“Hawaii, particularly east Hawaii Island, is the epicenter for angiostrongyliasis in the United States. Case numbers have been increasing and appear to parallel the introduction and spreading of the semislug (Parmarion marensi) to east Hawaii. The infective larvae in rainwater catchment as a source for household and agricultural water may also play a role. The spread of Angiostrongylus cantonensis as well as the potential introduction of the semislug P. martensi should be a concern to the mainland United States. The State of Hawaii should recognize the seriousness of this growing problem and thus collaborate to find studies to address the growing challenges surrounding angiostrongyliasis in the United States.” Kathleen Howe and Susan L. Jarvi Department of Pharmaceutical Science Daniel K. Inouye College of Pharmacy University of Hawaii at Hilo

1. Angiostrongyliasis (Rat Lungworm Disease): Viewpoints from Hawai‘i
Island
Kathleen Howe and Susan I. Jarvi*
Department of Pharmaceutical Sciences, Daniel K. Inouye College of Pharmacy, University of Hawai‘i at Hilo, Hilo, Hawai‘i 96720,
United States
ABSTRACT: Hawai‘i, particularly east Hawai‘i Island, is the epicenter for angiostrongyliasis in the United States. Case numbers
have been increasing and appear to parallel the introduction and spread of the semislug (Parmarion martensi) to east Hawai‘i. The
infective larvae in rainwater catchment as a source for household and agricultural water may also play a role. The spread of
Angiostrongylus cantonensis as well as the potential introduction of the semislug P. martensi should be a concern to the mainland
United States. The State of Hawai‘i should recognize the seriousness of this growing problem and thus collaborate to fund studies
to address the growing challenges surrounding angiostrongyliasis.
KEYWORDS: Angiostrongylus cantonensis, rat lungworm, angiostrongyliasis, Hawai‘i
The rat lungworm (Angiostrongylus cantonensis) is a
nematode that causes human angiostrongyliasis or rat
lungworm disease. Rats (Rattus spp.) are the definitive host,
while gastropods are obligatory intermediate hosts. Angio-
strongyliasis is a global, emerging disease of growing
importance in Hawai‘i, particularly on Hawai‘i Island, where
the majority of the cases have originated in the United States.
A. cantonensis has been established throughout the state of
Hawai‘i since the 1950s, and on the United States mainland in
Louisiana, Texas, Oklahoma, and Florida. While A. cantonensis
has been described as a tropical parasite, recent findings of
range expansion indicate it appears to be adapting to gastropod
hosts found in more temperate climates.1
In Hawai‘i, the
number of cases of angiostrongyliasis cases has been increasing
since the turn of the millennium. This increase parallels the
introduction of the semislug (Parmarion martensi) to east
Hawai‘i Island ca. 2004. This gastropod is now spreading across
Hawai‘i Island and State. P. martensi reaching the mainland
United States via the Caribbean, Hawai‘i, or other Pacific
Islands is a real concern.
It is generally acknowledged that the number of angios-
trongyliasis cases continues to be underreported in the State of
Hawai‘i. Contributing factors likely include the difficulty of
diagnosis, inadequate healthcare provider education and
awareness, and lack of a comprehensive reporting system. A
total of 24 angiostrongyliasis cases were reported in Hawai‘i
from 2001 to 2005,2
but angiostrongyliasis cases were not
officially reported by the Hawai‘i Department of Health
(HDOH) until 2007, at which point it became a (physician-
based) reportable disease. The nonprofit Hawai‘i Health
Information Corporation (HHIC) provides statewide health
data using diagnostic codes and is based on discharge data from
hospitals and emergency rooms. A comparison of angios-
trongyliasis cases reported between 2007 and 2017 by HDOH
and HHIC is provided in Figure 1.
Discrepancies between case numbers reported might be
attributed to lack of HDOH reporting of nonresident cases
until 2015, cases not being reported to the HDOH, patients
being diagnosed and treated outside a hospital-based setting,
and patients being diagnosed and treated in non-Hawai‘i
hospitals. Ideally, every case HHIC receives from a Hawai‘i
hospital-based provider with a patient diagnosis of angios-
trongyliasis should be reported to the HDOH by the provider,
so theoretically HHIC counts should be lower than the HDOH
counts. HDOH reports only confirmed cases, which require
molecular detection of the parasite DNA in cerebral spinal fluid
(CSF). Spinal taps are only conducted in a hospital setting, so
all cases diagnosed in Hawai‘i hospitals should theoretically be
reported by both HDOH and HHIC. What is obvious is the
upward trend in the number of cases more recently. From
January to April 2017, HHIC reported 16 cases and HDOH
reported 15 cases of angiostrongyliasis in Hawai‘i including an
outbreak on Maui. The invasive semislug has only recently been
documented on Maui (for the first time) by one of the authors
of this paper (K.H.), and an outbreak of five (HHIC) and six
(HDOH) angiostrongyliasis cases were reported in the first two
quarters (January to April) in 2017 from Maui. A
comprehensive reporting system is needed for the State of
Hawai‘i to provide more accurate data on the true number of
angiostrongyliasis cases in both residents and nonresidents that
have originated in Hawai‘i.
