Rheumatic fever and heart disease

I mean, fancy one disease which can have such diverse manifestations. One patient's got sore joints, the other's got abnormal movements and you're telling them they've got the same condition. That's quite confusing, especially for kids in the same family for instance.

[Music] Welcome to the Australian Prescriber Podcast. Australian Prescriber, independent, peer-reviewed and free.

I'm Dhineli Perera, your host for this episode. It's a pleasure to be speaking to Professor Anna Ralph today. Anna is the Division Lead of the Global and Tropical Health Division at Menzies School of Health Research in Darwin. Anna and her team refresh us on the practical and pertinent points of managing rheumatic fever and rheumatic heart disease in the August issue of Australian Prescriber. Anna, welcome to the program.

Thanks. Hello.

Anna, I wanted to start off by saying that although rheumatic fever and rheumatic heart disease are by no means unheard-of conditions, I think it would be pretty fair to say that many of us health professionals have a limited understanding of what it is and how to manage it. Why do you think that's the case and are they considered rare conditions?

Essentially in lots of parts of Australia, these are quite rare conditions. When I say rare, I mean less than about 40 per 100,000 population. But the really important thing is that there are pockets of Australia where these rates are way higher. So more like 300 plus per 100,000 population. That's rates of rheumatic fever I'm talking about. So lots of people might never come across it in their whole medical career, depending on where they're living and working, or if they come across rheumatic heart disease, they might only see it in fairly elderly people. So this is a really geographically different disease where the rates are really different depending on where you are in the country.

So it's really an exposure thing. Unless you're living in those areas where it is more common, you might just not get the exposure to become familiar with it.

As a healthcare provider, that's right. Having said that, doesn't matter where you live and work in Australia, it's really important for everyone to know about these conditions because they can pop up in any environment and some people considered to be at high risk such as migrants from low- or middle-income countries and also Maori and Pacific Islanders living here in Australia who are considered at higher risk for instance, you need to be able to pick it, recognise it, know how to diagnose it. So it's important for everyone to know about.

Would you mind clarifying the exact difference between acute rheumatic heart, sorry, acute rheumatic fever and rheumatic heart disease?

Yeah, sure. And look, that's the slip-up that a lot of us make, calling it various combinations of those words. Acute rheumatic fever is the acute bit as you expect. And then rheumatic heart disease is the chronic long-term condition that can set in afterwards. Acute rheumatic fever is essentially an autoimmune condition triggered by a streptococcal infection. Those strep infections typically of the throat or also of the skin can then trigger this autoimmune response in certain people. That's then called acute rheumatic fever.

And just to make things even more confusing, acute rheumatic fever is a really diverse condition. It can present with fever and joint pain, it can present with chorea, abnormal movements, it can present with fever and carditis. So that's acute rheumatic fever. That is a condition which can last from days to weeks, sometimes up to months, but then it resolves and, in most cases, you get a complete resolution. If you get a really bad bout of rheumatic fever or you get it repeatedly, that's when you can end up with that chronic condition, which is called rheumatic heart disease, where those heart valves have been damaged through episodes of rheumatic fever.

So if we were going to talk about it as a Venn diagram, if you like, acute rheumatic fever would be your larger bubble and then rheumatic heart disease would be smaller within it, and not all rheumatic fevers will end up as rheumatic heart disease.

Yep, exactly. That's a good way of thinking about it. What we actually find in our data is that of all the people with rheumatic heart disease, only a minority of them have ever had a rheumatic fever episode detected previously. The hypothesis goes that you have to have rheumatic fever to have triggered the rheumatic heart disease, but we are just not that good at diagnosing rheumatic fever each time. Sometimes the patient might not be very symptomatic, they might not seek healthcare. Sometimes they might seek healthcare and the doctor doesn't diagnose it. That's why we think probably everyone who's had rheumatic heart disease must have had rheumatic fever, but it just wasn't always picked up.

And you mentioned, Anna, that the Streptococcus pyogenes is typically found in the throat and I think skin. Are they the two main reservoirs for the bacteria that would be associated with acute rheumatic fever?

So there's been this really interesting debate over decades really about what triggers rheumatic fever. Is it only the throat? Is it just pharyngitis? Group A strep or Strep pyogenes infecting the throat that triggers it or can it also come from other sites of infection as well? The parts of Australia that have high rheumatic fever rates have very high rates of skin infection with group A strep. That skin infection is typically what we'd call impetigo or school sores. They look really innocuous. They're just little rounded ulcers, maybe just like a centimetre in diameter. And that's the really common manifestation of Strep pyogenes. These are circumstantial evidence and now also some direct evidence from Australia and New Zealand linking those skin infections with rheumatic fever really illustrates that it's skin as well. It's not just throat.

