PATHOGENS

CLINICAL

  • Acute rheumatic fever (ARF): syndromic immunologic (non-suppurative) aftermath of Group A streptococcal (GAS) pharyngitis.
    • In 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.
        • Annual incidence in lower 48 states declined in last few decades to ~0.04–0.06 cases per 1,000 children.
        • Exceptions in U.S.: Hawaii, American Samoa have higher incidence ARF.
      • Low risk defined as < 2 cases per 100,000 school-aged children/yr or overall population basis of ≤1 case per 1000/yr.
        • Highest rates rheumatic heart disease (RHD) as 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 low-risk environment should be considered moderate to high risk depending on reference population.
    • Most frequent in ages 6-15 yrs.
  • Average latent period following sore throat is 19d, but range 1-5 weeks.
  • Clinical symptoms: first episode, profile generally similar in high-income v. lower-income countries. Variability in ARF manifestations increasingly described in certain, higher-risk populations.
    • Carditis (50-50%)
      • Carditis more common in younger children.
      • Spectrum ranges from asymptomatic to congestive heart failure.
      • Usually pancarditis and/or valvulitis.
        • Isolated pericarditis or myocarditis considered as rarely 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 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
    • Arthritis (35-66%)
      • Rates of arthritis tend to increase w/ age.
      • Tends to be a migratory arthritis involving knees, elbows, ankles and wrists but not small joints.
      • Rapid improvement with use of aspirin or NSAIDs characteristic.
      • Usually self-limiting, < 4 wks.
      • India, Australia and Oceania: descriptions of sterile monoarthritis described as part of ARF. May consider as a major manifestation in certain high-risk populations.
      • Polyarthalgia: now considered a major manifestation if in moderate to high-risk population, or if after careful exclusion of other causes (autoimmune, viral or reactive).
    • Chorea (10-30%)
      • Female > male
      • Sydenham’s chorea tends to be a late finding.
        • Irregular, abrupt, and relatively rapid involuntary movements are seen in the face, neck, trunk and limbs.
    • Subcutaneous nodules (0-10%)
      • 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 trunk and extremities [ Fig].

DIAGNOSIS

  • Revised Jones Criteria (2015, AHA) [1]: for all w/ evidence of preceding GAS infection.
    • Evidence of GAS preceding infection:
      • Increased or rising ASO or anti-DNASE B titers.
        • Rising titer considered more reliable than single titer result.
      • Positive throat culture for GAS.
      • Positive rapid GAS antigen test in 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

      Major Criteria

      Low-risk populations

      Moderate-to-high risk populations

      Revised Jones Criteria: Major Criteria

      Carditis

      Clinical or sub-clinical (echo evidence as above)

      Clinical or sub-clinical (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

      Low-risk populations

      High-risk populations

      Arthalgia

      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 dz, endocarditis, leukemia, microcrystalline arthritis, reactive arthritis, HSP.
    • Carditis: MV prolapse, myxomatous MV, congenital valve changes, myocarditis, Kawasaki’s dz.
    • Chorea: drug-related, Wilson’s dz, 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 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 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 believed important for GAS eradication from 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 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 prevention of ARF.

Secondary prevention ARF

  • To prevent recurrent attacks of GAS infection and therefore ARF.
    • 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 discouraged.
  • Duration of secondary prevention uncertain, many discontinue by late teenage/early adult years OR 10 yrs after last attack if adult.
  • Oral antibiotics inferior to injectables for prophylaxis. Oral therapy only recommended if patient is truly hypersensitive to penicillins.
  • Though effective, secondary prevention 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 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 risk of future bouts of ARF and rheumatic heart disease in both children and adults.
  • 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 echos suggested to be performed in all suspected or proven cases.
    • Echocardiography superior sensitivity but expensive in lower resource settings, especially.
    • Advanced RHD should be evaluated at center with expertise in valvular surgery.

Basis for recommendation

  1. 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. Circulation 131:1806, 2015  [PMID:25908771]

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

  2. Marijon E et al: Rheumatic heart disease. Lancet 379:953, 2012  [PMID:22405798]

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

  3. Carapetis JR, McDonald M, Wilson NJ: Acute rheumatic fever. Lancet 366:155, 2005 Jul 9-15  [PMID:16005340]

    Comment: Recent review article that serves along with the Jones criteria as the basis for recommendations in this module.

  4. Rheumatic fever and rheumatic heart disease. World Health Organ Tech Rep Ser 923:1, 2004  [PMID:15382606]

    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

  1. Beaudoin A et al: Acute rheumatic fever and rheumatic heart disease among children--American Samoa, 2011-2012. MMWR Morb Mortal Wkly Rep 64:555, 2015  [PMID:26020139]

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

  2. Cilliers A, Adler AJ, Saloojee H: Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev 5:, 2015  [PMID:26017576]

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

  3. Miyake CY et al: Characteristics of children discharged from hospitals in the United States in 2000 with the diagnosis of acute rheumatic fever. Pediatrics 120:503, 2007  [PMID:17766522]

    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.

  4. Cunningham MW: Streptococcus and rheumatic fever. Curr Opin Rheumatol 24:408, 2012  [PMID:22617826]

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

  5. Van Howe RS, Kusnier LP: Diagnosis and management of pharyngitis in a pediatric population based on cost-effectiveness and projected health outcomes. Pediatrics 117:609, 2006  [PMID:16510638]

    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.

  6. Lennon DR et al: Once-daily amoxicillin versus twice-daily penicillin V in group A beta-haemolytic streptococcal pharyngitis. Arch Dis Child 93:474, 2008  [PMID:18337284]

    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.

  7. Parnaby MG, Carapetis JR: Rheumatic fever in indigenous Australian children. J Paediatr Child Health 46:527, 2010  [PMID:20854325]

    Comment: Observations in patients a region endemic for acute rheumatic fever (North Queensland, Australia) found monarthritis, subclinical carditis (SCC) and low-grade fever in a proportion of patients, such that if included into the Revised Jones Criteria would raise 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.

  8. Aviles RJ et al: Poststreptococcal reactive arthritis in adults: a case series. Mayo Clin Proc 75:144, 2000  [PMID:10683652]

    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 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.

  9. McDonald M, Currie BJ, Carapetis JR: Acute rheumatic fever: a chink in the chain that links the heart to the throat? Lancet Infect Dis 4:240, 2004  [PMID:15050943]

    Comment: Review articles explore why in the developing word 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.

  10. Roberts K et al: Screening for rheumatic heart disease: current approaches and controversies. Nat Rev Cardiol 10:49, 2013  [PMID:23149830]

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

  11. 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. Heart Lung Circ 21:632, 2012  [PMID:22726405]

    Comment: Hits on hot topics including: 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 specialized center. Tensions arise since the populations most at risk for ARF and RHD are most often in low resource settings.

  12. Martin JM, Barbadora KA: Continued high caseload of rheumatic fever in western Pennsylvania: Possible rheumatogenic emm types of streptococcus pyogenes. J Pediatr 149:58, 2006  [PMID:16860129]

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

  13. Mert A et al: Fever of unknown origin: a review of 20 patients with adult-onset Still's disease. Clin Rheumatol 22:89, 2003  [PMID:12740670]

    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.

Media

Erythema marginatum

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

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Last updated: January 29, 2016