.

 Rheumatic fever (RF) is an acute, immunologically mediated, multisystem inflammatory disease that occurs a few weeks following an episode of group A streptococcal pharyngitis.

It is believed to be caused by antibody cross- reactivity and can involve the heart, joints, skin, and brain. In about 3%,RF occurs 10 days to 6 weeks after an episode of pharyngitis caused by group A streptococci. Acute rheumatic fever commonly appears in children ages years, but about 20% of first time attacks occur in middle to later life. In developing countries, it is still the most common cause of acquired heart disease in childhood and adolescence. Abnormal response to infection with specific strain of Group A β- Haemolytic streptococcus (serotypes 1,3,5,6,18 etc), extracellular products (e.g. M protein) of streptococcus act as antigen. 3

Streptococcus pyogenes bacteria 4

 Etiology is unknown  Strong association with beta hemolytic streptococci of group A is indicated by a number of observation:  1. H/O sore throat in 50% of patient  2. Epidemics of streptococcal infection are followed by higher incidence of rheumatic fever  3. Seasonal variation of rheumatic fever and streptococcal infection are identical  4. Patient with established rheumatic heart disease streptococcal infection is followed by reccurence of acute rheumatic fever.

▪ 5. Penicillin prophylaxis for streptococcal infection prevents recurrence of rheumatic fever in those patients who have had it earlier ▪ 6. More than 85 % of the patients with acute rheumatic fever consistently show elevated levels of anti – streptococcal antibody titer.  Note : - Although these feature indicate the association of RF with streptococcal infection, streptococci have never been isolated from rheumatic lesions in joints, heart or the blood stream.

 Considerable evidence suggests that the RF is an antigen – antibody reaction.  Following streptococcal sore throat there is latent period of 10 days to several weeks before the onset of RF. This latent period is similar to the antigen – antibody diseases like serum sickness (type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum).

 Patients suffering from RF produce antibodies against streptococcal cell wall and cell membrane proteins  Streptococcal antigen and human myocardium appear to be identical antigenically. These antibodies have the capacity to react with human connective tissue specially the cardiac muscle, straited muscle and vascular smooth muscle.  Note : by immunofluorescent technique the antibodies are shown to be attached to the sarcolemma of the cardiac muscle.

 Note : -  Streptococcal products against which antibodies can be demonstrated are streptolysin, hyaluronidase, erythrogenic toxin, streptokinase, deoxyribonuclease etc. These antibodies are utilized for the identification of a previous streptococcal infection.

 Streptococcus has a hyaluronic acid capsule  Hyaluronic acid capsule prevents phagocytosis by the leukocytes  Below the capsule hair – like fimbriae containing lipoteichoic acid as well as the M,T and R proteins are present  lipoteichoic acid provides the mucosal attachment (penicillin destroy this).  M,T and R proteins are utilized for typing the streptococci.  M protein is believed to be the virulence factor of the streptococcus

 Antibodies which the immune system generates against the "M proteins" may cross react with cardiac myofiber protein myosin, heart muscle glycogen and smooth muscle cells of arteries, inducing cytokine release and tissue destruction

 One component of the streptococcal cell wall carbohydrate is N – acetyl glucosamine which is present in human connective tissue  N – acetyl glucosamine is an immunulugically active sugar  The compounds containing N – acetyl glucosamine cross – react with antiserum against human connective tissue

 Streptococcal cell wall proteins as well as carbohydrates have the capacity to produce antibodies capable of reacting with human connective tissue, resulting in RF  RF appears to be the result of the host`s unusual response at both the cellular and humoral level to the streptococcus.  Note : - Antibodies against the heart muscle (anti – heart antibodies) and nervous tissue (anti – nuronal antibodies) are found in high titers in patients with carditis and chorea

 Antibodies are specific in that they react with rheumatic tissue but not with non – rheumatic tissue.  Exact significance is not clear why some people are susceptible while others are not so susceptible to the occurrence of RF following the streptococcal infection

 Genetic susceptibility to RF : - ▪ 1. HLA – DR3 ▪ 2. serum 883 (85%) ▪ 3. D 8/17 (100% in USA)

Extra cardiac involvement is seen mostly in joints and skin. Histologically: Fibrinoid degeneration can be seen in the collagen of the connective tissues of these organs. Aschoff nodule (multinucleated giant cells surrounded by macrophages and T -lymphocytes, occuring in Heart) and Anitschkow cells are pathgnomonic histological lesion. 16

