Biting back

Mick Humphreys says one bite from a mosquito left him with permanent brain damage. Ten months after that bite he gets monster headaches, he has to use a walking stick and his short-term memory is shot. The 71-year-old retiree lives near the Murray River in far north Victoria and a mosquito infected him with the Japanese encephalitis virus in March last year. He wound up in intensive care and spent five weeks in hospital, where he caught Covid.

“I was very, very sick,” he says. “I didn’t know what was going to happen to me.” Before he was bitten, he says, he was fit and alert. The ongoing physical and mental damage caused by the virus has changed his life. “Some days are better than others, some days I’m fine, other days I’m all over the place.” Now he’s nervous about being out and about after dark when the mosquitos are biting. “You’ve only got to go out to the clothesline and get some clothes or turn off the tap and a mozzie bites you. It just takes one.”

The potentially fatal Japanese encephalitis virus (JEV) arrived in mainland Australia for the first time last year, startling scientists and public health experts and spawning a substantial government-funded vaccination and public awareness program. So far at least 45 people have been infected with the virus and seven have died.

The disease is the latest recruit to the rogues’ gallery of mosquito-borne diseases floating around in Australia, many of them leaving people sick, aching, in pain and unable to get back to normal life for months or years on end. Global warming and the big wets now regularly washing across the nation provide ideal conditions for the growing swarms of disease-carrying mosquitos. These little biters are the world’s number one killers, with an annual death toll in the hundreds of thousands: mostly from malaria and yellow fever. Now Japanese encephalitis has arrived in Australia, it’s here to stay and there may be more mosquito-borne diseases on the way as conditions change and mosquitos adapt.

Humphreys expects to take drugs for the rest of his life to control the headaches he now gets from the disease. He says he was put on a combined antibiotic and steroid drip for five days while he was in hospital. When he thanked the specialist for saving his life the doctor said he didn’t think the drip made any difference at all. Like so many diseases carried by mosquitos, there is no real cure for Japanese encephalitis. Australians have died from the disease after spending weeks in hospital: in rare cases the virus can lead to seizures, brain swelling, coma and death.

Humphreys says that after he left hospital he pushed hard for a widespread vaccination program, talking to local politicians about the issue and getting the word out. He is a little bitter because he was denied a vaccination when Japanese encephalitis originally surfaced at a piggery 15 kilometres from his home.

Now, he says, he has heard a mosquito carrying the potentially fatal Murray Valley encephalitis (MVE) has been detected in Menindee in western NSW. The disease is specific to Australia and there is no vaccine.

Paul Horwood, an associate professor of virology and viral diseases at James Cook University in Townsville, Queensland, contributed to a paper estimating the Australian spread of the birds, animals and insects known to carry the Japanese encephalitis virus. He says it’s widely thought the virus was first brought to mainland Australia by wild water birds, maybe attracted by the massive floods that have washed across the nation in recent years. Mosquitos of various species can get the virus from birds and pass it on to pigs and humans.

Mozzies are the demons in this picture. Enjoying warmer weather and the abundance of water across the mainland, they are swarming through the nation and they can carry potentially severe diseases. Every time a mosquito bites, seeking blood, it swallows viruses and parasites living in the blood and it can then pass them on to the next person or animal it bites. There are day-biting mosquitos and night-biting mosquitos, and every Australian knows the itch of a mozzie bite and the whine of a mozzie getting too close.

Australia had one of the deadliest mosquito-borne diseases – malaria – in the past. Caused by parasites spread by certain species of anopheles mosquito, malaria was declared eradicated from the country in 1981 and only one case of locally-acquired malaria has been documented by the federal health department since the beginning of 2017.

“We’re fairly fortunate in Australia because although we do have vectors that can transmit malaria, they don’t seem to live close to human habitations or close to human population centres,” Horwood says, adding that although malaria had been introduced to Australia, it hadn’t become established.

Yet health authorities have warned that those parts of Australia north of parallel 19 south, stretching from just north of Townsville across the continent to just south of Broome, and including most of far north Queensland, a large chunk of the Northern Territory and the Kimberley, remain susceptible to malaria.

 “With climate change we may see more extreme storms, this can result in large increases in mosquito numbers that can lead to an increase in these types of pathogens,” Horwood says, referring to the broad spectrum of mosquito-borne diseases, including local infections such as Ross River virus. “Ross River virus, in particular, can be spread by over 40 different species of mosquitos.”

