Rheumatic Fever Causes, Symptoms, Treatment

Rheumatic Fever Causes








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Rheumatic Fever Causes/Rheumatic fever (RF) is an autoimmune, multiorgan inflammatory disease that occurs as a result of group A β-hemolytic streptococcal infection in genetically syusceptible individuals [].

Rheumatic fever is an immunologically mediated inflammatory disease, that occurs as a delayed sequel to group A streptococcal throat infection, in genetically susceptible individuals. Chronic rheumatic heart disease remains an important public health problem in developing countries. Aetiopathogenesis and guidelines for the diagnosis, prevention and treatment of acute rheumatic fever are reviewed.

Pathophysiology

Although epidemiological and immunological studies have clearly identified group A β-hemolytic streptococcus (GAS) as the etiologic agent triggering ARF in a susceptible host, the molecular pathways linking GAS to ARF are still poorly understood. Molecular mimicry and autoimmunity probably play a pivotal role in the pathogenesis of ARF and carditis [] since it was shown that the streptococcal M protein shares an α-helical coiled structure with cardiac proteins such as myosin and that antibodies isolated from ARF patients cross-react with both M protein and heart tissue. Elevated in patients with valvular involvement, these antibodies are significantly reduced after surgical removal of inflamed valves and they correlate with poor prognosis []. Moreover, heart-M protein cross-reactive T cells have been isolated from the myocardium and the valves of RHD patients suggesting their involvement in the pathophysiology of the disease [, ]. However, the role of collagen should not be underestimated, as shown by recent studies demonstrating pathological findings in subendothelial and perivascular connective tissue in ARF [].

Causes of Rheumatic Fever

  • Rheumatic fever – may develop after strep throat or scarlet fever infections that are not treated properly. Bacteria called group A Streptococcus or group A strep cause strep throat and scarlet fever. It usually takes about 1 to 5 weeks after strep throat or scarlet fever for rheumatic fever to develop. Rheumatic fever is thought to be caused by a response of the body’s defense system — the immune system. The immune system responds to the earlier strep throat or scarlet fever infection and causes a generalized inflammatory response.
  • Rheumatic fever – is an inflammatory condition that may develop approximately 14-28 days after infection with group A Streptococcus bacteria, such as strep throat or scarlet fever. About 5% of those with untreated strep infection will develop rheumatic fever. Although group A Streptococcus bacterial infections are highly contagious, rheumatic fever is not spread from person to person.
  • Bacteria called group –  A Streptococcus (group A strep) can cause many different infections. These infections range from minor illnesses to very serious and deadly diseases. Learn more below about some of these infections, including symptoms, risk factors, treatment options, and how to prevent them.
  • Strep Throat – When is a sore throat “strep throat”? Your doctor can do a quick test to see if you or your child has strep throat.
  • Scarlet Fever – Have a sore throat and rash? It could be scarlet fever. Your doctor can do a quick test to find out…
  • Necrotizing Fasciitis – Sometimes called “flesh-eating” disease, this infection is not common. Good hygiene, proper wound care, and quick recognition and treatment are important.
  • Rheumatic Fever – This disease affects the heart and other organs. It is not common but can happen if strep throat or scarlet fever aren’t treated properly
  • Post-Streptococcal Glomerulonephritis – This disease affects the kidneys and is not common but can happen after strep throat or impetigo

Symptoms of Rheumatic Fever

Symptoms of rheumatic fever include

  • Joint swelling and pain This may include redness and warmth, mainly of the larger joints like the knees, ankles, wrists and elbows
  • Fever Hot and cold fevers which may feel like symptoms of a cold or flu
  • Sydenham’s Chorea – Jerky, uncontrollable movements called chorea
  • Erythema marginatum – A rare skin rash, mainly found on the trunk of the body (this is a very a rare symptom)
  • Subcutaneous nodules – Round, painless nodules over the elbows, wrists, knees, ankles and areas near the spine (also very rare)
  • Heart problems – Swelling of the heart may cause chest pain, and if severe there may be signs of heart failure (breathlessness, swollen legs and face).
  • Painful – tender joints (arthritis), most commonly in the knees, ankles, elbows, and wrists
  • Symptoms of congestive heart failure – including chest pain, shortness of breath, fast heartbeat
  • Jerky uncontrollable body movements (called chorea)
  • Painless lumps (nodules) under the skin near joints.
  • Rash that appears as pink rings with a clear center.
  • Red raised, lattice-like rash, usually on the chest, back, and abdomen.
  • Uncontrolled movements of arms, legs, or facial muscles
  • Swollen, tender, red and extremely painful joints
  • Weakness and shortness of breath
  • Nodules over swollen joints
  • Stomach pains
  • Weight loss
  • Fatigue
  • Fever
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Diagnosis of Rheumatic Fever

The diagnostic tests can be considered as those meant for (i) diagnosis of RF, (ii) presence of active vs. inactive RF in recurrences, and (iii) identification of carditis and valve damage in RHD.

