mandrillaris GAE
often has a slow, insidious onset and develops into a subacute or chronic disease lasting several
weeks to months; however, B. mandrillaris infections associated with organ transplantation have
an especially rapid clinical course. B. mandrillaris GAE affects both immunocompetent persons
and persons who are immunosuppressed from a variety of causes (e.g., HIV/AIDS, organ
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transplantation). Initial symptoms of B. mandrillaris GAE might include headache, photophobia,
and stiff neck accompanied by positive Kernig’s and Brudzinski’s signs. Other symptoms might
include nausea, vomiting, low-grade fever, muscle aches, weight loss, mental-state
abnormalities, lethargy, dizziness, loss of balance, cranial nerve palsies, other visual
disturbances, hemiparesis, seizures, and coma. Painless skin lesions appearing as plaques a few
millimeters thick and one to several centimeters wide have been observed in some patients,
especially patients outside the U.S., preceding the onset of neurologic symptoms by 1 month to
approximately 2 years. Once the disease progresses to neurologic infection, it is generally fatal
within weeks or months; however, a few patients have survived this infection.
Laboratory criteria for diagnosis
Laboratory-confirmed B. mandrillaris infection is defined as the detection of B. mandrillaris
1) Organisms in CSF, biopsy, or tissue specimens, or
2) Nucleic acid (e.g,. polymerase chain reaction) in CSF, biopsy, or tissue specimens, or
3) Antigen (e.g., direct fluorescent antibody) in CSF, biopsy, or tissue specimens.
Case classification
Confirmed: a clinically compatible illness that is laboratory confirmed.*
* When available, molecular characterization should be documented (e.g., genotype).
Comment
B. mandrillaris and Acanthamoeba spp. can cause clinically similar illnesses and might be
difficult to differentiate using commonly available laboratory procedures. Definitive diagnosis
by a reference laboratory might be required. A negative test on CSF does not rule out B.
mandrillaris infection because the organism is not commonly present in the CSF.
3) Acanthamoeba Disease (excluding keratitis)
Clinical description
The genus Acanthamoeba includes several species of opportunistic free-living amebae that might
invade the brain through the blood, probably from a primary infection in the skin (from ulcers or
dermatitis) or sinuses. Once in the brain, the amebae cause granulomatous amebic encephalitis
(GAE). Acanthamoeba GAE has a slow and insidious onset and develops into a subacute or
chronic disease lasting several weeks to months. Acanthamoeba GAE affects both
immunocompetent persons and persons who are immunosuppressed from a variety of causes
(e.g., HIV/AIDS, organ transplantation). Initial symptoms of Acanthamoeba GAE might include
headache, photophobia, and stiff neck accompanied by positive Kernig’s and Brudzinski’s signs.
Other symptoms might include nausea, vomiting, low-grade fever, muscle aches, weight loss,
mental-state abnormalities, lethargy, dizziness, loss of balance, cranial nerve palsies, other visual
disturbances, hemiparesis, seizures, and coma. Once the disease progresses to neurologic
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infection, it is generally fatal within weeks or months. However, a few patients have survived
this infection.
Laboratory-confirmed Acanthamoeba spp. infections (excluding keratitis) are defined as the
detection of Acanthamoeba spp.
1) Organisms in CSF, biopsy, or tissue specimens, or
2) Nucleic acid (e.g,. polymerase chain reaction) in CSF, biopsy, or tissue specimens, or
3) Antigen (e.g., direct fluorescent antibody) in CSF, biopsy, or tissue specimens.
Case classification
Confirmed: a clinically compatible illness that is laboratory confirmed.*
*When available, species designation and molecular characterization (e.g., genotype)
should be documented.
Comment
Acanthamoeba and B. mandrillaris can cause clinically similar illnesses and might be difficult to
differentiate using commonly available laboratory procedures. Definitive diagnosis by a
reference laboratory might be required. Several species of Acanthamoeba are associated with
infection (i.e., A. castellanii, A. culbertsoni, A. hatchetti, A. healyi, A. polyphaga, A. rhysodes, A.
astonyxis, A. lenticulata and A. divionensis). A negative test on CSF does not rule out
Acanthamoeba infection because the organism is not commonly present in the CSF.
4) Acanthamoeba keratitis
Clinical description
Acanthamoeba keratitis is a local infection of the cornea (outer layer of the visual pathway of the
eye) caused by a microscopic, free-living ameba belonging to the genus Acanthamoeba.
Symptoms include foreign body sensation, photophobia, decreased visual acuity, tearing, pain,
and redness of the eye. It occurs most typically among healthy, contact lens users, but can occur
in anyone. Although treatable with topical medications, affected individuals are at risk for
permanent visual impairment or blindness. Acanthamoeba organisms are ubiquitous in nature
and can be found in bodies of water (e.g., lakes and oceans), soil, and air.
