The Potential Danger of Eating Wild Lettuce: A Brief Review of Human Rat Lungworm Infection

Abstract

Angiostrongylus cantonensis, the causative agent of human rat lungworm disease, is the most common cause of eosinophilic meningitis worldwide and is endemic throughout Asia Pacific. It is acquired through the consumption of infected freshwater mollusks or contaminated produce. Human angiostrongyliasis is usually a self-limited disease presenting with headache and various neurologic sequelae varying from cranial nerve palsies to radiculitis and/or paresthesias. Fatal cases are rare, and manifest as fulminant meningomyeloencephalitis. The diagnosis is made through the use of clinical history, exam, and laboratory data including peripheral blood counts, cerebrospinal fluid (CSF) examinations, and serologic or molecular diagnostic techniques. Medical therapy is largely focused on symptomatic relief, and includes analgesics, lumbar puncture, and corticosteroids. In resource-limited settings, prevention is key, and the use of analgesics can provide symptomatic relief after infection. Efforts to increase disease awareness have been made in endemic areas, as evidenced by the recent Rat Lungworm Disease Scientific Workshop which was held in Honolulu in 2011. The proceedings of the workshop were published in a supplement to this journal (Hawaii J Med Public Health. Jun 2013;72(6):Supp 2). However, wilderness medicine and travel medicine specialists must also be aware of the disease, how it is contracted, its presentation, and treatment options should they encounter a patient who is in or has returned from an endemic area. This brief review highlights eosinophilic meningitis caused by A. cantonensis, including an example case, an overview of its clinical presentation, treatment options, and prevention.

Background

The parasitic nematode Angiostrongylus cantonensis is the causative agent of rat lungworm disease, and the most common identified cause of eosinophilic meningitis worldwide. Although first isolated from the pulmonary artery of a rat by Chen in 1935, it was not identified as a human pathogen until it was isolated from a case of eosinophilic meningitis in Taiwan ten years later.¹ Approximately 2900 cases of eosinophilic meningitis have been reported in the literature since 1944 as a result of rat lungworm infection, although it is believed this number is largely underreported, as many infections may be subclinical or occur in areas where specific diagnostic testing is not routinely performed.² Today, rat lungworm is considered endemic in most parts of the Asia-Pacific region, and new cases are now routinely being identified in previously non-endemic areas.

Much is unknown about specific pathogenic mechanisms involved in human rat lungworm infection producing clinical disease, but the biology and life cycle of A. cantonensis are well described in the scientific literature.^2–5 Angiostrongylus cantonensis is a member of the family Angiostrongylidae in the superfamily Metastrongyloidae, of which only 20 species in the genus Angiostrongylus are known. Of these, two species—A. cantonensis and A. costaricensis—cause disease in humans, although the latter is only associated with a gastrointestinal illness most prevalent in Central and South America. The definitive hosts of A. cantonensis include the rat species of Rattus norvegicus, R. rattus, and R. exulans, which acquire the infection through ingestion of third-stage (L3) larvae by eating a slug or snail. Ingested worms travel from the rat's gut to the bloodstream, eventually making their way to the central nervous system. In the brain, they develop into the fifth stage (L5) young adults, and travel via the cerebral venous system and make their way to the pulmonary arteries, where the females lay eggs. The eggs make their way to the distal lung, where they hatch into first-stage larve (L1), extravasate, and migrate up the trachea where they are swallowed and excreted in the rat's feces. Once in the environment, the L1 larvae mature into L3 larvae, and are ingested by a snail, slug, or other intermediate or paratenic host.⁵ If the snail or slug is consumed by a rat, the life cycle is repeated. However, the infection of accidental hosts, such as species of crustaceans, frogs, monitor lizards, and planaria results in larvae remaining in the L3 stage inside that animal, which makes them capable of infection once consumed by rats, humans, or other mammals. If consumed by a human, the larvae make their way to the CNS, but are unable to adequately mature to complete their life cycle.

Human infection with rat lungworm results from the ingestion of either infected snails, prawns, crabs or contaminated fruits and vegetables. Since it was first identified as a human pathogen in 1944, a number of outbreaks of eosinophlic meningitis occurring in China, Taiwan, Japan, Southeast Asia, Australia, Hawai‘i, and the South Pacific have been attributed to A. cantonensis, and cases have been identified on the six inhabited continents.² Although the increasing identification of clinical cases is likely multifactorial, it is widely accepted that international commerce and shipping have contributed to the nematode's spread through the transportation of either infected rats, snails, slugs, or other hosts. Recently, A. cantonensis has been found to be the etiologic agent of eosinophilic meningitis in a number of travelers returning to northern climates from endemic areas.⁶ This has highlighted the importance of proper education and increased awareness of both travelers and physicians. Travelers who enjoy camping, consuming wild foodstuffs, or sampling local or cultural cuisine in endemic areas should be aware of the potential risks, and how to mitigate them.

