Rheumatic fever is a cruel disease that can lead to heart damage and death. Yet we may have missed an important trigger.
Rheumatic fever is a cruel disease that can lead to heart damage and death. Yet we may have missed an important trigger.
Rheumatic fever has a particular taste for Maori and Pasifika kids. It’s still hauling them down – licking their joints and biting their hearts, as the old saying goes – despite a six-year public health campaign that cost
Fitting, then, that it’s a Maori boy from Kaitaia who is defying the medical textbooks and adding to the evidence that’s causing experts to rethink the causes of this plague on his people. Appropriate, too, that his doctor is lionised Maori GP Lance O’Sullivan.
The boy came to the doctor in 2015. He was six years old and very sick. He had a fever, he was lethargic and his left knee was so painful he could not put any weight on it. O’Sullivan looked at him and saw rheumatic fever. And he saw failure. Shattered and wondering how the boy had eluded throat swabbing at school, he referred him to hospital.
There, a blood test showed the boy’s immune system was producing antibodies consistent with the rare selfsabotaging immune response that is rheumatic fever. He spent five weeks in hospital, joining the 97 other young people hospitalised that year with their first recognised bout of the disease.
According to conventional wisdom, a bout of acute rheumatic fever is preceded by a sore throat involving group A streptococcus (strep A). The boy did have a sore throat about a month before he got really sick. It was swabbed at school.
But here’s the thing: it came back negative for strep A. Crucially, six days before that swab, the boy had been to see O’Sullivan with impetigo – and that skin infection did involve strep A.
O’Sullivan and co-authors report the case in this month’s Pediatric Infectious Disease Journal. It’s impossible, they write, to know exactly what role was played by the strep on the boy’s skin and how another strain of strep, G, that was found in his throat might have contributed. Perhaps they somehow bounced off each other, tripping his immune system into rheumatic fever. But group A strep in the throat was not “the driver”.
This is just one case, experts warn. Much more research is needed. But O’Sullivan et al write that it “clearly demonstrates” that rheumatic fever can hit in the absence of strep A in the throat. They note that it comes on top of epidemiological evidence from Australia, as well as New Zealand microbiological evidence, that strep in skin infections may cause rheumatic fever.
And they point out that the Government’s rheumatic fever prevention programme, which wound up in June, was geared around swabbing throats – not skin – for strep A.
CASES FALL THEN RISE
A strep A sore throat is basically an early warning system. Leave it untreated, especially in those most at risk – that is, between the ages of four and 19, Maori or Pasifika, living in crowded, cold or damp homes and from low socio-economic areas – and rheumatic fever will hit a handful of them one to five weeks later. But treat those throats early with 10 days of penicillin and the bug is wiped out. A few more kids safe.
This is why the prevention programme carpeted the country with free swabbing and the “sore throats matter” message. The programme got a huge boost in 2012 when the Government made cutting the rheumatic fever rate one of its top 10 “Better Public Service” targets. As the campaign kicked in, the national rate came down, from four cases per 100,000 people to a low of 2.4.
Certain areas saw remarkable drops – a recent study of 61 schools in South Auckland, for example, found 58% fewer cases of rheumatic fever two years after school throatswabbing clinics began. That’s a difference of 51 kids.
The May Budget halved funding for the prevention programme to $5 million a year, to be shared by the 11 district health boards that most need it. Yet Health Minister Jonathan Coleman says the programme was effective. It focused attention on the disease, he says, and “a lot of kids got treated [for strep throat] who wouldn’t have otherwise”.
He has previously cited the 23% drop from the 177 new cases of rheumatic fever in 2012 to 137 last year. But now the lines on the graphs are ticking back up again. The target was 1.4 cases per 100,000 people and the deadline was June. Now the rate is 3 and rising. And as ever, ethnicity confers vulnerability: 45 of 2015’s 98 cases were Maori; 44 Pasifika. That was an exceptionally lean year for rheumatic fever. Of last year’s 137 new cases, 50 were Maori and 75 Pasifika.
“It’s always been a tough one to catch,” says Coleman, a former GP. “But maybe this skin [research] might be a way of really getting that number down a bit more. It’s interesting.”
