“Infectious disease is going to have a larger impact than terrorism on our future,” Lieutenant Governor Josh Green said in his introductory remarks to the 6th International Workshop on Angiostrongylus and Angiostrongyliasis, held last month in Hilo.
In his official capacity, Green regularly receives updates on security threats to the state. Because he also moonlights as an emergency room physician, Green has witnessed the harmful effects infectious diseases have had here and abroad, as well.
Green cited his recent experience in Samoa, where he helped vaccinate a population that had seen measles vaccinations rates plummet in recent years, leaving it vulnerable to an epidemic of the life-threatening disease. He then called out the state’s epidemic of dengue fever a few years back and the outbreak of zika in South America. “All of these have had a much greater impact on the loss of life, on the development of newborns, and on economics across the globe.”
During the course of the workshop, it became apparent that the state’s efforts to address neuro angiostrongyliasis, the disease caused by the rat lungworm, Angiostrogylus cantonensis, were too little and too late for many of those who count themselves its victim.
When a presenter asked how many in the audience had been infected with rat lungworm disease, approximately two dozen raised their hands. But in response to the next question – how many had had their diagnoses confirmed – the show of hands was far less.
That gap between the self-diagnosed but unconfirmed and those whose diagnosis had been given official recognition by the state Department of Health (DOH) was a near-constant theme of the workshop. In Hawai‘i, an official diagnosis requires confirmation of the presence of rat lungworm DNA by a PCR test of spinal fluid, but generally no testing is done until the level of white blood cells showing a response to parasites in spinal fluid reaches 10 percent, or when there are 10 of those cells, called eosinophils, per microliter. This diagnostic threshold is often crossed only after the larvae are well established and the opportunity for effective early treatment has passed.
Since the state added rat lungworm disease to the list of reportable diseases in 2007, the DOH has counted 64 laboratory-confirmed cases and 40 probable cases. A probable case is one that was not lab-confirmed, but the individuals had symptoms consistent with those of the disease, eosinophils in spinal fluid, and a history of contact with snails or slugs.
The disease was known in Hawai‘i well before it was reportable. According to the DOH, from 1959 to 1965, there were 19 documented cases of rat lungworm disease in Hawai‘i. Incidence of the disease ramped up starting in 1996, when the semi-slug Parmarion martensiwas first detected on O‘ahu and the BigIsland. That species of gastropod seems to be able to harbor a higher concentration of rat lungworm larvae than most other snails and slugs. As the semi-slug has spread across the Big Island district of Puna north to Hilo and beyond, so, too, have the documented cases of rat lungworm disease.
In 2019, the DOH confirmed a total of eight cases of rat lungworm disease (five residents, three visitors). All are believed to have received their exposure to the rat lungworm larvae while on the Big Island.
A Case Study
Just how damaging this failure to diagnose Angiostrongyliasis early can be was brought home in dramatic fashion by the presentation – the first of the workshop – made by a young couple, Mark LeRoy and Maya Parish, who live in Hawi, on the northern tip of the Big Island.
On January 9, 2019, LeRoy ate a salad made with lettuce grown in their own garden. It had been a wet winter in North Kohala, and for the first time, the semi-slug was showing up in the area.
LeRoy had washed the lettuce, but, he said, he had noticed a slug in the salad and maybe even ate a juvenile slug, which, though small and hard to detect, can also carry the larvae. “I thought about forcing vomiting, but didn’t. Maybe I should have,” he said.
Nine days after eating the salad, LeRoy experienced his first symptoms, which included a feeling of strong pressure on his upper middle back and chest, headache, cough, tingling in neck, toes, feet, and hands, and fever.
He was in Honolulu at the time and went to the emergency room at Queen’s Hospital. A spinal tap showed an elevated eosinophil count, but not high enough to warrant the confirming PCR test, and LeRoy was discharged with a prescription for pain and nausea.
Three days later, and with no abatement in the symptoms, LeRoy went to the emergency room at the North Hawai‘i Community Hospital in Waimea. He told the doctor that he suspected he had rat lungworm disease. No spinal tap was done. Again, he was discharged with a prescription for pain and a muscle relaxer.
Both symptoms and the pain intensified.
On January 25, LeRoy and Parish made multiple visits to doctors and to the Waimea hospital, seeking treatment. The ER doctor “was impatient and did no blood work. I was discharged with no treatment whatsoever,” LeRoy said.
They called the Department of Health. Again, they received no relief.
By January 28, “Panic was setting in,” Parish said. “Mark began vomiting and shaking,” she said, and for the third time, they drove to the emergency room in Waimea. Only then did the attending physician begin to give credence to the claim that LeRoy was suffering from rat lungworm disease. He was given steroids and pain relievers and was advised that Dr. Jon Martell in Hilo was the most knowledgeable physician on the island when it came to diagnosing and treating the disease.