Relevance to Hawai‘i and Asia Pacific

Angiostrongylus cantonensis has been well-established as a causative agent of eosinophilic meningitis in Hawai‘i since 1960, although it did not become a reportable disease in the state of Hawai‘i until 2007.^7,8 Hochberg, et al, identified 24 cases of eosinophilic meningitis caused by A. cantonensis in Hawai‘i between 2001–2005, with cases reported in the islands of O'ahu, Maui, Lana'i, and the island of Hawai‘i, which had the highest incidence.⁹ Since 2007, 33 cases of eosinophilic meningitis due to A. cantonensis have been reported in the state.⁸ In many of these cases, patients have consumed either contaminated vegetables or snail species acting as intermediate hosts. In Hawai‘i, several species of snails have been identified as carriers of the rat lungworm nematode, including the giant African snail Achatina fulica, and the relatively new, invasive semi-slug Paramarion martensi, which is now abundant throughout the Hawaiian archipelago.^10–12 Environmental evaluation of mollusk species on the islands of O‘ahu and Hawai‘i have demonstrated infection rates ranging from 24–88% depending on species and location.^12,13

A. cantonensis has also been identified as the causative agent of eosinophilic meningitis throughout the South Pacific since the early 1960s, with cases reported in French Polynesia, Samoa, and the Marshall Islands between 1961 and 1964.^7,14,15 Numerous outbreaks have occurred in Asia, particularly in the northeastern provinces of Thailand, and throughout inland China and Taiwan, where cases are still routinely documented. Of the nearly 2900 cases that have been reported in the medical literature, approximately 75% have been reported from Thailand and China.² Many cases in these regions result from the consumption of raw snails in cultural dishes, or consumption of contaminated raw vegetables or their juices.^16–19 For visitors, it is important to be mindful that in certain areas eating local cuisine can result in serious illness. This should also serve as a reminder to travel medicine specialists to discuss potential risks with patients traveling to these areas, particularly if they are planning on camping, or immersing themselves in local culture.

Example Case

A seven-year-old previously healthy boy re-presented to a pediatric clinic with his mother for headache, vomiting, and fatigue. The patient was in his usual state of health until eight days earlier, when he complained of a headache which improved following administration of acetaminophen. The mother noted that the patient seemed more fatigued, preferring to watch television instead of playing with his older siblings. Seven days earlier he began to have intermittent, non-bloody, non-bilious vomiting. Five days prior he was evaluated in the clinic for headaches and vomiting, and diagnosed with gastroenteritis. His mother was instructed to encourage increased fluid intake, and return should his symptoms not resolve. At the time of re-presentation, the mother denied any fevers, rashes, diarrhea, or upper respiratory symptoms.

On exam, the patient was a non-toxic appearing male who was alert, although slightly irritable. Vital signs included temperature of 38.6 C, blood pressure of 104/64, heart rate 98, and respiratory rate of 22. Mucous membranes were dry. The patient was protective of his neck and would not voluntarily move it. Passive range of motion of the neck was made difficult by patient non-compliance with exam. The patient was admitted for mild dehydration and concern for meningitis. Complete blood count showed a leukocytosis of 14,000, hemoglobin of 14.3 g/dl, hematocrit of 41%, and platelets of 420,000. Leukocyte differential was notable for eosinophilia of 18%. Lumbar puncture was unremarkable with protein of 60 mg/dL, glucose of 70 mg/dL, no red blood cells and few eosinophils without organisms on gram stain. Notably, the patient had decreased complaint of headache after the procedure. On day 2 of admission, patient complained of worsening headache, and a repeat lumbar puncture resulted in symptomatic relief of the patient's headache. Test performed on CSF were negative for enterovirus, herpes simplex virus, syphilis, and bacterial organisms.

Further history taken during admission revealed he ingested a snail from the family garden after being “dared” by his older brothers three days before the onset of symptoms. Based on this history and continued peripheral eosinophilia throughout admission, he was diagnosed with eosinophilic meningitis. At the time of discharge, the patient continued to complain of headache which was controlled with oral ibuprofen and acetaminophen. He was followed closely by his outpatient provider and did not develop any further neurologic symptoms with resolution of headache by one month after admission.