 Usually follows 2-3 weeks after streptococcal Pharyngitis.  Arthritis occurs in about 75%.  Skin rash, Carditis and Neurological changes may occur  Other symptoms include : SOB,Chest pain, purposeless involuntary movement, Fever, Anorexia, and Lethargy. 17

 Symptoms characteristically occur 2-3 weeks after the initial attack of pharyngitis but the patient may give no history of sore throat.  Jones criteria are used to make diagnosis. The following criteria must be present for diagnosis: 1. Two or more major criteria plus Essential criteria. Or 2. One major plus Two or more minor criteria plus Essential criteria Or 3. Two major or one major and two minor criteria plus Essential criteria 18

 Major criteria : 1. Carditis 2. Migratory Polyarthritis 3. Sydenham’s chorea 4. Erythema marginatum 5. Subcutaneous nodules. 19

 Minor criteria:  A. Clinical 1. Fever 2. Arthralgia 3. Previous Rheumatic fever or RHD B. Laboratory 1. Leukocytosis, raised ESR and C reactive protein 2. Prolonged PR interval in the ECG. 20

 Essential criteria:  Supporting evidence of recent Streptococcal infection as indicated by: 1. Raised ASO titer or other Streptococcal antibody titer 2. Positive throat swab culture 3. Recent Scarlet fever 21

Early manifestation and occurs in about 75% of the patients. Early features: There is acute, painful, asymmetry and migratory inflammation of large joints (knee, ankle, wrist, elbow) Affected joints are red, warm, swollen, pain and limitation of movement. Pain and swelling appear more quickly, last 3 to 7 days and subside spontaneously to appear in some other joint. 22

Arthritis 23

There is no residual damage or erosion after recovery. Arthritis responds well to Aspirin. Note : - younger the patient with acute rheumatic fever, the less the arthritis and the older the patient the more the arthritis

It is a pancarditis involving endocardium, myocardium and pericardium. Seen in 50-60% of patients. Early manifestation of RF so that by the time a patient seeks helps, he already has evidence of carditis. 80 % of those patients who develop carditis do so within the first two weeks of the onset of rheumatic fever. 25

 Seen in 15 % of patients  C/F : severe precordial pain  On auscultation : friction rub  ECG shows : ST elevation and T wave inversion  After the disappearance of pericardial friction rub, one can safely exclude rheumatic fever as the cause of pericarditis.

 Features diagnostic of myocarditis are :  1. cardiac enlargement  2. soft first sound  3. congestive cardiac failure  4. Carey Coombs murmur (delayed diastolic mitral murmur): -  Disappear after the myocarditis subsides  Due to increased diastolic flow, secondary to mitral regurgitation, across inflamed rigid cusps  Disappearance can be explained by the decrease in the left ventricular size following subsidence of myocarditis, and better function of the mitral valve – papillary complex

 Pansystolic murmur  Pathologically mitral valve is involved in 100 % of cases of RF who have carditis.  Clinically : -  5 – 8 % (pure aortic regurgitation)  95 % (mitral regurgitation murmur)  Tricuspid valvulitis resulting in tricuspid regurgitation in 10 – 30 %  Pulmonary valve involvement never seen

 Acute hemodynamic overload resulting from mitral regurgitation and / or aortic regurgitation leads to left ventricular failure (LVF) and is the main reasons for the morbidity and mortality of rheumaticfever and RHD  The severity of the valvar endocarditis causing acute and later chronic hemodynamic overload determines the prognosis of individuals patients

 Late manifestation occurring after about 3 months of acute attack  Generally by the time a patient manifests chorea, the signs of inflammation in the form of ESR have returned to normal  More common in females and observed in about one – third cases.  Chorea is purposeless, involuntary, dancing movements of hands, feet and face (St. Vitus dance), weakness.  Untreated, it has a self – limiting course of two to six weeks 30

 Late manifestation occurring after about 6 weeks of acute attack Found in about 3 – 5 % patients after a few weeks of illness. Appear on bony prominences like elbows, occiput and spine and are small(0.5-2cm),firm and painless nodules. Patients who have subcutaneous nodule almost always have carditis. Last from a few days to weeks but have been known to last for almost a year.

Subcutaneous nodule on the extensor surface of elbow 32

 It is rare manifestation  Rash : faintly reddish, not raised above the skin (macules) and non – itching  It is early manifestation, predominently seen over the trunk and proximal extremities.