“At 2 in the morning, we drove from the North Hawai‘i Community Hospital to Hilo to see Dr. Martell,” Parish said. “We arrived in Hilo on January 29 at 4 in the morning. We called Dr.Martell’s office and were told he doesn’tsee patients.”
At this point, Will Chapple, a family physician in Waimea, returned a call that LeRoy had left with his office. He had looked at the results of the bloodwork done at Queen’s hospital and agreed to see LeRoy later that day. “It was the first time we truly felt helped,” Parish said.
Chapple prescribed Vicodin for pain, Ambien for sleep, and dexamethasone for inflammation. Parish called him “ourhero at a desperate time.”
But the symptoms continued to worsen. There were new symptoms involving cognition. LeRoy became unable to distinguish between past, present, and dream states. Chapple then prescribed the anthelmintic Albendazole, but the pharmacy in Waimea did not have it in stock.
LeRoy and Parish made a fourth visit to the Waimea hospital, where they waited four and a half hours before leaving, with no doctor having seen LeRoy. “We felt desperate for care,” Parish said.
Over the next week, LeRoy said he “experienced pain like I had never experienced – level 9-10 pain. I felt I was being electrocuted from inside of my body out. Screaming at the top of my lungs. It was very scary.”
On February 11, while in Chapple’soffice, LeRoy had a massive pain attack. Chapple sent him to the North HiloCommunity Hospital – the fifth time in three weeks. A lumbar puncture showed an eosinophil count of 7 percent, still not high enough to warrant a PCR test, under Department of Health standards.
LeRoy was hospitalized for a week.The DOH finally ran a PCR test of his spinal fluid on February 18. At that time, he became Hawai‘i’s second confirmed case of rat lungworm disease for 2019.
Even after diagnosis and discharge, LeRoy continued to experience symptoms. He and his wife sought relief from “different healing modalities,” as they put it – including acupuncture, naturopathic remedies, mushrooms, massage therapy, and nutritional supplements.
To this day, LeRoy has lingering symptoms, including numbness in his legs, weakness, fatigue, and tingling in his skin.
A New Protocol
On the five emergency room visits and three visits to doctors they made, LeRoy and Parish took with them a written record of his exposure to a slug suspected of harboring rat lungworm larvae as well as a printout of the Department of Health’s guidelines for diagnosing and treating rat lungworm disease.
“I had all the symptoms, and I was communicating them, but the doctors weren’t able or willing to connect my symptoms to a diagnosis. They were only connecting a blood test … as the single means to consider that I had rat lungworm, despite all the evidence,” LeRoy said.
If he were to present himself today to the Hilo Medical Center’s emergency room, it’s just possible that treatment under the hospital’s newly released protocol could have saved him a year of pain and suffering.
On January 15, Martell, the hospital’s chief medical officer, released the new protocol for early treatment.
And the new protocol?
It’s the use of an ordinary, over-the- counter pinworm medication, pyrantel pamoate, as soon as someone suspects they may have ingested an infected slug or snail.
“Information we learned from the recent international rat lungworm conference … has encouraged us to strengthen our treatment protocol,” Martell said. The updated guidance is intended “to improve the process for patients and providers.”
The new advisory is based on an unpublished study of the effectiveness of anti-worm (anthelmintic) drugs conducted by researchers at the University of Hawai‘i Hilo’s Daniel K. Inouye College of Pharmacy. In that study, pyrantel pamoate immobilized rat lungworm larvae in lab conditions. “This data suggests the potential of immobilizing ingested Angiostrongylus larvae as well, which could then be expelled through stool without causing an infection, if given early,” the hospital’s press release stated.
Martell added: “Based on this recent research, we will inform patients that pinworm medication might have benefit if taken immediately after accidental consumption of a snail or slug. Thepotential, though not proven, benefitsappear to outweigh the minimal risk of the treatment. Snails and slugs in east Hawai‘i often carry the parasite and the pinworm medicine is available over the counter and safe if given as instructed on the package…. The sooner you take the pinworm medication the more likely it is to help.”
The hospital also recommends that if any part of the snail or slug that caused the rat lungworm exposure is still available, it be tested for the presence of larvae. Also, he added, “absolutely go to see your primary care provider within a couple of days for assessment and possible use of additional treatment.”
Finally, Martell noted that last September, the Queensland (Australia) children’s hospital updated its guidelines on the use of Albendazole, a prescription anthelmintic, in children. (Australia has, like Hawai‘i, seen an uptick in recent cases of rat lungworm disease.)
Those guidelines call for early administration of Albendazole (within seven days of exposure, but not later than 14 days from the time of exposure) once a day for seven days. (The Queensland pediatric guidelines may be viewed online at “Paediatric guideline: Snail and Slug Ingestion: Prophylaxis against Angiostrongylus cantonensis infection.”)
Caution at the DOH
“What we worry about is people taking this medicine and assuming they’re fine. That’s the concern.”