Every year, thousands of Australians are infected with Ross River virus, also known as Ross River fever.  In 2017, nearly 7,000 people contracted the specifically Australian disease severely enough to go to the doctor, in 2018 and 2019, around 3,000, in 2020 more than 6,300, in 2021 and 2022 about 3,000. Many people recover quickly but for some it’s a hammer blow that brings long-term crippling pain and fatigue. There is no vaccine and to date no effective treatment, although Australian science is on the verge of a breakthrough.

Two Facebook groups have been set up for those Australians who have trouble coping with the crushing muscle and joint pain of the virus, the fatigue and the confusion. Together the on-line groups have a total of more than 4,600 members. The posts on both sites repeat a story of pain and loss.

“I’m about seven weeks into my RRV diagnosis,” one member writes. “This is hell!! The pain is sometimes overwhelming. I wake every night feeling like I have broken bones. I’m now using a walking stick just to get out of bed and move about.”

The desperation is there for all to read. “I was diagnosed with RRV two days ago but now going into my third week,” another member writes in a recent post. “Pretty much bed-bound, can barely walk, can’t bend my knees, feet are like walking on glass, can’t bend some fingers or twist one wrist and my neck and shoulders are on fire.”

Judith Hunt knows the enduring agony of Ross River virus. The disease hit her so hard that at one point her husband had to carry her to the bathroom. The 54-year-old nurse and midwife from Berowra, north of Sydney, nearly collapsed on her way to ask her doctor why she suddenly felt so sick. “I had so much trouble getting off my chair,” she remembers, her voice breaking. “Walking to the car was like someone sticking knives in my feet. Then when I got to the GP I couldn’t get out of the car.”

She thinks she was probably bitten by an infected mosquito on a family caravan trip about two years ago: one little itchy bite that left her with months of crippling pain and outright despair. She’s been afflicted with immense fatigue ever since, but her three teenaged kids and her husband have helped her get through the worst of it.

“It was dreadful,” she says. “I would never wish it on anyone. It was just horrific.”

Hunt tried eliminating sugar and alcohol from her diet, and sticking to healthy foods, but it made little difference. She resigned from her permanent position at Hornsby hospital because she couldn’t physically manage the demands of the job.

Her doctor prescribed the powerful steroid prednisone which she took for just over a year. Long-term use of prednisone has been associated with cataracts, osteoporosis and a weakened immune system, but the drug allowed Hunt to function, and 18 months after the RRV diagnosis, she returned to work two days a week.

“Now it’s major fatigue,” she says. “My kids used to laugh because I was a gutter girl. Every day I was sick after I got out of hospital, I would still try to walk. I got exhausted, even 30 metres from our home. I had to sit there in the gutter and wait half an hour to an hour until my body had rested to be able to walk home again. It was totally debilitating.”

She still feels the pain and weakness. “One day of too much physical activity, or just the day-to-day running of a normal household, I’ll come a cropper and I’ll spend the next day physically and mentally exhausted on the lounge,” she says.

Ross River virus upended Hunt’s world, laying waste to her career, her plans, her everyday existence. “For my husband and myself it has been a total change of life, for both us. My kids as well. It changed everything. Work and financially is one thing, but RRV, it changed everything.”

Viruses are some of the most mysterious and dangerous organisms on Earth: Covid, HIV, Ebola, hepatitis, flu, and measles are all viral diseases. Some of the deadliest of the viruses are carried by mosquitos, like yellow fever, which has the highest case fatality rate of any mosquito-borne disease and which kills about 30,000 people a year, mostly in Africa and Latin America, and dengue which plagues Asia, South America and the Pacific, with an annual global death toll of as many as 36,000.

In the past, hundreds of Australians were laid low by dengue, sometimes known as break-bone fever, a painful and debilitating disease of sweats, rashes and joint and muscle pain, once endemic in far north Queensland. In the early 1990s, there were 900 or so cases of dengue in and around Townsville and Charters Towers.

Now, though, pioneering Australian scientists from the non-profit World Mosquito Program have developed a way to prevent the largely urban Aedes egypti species of mosquito from infecting humans with dengue, and over the past ten or so years this system has largely eradicated local dengue transmission in northern Queensland.

The World Mosquito Program system is a world first. Mosquitos infected with naturally-occurring Wolbachia bacteria are released in dengue-plagued districts. These bacteria prevent the mosquitos from infecting humans with the dengue virus. The bugs still bite, but they don’t spread the painful and debilitating disease. As time goes by, the Wolbachia bacteria are inherited through generations of mosquitos, and these mosquitos take over from other mosquitos, eventually creating a perpetual and self-sustaining safety net for those once dengue-afflicted towns.

