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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
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he 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. Angiostrongyliasis 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 angiostrongyliasis 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 (physicianbased) 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 angiostrongyliasis 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, © XXXX American Chemical Society
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 angiostrongyliasis 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
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DOI: 10.1021/acschemneuro.7b00299 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
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.
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 angiostrongyliasis. 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 neurological 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 2. Microscopic L3 larvae isolated by acid digest from a P. martensi (40×). Photo by Jarvi Lab.
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 B
DOI: 10.1021/acschemneuro.7b00299 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
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ACS Chemical Neuroscience
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.
(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 antiinflammatory 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 angiostrongyliasisif proper treatment and support is providedand speaks, in addition to corticosteroids and antiparasitic drugs, to the potential importance of nontraditional 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
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AUTHOR INFORMATION
ORCID
Susan I. Jarvi: 0000-0002-9824-0509 Notes
The authors declare no competing financial interest.
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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: Barratt, J., Chan, D., Sandaradura, I., Malik, R., Spielman, D., Lee, R., Marriott, D., Harkness, J., Ellis, J., and Stark, D. (2016) Angiostrongylus cantonensis: a review of its distribution, molecular biology and clinical significance as a human pathogen. Parasitology 143, 1087−1118. (3) Eamsobhana, P., and Yong, H. S. (2009) Immunological diagnosis of human angiostrongyliasis due to Angiostrongylus cantonensis (Nematoda: Angiostrongylidae). Int. J. Infect. Dis. 13, 425−431. (4) Jarvi, S. I., Pitt, W. C., Farias, M. E. M., Shiels, L., Severino, M., Howe, K., Jacquier, S., Shiels, A. B., Amano, K., Luiz, B., Maher, D., Allison, M., Holtquist, Z., and Scheibelhut, N. (2015) Detection of Angiostrongylus cantonensis in the blood and peripheral tissues of wild Hawaiian rats (Rattus rattus) by a quantitative PCR (qPCR) assay. PLoS One 10, e0123064. (5) Howe, K. (2013) A severe case of rat lungworm disease in Hawai‘i. Hawai‘i. J. Med. Public Health 72, 46−48.
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DOI: 10.1021/acschemneuro.7b00299 ACS Chem. Neurosci. XXXX, XXX, XXX−XXX