34

 Clinical  Fever :  Temperature rarely goes above 39.5 degree C  In the initial attack it is almost present 90 % of the patients.  Arthralgia :  Subjective pain  Occurs in about the 90 % of the patients  Previous RF or RHD is applicable only for a second attack of RF

 Acute phase reactants :  Leukocytosis (1oooo – 15000/cmm)  Increased ESR (for 4 – 10 weeks in 80 %) and  Presence of C – reactive protein (absence after use of steroids)

 Presence of antibodies against the streptococci (ASO titer)  Rising ASO titer is a strong evidence of a recent streptococcal infection  Positive throat culture for streptococci is relatively uncommon, when a patient presents with ARF  Positive throat culture means that streptococci are present in the throat and the patient may or may not have RF  Finding of scarlet fever : desquamation of skin of palms and soles indicates that the patient has had scarlet fever within the previous two weeks.

Carditis Rheumatic heart disease at autopsy with characteristic findings (thickened mitral valve, thickened chordae tendineae, hypertrophied left ventricular myocardium).autopsymitral valvechordae tendineae myocardium 38

 Evidence of systemic illness: Leucocytosis, raised ESR, raised CRP.  Evidence of preceding Streptococcal infection: Throat swab culture, Group A Beta-hemolytic Streptococci (25-40%positive).  Anti streptolysin O (ASO) antibodies : Rising titer or levels of >200 units.  Evidence of carditis : 1. Chest X-Ray- Cardiomegaly 2. ECG-First degree heart block 3. Features of Pericarditis 4. Echocardiography-Cardiac dilatation or Valve abnormality 39

 No specific treatment.  Management is symptomatic combined with suppressive therapy  1. Bed rest :  Patients who do not have cardiac involvment can be ambulatory in two to three weeks whereas when carditis is present, immobilization may have to be continued for two to three months specially in the presence of congestive failure.

 2. Diet : salt is restricted in case of congestion cardiac failure.  3. Penicillin : After obtaining throat cultures the patient should be put on penicillin.  Dose :  Initially 400,000 units of procaine penicillin, I.M x BD for 10 days.  Followed by prophylactic penicillin using benzathine penicillin 1.2 mega units every 21 days, or 0.6 mega units every 15 days.

 4. Suppressive therapy :  Aspirin or steroids  Untreated rheumatic fever subsides in 12 weeks in 80 %.  Steroids are more potent than aspirin.  Pericardial friction rub tends to disappear within three to five days after starting the steroids and a new friction rub does not appear  Subcutaneous nodules tend to disappear faster with the use of steroids as compared to aspirin.  Patients who carditis with congestive cardiac failure have a much higher mortality if aspirin is used as against steroids.

 Guidelines for selecting the suppressive drug:  1. carditis with CCF, use steroids  2. carditis without CCF, use either steroids or aspirin, however, steroids are preferred  3. no carditis, use aspirin

 Total duration course : for 12 weeks  Dose :  Aspirin  90 – 120 mg/kg/day in 4 divided dose  Full dose for 10 weeks than tapered off in next 2 weeks  Steroid :  60 mg/ day for weight >20 kg  40 mg/ day for weight < 20 kg. Continued for 3 weeks then 50 mg/day for 1 week and 40 mg/day for another week. Following this the reduction in dose is by 5 mg/ week till it is finished

 Acute hemodynamic overload due to mitral and/ or aortic regurgitation during ARF is the main cause of RF mortality.  Management of chorea :  ESR and ASO titer may be normal  Reassured the patient and parents and told the self – limiting course of the disease  Complete physical and mental rest  Phenobarbitone 30mg X TDS  Others drugs : promethazine, chlorpromazine, valium

 Penicillin prophylaxis is essential to prevent recurrence of RF  Primary prophylaxis :  Identification of streptococcal sore throat and its treatment with penicillin.  Educate the community regarding the consequences of streptococcal sore throat.  30 – 80 % of sore throats resulting in rheumatic fever can be asymptomatic  If RF present than oral penicillin is not sufficient to prevent, so I.M benzathine penicillin is mandatory for prevention of RF

 For prevention of recurrent attack of rheumatic fever:  Long term intramuscular Benzathine Penicilline is given 1.2 million unit 3-4 weekly or 0.6 mega units veery alternate week.  Oral Penicillin V 250mg twice a day is another choice.  Erythromycin can be used in case of Penicillin allergy 47

Prophylaxis should be continued:  For at least 5 years after last attack Or  Up to the age of 21 years Or  Life long if there is documented Rheumatic heart disease. 48

 The prognosis for the primary attack is generally good, and only 1 % of patients die from fulminant RF 49