RHEUMATIC FEVER

Rheumatic fever (RF), the leading cause of heart disease in school-age children, is an acute inflammatory disease affecting the joints, heart, skin, subcutaneous tissue and nervous system, following streptococcal sore throat (SST).

Incidence: RF is widely prevalent in overpopulated developing countries like India, though the incidence has declined in recent years to ~1-3% of school children. However some western countries have witnessed resurgence of RF during last two decades. Recent data suggests ~0.5-1.0% of Indian school children have evidence of rheumatic heart disease.

Epidemiology of RF closely follows the epidemiology of SST, both being common in—(a) school-children aged 5-14 years, (b) low socioeconomic status, (c) overcrowded slum population, and (d) rainy, winter or early spring season. Both sexes are equally affected, though chorea and mitral valve disease is more common in females, while aortic valve disease is common in males.

Etiopathogenesis: RF follows an attack of pharyngeal infection by ~2-3 weeks, due to rheumatogenic strains of Group A ^-hemolytic streptococci (M type 1, 3, 5, 6, 18 and 24).

While the association between RF and streptococcal sore throat (SST) is well known, exact pathogenesis of RF is not clearly established, seems to be an abnormal immune- mediated damage to various tissues, due to:

• Cross-reactivity of anti-streptococcal antibodies with some human tissues antigens in susceptible organs,

e. g. heart, bones and CNS, which are structurally similar to streptococcal antigens;

• Autoimmunity due to modification of human tissues by direct streptococcal infection, which are then themselves recognized as foreign and initiate autoantibody production.

As only 1-3% of SST develop RF, an underlying genetic susceptibility has also been postulated.

Pathology: RF is characterized by involvement of various organs and tissues including the heart, joints, skin and nervous system.

Cardiac pathology affect all the layers of the heart (pancarditis) including:

• Valvulitis, with formation of vegetations on valvular edges, which heals with fibrosis to cause residual deformity and RHD.

• Myocarditis, characterized by perivascular aggregation of pathognomonic Aschoff bodies-large multi-nucleated giant cells around a vascular core of fibrinoid material.

• Serofibrinous pericarditis, pathologically resembling bread and butter appearance.

Joint pathology presents with inflammatory swelling of articular and periarticular structures with minimum exudation, but no erosion, pannus formation or residual lesion (d/d rheumatoid arthritis).

Subcutaneous nodules are localized granulomas (resembling Aschoff bodies) with fibrinoid swelling of collagen bundles and perivascular collections of histio­cytes, fibroblasts and lymphocytes.

Neuropathology is non-specific (cellular degeneration and hyalinization of small blood vessels), non-localized and does not correlate with clinical findings. Aschoff bodies are never seen in brain.

Clinical manifestations of RF begin after a latent period of 2-3 weeks of SST, with or without nonspecific complaints, e.g. low/moderate fever and constitutional symptoms.

Characteristic manifestations of RF include arthritis, carditis, chorea, subcutaneous nodules and erythema marginatum, though not more than one or two of them develop during the same episode. Natural history is highly variable with different manifestations on different time-frames—arthritis and carditis as early manifestations (2-3 weeks), subcutaneous nodules as an intermediate manifestation (3-6 weeks), and chorea as late manifestation (gt;3 months).

Rheumatic arthritis, is the commonest manifestation of RF (75%), characterized by:

• Polyarticular involvement of large joints, e.g. knee, ankle, elbow and wrist, sparing digital joints and spine.

• Migratory character, involving only 1-2 joints at one time, which spontaneously recover within 48-72 hours, only to recur in other joints.

• Disproportionately more pain than other signs of inflammation, e.g. swelling. Some cases have only arthralgia. Joint X-rays.

• Complete recovery, without residual deformity. Chronic Jaccoud's arthropathy is an extremely rare complication after multiple, prolonged attacks.

Rheumatic carditis, seen in 40-50% cases of first attack and 70-80% cases of subsequent attack, is the most dreaded manifestation of RF due to acute morbidity as well as risk of residual heart disease.

Usually seen after 2-3 weeks of arthritis, rheumatic carditis may be asymptomatic or present with palpitation, exertional dyspnoea and various signs of pancarditis (Table 17.24). One or more valves may be involved, commonest being mitral valve (95%), followed by tricuspid (10-30%) and aortic valve (5%). Pulmonary valve is almost always spared. Active carditis may continue for 3-4 months, irrespective of treatment. Residual lesions develop in ~50-75% cases of first attack and in almost all cases on subsequent attacks.

Rheumatic (Sydenham) chorea, seen in ~10-15% cases, is a late manifestation of RF which presents after many months with insidious onset of:

• Emotional instability, e.g. inappropriate smiling, crying or restlessness (earliest indicator).

• Clumsy movements with deterioration of handwriting.

• Typical choreiform movements — rapid, jerky, quasi­purposeful movements at proximal joints, e.g.

TABLE 17.24: Clinical signs of rheumatic carditis

• Tachycardia — disproportionate to fever

• Muffling of heart sounds

• Abnormal gallop/tic-tac rhythm

• Changing murmurs or Carey Coombs' murmur

• Cardiomegaly

• Congestive cardiac failure

• Pericardial rub shoulder, which disappear in sleep and aggravate during activity.

• Generalized hypotonia/dystonia.

• Occult signs, e.g. milk-maid grip (intermittent contraction and relaxation of hand-grip, while holding the examiner's finger) and Lizard-tongue or tongue in jack-box appearance (fasciculations and ill-sustained protrusion of tongue)

Evidences of preceding SST, e.g.

Erythema marginatum is an evanescent, non-pruritic, pinkish-red macular rash with serpiginous margins, not well visible in dark-skinned Indian children.