The life cycle of the parasite involves rats as the definitive
host. After ingesting third stage larvae (L3) (Figure 2) in
infected gastropods, the larvae migrate to the central nervous
system where they develop through L4 to L5 (subadult) larvae.
The subadult worms migrate to the pulmonary artery, develop
to sexual maturity, and lay eggs. The eggs hatch into L1 larvae,
migrate up the bronchial tree, and are swallowed, and 6−8
weeks after infection are excreted with feces. Gastropods are
the obligatory intermediate hosts for A. cantonensis, acquiring
the L1 larvae in rat feces and supporting parasite development
from the L1−L3 larval stages. If humans ingest L3 stage larvae
through contaminated food or water, they penetrate the small
Received: August 3, 2017
Accepted: August 7, 2017
Viewpoint
pubs.acs.org/chemneuro
© XXXX American Chemical Society A DOI: 10.1021/acschemneuro.7b00299
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2. intestinal mucosa and travel via the bloodstream to the central
nervous system and brain.2
It is not known, but it is possible
that one can get infected through skin or mucosal contact with
contaminated water. Hawai‘i Island has the highest number of
cases, and also has unregulated, widespread use of rainwater
catchment to supply household and agricultural water. Our
studies show drowned gastropods, which can be found in
catchment tanks, are capable of shedding live L3 parasites
which can live for weeks. A single gastropod has the potential to
harbor thousands of A. cantonensis parasites. The HHIC reports
5 angiostrongyliasis cases among children under the age of one
from 2010 to April 2017. Some babies diagnosed with
angiostrongyliasis from east Hawai‘i Island were reported to
have no direct exposure to slugs or snails. One baby
subsequently died. It is possible they were infected in
contaminated bathwater. The unregulated, widespread use of
rainwater catchment, combined with the introduction of highly
mobile semislugs, may be contributing factors to the increase in
numbers of cases of angiostrongyliasis originating in east
Hawai‘i Island.
Clinical symptoms of angiostrongyliasis vary and can range
from mild to irreversible. On a global level, a main (but not
only) cause of eosinophilic meningitis is infection with A.
cantonensis. Other symptoms can be flu-like (e.g., nausea,
diarrhea, fever, muscle aches, general malaise), paresthesia,
headache, stiff neck, eosinophilic enteritis, hydrocephalus,
encephalitis, coma, and death.2
The variability in symptoms
makes diagnosis difficult. Angiostrongyliasis victims often
report to us chronic pain in areas of previous injury. This
could be the result of further damage to previously injured
nerves. Demyelination or injury of the vagus nerve, which is the
longest cranial nerve in the body, could result in the myriad of
symptoms often associated with angiostrongyliasis. This nerve
interfaces with parasympathetic control of the heart, lungs, and
digestive tract and could explain heart, lung, and other
seemingly disassociated complications observed with angios-
trongyliasis. It should be noted that, upon autopsy, adult,
seeming reproductively capable A. cantonensis have been found
in the heart and lungs of several infected children, although
eggs have yet to be found in human feces. This should also be
considered in patients with heart and lung irregularities.
Discussion with victims and findings in the lab are leaving us
to question how long and where the larvae can survive in the
accidental human host and potentially continue to cause
damage. Answers to these questions could help us understand
differences in severity and why onset of symptoms can vary
from days to months. The potential for larval longevity and
migration in the human host may play a role. For those
residents and any visitors to Hawai‘i presenting with neuro-
logical symptoms, a diagnosis of angiostrongyliasis should be
considered.
Diagnosing angiostrongyliaisis presents a challenge, in part,
because of the variability of symptoms and the lack of a
noninvasive diagnostic test in the United States. In humans it
involves history of exposure, clinical features, and laboratory
testing of the CSF for the presence of the parasite.2
A definitive
diagnosis can be made by visualizing L3 larvae in the cerebral
spinal fluid or eye (ocular angiostrongyliasis), but the
nematodes are often not visually detectable in the CSF.
Definitive diagnosis can also be made using a molecular test to
detect parasite DNA in the CFS.2
These tests require a spinal
tap to examine the CSF, which is so risky and invasive that
many victims choose not to participate. The lack of a definitive
diagnosis by less invasive methods results in fewer reportable
cases.
A presumptive diagnosis can be made based on patient
history and clinical findings. Elevated eosinophil count in the
blood or CSF is another, but not definitive, indication of
angiostrongyliasis. Imaging by CT scan or MRI can also be
helpful.2
Immunological tests can be used to detect RLW
antigens or antibodies in the blood against RLW antigens. Key
to a reliable, blood-based diagnostic test for the detection of A.
cantonensis antibodies in plasma or serum is the use of the
appropriate antigen(s). Researchers in Thailand have developed
currently the most reliable antibody-based diagnostic test to
date.3
They isolated 31 kDa glycoproteins from adult worms
Figure 1. Number of angiostrongyliasis cases reported by Hawai‘i Department of Health (HDOH) from 2007 to May 2017 and Hawai‘i Health
Information Corporation (HHIC) from 2010 to April 2017.
