Acute Rheumatic Fever

PATHOGENS

CLINICAL

  • Acute rheumatic fever (ARF): syndromic immunologic (non-suppurative) aftermath of Group A streptococcal (GAS) pharyngitis.
    • In the U.S., now rare w/ attack rate declining (likely well < 0.4%) after GAS pharyngitis, but more common in developing world.
      • Reasonable to consider individuals at low risk for ARF in most industrialized countries, locales.
        • The annual incidence in the lower 48 states declined in the last few decades to ~0.04–0.06 cases per 1,000 children.
        • Exceptions in the U.S.: Hawaii, American Samoa have a higher incidence of ARF.
      • Low risk is defined as < 2 cases per 100,000 school-aged children/yr or an overall population basis of ≤1 case per 1000/yr.
        • The result of ARF yields a global pooled prevalence of latent rheumatic heart disease (RHD) estimated at 1.3%
        • Highest rates of RHD, as a surrogate for ARF
          • Sub-Saharan Africa (~5.7 cases per 1,000 children aged 5–14 years)
          • Oceania/Pacific region, indigenous populations of Australia and New Zealand (3.5 cases/1,000)
      • Children not clearly from a low-risk environment should be considered moderate to high risk depending on the reference population.
    • Most frequent in ages 6-15 yrs.
  • The average latent period following sore throat is 19d but ranges from 1-5 weeks.
  • Clinical symptoms: first episode, profile generally similar in high-income v. lower-income countries. Variability in ARF manifestations is increasingly described in certain, higher-risk populations.
  • ARF may present including involvement of the heart, joints, or CNS.
    • Carditis (50-70%)
      • Carditis is more common in younger children.
      • The spectrum ranges from asymptomatic to congestive heart failure.
      • Usually pancarditis and/or valvulitis. Historically detected by new heart murmur (aortic or mitral), pericardial friction rub, pericardial effusion, and congestive heart failure.
        • Isolated pericarditis or myocarditis is considered rare due to ARF.
      • Updated Jones Criteria now account for echocardiographic findings in addition to clinical carditis that was part of older criteria.
        • Subclinical echocardiographic evidence of carditis or valvulitis now considered part of criteria.
        • Echocardiography is recommended in all suspected ARF cases even without clinical (auscultatory) carditis.
        • Echo findings not consistent with ARF (see below) should exclude the diagnosis of ARF.
      • Echo Doppler findings: serial exams can be performed if not present on initial testing.
        • Rheumatic valvulitis:
          • Pathologic mitral regurgitation (need all 4)
            • Seen in 2 views
            • Jet length ≥ 2 cm in at least 1 view
            • Peak velocity > 3 m/s
            • Pan-systolic jet in at least 1 envelope
          • Pathologic aortic regurgitation (need all 4)
            • Seen in 2 views
            • Jet length ≥ 1 cm in at least 1 view
            • Peak velocity > 3 m/s
            • Pan-diastolic jet in at least 1 envelope
          • EKG: prolonged PR interval may be seen.
        • Rheumatic heart disease remains a significant problem globally, with an estimated 40.5 million people afflicted, causing 306,000 deaths annually.
    • Arthritis (35-66%)
      • Rates of arthritis tend to increase w/ age.
      • Tends to be migratory, polyarthritis involving knees, elbows, ankles, and wrists but not small joints.
        • Involvement may range from arthralgia to frank inflammatory arthritis.
      • Rapid improvement with the use of aspirin or NSAIDs characteristic.
      • Usually self-limiting, < 4 wks.
      • India, Australia and Oceania: descriptions of sterile monoarthritis described as part of ARF. Considered a major manifestation in certain high-risk populations.
      • Polyarthalgia: now considered a major manifestation if in moderate to a high-risk population, or if after careful exclusion of other causes (autoimmune, viral or reactive).
    • Chorea (10-30%)
      • Female > male
      • Sydenham’s chorea (aka St. Vitus dance) tends to be a late finding, and occasionally the only manifestation of ARF.
        • Irregular, abrupt, and relatively rapid involuntary movements are seen in the face, neck, trunk and limbs.
    • Subcutaneous nodules (0-10%), tend to be firm with a range from 2-3mm to 2 cm, typically over extensor joint surfaces.
      • Associated w/ severe carditis and erythema marginatum
    • Erythema marginatum (6%)
      • Uncommon, but highly specific for ARF.
      • Pink or red rings, slightly raised and non-pruritic seen on the trunk and proximal extremities [Fig].