And so you've talked about the at-risk populations, especially in northern Australia. Why are these populations considered to be the most at risk?

Rheumatic fever is essentially what we call a disease of poverty or of disadvantage or disparity depending on how you want to frame it. There's been systematic reviews which really try to tease out what is it about socioeconomic disadvantage that drives rheumatic fever. And it's likely a combination of things, in particular household crowding and limited access to healthcare, especially in a timely way to get onto antibiotics once a streptococcal infection is diagnosed, and access to washing facilities. We know a lot of remote housing, particularly for Aboriginal communities, is pretty suboptimal.

There's not a lot of maintenance out bush sometimes, and the heat itself helps things to deteriorate more quickly. So often, being able to wash kids every day to reduce the burden of streptococcal infection on the skin is not available. So those issues around healthcare access, household crowding are really key drivers of rheumatic fever. It's an important marker in Australia of how well we're doing in closing the gap for instance. And it's a clear marker that we are actually not doing very well. And if we could do better in reducing rheumatic fever rates by addressing those environmental health conditions, it would have major impacts not just on rheumatic fever, but on so many other transmissible diseases of childhood.

Perhaps regardless of socioeconomic background, children who are maybe typically exposed to crowded childcare or kinder or school areas, even in southern parts of Australia, are they considered to be at risk? And what is it that sets them apart that puts them less at risk?

It's a good point and there's perhaps a two-pronged answer to that. The first is to say that it's repeated infections from early childhood that seems particularly to drive that abnormal immune response that then develops. It seems like the immune system just gets sick of seeing the strep all the time and it triggers this autoimmune response instead where things go a bit haywire and, instead of just killing off the strep germ, you end up with this rheumatic fever condition. A single episode of impetigo usually doesn't cause any troubles other than the fact that it's at risk of transmitting it to other people. Just to mention actually, especially when we think of those repeated childhood infections, scabies, which is a parasitic infection, can get this super infection with the strep. So kids that are getting a lot of scabies episodes are at risk there.

Among those kids that are getting repeated infections, just a small proportion end up with that abnormal autoimmune response and then getting people onto the right treatment in a timely way, so getting access to the antibiotic promptly, is really important. The other part of that answer though is also to say that in some more recent epidemiological data from Australia, what's evident is that even though there's this big gradient where the rates are low in southern Australia, the rates are high in northern Australia. But despite that, there are occasional cases that just pop up in southern hospitals, in metropolitan areas, in areas that you would think are not socioeconomically deprived. Again, it just highlights that it can occur and it's important for physicians to know about this.

There's been a drive to reduce antimicrobial prescribing for sore throat presentations to GPs, and I was wondering whether there'd been any spikes or shifts in occurrences of acute rheumatic fever given that we are using less antibiotics that would typically cover strep, things like amoxicillin, etc. But I think you said to the contrary?

Luckily, all we've really noticed in recent years in most parts of Australia, not talking about these high endemic parts of northern and central Australia, is that overall the rates of rheumatic fever have just gone down and down over the decades. Very high in the pre-antibiotic era in the 1930s, 1940s. From the mid-1940s onwards, rates just really plummeted. And that was probably a combination of better standard of living post-Depression and post the World Wars, but also access to antibiotics. The guidelines around restricting antibiotic use to bacterial throat infections makes a lot of sense in parts of Australia where rheumatic fever risk is low and that approach doesn't appear to drive rates of rheumatic fever.

Good. So we don't have to change that.

No, definitely not. So in a high-risk area, the default position is, if it's a sore throat and the kid’s at risk, give them antibiotics.

Excellent. Can you walk us through briefly how acute rheumatic fever is diagnosed and what exactly the Jones criteria are?

What we would love for rheumatic fever that we don't have is a diagnostic test, a blood test for instance. No such single blood test exists. So instead of that, we do have to be guided by this set of clinical criteria called the Jones criteria, which were first devised decades ago when rheumatic fever was really common. And in Australia what we use is a revised set of criteria, which is specifically set to pick up cases, so high sensitivity, but at the cost of specificity. In other words, you can qualify for those criteria even if you don't have rheumatic fever. So it's really important to actively exclude other conditions that could accidentally fulfill those criteria.

