Dr Nathan Hunter
Peer review: Dr David McCreary
A disease of poverty and health inequality
If you’ve trained and worked solely within an affluent, non-Indigenous population, then chances are you’ve never seen a case of acute rheumatic fever (ARF). Clinicians working in endemic areas on the other hand, will likely be all too familiar with the high burden this disease places on patients, often across their whole lifespan.
ARF almost exclusively affects the Indigenous population of Australia. A new diagnosis will burden children (usually between 5-14 years old) with up to a decade of monthly injections, aiming to prevent the progressive damage from repeat episodes which results in Rheumatic Heart Disease (RHD). Despite these efforts, 50% of patients diagnosed with ARF will go on to develop RHD within 10 years, with severe life limiting disease in a third of these.
We are missing the diagnosis
In northern Australia, up to 75% of new diagnoses of RHD have not had a prior recorded diagnosis of ARF. Subsequent review of patient notes often shows previous presentations in keeping with misdiagnosed ARF. By improving our skills in spotting this diagnosis, we can potentially make a huge change to the burden of disease caused in this already disadvantaged population.
What is Acute Rheumatic Fever?
ARF is triggered by an infection with Streptococcus pyogenes, the single member of the Group A Streptococcus (GAS) family. This infection is classically streptococcal pharyngitis however cases are increasingly being attributed to skin sources, such as impetigo or pyoderma. Antigens from the bacteria are used by the host immune system to generate specific antibodies and activated T-cells, however in people with a certain genetic susceptibility, these have some cross-reactivity with tissues in the brain, heart, joints, and skin. The resulting autoimmune reaction then causes a range of symptoms, which begin to manifest between 10 days to 6 weeks after the initial infection. Patients may present febrile, acutely short of breath with overt heart failure, complaining of joint pain, skin changes, and debilitating chorea. Commonly however, the full constellation of these symptoms is not present, which can lead to some difficulties with diagnosis. Dr Jones kindly categorised these manifestations into a scoring system (the Jones Criteria), which is used to formally make the diagnosis. The Jones Criteria have been modified multiple times over the years, with the most recent modification made as recently as 2020. As such, much current literature and FOAMed is a little behind on the most up-to-date criteria.
The Jones Criteria
Before discussing the presenting symptoms, it’s important to first define High-Risk patients, who consist of the following four groups of people:
The most common manifestation, it’s usually a migratory poly-arthritis affecting the large joints. However, in high-risk patients a mono-arthritis or even poly-arthralgia will qualify.
Can present as anything from subtle fatigue to overt heart failure. As of 2020 guidelines, this criteria now also includes subclinical valve disease found on echocardiogram.
This is a pattern of jerky involuntary movements, sometimes with associated emotional lability, which are seen to ease during sleep. It occurs much later than the other manifestations, around 6-9 weeks post the initial GAS infection. Check out the videos below for some examples.
Erythema marginatum and subcutaneous nodules are quite rare, present in less than 2% of cases, but are highly specific when they are seen. The textbooks typically show images of erythema marginatum on white skin, meaning the much more subtle appearance it takes on darker pigmented skin may not be immediately recognised.
Erythema Marginatum on White Skin (Source)
Erythema Marginatum on Dark Skin (Source)
Subcutaneous Nodules (Source)
Typically found over bony surfaces or tendons, e.g. over the spine, elbows, knees, ankles or occiput.
Don’t forget that the cut-off for this is shorter in children.
Making the diagnosis
Diagnosis requires a combination of biochemical evidence of GAS infection (such as ASO titre, or throat culture), and a combination of major and minor symptoms. The exact requirements differ for initial and subsequent diagnoses, as shown below.
- E.g. ASO titre, positive throat culture
- PLUS EITHER:
- 2 Major manifestations OR
- 1 Major & 1 Minor manifestation
- OR (if the patient has a past history of ARF)
- 3 Minor manifestations
There is one other exception to this rule: the presence of chorea alone is enough for a diagnosis, regardless of the presence of GAS evidence or any other criteria. A key learning point here is that the criteria cannot be fully assessed without an echo to look for subclinical changes.
As shown above, diagnosis is mostly clinical, however to assess for all criteria a panel of investigations are required
- Serum ASO (Anti-strepsolysin O) titre
- Throat swab
- ESR and CRP
Acute treatment of ARF has two aims:
- to eradicate the inciting infection, and
- to manage symptoms of ARF
Treatment in the broader sense also includes primary prevention, aiming to identify and treat GAS infections early, and secondary prevention, which is long term antibiotic prophylaxis treatment. These are discussed in greater detail in the RHD Australia guidelines. The upshot is that any definite diagnosis of ARF will need some kind of long-term antibiotic coverage. Getting this arranged and ensuring a solid discharge plan with a high chance of compliance is best done as an inpatient. This way, an MDT approach can be utilised, and a prompt echocardiogram can be obtained to decide on the duration of prophylaxis and frequency of reviews.
1) Eradication therapy
Symptoms of throat or skin infection may not be present by the time ARF manifests, and cultures are often negative. However, eradication therapy for possible persisting infection is still recommended. The 2020 guidelines advise giving:
Benzathine benzylpenicillin G, intramuscular, single dose
- <10kg = 450,000 units
- <20kg = 600,000 units
- >20kg = 1.2 million units
PO alternative: Penicillin V 15mg/kg (up to 500mg) BD for 10 days, but this regime is shown to have much poorer adherence. For non-severe penicillin allergy: Cephalexin 25mg/kg (up to 1g) BD 10 days For severe penicillin allergy: Azithromycin 12mg/kg (up to 500mg) OD 5 days
2) Managing Symptoms
Paracetamol and NSAIDs are generally sufficient. Naproxen has better evidence supporting its use in ARF, and with BD dosing reduces the medication load, potentially helping compliance.
Mild symptoms alone should not be treated. Pharmacological treatment is indicated only when chorea significantly impact function. Recommended therapy is:
- Carbamazepine 3.5-10mg/kg PO or
- Sodium valproate 7.5mg/kg PO
If chorea are very severe, consider adding:
- Prednisolone 1-2mg/kg (up to 80mg) OD
Treatment should only be commenced after discussion with a cardiologist and generally involves steroids, alongside furosemide, enalapril, or spironolactone to address heart failure.
Some patients may clearly require admission for symptomatic management. However, in less severe cases routine admission is still recommended. Even if not fully meeting the Jones criteria, any patient with significant suspicion of ARF should be admitted for an inpatient echocardiogram. This is important as guidelines still recommend an abridged course of prophylactic antibiotics in high-risk patients who fall short of criteria by one major or minor manifestation, or through lack of GAS evidence.
- The most recent Australian guidelines for the management of ARF and RHD, published by RHD Australia.
- The RCH have made this useful guideline on when to use antibiotics for sore throats in kids.
- A useful review on Nature.com, which goes a bit more in-depth to the pathophysiology of ARF, with some good diagrams.
And a final plug for the excellent free app made by RHD Australia, a concise reference guide with a useful Jones criteria calculator tool built-in.