Diagnosis of RF

The diagnosis of RF is dependent on some laboratory tests included as minor criteria and consist of the following:

  • (i)Acute phase reactants (leukocytosis, elevated sedimentation rate and presence of C reactive protein CRP).
  • (ii)Prolonged PR interval in the electrocardiogram.
The diagnosis requires presence of essential criteria in the form of evidence for recent GAS infection and consists of:
  • (i) elevated antistreptococcal antibodies,
  • (ii) positive throat culture for GAS, and
  • (iii) evidence for recent scarlet fever- rare in India.

Diagnostic criteria for rheumatic fever – modified 1992 Jones criteria []

Major criteriaMinor criteria
Carditis
Arthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Hyperpyrexia
Arthralgia, without other signs of inflammation
Laboratory indicators of acute phase:
ESR, CRP
Prolonged PR interval in ECG
And evidence of antecedent streptococcal infection
– Throat swab culture or rapid antigen test
– Elevated/increasing anti-streptococcal antibody titer in serum

ESR – erythrocyte sedimentation rate; CRP – C-reactive protein; ECG – electrocardiography

Major criteria

  • Polyarthritis – [rx] A temporary migrating inflammation of the large joints, usually starting in the legs and migrating upwards.
  • Carditis – Inflammation of the heart muscle (myocarditis) which can manifest as congestive heart failure with shortness of breath, pericarditiswith a rub, or a new heart murmur.
  • Subcutaneous nodules – Painless, firm collections of collagen fibers over bones or tendons. They commonly appear on the back of the wrist, the outside elbow, and the front of the knees.
  • Erythema marginatum – A long-lasting reddish rash that begins on the trunk or arms as macules, which spread outward and clear in the middle to form rings, which continue to spread and coalesce with other rings, ultimately taking on a snake-like appearance. This rash typically spares the face and is made worse with heat.
  • Sydenham’s chorea (St. Vitus’ dance) – A characteristic series of involuntary rapid movements of the face and arms. This can occur very late in the disease for at least three months from onset of infection.

Minor criteria

  • Fever of 38.2–38.9 °C (100.8–102.0 °F)
  • Arthralgia – Joint pain without swelling (Cannot be included if polyarthritis is present as a major symptom)
  • Raised erythrocyte sedimentation rate or C reactive protein
  • Leukocytosis
  • ECG showing features of heart block, such as a prolonged PR interval[rx][rx] (Cannot be included if carditis is present as a major symptom)
  • Previous episode of rheumatic fever or inactive heart disease

Diagnostic criteria for rheumatic fever – modified 2015 Jones criteria []

Major criteria
Low risk populationHigh risk population
Carditis (clinical or subclinical)
Arthritis – only polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Carditis (clinical or subclinical)
Arthritis – monoarthritis or polyarthritis
Polyarthralgia
Chorea
Erythema marginatum
Subcutaneous nodules
Minor criteria
Low risk populationHigh risk population
Polyarthralgia
Hyperpyrexia (≥ 38.5ºC)
ESR ≥ 60 mm/h and/or CRP ≥ 3.0 mg/dl
Prolonged PR interval (after taking into account the differences related to age; if there is no carditis as a major criterion)
Monoarthralgia
Hyperpyrexia (≥ 38.0ºC)
ESR ≥ 30 mm/h and/or CRP ≥ 3.0 mg/dl
Prolonged PR interval (after taking into account the differences related to age; if there is no carditis as a major criterion)

ESR – erythrocyte sedimentation rate; CRP – C-reactive protein

The modifications introduced in 2015 in the Jones criteria are as follows

In the major criteria

  • Low risk population – clinical and/or subclinical carditis. AHA recommends that all the patients with suspected RF undergo Doppler echocardiographic examination, even if no clinical signs of carditis are present []. In doubtful cases it is recommended that echocardiography is repeated.
  • Medium and high risk population – also clinical and/or subclinical carditis and arthritis – monoarthritis or polyarthritis, possibly also with polyarthralgia [, ].

In the minor criteria

  • Low risk population – the parameters of inflammation and the level of fever were defined precisely.
  • Medium and high risk population – monoarthralgia, also with defined parameters of inflammation and the level of fever.