The criteria, they're divided into major and minor. The major ones are carditis, which means inflamed heart valves. Classically that causes regurgitation, particularly of the mitral valve. Arthritis, sore joints and it's classically a polyarthritis and migratory. The subcutaneous nodules, which are really uncommon in Australia. Erythema marginatum, a particular skin manifestation, which is also pretty uncommon in Australia. And chorea, which is otherwise known as Sydenham's chorea, abnormal involuntary movements of the body that occurs in probably about 12% of Australian cases.

So that's the major criteria, which just goes to show how incredibly complex this disease is. I mean, fancy one disease which can have such diverse manifestations. As you can imagine, it's pretty hard to be explaining that to patients. One patient's got sore joints, the other's got abnormal movements and you're telling them they've got the same condition. That's quite confusing, especially for kids in the same family for instance.

But then you've got the minor criteria, so that is fever. With the cardiac involvement, you can get first-degree heart block, which manifests as prolongation of your PR interval on your ECG. And raised inflammatory markers, so the C-reactive protein and the ESR. And in addition to all those criteria, you have to have a certain number in each. You also need proof of recent streptococcal infection and usually that's based on streptococcal serology results. So a blood test. But you have to put it all together in this big picture to come up with that diagnosis of rheumatic fever. And just making sure that things like flu could even meet those criteria. COVID could as well. You can get sore joints with COVID.

But at least those can be swabbed easily enough.

Yeah. So the important thing is to actively think of it and exclude those differential diagnoses basically.

And so given the difficulty with the diagnosis, do you believe that the current figures of disease incidence are actually understated?

They certainly could be. And that then makes it difficult to know what to make of rising numbers. The Australian Institute of Health and Welfare reports rates of rheumatic fever in Australia, and largely what we've seen is actually an increase in rate despite all the effort that has gone into trying to reduce rheumatic fever rates. But does it actually mean that people are getting better at detecting it and diagnosing it, or does it mean that actually there's more true cases occurring? To tease it out, we also need to be monitoring rheumatic heart disease rates, complication rates, how many people are going for surgery, all those other end points as well. Also, just to mention that not all states in Australia have rheumatic fever as a notifiable condition. New South Wales does now have a register along with Northern Territory, Queensland, Western Australia and South Australia, but that leaves out Victoria, ACT and Tasmania, which don't report rheumatic fever. So we actually have no idea what their case rates are like.

And if it is to be considered for all unexplained fevers and you've excluded the other conditions that can present in a similar way, should bacterial throat swabs be done more routinely via GPs for children that do present with all of these symptoms?

If it's rheumatic fever, by the time the rheumatic fever symptoms are coming along, which is often about two or three weeks after the actual streptococcal infection…

It can be negative, right?

…You're often getting a negative throat swab anyway. And then just to complicate things, you can also have carriage and therefore get a positive throat swab even when you never had an infection in the first place.

So you could actually muddy the picture more than anything else.

But if a child's presenting with what you think could be acute rheumatic fever and they're reporting that they've either had or they've got a sore throat, then yes, I think it would be valuable to do a throat swab. But perhaps the more reliable thing is the streptococcal serology in that setting because of that time lag between the strep infection and the rheumatic fever symptoms coming on.

In your article, Anna, you highlight that there have been important changes to the 2020 Australian Guideline for the Prevention, Diagnosis and Management of Acute Rheumatic Fever and Rheumatic Heart Disease. Can you talk us through maybe a couple of the most important changes that you think listeners should be aware of?

In the past, once you got a diagnosis of rheumatic fever, there was always this 10-year sentence as such of needing penicillin injections, minimum 10 years or up to the age of 21, whichever is longer.

So there's a subgroup of people who no longer need 10 years but can get away with five years, and that's people that never had any cardiac involvement. So the cardiac involvement, which is shown on echocardiogram as being mitral valve thickening or regurgitation, or it can also involve the aortic valve. If there's no sign of that at all during your episodes of acute rheumatic fever and you have a normal echo repeatedly including after five years, then you can actually get away with just a 5-year penicillin course.

And that's also in line with international guidelines. So that's good news for some.

That is great news.

One of the practices that's changed is when people think of rheumatic fever, often they think of high-dose aspirin because that was always the first-line treatment for the arthritis of rheumatic fever. That's an effective therapy. But because of the side effect profile, including the rare possibility of Reye's syndrome in children that might happen to have flu, we've shifted away from that to using non-steroidal anti-inflammatories such as naproxen and ibuprofen.