To be clear: the real worry is not rheumatic fever itself but what happens when it gets the chance to burn long and hot through a body or flare up again and again.
The medical term for this is rheumatic heart disease. The damage it does to the heart is permanent, although surgeons can repair or replace valves. It tends to bring death early to those it strikes and kills between 150 and 180 New Zealanders every year. It got to the six-year-old boy. He is now living with “quite significant heart disease”, O’Sullivan says. “It’s pretty rugged.”
THE ROLE OF SKIN INFECTIONS
The idea that strep in skin infections may also play a causal role in rheumatic fever was first mooted in Australia 15 years ago. There, it’s indigenous Australians who are stricken. Yet they rarely get sore throats. It doesn’t make sense – until their high burden of skin infection is taken into account. Fiji, another hotspot for what is internationally a rare disease, has a similar pattern.
“You can make a link, based on what’s happening in the population, that those skin infections are probably contributing to rheumatic fever,” says immunologist Nikki Moreland.
An associate at the Maurice Wilkins Centre for Molecular Biodiscovery at the University of Auckland, Moreland leads a team examining how strep infections trigger rheumatic fever, with the end goal of developing a vaccine. She says most people she knows in the field now see a causal role for skin infections as a “plausible hypothesis” – and a research area that must be given priority. The 10 medical experts and academics interviewed for this story share that view.
Helpfully, the types of strep A that tend to settle on skin don’t look quite like those normally associated with sore throats. Researchers assign them what’s called a serotype based on subtle differences in a certain protein on the surface of the bacteria.
So what does New Zealand’s strep A look like?
Moreland and her team analysed the throat swabs of 74 Kiwi kids with rheumatic fever. Half of the strep A on those swabs – from throats – turned out to be skin serotypes. It was an “Aha!” moment.
Next, the researchers analysed more than 450 throat and skin swabs that had tested positive for strep A. One set came from children in South Auckland – the area worst afflicted by rheumatic fever – and a set of throat swabs came from Dunedin, an oasis that remains all but clear of the disease.
Dunedin’s strep A was by the book. Only 4% were classed as skin strains. But about half the strep in the South Auckland skin swabs and a third of the strep in its throat swabs looked like the skin serotypes that are rife in Australia and Fiji. Translation: where our kids are getting sick with rheumatic fever, skin strep is very much in play.
Unpacking the exact mechanisms at work here could take years, Moreland warns.
First, we need to find out whether the Maori and Pasifika burden of skin and throat strep looks like the patterns coming through so strongly in Australia and Fiji.
A TRICKY SPOT
In Kaitaia, O’Sullivan has his own informal study going. For five years he has been swabbing the skin infections of all his Maori patients. With 30% of the skin swabs coming back positive for strep A– a much higher hit rate than the 12% thrown up by sore throats – O’Sullivan started to wonder: “Is it actually skin infections that are causing rheumatic fever?”
The boy’s case has crystallised things for him somewhat. But it also puts him in a tricky spot. He knows that when strep A is in the throat, it takes 10 days of penicillin to protect that person from rheumatic fever. Yet the guidelines for strep A in skin infections say antibiotics for five to seven days.
Of course, these guidelines are not about fending off rheumatic fever – just dealing with the infection on the skin. This is how O’Sullivan treated the boy’s impetigo.
“Now I’ve got this big tension,” O’Sullivan explains. “I just continue to treat [skin infections] with seven or five [days], but I’m hoping that someone will give us the evidence that, yeah, we should treat with 10 days, like strep throats.”
That’s already happening in parts of Australia. Three years ago, GPs were advised to treat strep skin infections in Aboriginal or Torres Strait Island patients with either a single long-acting injection of penicillin or a 10-day course of antibiotics. Similar treatment is now advised for all skin infections in central, northern and remote parts of the country where strep is common.
As the evidence mounted – and because skin infections themselves are painful and dangerous – some nurses and clinics involved with our rheumatic fever prevention programme did treat skin infections as well as sore throats. But every area took a different approach, and the concern is that the recommended short courses of antibiotics rendered any protection against rheumatic fever piecemeal.