Other manifestations, e.g. abdominal pain, epistaxis and pneumonia are not uncommon in RF but have no diagnostic or prognostic value.

Diagnosis of RF depends on Revised Jones criteria 2015 (Table 17.25) which differs in low-risk populations and moderate/high-risk population, classified according to incidence of RF in school children (lt;/gt;2/100,000) or prevalence of RHD in general population (lt;/gt;1/1000).

Presence of two major criteria or one major and two minor criteria in presence of essential criteria, i.e. any evidence of previous streptococcal infection, e.g. positive throat culture, history of scarlet fever or raised antistreptolycin (ASO) titers, suggests diagnosis of RF. Even the presence of three minor criteria (without major criteria) is considered as suggestive of RF in a case with past history of RF.

*ⁱncluding subclinical carditis on echocardiography

**for age

***Positive throat culture or history of scarlet fever or elevated ASO titer

Laboratory investigations: No single test is diagnostic of RF, though supporting investigations include:

• Evidence of streptococcal infection (Essential criteria) like:

- Elevated ASO titers (gt;333 Todd units or gt;200 Todd units and rising). Elevated anti-DNAase-B or anti­hyaluronidase titers are more specific, while anti- streptozyme test is more sensitive that also detects extra-cellular streptococcal antigens.

- Positive throat culture is not necessarily diagnostic, as carriers are common. Similarly, negative culture does not exclude RF.

• Evidence of inflammatory process (acute phase reactants), e.g. elevated ESR gt;30 mmFHR (gt;60 mm in low-risk population) or CRP gt; 3 mg/dl is considered as a minor criteria for diagnosis of RF. ESR also has important prognostic value in assessing the course and therapeutic response.

• Evidence of cardiac involvement on:

- ECG: Prolonged PR interval for the age is common in RF, even without clinical carditis.

- Echocardiography may reveal cardiac dilatation, valvular abnormalities, pericardial effusion and LV dysfunction. Vegetations are rarely seen. Echocardiographic evidence of carditis is enough as a major criteria, even in absence of clinical carditis.

Management of RF needs hospitalization for monitoring the progression of disease, though chorea, if not debilitating, may be managed at home. Important steps in management include:

a. Eradication of streptococcal infection with penicillin, either as single IM benzathine penicillin (12,00,000 U gt;9 years/6,00,000 U lt;9 years) or daily IM procaine penicillin (50,000 U/kg/OD) for 10 days. In penicillin-allergy, Erythromycin (40-50 mg/kg/d q8hrx 10 days) or Azithromycin (10 mg/kgOD x 5days) may be used.

b. Anti-inflammatory therapy with salicylates or steroids, is the cornerstone of management in rheu­matic arthritis or carditis, as follows:

- Rheumatic arthritis or rheumatic carditis without CCF or cardiomegaly is treated with PO Aspirin 50-70 mg/kg/day q6hr for 3-5 days, then 50 mg/kg/ day q6hr for 3 weeks, and then 25 mg/kg/day for next 4-6 weeks.

- Rheumatic carditis with CCF or cardiomegaly is treated with PO Prednisolone 2 mg/kg/day q6hr for 2-3 weeks, followed by 1 mg/kg/day q6hr for 2-3 weeks and then tapered by 5 mg/kg/day every 2-3 days. While initiating the tapering doses of steroids, Aspirin PO 50 mg/kg/day q6hr must be added for 6 weeks.

- Rheumatic Chorea or other manifestations do not need anti-inflammatory therapy, but presence of carditis must be excluded.

c. Supportive treatment includes bed rest, and treatment of CCF or other symptoms.

- Strict bed rest is indicated only in cases with impending or established CCF, though restriction of strenuous activity is desirable in presence of carditis or arthritis.

- Arthralgia, without arthritis must be treated only with paracetamol or codeine, so as not to mask the progression.

- Chorea may be treated with usual doses of non­specific sedatives, e.g. phenobarbitone, halo­peridol, diazepam and chlorpromazine, etc., for symptomatic relief.

- No treatment is required for subcutaneous nodules or erythema marginatum.

d. Monitoring: Cases with arthritis or carditis should be closely monitored for appearance of carditis or CCF respectively, and to assess the response to anti­inflammatory therapy. ESR is a reliable indicator for laboratory monitoring of rheumatic activity.

Prevention of RF includes:

Step I. Primary prevention, before the first attack of RF involves:

• Prevention of SST in general population by community measures, e.g. avoidance of overcrowding.

• Early diagnosis and treatment of SST with single dose of IM Benzathine Penicillin 12 Lac U (6 Lac U in children lt;27 kg) or PO Penicillin V 250 mg QID for 10 days. Alternatively, PO Cephalexin 15-20 mg/kg BD for 10 days or PO Azithromycin 12.5 mg/kg OD for 5 days may also be used.

Step II. Secondary prevention to prevent recurrence of RF after the first attack. Since children with past history of RF are at higher risk of recurrence after subsequent SST (gt;30% vs 1-3% in general population), all of them should receive secondary prophylaxis with IM Benzathine penicillin G (12 Lac U every 21-28 days (6 Lac U every 15 days in children lt;27 kg). Alternatives include-PO Penicillin V (250 mg BD daily) in cases who refuse to take IM injections, or PO Erythromycin (20 mg/kg BD daily) in penicillin allergy.

While recommendations for the duration of secondary prophylaxis vary, IAP recommends that it should continue for at least:

• 5 years after the last attack or till 21 years of age, whichever is later, in cases of RF without carditis,

• 10 years after the last attack or till 21 years of age, whichever is later, in carditis without residual heart disease.

• 10 years after the last attack or till 40 years of age, whichever is later, in cases with residual heart disease

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