Cameron Simmons is the director of the Institute of Vector-Borne Disease at Monash University and the director of global implementation at the World Mosquito Program, which is now operating in 12 nations around the world from Brazil to Vanuatu.

As well blocking dengue transmission, the Wolbachia bacteria can prevent Aedes egypti mosquitos from spreading yellow fever, which leaves patients with headaches and nausea, and in serious cases, kidney and liver illness; chikungunya, a disease which brings fevers, rashes, and fatigue; and zika, the virus known to damage unborn babies, sometimes leaving them with very small heads.

In principle, Simmons says, the Wolbachia bacteria method could be used to combat other types of mosquito-borne disease such as the Australian Ross River virus. But Ross River is carried by several different mosquito species across Australia, and mostly in rural areas, which makes it impossible to control with the World Mosquito Program Wolbachia mosquitos. “Ross River pops up in generally rural communities, and it’s very unpredictable where it’s going to pop up,” Simmons says. “There’s the very practical problem of how you do a Wolbachia deployment against multiple species of mosquitos in a rational way. It’s a much harder implementation problem.”

A wet winter, spring and now summer have given mosquito populations the warm, damp conditions best suited for breeding, spawning huge populations across Victoria, he adds. “Everyone’s feeling it. It would be surprising if we got through the summer without a Ross River outbreak.”

The Ross River virus is a zoonotic infection that jumps to humans via mosquitos from animals, probably marsupials – likely from the kangaroo and wallaby family. Mosquitos are not known to spread the disease from person to person (unlike dengue, which can be transmitted from person to person via an infected mosquito).

It’s the Ross River brain fog, as well as the joint pain, that upsets Tanya Piromalli. The 52-year-old first thought her strange achy feelings were the start of menopause but as the virus took hold she had second thoughts and guessed she had Ross River virus. Her diagnosis confirmed by a blood test in March last year.

“I was walking beside my dad who’s 82 and I felt like I was 182,” she remembers. “I’ve never felt like that in my life. I dreaded going to bed, I had a kitten who jumped on my chest and I couldn’t even lift my arm up to pick the kitten up to take it off me. It was just horrific. I’ve still got the pain.”

Home is just outside the rural town of Griffith in NSW, but Piromalli thinks she caught the virus from a mosquito bite in Queensland. By the time she got home to Griffith she felt terrible. “I’d walk out the back to the chook pen and then I’d have to come back in,” she says. “I just couldn’t do it.”

To begin with she took various drugs including analgesics and non-steroidal anti-inflammatories but they didn’t make much difference. Finally, like Hunt, she wound up taking the steroid prednisone. She took it for a month, stopped for a while, then took it for another month. She tried a strict no carbs, no dairy diet, and she thought it helped a little. She stopped taking prednisone a week before we spoke and she had begun to feel the pain in her joints again.

Piromalli has a children’s party equipment business – renting jumping castles, water slides and the like, setting them up and take them down. The virus brain fog has made her forget three jobs in recent months, lapses which she takes very seriously. Like so many others with Ross River, she wants to be cured, once and for all.

It seems an effective treatment may finally be on the way, born of a flash of inspiration from someone deeply imbued with two important qualities – a bone-deep understanding of the virus and a narrowly-focused scientific expertise.

It took virologist Lara Herrero two years to recover from Ross River fever. “For one year it was muscle and joint pain that I had all the time,” she says. “And for the subsequent year I had little relapses of it. It seemed to be when I was challenged with anything else, like a cold, the first thing I would feel would be muscle and joint pains flaring up and then two days later I would come down with a cold.”

A scientist based at Griffith University on Queensland’s Gold Coast, Herrero says her struggles with the virus caught her scientific interest. She began looking into possible treatments, zeroing in on a pharmaceutical called Elmiron, a prescription-only drug with anti-inflammatory and anti-viral properties first developed in Germany. Mainly consisting of pentosan polysulfate sodium (PPS) in a tablet form, the drug had originally been approved by Australia’s Therapeutic Goods Administration to treat bladder inflammations.

Herrero’s tests, using an injectable form of PPS to treat Ross River virus, are likely to lead to a commercially-available treatment for the disease, but she says there’s still a lot to be learned about the basics of the virus itself.

“We don’t know why person A might be bitten by a mosquito with Ross River and won’t get sick, but person B will,” she says. “We have no idea. And that’s the same for all mosquito-transmitted viruses. They all have a differing range of who gets sick and who doesn’t. With the Japanese encephalitis virus, 100 people will get bitten and infected, ten will get sick, one will get encephalitis. That one could be an otherwise healthy person.”

