Rheumatic fever: diagnostic aspects

Alessandro Consolaro, MD PhD

Clinica Pediatrica – Reumatologia, Istituto Giannina Gaslini

University of Genova

Genova Italy

Acute Rheumatic Fever

• Inflammatory disease that represents a complication of a group A streptococcal (GAS) pharyngitis in a predisposed human host

• The majority of cases occur in children between the ages of 5 and 14 years

• The onset of the disease is rare before the third year of life and in individuals older than 15 years

• The incidence is comparable between females and males.

Epidemiology• Current incidence rate of the first attack of ARF per year:

• 5 - 51 cases /100,000 children• Mean: 19 cases /100,000 children

• A widely variable incidence rate has been found in different geographic areas• Highest annual incidence in a single Indian study (51/100,000 per year), • Subgroup analysis of the Maori community in New Zealand >80/100,000 per year • In developed countries less than 5 cases per 100,000 children

• A systematic review including only recent, population-based data estimated that more than 336,000 cases of ARF occur in 5–14-year-old children worldwide the annual total number of cases of ARF in all paediatric ages may be greater than 471,000

cases

• The global burden of this disease is probably better appreciated considering the overall prevalence of Rheumatic Heart Disease (RHD), which was estimated to exceed 2.4 million children aged 5–14 years

Tibazarwa KB, et al. Heart, 2008Seckeler and Hoke, Clin.Epidemiol 2011Carapetis et al., Lancet Infect.Dis 2005

Between 1990-2015 the age-standardized prevalence declined in most regions, but remained

highest in

Oceania > Sub-Saharan Africa and South Asia

These countries have also the highest age-standardized mortality rates

• In 2015 the countries with the largest estimated number of cases of RHD were:

1) India (13.17 millions)

2) China (7.07 millions)

3) Pakistan (2.25 millions)

4) Indonesia (1.18 millions)

5) Congo (805,000)

73% of global cases

Epidemiology

Carapetis et al., Nat Rev Dis Primers 2016

Tissue and organ-specific manifestations

10-30%

Chorea

GAS infectionErythema

marginatum

<10%

Subcutaneous

nodules

Skin

manifestations

<10%

35-66%

Arthritis

50-70%

Carditis

Carapetis et al., Nat Rev Dis Primers 2016

GAS antigen processing and presentationto T and B cells

Generation of cross-reactiveB and T cells

Pathogenesis

Clinical manifestations

GAS infection Weeks

50%

Consolaro A et al., EULAR/PRES Textbook on Paediatric Rheumatology

Polyarthritis

70% of patients with ARF

arthritis affects primarily the large joints, particularly the knees, ankles, elbows and wrists

involvement of small peripheral joints is uncommon

axial disease is extremely rare

onset of arthritis in one joint is common

usually described as “migratory”

in a single joint the inflammatory symptoms last for a few days

Different timing of presentation in different joints

Pain, redness, swelling, warmth, tenderness and limited range of motion

ARF generally responds exquisitely to NSAIDs

• PSRA is defined by the occurrence of arthritis following a recent GAS infection in a patient who does not fulfil the criteria for ARF

• In 1997, Ayoub and Ahmed proposed a set of diagnostic criteria for PSRA, based on the characteristics of arthritis, the evidence of an antecedent GAS infection, and the lack of fitting in the Jones criteria

• A score based on ESR and CRP levels, time to resolution of joint symptoms, and recurrence of arthritis was developed in 2008. These criteria showed a sensitivity and specificity of 79% and 87%, respectively

• In a recent multicentre study conducted in Israel, no late cardiac involvement was found in 146 paediatric PSRA patients

Post-streptococcal reactive arthritis

Ahmed et al., Arthritis Rheum 1998 Barash et al., J Pediatr 2008 Perl et al. Clin Exp Rheumatol 2009

PSRA vs ARF Post streptococcal reactive

arthritis

Acute rheumatic fever

Time distance from

streptococcal infection

7-10 days 10-28 days

Features of joint

involvement

Persistent and additive;

large and small joints

affected

Migratory, transient

(occasionally additive);

large joints mainly affected

Axial joints involvment Not rare No

Acute phase reactants Moderately elevated Markedly elevated

Response to aspirin or

NSAIDs

Poor or moderate Dramatic

Risk of carditis A few patients were

descripted to develop carditis

About 50% of cases

Carditis

30–80% of patients during their first episode of ARF

Clinically silent pancarditis serious, life-threatening congestive heart failure

heart inflammation usually involves the myocardium and endocardium

Isolated pericarditis is uncommon

Myocarditis: tachycardia at rest e PR interval prolongation

Endocarditis: valvular insufficiency

o 65% mitral v.

o 10% aortic v.

o 25% both

Acute heart failure : 5%

Sydenham’s Chorea Prevalence in ARF ranges from 5 to 36%

Latency between GAS infection and choreic symptoms may be as long as 8 months or longer (usually 6 to 8 weeks)

secondary to the inflammatory involvement of the basal ganglia and of the caudate nucleus

emotional lability, uncoordinated movements, and muscular weakness

emotional disturbances, such as anxiousness, irritability, or inattention, may precede the motor symptoms

Loss of physical coordination, involuntary and purposeless, awkward movements of the extremities and face

dysarthria, clumsy handwriting

self-limiting condition (2 to 3 weeks)