Clinical Discussion

As in this example case above, ingestion of larvae occurs either by direct consumption of contaminated mollusk species, or through the ingestion of contaminated produce. In Hawai‘i, both kinds of exposures have been reported in the clinical literature, and similar exposures resulting in outbreaks in Thailand, China, and the South Pacific. Incubation periods typically last from 5–40 days post exposure. In a study of eosinophilic meningitis in Thailand, 83% of patients reported symptom onset by 20 days following ingestion of a raw freshwater mollusks, with the majority of patients developing symptoms by two weeks following the inciting event.¹⁸ However, incubation periods as short as one day have been reported.²⁰

The manifestations of the infection are primarily localized to the central nervous system, where it is known to cause mild, subacute, or fulminant eosinophilic meningitis. Rarely, ocular manifestations can occur with nematode invasion in the 3 major chambers of the eye.²¹ The most common presenting symptoms of human angiostrongyliasis and various clinical manifestations have been well-described in case reports, series, and epidemiologic studies on the disease.^{2,6,18,19,22,23} Headache is the most common early symptom and often the presenting complaint, typically occurring in greater than 90% of those afflicted. Headache, as well as nausea and vomiting, is attributed primarily to increased intracranial pressure, or direct neuronal damage caused by both dying larvae and the host immune response. In some cases, serial lumbar punctures have resulted in symptomatic decrease of a patient's headache, although these have not been associated with curing infection.^24,25 Subjective neck pain and stiffness, fatigue, fever, visual complaints, and paresthesias develop between 30%–50% of patients, occurring in the early course of the disease. The paresthesias experienced are often profound, and range from burning and tingling, to symptoms reflective of an acute painful radiculitis with hyperesthesia. Neurologic symptoms and signs can also result in cranial nerve palsies, and rarely, altered sensorium. Upper respiratory symptoms including sinus congestion, rhinorrhea, sore throat, and dry cough can be seen early in the disease course. In ocular cases, the presenting complaint is usually blurred vision developing over several weeks. Overall, the clinical presentation of A. cantonensis varies broadly, and can include mild self-resolving symptoms to fulminant meningomyeloencephalitis resulting in coma and permanent neurologic deficits. Death has been reported in only a few cases.^20,25 These catastrophic cases are associated with heavy infections found to have large nematode burden and advanced inflammatory reaction involving macrophages, T-cells, eosinophils, and neutrophils on pathologic review.

Physical findings are related to the onset of neurologic sequelae and can include decreased reflexes, bowel or bladder dysfunction, muscle weakness, cranial nerve deficits, and evidence of increased intracranial pressure. Non-suppurative pharyngitis and cervical adenopathy have been reported. Meningeal signs are inconsistently reported in association with eosinophilic meningitis.¹⁸ In cases of ocular angiostrongyliasis, living larvae can be observed in the anterior, vitreal, or retinal chambers, with accompanied findings of epithelial alteration and subretinal tracking.²¹

Diagnosis of rat lungworm infection is often difficult to establish. Typically, a combination of patient history, symptoms, clinical findings, and laboratory tests are required to make the diagnosis. The “gold” standard is isolation of the nematode from the CSF, occurring in only 2–12% of cases.^18,25 However, it should be noted that nematode isolation from CSF is more common in pediatric patients than in adults. Absolute peripheral eosinophilia (> 450/µL) as seen on CBC, particularly in the setting of leukocytosis, and the presence of eosinophils in CSF are frequently seen in human infections. Chemical examination of CSF also demonstrates elevated protein, and normal to slightly decreased glucose.^{18–20,22–26} Serologic studies can also be employed in the diagnosis. Tsai, et al, reported the presence of anti-Angiostrongylus antibodies in the serum in 100% of patients as well as in the CSF of 80% of patients, indicating that even during acute infection serologic testing plays an important role in assisting with diagnosis.¹⁹ Recently, gene amplification using polymerase chain reaction has been employed to identify the presence of nematodes in both serum and CSF.²⁴ As molecular and point-of-care diagnostic techniques for parasitic diseases improve in the coming years, rapid definitive diagnosis using CSF samples might become possible, and have great utilization in endemic areas.

Since the 1990s, advances in neuroradiology has also played a role in assisting with diagnosis of eosinophilic meningitis. Hyperintense areas in white matter seen on T2-weighted images have been observed in patients with human angiostrongyliasis, as well as post-gadolinium enhancement of subcortical white matter and affected cranial nerves on T1-weighted images. Leptomeningeal enhancement is also frequently seen.^22,24,27 Interestingly, Tsai and colleagues observed a significant correlation (P <.05) between T1 signaling on MRI and clinically more severe headache, as well as CSF and peripheral eosinophilia. To date, there has been no associated pathognomonic radiographic finding in patients with eosinophilic meningitis. However, neuroradiology can be used to support the diagnosis and rule out other potential causes—amebiasis, neurocysticercosis, gnathostomiasis, and paragonamiasis, among others.