At the same time, she says, it’s not yet known whether the Ross River virus triggers an immune response that lingers for a long time and changes the immune system, adding that this particular Australian virus is more complicated than most mosquito-borne viruses.

Herrero thinks more research funding is essential to understand insect-borne viral diseases, especially in light of global warming and the march south of increasing numbers and varieties of disease-carrying bugs.

While the Covid pandemic sucked away a lot of the virology research funding in Australia, Herrero says the pandemic and the subsequent emergence of debilitating long Covid underscored the importance of research into the long-term consequences of viral diseases. “At the very least, this horrible pandemic we’ve all gone through is bringing to light the idea that these viral infections do have long-term effects,” she says.

Only doctors can apply to the Therapeutic Goods Administration, via a special access scheme, to get pentosan polysulfate sodium (PPS) to treat their Ross River virus patients. But news of Herrero’s work has filtered out and she gets despairing emails from people laid low by the life-altering and painful disease. There’s nothing much she can do because she doesn’t control any of the clinical trials nor does she have access to the drugs.

“The emails are always pleading and you know people are desperate,” she says. “I get it. I’m the first one to get it. I felt that way too.”

Herrero published her PPS research in a scientific journal. Paul Rennie, who founded the Melbourne-based Paradigm Biopharmaceuticals company in 2015, took note. “We were very interested because this was the compound we were developing for osteoarthritis,” he says. “Her work was groundbreaking and very exciting, but we thought it probably needed to be scientifically proven in a human clinical trial.”

Herrero’s findings, he adds, were shored up by the work of another researcher who had found the drug could be used to effectively treat osteoarthritis. Ross River virus is also known as epidemic polyarthritis, and it shares some of the characteristics of osteoarthritis.

Paradigm came to a licensing agreement with Griffith University to continue developing PPS for Ross River virus. The company’s human clinical trials have already demonstrated the drug reduces pain and increases hand grip strength, as well as showing remission or near remission of the virus in 62 per cent of trial subjects.

The company has reformulated pentosan polysulfate sodium (PPS) into an injectible treatment named Zilosul for Ross River virus, consisting of 12 injections in the midriff over six weeks, followed 12 months later by a maintenance dose. The injections are subcutaneous, or under the skin – the type of injection many diabetic patients administer to themselves every day.

Rennie says Zilosul is likely to also be an effective treatment for other insect-borne viruses, such as the Australian Barmah Forest virus – which has symptoms much like Ross River virus. It seems this disease, too, is on the march with warmer weather – it emerged in Tasmania for the first time in 2019. Rennie expects Zilosul will also help treat chikungunya which is a blight across much of Asia, Africa and South America, so there is export potential for the medication as well.

Herrero’s Ross River virus research found significant changes in joint biochemistry, Rennie says, demonstrating the disease does destroy joints and waste muscles. “Those effects are real, they’re quantifiable,” he says. “There are a lot of people who are really suffering. With climate change will be a lot more of this as time goes on.”

Like Herrero, Paradigm receives emails from Australians with Ross River who hope to get hold of an effective medication; who have somehow heard of the PPS treatment even though it seems many doctors haven’t. But Rennie says it’s impossible to act outside the regulatory mechanism.

“If we could, we would make it available,” he says. “They’re in a lot of pain, it has affected a lot of people’s lives. I don’t think the medical fraternity sometimes understands just how debilitating this is. A lot of doctors say take some Panadol and you’ll get over it. And in some cases, people do recover quite quickly without too many associated health problems, but at the same time there’s a large number of people who don’t.”

Only a handful of doctors have successfully applied to the TGA for access to the drug, and Paradigm has supplied it for about 25 to 30 patients, Rennie says. “There is a lack of knowledge and information around the disease. There are some doctors who think this is something that will resolve on its own, given enough time.”

There will be no quick and easy fix for the legions of insect-borne virus sufferers struggling with everyday life and pushing themselves hard to even get out of bed. Paradigm now has phase three human trials underway for the PPS osteoarthritis drug application, and once those trials are completed the company will seek provisional TGA approval for the PPS Ross River virus treatment.

“We would hope that we get provisional approval in the calendar year 2026,” Rennie says, noting that pharmaceutical approvals always take time.

He understands the urgency. “A lot more could be done obviously, but there’s always the question of priorities,” he adds. “If people understand that there are some people who don’t have the strength to lift a knife and fork, and who are in incredible pain just with very basic duties at home, I’d think there’d be much more acceptance of the need to do something and maybe bring therapies like this through the regulatory focus much faster.”

The Weekend Australian magazine