Figure 2. Microscopic L3 larvae isolated by acid digest from a P.
martensi (40×). Photo by Jarvi Lab.
ACS Chemical Neuroscience Viewpoint
DOI: 10.1021/acschemneuro.7b00299
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3. (from Thailand) and have shown them to be diagnostic for
human A. cantonensis. Our lab is collaborating with P.
Eamsobhana (Mahidol University, Bangkok, Thailand) using
the Thailand A. cantonensis isolation of 31 kDa proteins in a
dot-blot immunoassay to estimate the exposure of people from
east Hawai‘i. Because there may be genetic differences between
the Thailand isolate and the Hawai‘i isolate of A. cantonensis, we
are currently in the process of similarly isolating the 31 kDa
proteins from Hawai‘i A. cantonensis for comparison. We are
also working with researchers at the Centers for Disease
Control and Prevention (S. Handali) who are isolating A.
cantonensis proteins using different isolation methods. We plan
on running a three-way comparison with the same human
serum samples to evaluate test efficacy. A number of molecular
tests based on PCR have been developed for the detection of A.
cantonensis DNA. The most promising is based on the ITS1
gene for detection in gastropods and CSF.2
A. cantonensis DNA
has also been detected in rat blood at certain time points
throughout experimental infection.4
While A. cantonensis is not
considered a blood parasite, there is potential for detection of
parasite DNA by PCR at certain time points in human blood as
the parasite is transported via the bloodstream throughout the
body or may be sequestered in tissues if it does not make it to
the CNS.
Treatment options for angiostrongyliasis are dependent on
the severity of the symptoms. Eosinophilic meningitis is one of
the more common symptoms, and the use of an anti-
inflammatory drug is critical to moderate inflammation (e.g.,
prednisone). A spinal tap (lumbar puncture) is sometimes
carried out to relieve pressure. Eradicating the worms is also
critical, and the drug of choice of many is albendazole. While
some question the use of antiparasitic drugs, administering a
combination corticosteroid plus albendazole therapy, especially
early in the infection, has been shown in many studies to
alleviate symptoms with no adverse effects.2
Given that the
longevity of A. cantonensis in the human brain or other tissues is
not known and likely varies, not administering albendazole may
allow the larvae to continue to thrive, potentially causing
further damage. Corticosteroids alone suppress the immune
system which could potentially result in increased larval
longevity. Pain medications and analgesics are also often
used. Alternative treatments such as vitamin therapy, natural
anti-inflammatories, and acupuncture might be especially
helpful for recovery from long-term chronic symptoms that
many people experience. Some alternative treatments are
described using rodent models,2
but an isolated case in a 23
year old man who was comatose for three months suggests that
alternative treatments did not cause adverse effects, and maybe
even helped long-term recovery.5
In light of the dim prognosis
given at onset of the disease, this case demonstrates the ability
to recover functionality from serious neurological damage from
angiostrongyliasisif proper treatment and support is
providedand speaks, in addition to corticosteroids and
antiparasitic drugs, to the potential importance of nontradi-
tional therapies especially for long-term recovery.
Early treatment could be a significant factor in improved
recovery, making the awareness of this disease and its treatment
a priority for Hawai‘i and elsewhere. The need for studies on
long-term recovery are equally important, for while most
victims have not succumbed to the disease, neither have they
fully recovered. Many victims in Hawai‘i have permanent
disabilities resulting from angiostrongyliasis. Based on our
interactions with many angiostrongyliasis victims, Hawai‘i has
had multiple serious cases yearly which require weeks or
months of hospitalization, some costing over $1 000 000 in
medical, plus added to that is the long-term loss of income for
the victim and the family members caring for them. Chronic
symptoms can last for years and possibly last a lifetime. The
long-term consequences of angiostrongyliasis are both physical
and financial and have yet to be addressed. Comprehensive
treatment strategies for these acquired brain injury patients
need to be developed and implemented. It is important for all
to agree collectively on the seriousness of the growing problem
and thus collaborate to fund studies to address the growing
challenges surrounding angiostrongyliasis.
■ AUTHOR INFORMATION
ORCID
Susan I. Jarvi: 0000-0002-9824-0509
Notes
The authors declare no competing financial interest.
■ REFERENCES
(1) Stockdale Walden, H. D., Slapcinsky, J. D., Roff, S., Mendieta
Calle, J., Goodwin, Z. D., Stern, J., Corlett, R., Conway, J., and
McIntosh, A. (2017) Geographic distribution of Angiostrongylus
cantonensis in wild rats (Rattus rattus) and terrestrial snails in Florida,
USA. PLoS One 12, e0177910.
(2) Please refer to this comprehensive review for original references:
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(3) Eamsobhana, P., and Yong, H. S. (2009) Immunological
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ACS Chemical Neuroscience Viewpoint
DOI: 10.1021/acschemneuro.7b00299
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