The diagnosis of RF in the whole population with evidence of antecedent group A β-hemolytic streptococcal infection requires a confirmation of two major criteria or one major and two minor criteria – the first episode of the disease. The echocardiographic criteria developed by AHA in 2012 are as follows [, ]

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Echocardiographic (Doppler) criteria: Pathological mitral regurgitation – 4 criteria (all must be met)

  • Visible at least in 2 projections.
  • Regurgitation jet length ≥ 2 cm at least in 1 projection.
  • Regurgitation peak velocity > 3 m/s.
  • Regurgitation pansystolic.

Pathological aortic regurgitation – 4 criteria (all must be met)

  • Visible at least in 2 projections.
  • Regurgitation jet length ≥ 1 cm at least in 1 projection.
  • Regurgitation peak velocity > 3 m/s.
  • Regurgitation pandiastolic.

Echocardiographic (morphological) criteria: In acute mitral valve involvement

  • Dilatation of mitral annulus.
  • Elongation of chordae tendineae.
  • Rupture of chorda tendinea with acute mitral regurgitation.
  • Prolapse of anterior (less often posterior) leaflet.
  • Nodular lesions on leaflets.

In chronic mitral valve involvement (invisible in acute involvement)

  • Thickening of leaflets.
  • Thickening of chordae tendinea, with their fusion.
  • Limited mobility of leaflets.
  • Calcifications.

Lesions in acute and chronic aortic valve involvement

  • Symmetrical or focal thickening of leaflets.
  • Disturbed leaflet coaptation (leaflet closing during systole).
  • Limited mobility of leaflets.
  • Prolapse of leaflets.

Presence of GAS in throat culture with low values of ASLO suggests a carrier state. As such a positive throat culture for GAS cannot be taken as recent infection unless the antibody titres are elevated.

  • Echocardiogram (echo) – This test uses sound waves to check the heart’s chambers and valves. The echo sound waves create a picture on a screen as an ultrasound transducer is passed over the skin overlying the heart. Echo can show damage to the valve flaps, backflow of blood through a leaky valve, fluid around the heart, and heart enlargement. It’s the most useful test for diagnosing heart valve problems.
  • Electrocardiogram (ECG) – This test records the strength and timing of the electrical activity of the heart. It shows abnormal rhythms (arrhythmias or dysrhythmias) and can sometimes detect heart muscle damage. Small sensors are taped to your skin to pick up the electrical activity.
  • Chest X-ray – An X-ray may be done to check your lungs and see if your heart is enlarged.
  • Cardiac MRI – This is an imaging test that takes detailed pictures of the heart. It may be used to get a more precise look at the heart valves and heart muscle.
  • Blood tests – Certain blood tests may be used to look for infection and inflammation.

Presence of active vs. inactive RF in recurrences Two investigations have been tried to assess the presence or absence of active RF in patients with recurrences besides ESR, CRP and evidence for recent GAS infection.

  • Induced subcutaneous nodules (SCN) Massell et al tried inducing SCN by injecting five dl autologous blood drawn from a vein and injecting over the olecranon process of one elbow and saline in the other elbow. Frictional pressure was applied to the injected sites. Appearance of a SCN in 5 to 10 days was accepted as indicating active RF. Vasan modified this test and used concentrated leukocyte injection instead of whole blood with 86 per cent sensitivity and 94 per cent specifically to identify active RF. The test offers the advantage of being cheap and easily available everywhere. The potential utility of the test lies in identifying active RF. However, additional validation studies are perhaps needed.
  • Myocardial biopsy A study of myocardial histology to identify active vs. inactive RF was utilized in patients of RF. Myocardial biopsies were performed in 89 patients of active RF and chronic RHD to identify active carditis Myocardial biopsies failed to improve on clinically assessed presence of active RF. Myocardial biopsy was felt to be insensitive for identifying presence of active carditis.