Laboratory-confirmed Acanthamoeba spp. keratitis infections are defined as the detection of
Acanthamoeba spp.
1) Organisms in corneal scraping, or biopsy specimens, or
2) Nucleic acid (e.g., polymerase chain reaction) in corneal scraping, or biopsy specimens,
or
3) Antigen (e.g., direct fluorescent antibody) in corneal scraping, or biopsy specimens.
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Case classification
Confirmed: a clinically compatible illness that is laboratory confirmed.*
*When available, species designation and molecular characterization (e.g.,
genotype) should be documented.
Probable: a clinically compatible illness with positive identification of Acanthamoeba
trophozoites or cysts using confocal microscopy.
B. Classification Tables
Table VII-B. Criteria for defining a case of free-living amebae infection.
Criterion
Clinical Evidence
Primary amebic
meningoencephalitis
Granulomatous
amebic encephalitis
Corneal keratitis
Laboratory evidence
Isolation of N. fowleri,
Acanthamoeba spp.,
or Balamuthia spp. in
culture from clinical
specimen
Detection of N.
fowleri,
Acanthamoeba spp.,
or Balamuthia spp.
antigen or nucleic acid
from clinical
specimen
Positive identification
of Acanthamoeba
trophozoites or cysts
using confocal
microscopy.
Confirmed
N. fowleri
causing
PAM
Confirmed
Balamuthia
mandrillaris
Disease
N
O
O
Confirmed
Probable
Confirmed
Acanthamoeba
Acanthamoeba Acanthamoeba
Keratitis
Keratitis
Disease (excluding
keratitis)
N
N
O
O
O
O
O
O
O
O
N
N
Notes:
S = This criterion alone is Sufficient to classify a case.
N = All “N” criteria in the same column are Necessary to classify a case.
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O = At least one of these “O” (Optional) criteria in each category (e.g., clinical evidence and
laboratory evidence) in the same column—in conjunction with all “N” criteria in the same
column—is required to classify a case
VIII. Period of Surveillance
Surveillance should be ongoing.
IX. Data sharing/release and print criteria




Data will be used to determine the burden of illness due to free-living amebae infections,
monitor trends in illness over time, assess the effectiveness of control measures, and
monitor progress in prevention.
Information may be distributed among states and territories or to CDC according to
jurisdiction specific protocols. Unusual situations may increase the need for
communication. For example, multi-state investigation of transplantation-related
infections might require sharing of data among health departments and/or state and
federal agencies in several jurisdictions involved in investigations.
State-specific data on cases, if shared with CDC, will be verified prior to publication.
Only de-identified case data will be released by CDC to the general public
X. References
1. Primary amebic meningoencephalitis--Arizona, Florida, and Texas, 2007. Centers for
Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep. 2008 May
30;57(21):573-7.
2. The epidemiology of primary amoebic meningoencephalitis in the USA, 1962-2008.
Yoder JS, Eddy BA, Visvesvara GS, Capewell L, Beach MJ. Epidemiol Infect. 2010
Jul;138(7):968-75. Epub 2009 Oct 22.
3. Pathogenic and opportunistic free-living amoebae: Acanthamoeba spp., Balamuthia
mandrillaris, Naegleria fowleri, and Sappinia diploidea. Visvesvara GS, Moura H,
Schuster FL. FEMS Immunol Med Microbiol. 2007 Jun;50(1):1-26. Epub 2007 Apr 11
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XI. Coordination
Agencies for Response:
(1)
Centers for Disease Control and Prevention
Tom Frieden, MD, MPH
Director, CDC
1600 Clifton Road NE; Mailstop D-14
Atlanta, GA 30333
(404) 639-7000
Txf2@cdc.gov
XII. Submitting Author:
(1)
Carina Blackmore, DVM, PhD. Dipl. ACVPM
State Public Health Veterinarian
Florida Department of Health
4052 Bald Cypress Way Bin A08
Tallahassee FL 32330
850-245-4299
Carina_blackmore@doh.state.fl.us
Co-Authors:
(1)
Tiffani Onifade, MS, PhD.
Statewide Coordinator of Food and Waterborne Disease
Florida Department of Health
4052 Bald Cypress Way Bin A08
Tallahassee FL 32330
850-245-4116
tiffiani_onifade@doh.state.fl.us
(2)
Michael J. Beach, PhD
Associate Director for Healthy Water,
National Center for Emerging and Zoonotic Infectious Diseases
Centers for Disease Control and Prevention
1600 Clifton Road NE
Atlanta, GA 30333
(770) 488-7763
mbeach@cdc.gov
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