The treatment for chorea is mostly anti-convulsants, so things like carbamazepine or sodium valproate. As second line, what's coming into practice now and does appear to be effective is steroids, although for now we're still recommending the anti-convulsants as first line.

There is evolving criteria on how to diagnose rheumatic heart disease. So in days gone by, it was all just based on good auscultation with your old stethoscope. But it's been shown that echo is way more sensitive and specific. So we use echo to help identify if there's any valve abnormality to help make a diagnosis. I think previously there was a lot of grey zone issues with, oh the mitral valve is a bit thickened, but is it thickened enough to be called rheumatic heart disease? Well, there's clear World Heart Federation criteria now which really helps to streamline that whole space.

There's been a minor change in the benzathine penicillin dosing for prevention just to make it easier based on weight. And that's been streamlined now just to three dose bands to make that a bit more simple.

Something that we do in Australia that's clearer in the most recent guidelines is we define three categories of rheumatic fever. It can be definite if you're meeting all of those Jones criteria and testing negative for alternative conditions. Then there can be a category called probable acute rheumatic fever, which is where you almost meet those criteria but not quite. And then there's another one called possible acute rheumatic fever, which is where you're missing the Jones criteria by a couple of points and it's uncertain, but you feel like it's going to be safer to put them in that category and follow them up to make sure that you're not missing a true case

Overall, the guideline really emphasises the importance of culturally safe care; that it doesn't matter how good your medical management is and whether you're prescribing the right drugs, if you're not communicating really effectively with your client and their family, making them feel welcome, they're not going to engage effectively with the care that's being offered. So that's really emphasised throughout the guidelines: recognising that, in Australia, the vast majority of people with rheumatic fever tend to be of the non-dominant cultural group. It's Aboriginal and Torres Strait Islander people, Maori and Pacific Islander people and other migrants from low- and middle-income countries.

How does prevention of infective endocarditis differ for your rheumatic heart disease patients versus non-rheumatic heart disease patients? So I guess we're talking about dental procedures and things like that.

Guidelines internationally have flip-flopped a bit on this in recent years. Because of the risk of endocarditis on a previously damaged valve, it's really important for people with established rheumatic heart disease to have antibiotic prophylaxis when they're going for a dental procedure that can disrupt the gum or the mucosa to the extent that it could cause a transient bacteraemia. Therapeutic Guidelines defines really clearly which dental procedures are the ones that are considered risky. Regardless of ethnicity, if you've got rheumatic heart disease and you're having one of those infection-prone procedures, then you should get the prophylaxis. There are other valve conditions such as congenital heart disease or if somebody's got a mechanical valve for some other reason that also need the same.

Absolutely. And so, Anna, your article finally also mentioned some super useful resources, which was called the Acute Rheumatic Fever, Rheumatic Heart Disease Guideline mobile phone app, as well as the Rheumatic Heart Disease Australia group. What are some useful tips to help health professionals best utilise these resources?

The app is very handy, in my opinion, for a couple of reasons. It summarises the guidelines, but what's really handy is that it's got a diagnostic calculator. With the app you can plug in, is the person considered to be in a risk group? So for instance, do they have a family history? Are they from a geographical area that's considered to be at risk? Are they Aboriginal or Torres Strait Islander or another recognised risk group? So that's the first page and you'd tick yes or no.

That then starts to take you through a whole series of other questions like, is there any chorea, is there any arthritis and so forth. And then at the end it pops out an answer of no ARF, definite ARF, probable ARF. And then the possible one is a bit tricky because it's a bit subjective. You have to think, well, do I think it's the most likely diagnosis or not? And then it will pop out an answer of either probable or possible rheumatic fever. We've evaluated that app and the users report that they really love it compared to having to try to work it out on paper or just to think through it. But don't forget to exclude alternative diagnoses, otherwise you'll end up getting to the end and saying definite ARF when in fact the patient's got something like disseminated gonococcal infection. You do need to remember to exclude those alternative diagnoses.

Well, wonderful. That's been fantastic, Anna. Thank you so much. And that's unfortunately all the time we've got for this episode, so we really appreciate you joining us today, Anna.

No worries, it's a pleasure. Thanks so much for having me on.

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Anna’s full article is available online. The views of the hosts and guests on the podcast are their own and may not represent Australian Prescriber or NPS MedicineWise. I'm Dhineli Perera and thanks for joining us on the Australian Prescriber Podcast.