DIAGNOSIS

  • Revised Jones Criteria (2015, AHA)[1]: for all w/ evidence of preceding GAS infection.
    • Evidence of GAS preceding infection: required either
      • Increased or rising ASO or anti-DNASE B titers.
        • A rising titer is considered more reliable than a single titer result.
      • Positive throat culture for GAS.
      • Positive rapid GAS antigen test in a child with consistent clinical presentation.
    • Initial ARF: 2 Major OR 1 Major and 2 Minor
    • Recurrent ARF: 2 Major OR 1 Major and 2 Minor OR 3 Minor
Revised Jones Criteria: Major Criteria

Major Criteria

Low-risk Populations

Moderate- to High-risk Populations

Carditis

Clinical or sub-clinical (echo evidence as above)

Clinical or subclinical (or echo evidence as above)

Arthritis

Polyarthritis (only)

Monoarthritis, polyarthritis or polyarthalgia

Chorea

Chorea

Chorea

Erythema marginatum

Erythema marginatum

Erythema marginatum

SQ nodules

SQ nodules

SQ nodules

Revised Jones Criteria: Minor Criteria

Minor Criteria

Low-risk Populations

High-risk Populations

Arthralgia

Polyarthalgia

Monoarthalgia

Fever

≥ 38.5°C

≥ 38.0°C

Inflammatory markers

ESR ≥ 60 mm/hr and/or CRP ≥ 3.0 mg/dL (or > ULN of assay)

ESR ≥ 30 mm/hr and/or CRP ≥ 3.0 mg/dL (or > ULN of assay)

EKG

Prolonged PR, age-correlated (unless carditis major criterion)

Prolonged PR, age-correlated (unless carditis major criterion)

  • Ddx: extensive
    • Arthritis: GC, inflammatory/autoimmune (e.g., JRA), viral, Lyme disease, sickle cell disease, endocarditis, leukemia, microcrystalline arthritis, reactive arthritis, HSP.
    • Carditis: MV prolapse, myxomatous MV, congenital valve changes, myocarditis, Kawasaki’s disease.
    • Chorea: drug-related, Wilson’s disease, tics, familial, Lyme disease, tumor, metabolic disorder, antiphospholipid syndrome, vasculitis, sarcoidosis, hyperthyroidism.
  • WHO Criteria (2004): less stringent than Jones criteria. Chorea and indolent carditis do not require evidence of antecedent group A streptococcus infection.
    1. First episode per Jones criteria
    2. Recurrent episodes:
      1. If no established RHD: as per the first episode
      2. If established RHD: requires two minor manifestations, plus evidence of antecedent group A streptococcus infection. Evidence of antecedent group A streptococcus infection as per Jones criteria, but with the addition of recent scarlet fever.

TREATMENT

Treatment of ARF

  • Arthralgia or mild arthritis, no carditis: analgesia only, e.g., codeine or propoxyphene.
  • Moderate or severe arthritis, no carditis or carditis w/o CHF: aspirin 90-100mg/kg PO in divided doses for 2-6 weeks.
  • Carditis w/ CHF +/- arthritis: prednisone 40-60mg PO once-daily with subsequent taper.
    • Steroid recommendation is not based on good, prospective randomized trial data.
  • If throat GAS (+), treat with benzathine PCN G 1.2 million units IM x 1.

Prevention

  • See GAS and pharyngitis modules for details.
  • Duration rather than dose is believed important for GAS eradication from the oropharynx.
  • Parenteral: PCN G benzathine 1.2 million units IM (single dose)
    • If wt. < 60lb dose 600,000 million units IM.
  • Oral: PCN VK 250mg PO three times a day (children), 500mg PO three times a day (adolescents, adults) for FULL 10 days.
    • Amoxicillin liquid is often preferred w/ young children, dose 25-50 mg/kg/day PO q8h for FULL 10d.
  • PCN allergic: erythromycin 40mg/kg/d 2-4 times daily (max. 1g/d) for FULL 10 days.
  • Treatment of Group A strep throat even 9d after onset is still effective in the prevention of ARF.