The same concern applies to the “refreshed” target – reducing the number of children needing hospital treatment for preventable conditions – that replaced the stand-alone rheumatic fever target on the Government’s top-10 list. Skin infections come under that umbrella, but they won’t necessarily be treated in a way that keeps rheumatic fever at bay.
Half of the strep A on those swabs – from throats – turned out to be skin serotypes. It was an “Aha!” moment.
Coleman echoes the researchers when he emphasises that decisions such as broadening the “sore throats matter” message and changing the treatment guidelines for strep on skin will have to be based on evidence. He notes that the Government has already improved access to GPs with its free consultations for kids under 13.
“If you start giving every kid with a strep A skin infection 10 days of antibiotics, that might have some unforeseen consequences.” For example, issues of antibiotic resistance would have to be explored.
For now, Coleman says what’s probably needed is for GPs to be aware of the possible link to rheumatic fever when treating a child with strep skin infections. “That’s probably not widely known at the moment.”
A contribution from skin infections could partially explain the startling fact that up to 60% of young New Zealanders diagnosed with the disease don’t recall having a sore throat beforehand. That’s at odds with the top-line public health messaging: “Rheumatic fever – it starts with a sore throat.”
That’s a lot of kids not protected by a system that relies on a sore throat being swabbed. And it’s a lot of parents left feeling guilty for missing a sore throat that never happened.
“Absolutely they feel they failed,” says University of Otago public health
researcher Ramona Tiatia, who works in Wellington. “The ramifications of heart surgery and a short lifespan are devastating for parents.”
Through her involvement with three major studies, Tiatia has interviewed hundreds of Pasifika and Maori families who are doing all they can to keep their kids well.
Tiatia makes a point of explaining to families that rheumatic fever is much more mysterious than “sore throats matter”. She warns them about a common but little-publicised symptom: sore joints (see sidebar page 18). “We know it could be associated with a skin infection as well, so that’s what we’re telling them.”
Families already visited by rheumatic fever are very surprised by that, she says. “They say, ‘Oh, we thought it was only strep throat.’ And you know what? They’re actually really relieved, as well.”
Part of the problem, she says, is that rheumatic fever has been presented as if it’s something that we’ve got all figured out. “As if we do. As if we do.”
Tiatia feels, too, that there’s a discourse of blame. Why don’t these people just move to a warmer house, stop the kids sharing beds, switch the heat pump on? They can’t, she says. The houses aren’t there. The money’s not there. Her team has inspected more than 5000 houses and found that in general, it’s private rentals – not state houses – that are the worst. “Families do the best they can with what they’ve got. I have to emphasise that.”
In her experience, sick children get to the doctor. Clutter is constantly assessed to maximise space; families follow the sun around the house, sleeping in the one room that gets the free heat. Often they make “incredibly difficult” decisions to place sick children with other family members who have better homes. “Maori and Pasifika are really practical. We’re used to navigating really difficult challenges.”
Indications from early genetic work, she points out, are that Pacific people have a particular susceptibility to rheumatic fever. That work has just been scaled up.
Arlo Upton, a clinical microbiologist and medical director of Labtests, flags that Pasifika have been worst served by the prevention programme. It’s pleasing that rates have dropped for Maori, she says – from 14.7 to 6.9 cases per 100,000 people.
But the Pasifika numbers started scarily high and barely budged, from 25.6 to 25.
“I wonder if the failure to meet targets in many DHBs and among Pacific people may be in part due to the complexity of our human relationship with [strep A] and the focus on sore throats and throat swabbing in the programme,” she notes.
Other factors could be feeding into that 30-60% group whose rheumatic fever happens without a sore throat, Upton says.
There is now some limited evidence that streps C and G, previously thought irrelevant to rheumatic fever and usually not treated, may be contributing – as is possible in the case of the Kaitaia boy.
Further, there is some evidence to suggest that re-infection with the same strain may not make the throat sore, resulting in a stealth infection.
Rheumatic heart disease tends to bring death early to those it strikes and kills between 150 and 180 New Zealanders every year.