Treatment in Resource-Constrained Environments

Campers, hikers, farmers, and adventurous eaters are among those individuals who should be educated regarding the risks of human angiostrongyliasis, including its mechanism of infection and the disease sequelae. Luckily, the vast majority of reported cases have occurred within some proximity to medical attention. The best way to manage eosinophilic meningitis is to limit exposure. This is accomplished by avoiding the consumption of raw freshwater mollusks including snails, slugs, prawns, crab, and even raw freshwater fish. This includes washing fresh fruits and vegetables, particularly lettuces, and ensuring that roadside juice stands are serving products made from properly washed and peeled produce.

Since snails and their slime can be found in and on fresh fruits and vegetables, washing the produce prior to consumption is an important step in the food preparation process. A comparison of salt, bleach, and vinegar solutions demonstrated no significant difference compared with tap water alone when used to remove snails/slugs from produce, although multiple washing/rinsing cycles was found to decrease snail burden.²⁸ However, the use of different household chemicals and treatments has been shown to decrease larval infectivity in rats. Eamsobhana, et al, reported that mixing raw snails in the traditional Thai “Koi-Hoi” marinade consisting of spices and citrus juice resulted in decreased larval infectivity, particularly when a local 80-proof spirit was added.¹⁷ In their study, an 80% decrease in motile larvae was seen after 60 minutes in the marinade alone, or 5 minutes in the marinade followed by 30 minutes in the alcohol drink. A 100% non-motile rate was seen when the snails were allowed to marinate for 25 minutes followed by soaking in alcohol for 30 minutes. This serves to demonstrate that household products, or those available to campers and hikers can be used to reduce risk. The use of vinegar, salt solution, and 1.5% bleach solution have also been shown to decrease larval infectivity in A. costaricensis after soaking contaminated produce in the solutions for 15 minutes.²⁹ To our knowledge, this study has not been replicated for A. cantonensis, and might be a direction for future research as cases of the disease are spreading globally and awareness is increasing.

Treatment in Non-Austere Environments

Clinical variability is broad and symptoms often guide medical intervention. Mild cases resolve spontaneously, requiring only symptomatic therapy. For highly symptomatic cases, serial lumbar punctures have been demonstrated to provide symptomatic relief for headache, nausea, and vomiting caused by increased intracranial pressure.^{18,22,24–26} Antihelmintic therapy is controversial due to the theoretical risk that immune reaction caused by rapidly dying worms can exacerbate patient's neurologic symptoms and lead to potentially catastrophic results. However, case-series and epidemiologic studies published in which antihelmintic therapy was used have not reported significant adverse reactions directly related to their use, and most of the treated patients have made full recovery.^15,19,20 The role of corticosteroids has also been evaluated in the treatment of eosinophilic meningitis, particularly with the goal of reducing cerebral inflammation caused by the immune response. In most situations, corticosteroids have not been shown to shorten disease course.^2,18,19 However, Chotmongkol, et al, reported in a randomized, controlled trial that two weeks of corticosteroids decreased headache duration when compared with placebo, as well as decreasing repeat lumbar punctures in the experimental group.³⁰ Additionally, the same author demonstrated their safety for use in patients with eosinophilic meningitis.³¹ Corticosteroids have also been evaluated when used concurrently with antihelmintics such as albendazole. In their study, Chotmongkol, et al, found that adding albendazole to the corticosteroid regimen did not result in shortened disease course or improved symptomatic relief when compared with steroids alone.³² Importantly, no adverse drug outcomes were reported in their study for either the control or treatment groups.

Based on the available evidence, there are no current official recommendations regarding treatment of eosinophilic meningitis caused by A. cantonensis. Generally, it is accepted that the use of corticosteroids (prednisolone at 20mg three times daily for 14 days) might provide some benefit in symptomatic reduction, with minimal adverse effects. The use of albendazole or another antihelmintic agent remains controversial due to theoretical risks, although these have not been demonstrated in limited clinical studies. However, their use is usually not required and should be reserved for case non responsive to symptomatic management, or those with severe systemic effects.

Conclusion

Angiostrongylus cantonensis is the most common cause of eosinophilic meningitis worldwide, and is endemic throughout the Asia-Pacific region. It has been shown to cause disease in returning travelers. Travelers to endemic areas, particularly those who camp, eat local cultural cuisine, consume raw freshwater mollusks, or eat raw fruits and vegetables are at risk of acquiring the nematode infection. Human angiostrongyliasis has a variable clinical presentation that can range from a short, self-limited illness, to fulminant meningoradiculomyelitis, or encephalitis, with permanent neurologic sequelae and death. The mainstay of treatment includes management of headache through LP, analgesics, and potentially steroids or antihelminthic agents, although the role of the latter is controversial.

Figure 1.

Life-cycle of Angiostrongylus cantonensis. Life cycle obtained from http://www.cdc.gov/parasites/angiostrongylus/biology.html. Accessed 15 December 2013.

Disclosures

The authors reported no conflicts of interest.

Disclaimer

The views expressed in this abstract/manuscript are those of the author(s) and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.