Secondary prevention ARF

  • To prevent recurrent attacks of GAS infection and therefore ARF leading to RHD.
    • Preferred: benzathine PCN G 1.2 million units IM q4wk (or q3wk if high risk)
    • Alternative: erythromycin 250mg PO twice-daily, only if truly PCN allergic
      • Consider beta-lactam desensitization.
      • Oral PCN Vk use is discouraged.
  • Prevention is viewed as key to reducing risks of RHD since there is no medical management, only ultimately surgical intervention by valve replacement.
    • A recent study in Uganda suggested significant effectiveness of monthly benzathine PCN G x 2 years in 5-17-year-olds at risk for RHD progression[4].
  • Duration of secondary prevention uncertain, many discontinue by late teenage/early adult years OR 10 yrs after the last attack if an adult.
  • Oral antibiotics are inferior to injectables for prophylaxis. Oral therapy is only recommended if the patient is truly hypersensitive to penicillins.
  • Though effective, secondary prevention is often hampered by compliance issues (long time-frame, painful infections).

Possible ARF

  • If genuine uncertainty:
    • Consider 12 mos of secondary prophylaxis, followed by re-evaluation.
  • If recurrent sx, and pt adherent to abx prophylaxis, lacks GAS serological evidence, lacks echo evidence--reasonable to conclude not ARF.

Selected Drug Comments

Drug

Recommendation

Clarithromycin

May be effective for GAS pharyngitis, but more expensive than PCN or erythromycin AND macrolide resistance may be prevalent in the US.

Erythromycin

Often prescribed for GAS infection in PCN allergic patients; however, macrolide resistance is common in Europe and may approach 20-25% in some US cities.

Penicillin

Treatment by benzathine PCN q 4 wks is the preferred choice for secondary prevention of ARF.

Amoxicillin

Often chosen over penicillin Vk since it can be dosed less frequently. One study (see Lennon ref) found 1500mg once daily equivalent to PCN V 500mg twice daily. Overall, oral therapy is viewed as inferior to injectable therapy.

FOLLOW UP

  • Hx of prior ARF significantly elevates the risk of future bouts of ARF and rheumatic heart disease in both children and adults.
  • The only long-term sequela of ARF is rheumatic heart disease (valvular).
    • Only 6% risk if no carditis at initial ARF, climbs to 40-65% w/ murmurs or CHF at initial disease.
  • ARF/Rheumatic heart disease:
    • Historically detected by auscultation but now echocardiography is suggested to be performed in all suspected or proven cases.
    • Echocardiography has superior sensitivity but is expensive in lower-resource settings, especially.
    • Advanced RHD should be evaluated at a center with expertise in valvular surgery.

Basis for recommendation

Gewitz MH, et al Revision of the Jones Criteria for the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: a scientific statement from the American Heart Association.131:1806, 2015United StatesCirculation01477630009-7322pp. 1806-1825908771

Comment: AHA guidelines that now are more in synch with international guidelines, as prior Jones Criteria guidance from 1992, originally developed in 1944. A significant change includes routine use of echocardiography in suspected ARF cases even when overt clinical findings are not present.

Marijon E, et al Rheumatic heart disease.379:953, 2012EnglandLancet2985213R0140-6736pp. 953-96422405798

Comment: Focus on the major complication of ARF worldwide with an emphasis on RHD screening as well as prevention.

Rheumatic fever and rheumatic heart disease.923:1, 2004SwitzerlandWorld Health Organ Tech Rep Ser79032120512-30541-122, back cover15382606

Comment: Extensive document in which WHO recommends in regions with rates of ARF, community-based screening and control programs along with prophylactic penicillin to prevent recurrent ARF and RHD.