20/12/2016 23/12/2016 26/12/2016

Erythema marginatum

uncommon (about 6% of patients)

evanescent, pink rash with pale centres

and rounded or vertiginous margins

the lesions are multiple and appear on the trunk or proximal extremities

not pruritic or indurated and blanch upon pressure

transient and migratory and may be exacerbated by the application of heat (lesions can appear and disappear in few minutes)

early stage of an acute disease

thought to be closely associated with the presence of carditis

Subcutaneous nodules

• observed in less than 4% of cases

• more prevalent in severe cases

• The nodular lesions have variable size, ranging from few millimeters to 2 cm

• No signs of inflammation on the overlying skin

• Not anchored

• Usually located over the joints, scalp and spinous processes of the thoracic or lumbar vertebrae or in the proximity of tendons

• From one single lesion to several dozens

Source: semanticscholar.org

Minor manifestations

Frequent but less specific disease features:

• Fever

• Arthralgia • joint pain without any other sign of active inflammation

• Pain usually involves the large joints with variable intensity

• Increase in the acute phase reactants in the acute phase of ARF• ESR and CRP can both be normal in the presence of chorea

• PR interval prolongation on ECG

2015 Revised Jones CriteriaLow-risk populations Moderate- and high-risk populations

MA

JOR

CR

ITER

IA

Carditis (Clinical and/or subclinical) Carditis (Clinical and/or subclinical)

Arthritis

• Polyarthritis only

Arthritis

• Monoarthritis or polyarthritis

• Polyarthralgia

Chorea Chorea

Erythema marginatum Erythema marginatum

Subcutaneous nodules Subcutaneous nodules

MIN

OR

CR

IT. Polyarthralgia Monoarthralgia

Fever (≥ 38.5 °C) Fever (≥ 38 °C)

ESR ≥ 60 mm/h and/or CRP ≥ 3.0 mg/dl ESR ≥ 30 mm/h and/or CRP ≥ 3.0 mg/dl

Prolonged PR interval (unless carditis is a major

criterion)

Prolonged PR interval (unless carditis is a major

criterion)

“Low-risk populations are those with ARF incidence ≤2 per 100 000 school-

aged children or all-age rheumatic heart disease prevalence of ≤1 per

1000 population per year”

2015 Revised Jones Criteria

• For all patient populations with evidence of preceding GAS infection

• Diagnosis: initial ARF• 2 major manifestations

or • 1 major plus 2 minor manifestations

• Diagnosis: recurrent ARF• 2 major manifestations

or • 1 major and 2 minor manifestations

or • 3 minor manifestations

Gewitz et al. Circulation 2015

…evidence of preceding GAS infection

Anyone of the following conditions may serve as evidence of antecedent group A streptococcal infection:

1) Increased or rising anti-streptolysin O titer or other streptococcal antibodies (anti-DNAse B)

2) A positive throat culture for group A ß-haemolytic streptococci

3) A positive rapid group A streptococcal carbohydrate antigen test

The ASO titer in the diagnosis of ARF

• Sierological indicator of a recent streptococcal infection

• Fundamental test when throat culture is negative (2/3 cases)

• It is not a criterion (major or minor)

• Problem of false positives

• Problem of false negatives

The ASO titer: false positives

• Titres may be elevated in the absence of recent streptococcal pharyngitis in populations with endemic streptococcal infections

• Non Group A Streptococcal infections are also accompanied by elevation of titres (e.g. Group C or G)

• ASO titres may be elevated in patients with chronic arthritis not due to ARF

ASO titer in healthy children

Age (years) IU/mL (95% CI)

4-5 120 (54-396)

6-9 480 (320-640)

10-14 320 (240-496)

Danchin MH et al. J Paediatr Child Health 2005;41:583-6

The ASO titer: false negatives

• ASO titres can be normal in 15-20% of ARF cases

• In case of subclinical, isolated carditis, diagnosis might be delayed of several months after ARF occurred, when ASO titres have normalized

• Chorea might be a late manifestation of ARF, possibly after ASO titresnormalization

Kinetic of ASO titer after GAS infection

Antibody test for streptococcal infection

Streptococcal antigen Antibody test

Streptolysin-O ASO

Streptokinase Anti-streptokinase

Ialuronidase Anti-ialuronidase

Deoxyribonuclease-B Antideoxyribonuclease-B

Multiple antigens Streptozyme

Frequency of elevation of ASO e Anti-DNAse B

Group ASO Anti-DNAse B ASO or

Anti-DNAse B

Normal controls 19% 19% 30%

ARF 83% 82% 92%

Sydenham chorea (isolated) 67% 40% 80%

Ayoub EM et al. Pediatrics 1962 and 1966

TAKE HOME MESSAGES

• The global burden of ARF is of major concern

• Consider ARF in a child with a systemic inflammatory condition and joint involvement

• If you suspect ARF, refer the patient to a cardiologist who isexperienced in RHD

• Increased ASO titer doesn’t make a diagnosis of ARF

Grazie!

• Angelo Ravelli

• Roberta Caorsi• Marco Gattorno• Gabriella Giancane• Clara Malattia• Paolo Picco• Silvia Rosina• Nicola Ruperto• Stefania Viola• Stefano Volpi

• Alessandra Alongi