Treatment of Rheumatic Fever

Antibiotics used in primary prevention and treatment of group A streptococcal throat infection (World Health Organization guidelines)

AntibioticRoute of administration and dosageDose
Benzathine benzylpenicillinIntramuscular injection; childen should be kept under observation for 30 minutesSingle dose 1.2 million U; <27 kg, 600 000 U
Phenoxymethylpenicillin (penicillin V)Oral, 2-4 times daily for 10 daysChildren 250 mg twice or three times daily, adolescents or adults 250 mg three or four times daily or 500 mg twice daily
AmoxicillinOral, 2-3 times daily for 10 days25-50 mg/kg/d in three doses; total adult dose 750-1500 mg/d
First generation cephalosporinsOral, 2-3 times daily for 10 daysVaries with formulation
Erythromycin if allergic to penicillinOral, 4 times daily for 10 daysVaries with formulation

or

AntibioticDoseDuration
Penicillin V250 mg by mouth 2 to 3 times daily (≤27 kg) or 500 mg by mouth 2 to 3 times daily (>27 kg)10 days
Benzathine penicillin G600,000 units intramuscular (≤27 kg) or
1,200,000 units intramuscular (>27 kg)
Once
Amoxicillin50 mg/kg by mouth daily10 days
Cephalosporin (first generation)Drug-dependent10 days
Clindamycin20 mg/kg/day divided in 3 doses by mouth10 days
Clarithromycin15 mg/kg/day divided in 2 doses by mouth10 days
Azithromycin12 mg/kg by mouth daily5 days
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Rheumatic fever treatment has not changed for many years. It covers:

  • anti-streptococcal treatment (primary and secondary prevention),

  • anti-inflammatory treatment.

Anti-Streptococcal Treatment

Primary prevention relies on the proper treatment of streptococcal pharyngitis, that is, prevention of the first RF episode.

  • The drug of choice is still phenoxymethylpenicillin orally at the following doses – adults and children with a body weight > 40 kg – 2–3 MIU/day in 2 divided doses every 12 hours for 10 days, children with a body weight < 40 kg – 100,000 to 200,000 IU/kg/day in 2 divided doses every 12 hours for 10 days.
  • Benzylpenicillin – administered intramuscularly at a single dose (only in hospital settings), is acceptable, for adults and children with a body weight > 40 kg – 1.2 MIU, children with a body weight < 40 kg – 600,000 IU. In patients with hypersensitivity to penicillin (except for immediate-type reactions), first-generation cephalosporins (cefadroxil or cefalexin) are used.
  • Cefadroxil – adults and children with a body weight > 40 kg – 1 g, children with a body weight < 40 kg – 30 mg/kg, in a single dose for 10 days.
  • Cefalexin – adults 500 mg twice per day, children 25–50 mg/kg/day in 2 doses for 10 days. Macrolides should only be administered in patients with immediate-type hypersensitivity to beta-lactam antibiotics. The following can be used: erythromycin, clarithromycin and azithromycin.
  • Erythromycin – adults and children with a body weight > 40 kg – 0.2–0.4 γ every 6–8 hours, children with a body weight < 40 kg – 30–50 mg/kg/day in 3–4 doses, for 10 days.
  • Clarithromycin – adults and children with a body weight > 40 kg – 250–500 mg every 12 hours, children with a body weight < 40 kg – 15 mg/kg/day in 2 doses, for 10 days.
  • Azithromycin – adults and children with a body weight > 40 kg – 500 mg on the first day, then 250 mg for three consecutive days, children with a body weight < 40 kg – a single daily dose of 12 mg/kg/day for 5 days or 20 mg/kg/day for 3 days [].
  • Secondary prevention is the prevention of subsequent rheumatic fever relapses through the chronic anti-streptococcal treatment – phenoxymethylpenicillin or benzathine benzylpenicillin or possibly macrolides. The duration of secondary prevention must be determined individually, depending on whether the patient has developed carditis and complications in the form of chronic valvular heart disease. Secondary prevention should be administered from 5 to 10 years from the last RF relapse, or up to 21 years of age (whichever is longer) [, ]. In RF cases with carditis leading to chronic valvular heart disease, the prevention should be administered for 10 years or until 40 years of age (whichever is longer) []. Secondary prevention makes use of benzathine benzylpenicillin, intramuscularly in adults and children with a body weight > 20 kg – 1.2 MIU, in children with a body weight < 20 kg – 600,000 IU every 4 weeks []. Phenoxymethylpenicillin is administered orally at a dose of 2 × 250 mg (i.e. 2 × 400,000 IU).
  • Anti-inflammatory drugs – Naproxen, for example, may help to reduce pain, inflammation, and fever.
  • Corticosteroids – Prednisone may be given if the patient does not respond to first-line anti-inflammatory medications, or if there is inflammation of the heart.
  • Aspirin – This is not usually recommended for children aged under 16 years because of the risk of developing Reye’s syndrome, which can cause liver and brain damage, and even death, but an exception is usually made in cases of RA because the benefits are greater than the risks.
  • Anticonvulsant medications – These can treat severe chorea symptoms. Examples include valproic acid, carbamazepine, haloperidol and risperidone.

References

Rheumatic Fever Causes

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