References

Beaton A, et al Secondary Antibiotic Prophylaxis for Latent Rheumatic Heart Disease.386:230, 2022United StatesN Engl J Med02555620028-4793pp. 230-24034767321

Comment: Study of utilizing benzathine G PCN q 4 weeks x 2 years vs. placebo among 916 at-risk 5-17-year-olds upon screening echocardiograms, with mITT of 799 included for results. In this group 3 (0.8%) in the prophylaxis group had evidence of progressive disease by echo compared to 33 (8.2%) in placebo, RR -7.5%, 95% CI -10.2 to -4.7, p< 0.001. Two in the prophylaxis group had serious AEs (1 w/ mild anaphylaxis) for a total of < 0.1%. The study reinforces that in a setting such as Uganda, where this was conducted and considered a low resource, there is a considerable impact by early intervention in childhood/adolescence to prevent progression of RHD.

de Loizaga SR, et al Diagnosing rheumatic heart disease: where are we now and what are the challenges?19:777, 2021EnglandExpert Rev Cardiovasc Ther1011823281477-9072pp. 777-78634424119

Comment: The use of portable echo devices can help identify latent RHD in low-resource settings, precisely where ARF leads to RHD on a substantial basis. Authors explore the avenue of a GAS vaccine.

de Loizaga SR, Beaton AZ Rheumatic Fever and Rheumatic Heart Disease in the United States.50:e98, 2021United StatesPediatr Ann03566570090-4481pp. e98-e10434038651

Comment: Rates of ARF remain low in the US, however, It is estimated that 1% to 3% of patients with untreated group A streptococcus (GAS) infection, most typically GAS pharyngitis, will develop ARF, and of these, up to 60% of cases will result in chronic RHD.

Beaudoin A, et al Acute rheumatic fever and rheumatic heart disease among children--American Samoa, 2011-2012.64:555, 2015United StatesMMWR Morb Mortal Wkly Rep78024290149-2195pp. 555-826020139

Comment: In US, Oceanic islands with highest rates of ARF. Also includes Hawaii.

Cilliers A, Adler AJ, Saloojee H Anti-inflammatory treatment for carditis in acute rheumatic fever.May 28EnglandCochrane Database Syst Rev1009097471361-6137p. CD00317626017576

Comment: Authors find that current recommendations based on old studies were not well structured, hence they conclude there is little evidence of benefit using corticosteroids or intravenous immunoglobulins. Modern studies are needed. Risks of treatments judged substantial.

Roberts K, et al Screening for rheumatic heart disease: current approaches and controversies.10:49, 2013EnglandNat Rev Cardiol1015000751759-5002pp. 49-5823149830

Comment: Authors review why echocardiography clearly superior to stethescope ausculation; however, increased sensitivity is burdened by some specificity issues that could be easily misjudged.

Rémond MG, et al Acute rheumatic fever and rheumatic heart disease--priorities in prevention, diagnosis and management. A report of the CSANZ Indigenous Cardiovascular Health Conference, Alice Springs 2011.21:632, 2012AustraliaHeart Lung Circ1009637391443-9506pp. 632-822726405

Comment: Hits on hot topics include 1) echo screening for RHD (not ready for primetime), 2) re-emphasizing the importance of using long-acting benzathine penicillin injections for secondary prophylaxis, 3) early referral for valve surgery in advanced RHD at a specialized center. Tensions arise since the populations most at risk for ARF and RHD are most often in low-resource settings.

Cunningham MW Streptococcus and rheumatic fever.24:408, 2012United StatesCurr Opin Rheumatol90008511040-8711pp. 408-1622617826

Comment: The comprehensive review focuses upon the pathophysiology known that leads GAS to cause ARF and RHD.

Parnaby MG, Carapetis JR Rheumatic fever in indigenous Australian children.46:527, 2010AustraliaJ Paediatr Child Health90054211034-4810pp. 527-3320854325

Comment: Observations in patients in a region endemic for acute rheumatic fever (North Queensland, Australia) found monoarthritis, subclinical carditis (SCC), and low-grade fever in a proportion of patients, such that if included into the Revised Jones Criteria would raise the diagnostic rate from 71.4% to 91.8% as SCC occurred in 27 of the 98 patients and long-term consequences were observed in a high proportion of patients with SCC.

