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Angiostrongylus cantonensis: Agent of a Sometimes Fatal Globally Emerging Infectious Disease (Rat Lungworm Disease) Robert H. Cowie* Pacific Biosciences Research Center, University of Hawaii, Honolulu, Hawaii 96822, United States ABSTRACT: Angiostrongylus cantonensis, the rat lungworm, is a dangerous invasive species that is the agent of a potentially fatal globally emerging infectious disease. Humans are infected most commonly by ingestion, deliberately or inadvertently, of the parasite larvae in their intermediate snail hosts. The larvae make their way to the brain where they can cause severe neurological damage before eventually dying. Symptoms of the disease are diverse, making it difficult to diagnose. Treatment is primarily with corticosteroids to reduce inflammation, while treatment with anthelmintics to kill the worms remains controversial. There have been almost 3000 cases globally, the majority in southern China, but the parasite is spreading and now occurs much more widely. In the USA, almost all cases have been in Hawaii, but the parasite is also present in southeastern states. As the climate warms, this tropical/subtropical parasite is likely to spread further. KEYWORDS: Albendazole, Angiostrongylus cantonensis, eosinophilic meningitis, nematode, parasite, prednisolone, rat lungworm
T
he rat lungworm, Angiostrongylus cantonensis, is a nematode, the definitive and intermediate hosts of which are rats and snails/slugs (snails from here on), respectively.1 Adult worms reproduce in the rat’s pulmonary arteries. Eggs hatch into first stage larvae in the lungs. The larvae then move up the trachea, and are swallowed and released in the feces. Snails feed on those feces, ingesting the worms, which develop in the snails through the second to the third, infective, larval stage. The natural cycle continues when a rat eats the infected snail. The larvae penetrate the intestinal wall, entering the circulatory system, and thence the central nervous system and ultimately the brain. In the brain they develop through the fourth stage to the subadult stage and then return via the circulatory system to the pulmonary arteries, where they become mature, mate, and lay eggs. Human infection, as accidental hosts, is by ingestion of third stage larval worms, most commonly by eating an infected raw snail, deliberately (as a delicacy, for instance in southern China, or even on a dare) or inadvertently (most commonly on contaminated produce).1,2 The worms reach the brain, just as in the rat, develop to the subadult stage, but then die rather than returning to the circulatory system and reproducing. The damage caused by the worms as they move around in the brain, combined with an immune reaction that seems particularly intense in response to the dying worms, causes neurological damage that can be severe and permanent. Infection generally manifests as eosinophilic meningitis, although this can be caused by other agents.3 The disease is commonly known as rat lungworm disease or angiostrongyliasis. However, the latter term is also applied to infection with Angiostrongylus costaricensis, which causes a gastrointestinal syndrome. Various other terms have therefore been coined to permit distinguishing the two syndromes, including neuroangiostrongyliasis and, because of the characteristic heightened level of eosinophils in the cerebrospinal fluid, angiostrongylus eosinophilic meningitis.3 Symptoms of the disease are diverse.3 A mild infection may result in headache, neck and shoulder pain, sensitivity and tingling of the skin, visual disturbance, various other symptoms, © 2017 American Chemical Society
and perhaps some fever, all of which may resolve spontaneously, even without the person realizing they were infected. In more severe cases, these symptoms may be much more intense and additional symptoms such as motor disturbance and digestive and urinary tract malfunction may occur. Extremely severe cases may lead to coma and occasionally death. The diverse array of symptoms is presumably related to the location of the worms and of the neurological damage they cause in different parts of the brain. As such, diagnosis is difficult and relies not only on clinical symptoms but also on food consumption history involving potential exposure to the parasite (via intermediate and paratenic hosts2), residence in or history of visiting areas where the parasite is present, supportive but not necessarily diagnostic CT and MRI scans, finding of eosinophils in the cerebrospinal fluid, and serological tests that as yet are not consistently reliable.3 Treatment protocols are not definitive.3 Analgesics can be used for pain. Spinal taps may decrease intracranial pressure and relieve headaches, at least temporarily, as well as decrease the likelihood of neurological damage. Corticosteroids (e.g., prednisolone) are generally used, sometimes in conjunction with spinal taps, and are postulated to provide relief by reducing inflammation and thereby intracranial pressure.3 At first sight, use of anthelmintics (benzimidazoles, most notably albendazole) to kill the worms would seem appropriate. However, this remains controversial.3 Since the immune reaction to dying worms seems greater than to the live worms, killing all at the same time may be worse than allowing them to die naturally. Nonetheless, anthelmintics may be effective in reducing severity and duration of headaches, although definitive evidence is limited.3 Furthermore, there is evidence, again limited, that a combination of steroids and anthelmintics may reduce severity and duration of illness,3 Received: September 1, 2017 Accepted: September 5, 2017 Published: September 13, 2017 2102
