Fever pitch

Rheumatic fever is a cruel dis­ease that can lead to heart dam­age and death. Yet we may have missed an im­por­tant trig­ger.

New Zealand Listener - - CONTENTS - By Cather­ine Woulfe

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

$65 mil­lion.

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.


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 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.

The dif­fer­ence?

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.


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.


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.


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.

Kaitaia Broad­wood

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.”

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