Lennon DR, et al Once-daily amoxicillin versus twice-daily penicillin V in group A beta-haemolytic streptococcal pharyngitis.93:474, 2008EnglandArch Dis Child03724340003-9888pp. 474-818337284

Comment: Non-inferiority trial in children with GABHS pharyngitis in 353 children randomized to amoxicillin 1500mg/d v. PCN VK 500mg bid for 10d. The once-daily amoxicillin was not inferior to twice-daily PCN. Treatment failures ranged from 5.8% at 3-6d, 12.7% at 12-16d and 10.7% at 26-36d. Only one case of ARF (not well substantiated) occured in the 7d amoxicillin group.

Comment: Clinical database examination of 503 children diagnosed with ARF in 2000. Hospitalizations were infrequent, but more common at academic medical centers, and averaged 3d.

Miyake CY, et al Characteristics of children discharged from hospitals in the United States in 2000 with the diagnosis of acute rheumatic fever.120:503, 2007United StatesPediatrics03764220031-4005pp. 503-817766522

Comment: Investigators believe that observation without treatment is probably ok with GAS pharyngitis as this group had the lowest morbidity. However, they note we don't have any good modern data on ARF prevalence to judge whether this would be a safe practice from a risk assessment.

Van Howe RS, Kusnier LP Diagnosis and management of pharyngitis in a pediatric population based on cost-effectiveness and projected health outcomes.117:609, 2006United StatesPediatrics03764220031-4005pp. 609-1916510638Martin JM, Barbadora KA Continued high caseload of rheumatic fever in western Pennsylvania: Possible rheumatogenic emm types of streptococcus pyogenes.149:58, 2006United StatesJ Pediatr03754100022-3476pp. 58-6316860129

Comment: Though rare in US adults, ARF still occurs in some localized and usually rural environs in US children. These investigators report continued ARF in western PA, believing that macrolide-resistant strains may be playing a role.
Rating: Important

McDonald M, Currie BJ, Carapetis JR Acute rheumatic fever: a chink in the chain that links the heart to the throat?4:240, 2004United StatesLancet Infect Dis1011301501473-3099pp. 240-515050943

Comment: Review articles explore why in the developing world efforts at controlling ARF through treatment of GAS pharyngitis/colonization have proven ineffective. Authors suggest group C and G streptococci have been shown to exchange key virulence determinants with GAS and are more commonly isolated from the throats of Aboriginal children. In the tropics, GAS pyoderma and/or non-GAS infections may be the driving forces behind ARF. This requires then a rethinking on how to address control issues.

Comment: Turkish study that delved into the diagnoses of 20 patients suspected of adult-onset juvenile rheumatoid arthritis. In this group, 3/20 were thought to have ARF, and an interesting 50% of them were found to have had a GAS positive throat culture in the preceding 6 months.

Mert A, et al Fever of unknown origin: a review of 20 patients with adult-onset Still's disease.22:89, 2003BelgiumClin Rheumatol82114690770-3198pp. 89-9312740670Aviles RJ, et al Poststreptococcal reactive arthritis in adults: a case series.75:144, 2000EnglandMayo Clin Proc04055430025-6196pp. 144-710683652

Comment: Poststreptococcal arthritis is a poorly understood and controversial problem in adults that may or may not fall within the spectrum of ARF. 29pts described over a >15yr. period presenting with arthritis thought related to GAS, but only six had criteria in retrospect for ARF. All adult patients had negative throat cultures. Most of the diagnoses were based on ASO titers. Even so, ARF remains a very rare problem in the adult population in patients without prior history of ARF.

WHO Fact Sheet, Rheumatic Heart Disease. https://www.who.int/news-room/fact-sheets/detail/rheumatic-heart-disease (accessed 2/16/22, last updated 11/6/2020)

Comment:
Brief document outlines issues but also includes a) link to 2018 WHO resolution to launch a coordinated response to ARF and RHD, and b) note that ensuring a steady supply of benzathine PCN G is a key priority of the 13th WHO General Programm of Work, and noted in the WHO Road map for access to medicines, vaccines and other health products 2019-2023 (link in fact sheet).


Media

Erythema marginatum

Descriptive text is not available for this image

Typical appearance of erythema marginatum.

Source: https://almostawesomecheese.wordpress.com/2014/11/08/erythema-marginatum-rheumatic-fever/

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Last updated: March 5, 2022