DOI: 10.1021/acschemneuro.7b00335 ACS Chem. Neurosci. 2017, 8, 2102−2104
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ACS Chemical Neuroscience presumably because the steroids counteract the increased inflammation caused by the dying worms. No dosage recommendations have been developed. Angiostrongylus cantonensis was described as a newly discovered species in 1935 in southern China. However, it was not until 1961, in Hawaii, that a definitive connection was made between the worm and the disease, when (1) worms were found in the brain of a patient who had become ill in late 1959 and died in 1960, and (2) clinical manifestations of the disease have been noted in a patient who had eaten raw slugs in late 1959 and also died in 1960.4 The parasite has now been reported widely in southern and eastern Asia, Australasia, the islands of the Pacific and Caribbean as well as the Indian Ocean, South America, Africa, the Canary Islands, and the southeastern USA, with cases of the disease in most of these places.1 Globally, almost 3000 cases have been recorded.5 In the continental USA, A. cantonensis has been found in snails and rats, occurring widely in Florida but also in Louisiana, and cases of the disease have been recorded in various accidental mammal and bird hosts in Florida, Alabama, Louisiana, Mississippi, Oklahoma, and California (Figure 1).5
There appear to be no available records for 1966−2000. Published records for January 2001 to February 2005 were gleaned retrospectively using a rigorous protocol,8 but unpublished data for 2005−2006 were collected only anecdotally by the Hawaii Department of Health (HDoH). Rigorous records have been kept by the HDoH only since 2007 and are available on line for 2007−2016 (http://health.hawaii. gov/docd/resources/reports/summary-of-reported-cases-ofnotifiable-diseases/). These later records, from 2001 (85 cases including three deaths), have thus for the most part been based on rigorous assessment protocols. The surveillance conducted by the HDoH focuses on detection of the more severe cases, especially as milder cases are thought to be self-limited and resolve without treatment, and may go unreported. Also, because of the difficulty of diagnosis, infections may be misdiagnosed and also not reported. The number of actual infections is probably greater than shown in Table 1. Until about 2004, the great majority of cases in the state of Hawaii were on Oahu, but since then, most cases have been on the island of Hawaii (Table 1). The reason for this is unclear. However, one possibility is the increased prevalence of an invasive snail species, Parmarion martensi, which was first noted on the island of Hawaii in 2004, although it had been present on Oahu since at least 1996. While many species of snails in Hawaii act as hosts of A. cantonensis, P. martensi is a particularly good host.9 In 2017, preliminary data (up to 1 September) that have not yet been assessed via the rigorous protocols noted above seem to indicate an increase in cases, notably on the islands of Hawaii and especially Maui. Maui in particular had only previously seen seven cases (Table 1). Coincidentally, Parmarion martensi was first formally identified on Maui in early 2017, although anecdotal reports suggest it may have been there for a number of years previously, and it is now locally abundant. Whether there is a direct causal relation between presence of P. martensi and increased numbers of cases is not known. In addition to the important public health concerns as A. cantonensis spreads, there are also major food safety issues associated with the inadvertent consumption of infected snails on produce, notably on leafy greens and perhaps in raw vegetable juice or smoothies.2 However, careful washing of produce and thorough cooking, if appropriate, can go a long way to ensuring food safety. In this regard, education and outreach to the community are key. It has been suggested that slime trails may also contain enough shed larvae to be of concern, although the few studies that have been done show that far fewer larvae occur in the slime and this may not represent a significant mode of transmission.2 Nonetheless, especially given the increasing move to organic produce, in particular sold at farmers’ markets, food safety is a major issue. For example, in Hawaii, this has become not only of direct
Figure 1. Distribution of Angiostrongylus cantonensis (rat lungworm) in the United States.5 AL − Alabama; CA − California; FL − Florida; HI − Hawaii; LA − Louisiana; MS − Mississippi; OK − Oklahoma. Red areas and dots represent records of A. cantonensis in its definitive (rats) and intermediate (snails) hosts; yellow dots represent records of A. cantonensis in other (nonhuman) mammals and birds.