The caution over the new Hilo protocol was voiced by Sarah Park, M.D., the state epidemiologist, in an interview with Environment Hawai‘i.
“Everything we do has to be evidence-based,” she added. “Pinworm medicines are safe as long as they’re used according to directions. There’s that. But is this something we want to put out there? It’s difficult.”
There’s “the risk that people will assume doing this will protect them. We can’t guarantee that. … We don’t know if it will be effective.
“That doesn’t mean I’m saying ‘No, don’t do it.’ I’m not saying yes. We’re on the fence. We need to discuss this, look at different perspectives, understand that if this is to be recommended, how will it be recommended,” she said.
Above all, she said, there needs to be in vivo research, research involving primate animals, and not just in vitro testing of the sort that has been done so far.
In the meantime, the state Department of Health guidelines, released in 2018 after nearly two years of study by a team of physicians and other experts, set a high bar for diagnosis while offering few options for treatment.
Under those guidelines, a “presumptive diagnosis” of rat lungworm disease requires three elements: suggestive symptoms and signs; eosinophils in the spinal fluid; and an exposure history.
LeRoy had all three, and yet, because his eosinophil count didn’t reach the Department of Health’s threshold for the lab work – real-time polymerase chain reaction (RTi-PCR) – that would have confirmed the diagnosis, treatment was delayed. It wasn’t until more than a month had passed from the time of his initial exposure, and a second spinal tap, that the Department of Health relented and green-lighted the lab work, even though the eosinophil count in his spinal fluid was below the threshold called out in the guidelines.
Park explained why the guidelines are written the way they are. “If a clinician feels, and we feel, that there is a concern, we have tested when the level of eosinophils is below” what the guidelines call for.
But, she added, “There’s a huge caveat. Often even when we do a test, we get a negative” for the presence of rat lungworm DNA in the spinal fluid. In those cases, if there is still a concern by the clinician that the patient has rat lungworm disease, “we advise them to get another specimen in about a week’s time. If you do the [lumbar puncture] too early, sometimes the test is negative.”
What’s more, the guidelines are lukewarm when it comes to administering Albendazole. “The addition of Albendazole … may provide additional benefits, although there is limited evidence of this in humans,” they say.
A year and a half after those guidelines were published, the authors appear to have changed their thinking on the drug. Vernon Ansdell, a professor in the Department of Tropical Medicine at the John A. Burns School of Medicine in Honolulu and lead author of the guidelines, stated in his poster presentation at the conference that the treatment of rat lungworm infections with Albendazole “appears to be safe, when combined with high dose corticosteroids, and effective, if given within the first 7-14 days after infection.”
The Department of Health has indicated that the guidelines will be updated by the fourth quarter of this year.
Park noted that even treatment with Albendazole has not been shown to be effective against rat lungworm infections through in vivo studies. “Part of the problem, too, is that Albendazole is not readily available. There’s just one company that makes it in the United States, and it’s prohibitively expensive,” she noted.
The DOH itself has no capacity to do this research. “I hope there will be research scientists – maybe at the National Institutes of Health or the Centers for Disease Control – to help elucidate what could be done,” Park said.
Unspent Funds
For many years, many of the people in East Hawai‘i most intimately involved with research, diagnosis, and treatment of rat lungworm disease have been associated with the Hilo Medical Center and the Daniel K. Inouye College of Pharmacy at the University of Hawai‘i-Hilo.
In 2017, the Legislature was considering a bill to give UHH nearly $1.4 million over two years to support this work. The bill made it to conference, but ultimately did not pass. Instead, the Department of Health received an appropriation of $2 million over two years to address rat lungworm disease.
In the first year, the DOH provedincapable of spending the full amount. In a report to the Legislature, then-DOH administrator Virginia Pressler stated that “a portion of the funding did go unused. It was supposed to fund a coordinator position for the initiative” – a “widespread, multifaceted public outreach and education campaign” – “but the department was unable to fill the position.The funding lapsed and was returned to the general fund.” That portion was $270,000, or 27 percent of the total appropriation for the year.
Go for the Rats
Park was asked if the DOH was monitoring the spread of the semi-slug, Parmarion martensi, throughout the state, since the virulence of rat lungworm infection seems to track pretty closely with the invasion of the semi-slug into new areas.
“Unfortunately, we can’t eradicate the slugs,” she replied. “Actually, I’d point out that these parasites can’t reproduce, can’t survive, without the rats. If you cut out the rat part of the equation, these things won’t exist. If we’re ever successful in eradicating rats, we’d get rid of not just rat lungworm, but a lot of other diseases.”
“Yes, the semi-slug is concerning for a number of reasons,” she continued. “But we can find this parasite in a number of other mollusks. … I just want to make sure people aren’t so focused on the semi-slugs that they think, if I just seek the property clean of the semi-slugs, I’ll be fine.
“It really just boils down to the rats.”
— Patricia Tummons
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