HOLES IN OUR RHEUMATIC FEVER DEFENCES
Because rheumatic fever is such an octopus of a disease, Upton and many others interviewed for this story question why the public prevention programme did not throw the net wider or at least spend more time researching the options first. (A 2009 randomised controlled trial, effectively a pilot of the programme, showed benefits that were not statistically significant – this may be because it did not swab and treat family members of children found to have strep A throats.)
Perhaps it would have been more effective, Upton says, to swab high-risk children regularly – say, every one or two months – regardless of symptoms.
At the University of Otago, professor of public health Michael Baker has long been concerned about the holes in our rheumatic fever defences. Yet he is shocked by new data that hints at the scale of the problem.
National hospitalisation data, analysed over the summer, found the majority of people under 40 hospitalised with rheumatic heart disease in recent years came in out of the blue. These people must have had acute rheumatic fever – many of them repeatedly – but it had never been picked up. “So in other words, they’re going straight to hospital with already damaged heart valves,” says Baker.
Other patients who had previously been diagnosed with rheumatic fever turned up with new heart damage. This is the group that should have been protected by the injection regimen (see sidebar, page 20). To Baker, the data “raise real alarm bells”. So what now? Baker has a tone of banging his head against a brick wall when he says it is long past time that we develop a fully functional national register to better track and treat those diagnosed with rheumatic fever and heart disease. Cheap, quick, easy and effective, he argues. He’s been saying that for 20 years. We’re still stuck with a fragmented system that lets people slip through cracks.
In the past four years, Baker has convened two national symposiums to try to refine and ramp up our approach to wiping out rheumatic fever. They were helpful, so far as they went, but now the group “desperately” needs a small amount of money to continue their efforts. That has not been forthcoming.
RESEARCH OFFERS HOPE
Yet there’s optimism too. It’s taken far too long to get to this point, Baker and others say, but at least now – largely thanks to the prevention programme and those who championed it, chiefly Professor Diana Lennon at the University of Auckland and Dame Tariana Turia – we’re paying attention. And significant research is under way.
Two strep A vaccines, developed in North America and Australia, have been shown to work on animals and have just been through the first phase of human trials. A third, in Brazil, is about to enter that stage. All three are still years from being widely available, but researchers here are watching closely, ready to help if the formulations are likely to be effective on “our” strains of strep A.
As for skin infections? Baker is involved in two major projects, both funded by the Health Research Council, that are likely to provide crucial planks in the evidence base.
In the first, researchers will compare four groups of children: a control group with clear throat swabs; those with strep A in skin infections; and two groups with strep A throats – split according to whether their immune system has the strong antibody response that can spiral into rheumatic fever.
“We’ll compare those four groups and their antibody response to see if skin infections look like a plausible cause of rheumatic fever.” Results are about three years off.
“At this stage, I would say the evidence is firming up that some forms of skin infection are also likely to be an important cause.”
The second strand of research will involve the analysis of 1.3 million strep A throat and skin swabs against seven years of rheumatic fever cases to work out the relative risk that skin infection poses.
Baker is also leading a case-control study with about 15 researchers that will look at the contributions of throat and skin infections alongside factors as disparate as tooth decay, poverty, overcrowding, deficiencies of vitamin D and iron, scabies, mould and second-hand smoke. “We’re trying not to be too constrained by what we currently know,” he says. “We’re trying to look at what are the causal factors, which are modifiable and what’s their relative contribution.”
It makes for appealing counterfactuals. “You imagine a world where everyone lives in fantastic houses that are warm, dry, free of mould and uncrowded: would we still have rheumatic fever? Similarly, if Maori and Pasifika children didn’t have their current high rates of skin infection and scabies, would we still have rheumatic fever? Those
Michael Baker has long been concerned , yet he is shocked by new data that hints at the scale of the problem.
Dr Lance O’Sullivan detailed a new “driver” for rheumatic fever.
Immunologist Nikki Moreland.
Broadwood’s Denise and Hemaima Proctor: what happened to Hemaima’s heart shows we still have a way to go.
Ramona Tiatia: “The ramifications of heart surgery and a short lifespan are devastating for parents.” Right, Roger Tuck: “It’s like chucking people who are floating down the river a life jacket.”