There has been one reported human case in Louisiana (1993) and three in Texas (2013, 2016).6 However, in Hawaii, A. cantonensis is widespread, occurring on at least five of the six largest islands, and there have been far more cases of the disease (Table 1). Prior to the connection being made between the disease and the parasite in 1961, based on the two cases noted above,4 there probably had been cases but of course they were not recognized. Between 1959 and 1965, 19 cases were reported.7
Table 1. Number of Rat Lungworm Disease Cases Reported in the Hawaiian Islands, 1959-2016a
a
Island
1959−1965
Kauai Oahu Maui Lanai Hawaii Total
2 15 1
1966−2000
1 19
0
2001−2004 11 3 1 4 19
2005
2006
2007
2008
2009
1 1
2 2
7 8
2011
2012
2013
1 1
1 5 5
2010
6 6
7 9
2014
2015
2016
Total
1
1
6 7
10 11
4 27 7 1 65 104
1 7 7
1 1
3 3
5 6
See the text for sources. 2103
DOI: 10.1021/acschemneuro.7b00335 ACS Chem. Neurosci. 2017, 8, 2102−2104
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ACS Chemical Neuroscience concern to consumers, but it is also having an impact on farmers’ income, as consumers have begun to avoid locally grown produce in the light of the recent spate of cases on Maui and the media attention that has prompted. As the climate changes, we can expect Angiostrongylus cantonensis, a tropical/subtropical species, to spread farther into locations that are currently too cool for it. Increasing awareness, in the medical community and among produce growers and consumers, of this poorly known parasite and the serious and potentially fatal disease it causes is important to ensure that future infections are minimized.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Phone: 808-956-4909. ORCID
Robert H. Cowie: 0000-0002-2986-7092 Notes
The author declares no competing financial interest.
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ACKNOWLEDGMENTS The author thanks Drs. Sarah Park and Kenton Kramer for valuable comments on a draft of this article. University of Hawaii School of Ocean and Earth Science and Technology publication number 10225.
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REFERENCES
(1) Cowie, R. H. (2013) Biology, systematics, life cycle, and distribution of Angiostrongylus cantonensis, the cause of rat lungworm disease. Hawaii J. Med. Publ. Health 72 (6, Supplement 2), 6−9. (2) Cowie, R. H. (2013) Pathways for transmission of angiostrongyliasis and the risk of disease associated with them. Hawaii J. Med. Publ. Health 72 (6, Supplement 2), 70−74. (3) Murphy, G. S., and Johnson, S. (2013) Clinical aspects of eosinophilic meningitis and meningoencephalitis caused by Angiostrongylus cantonensis, the rat lungworm. Hawaii J. Med. Publ. Health 72 (6, Supplement 2), 35−40. (4) Horio, S. R., and Alicata, J. E. (1961) Parasitic meningoencephalitis in Hawaii. A new parasitic disease of Man. Hawaii Med. J. 21 (2), 139−140. (5) Stockdale Walden, H. D., Slapcinsky, J. D., Roff, S., Calle, J. M., 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 (5), e0177910 DOI: 10.1371/journal.pone.0177910. (6) Al Hammoud, R., Nayes, S. L., Murphy, J. R., Heresi, G. P., Butler, I. J., and Pérez, N. (2017) Angiostrongylus cantonensis meningitis and myelitis, Texas, USA. Emerging Infect. Dis. 23 (6), 1037−1038. (7) Rosen, L., Loison, G., Laigret, J., and Wallace, G. D. (1967) Studies on eosinophilic meningitis. 3. Epidemiologic and clinical observations on Pacific islands and the possible etiologic role of Angiostrongylus cantonensis. Am. J. Epidemiol. 85 (1), 17−44. (8) Hochberg, N. S., Park, S. Y., Blackburn, B. G., Sejvar, J. J., Gaynor, K., Chung, H., Leniek, K., Herwaldt, B. L., and Effler, P. V. (2007) Distribution of eosinophilic meningitis cases attributable to Angiostrongylus cantonensis, Hawaii. Emerging Infect. Dis. 13 (11), 1675− 1680. (9) Kim, J. R., Hayes, K. A., Yeung, N. W., and Cowie, R. H. (2014) Diverse gastropod hosts of Angiostrongylus cantonensis, the rat lungworm, globally and with a focus on the Hawaiian Islands. PLoS One 9 (5), e94969 DOI: 10.1371/journal.pone.0094969.
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DOI: 10.1021/acschemneuro.7b00335 ACS Chem. Neurosci. 2017, 8, 2102−2104
