Rheumatic fever

Rheumatic fever (RF) is a post-infectious complication of A-streptococcal tonsillitis or pharyngitis in predisposed individuals with the development of an autoimmune response to epitopes of group A streptococcus and cross-reactivity with similar epitopes of human tissues (heart, joints, CNS).

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Epidemiology of rheumatic fever

The epidemiology of rheumatic fever is closely related to the epidemiology of A-streptococcal upper respiratory tract infections. The high incidence of rheumatic fever began to decline even before the use of antibiotics in clinical practice, and the use of antibiotics since 1950 has rapidly accelerated this process. Thus, in developed countries, the incidence of rheumatic fever has decreased from 100-250 to 0.23-1.88 per 100,000 population. Nevertheless, about 12 million people in the world currently suffer from rheumatic fever and rheumatic heart disease. Most of them live in developing countries, where the incidence of rheumatic fever ranges from 1.0 per 100,000 population in Costa Rica, 72.2 per 100,000 in French Polynesia, 100 per 100,000 in Sudan to 150 per 100,000 in China. In some areas, such as Havana (Cuba), Costa Rica, Cairo (Egypt), Martinique and Guadeloupe, where preventive programs have been introduced, a marked reduction in mortality, prevalence and severity of rheumatic fever and RHD has been noted. Socioeconomic indicators and environmental factors play an indirect but important role in the prevalence and severity of rheumatic fever and RHD. Factors such as lack of resources to ensure quality health care, low level of awareness of the disease in the community, crowded populations can significantly affect the incidence of the disease in the population. At the same time, rheumatic fever is not a problem only for socially and economically disadvantaged populations. This was demonstrated by local outbreaks of rheumatic fever recorded in the 80-90s of the 20th century in some areas of the USA, Japan and a number of other developed countries.

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Causes of Acute Rheumatic Fever

The etiologic relationship between GABHS infections and subsequent development of acute rheumatic fever (ARF) is well established. Although there is no evidence of direct involvement of group A streptococci in tissue damage in patients with acute rheumatic fever, there is considerable epidemiologic immunologic evidence for indirect involvement of GABHS in disease initiation:

• outbreaks of rheumatic fever closely follow every epidemic of sore throat or scarlet fever;
• Adequate treatment of documented streptococcal pharyngitis significantly reduces the incidence of subsequent attacks of rheumatic fever;
• Appropriate antimicrobial prophylaxis prevents relapses of the disease in patients who have had ARF;
• the presence in most patients with ARF of elevated titers of at least one of the antistreptococcal antibodies.

Rheumatic fever and rheumatic heart disease are seen only after upper respiratory tract infections caused by group A streptococci. Although beta-hemolytic streptococci of serogroups B, C, O, and P can cause pharyngitis and trigger the host immune response, they are not associated with the etiology of RL.

Streptococcal pharyngitis/tonsillitis is the only infection associated with ARF. For example, there are many descriptions of outbreaks of cutaneous streptococcal infections (impetigo, erysipelas) that were the cause of poststreptococcal glomerulonephritis, but never the cause of rheumatic fever.

Strains of group A streptococci colonizing the skin differed from those causing rheumatic fever. Bacterial genetic factors may be an important determinant of the site of onset of group A streptococcal infection. The antigen structure encoding the M- and M-like streptococcal surface proteins is recognized and labeled A through E. Pharyngeal strains have the A-C structure, whereas all cutaneous strains have the D and E structure.

Another factor influencing pharyngeal localization may be the CD44 receptor, a hyaluronic acid-associated protein that serves as a pharyngeal receptor for group A streptococci. In an experiment, group A streptococci were shown to colonize the oropharynx of normal mice after intranasal administration but not in transgenic mice that do not express CD44.

Many theories have been proposed to explain why acute rheumatic fever is associated only with streptococcal pharyngitis, but a definitive explanation has not yet been found. Group A streptococci are divided into two major classes, based on differences in the C sequences of the M protein. One class is associated with streptococcal pharyngeal infection, the other (with some exceptions) with the strains most commonly causing impetigo. Thus, the characteristics of the streptococcal strains may be decisive in initiating the disease. Pharyngeal infection, with its involvement of large amounts of lymphoid tissue, may itself be important in initiating an abnormal humoral response to microbial antigens, with cross-reactivity to host tissues. Cutaneous strains may colonize the pharynx, but they are unable to elicit as strong an immunologic response to the M protein as pharyngeal strains.

Rheumatic fever results from an abnormal immune response to pharyngitis caused by group A streptococci. The clinical manifestations of this response and its severity in a particular individual depend on the virulence of the microbe, the genetic susceptibility of the host, and "appropriate" environmental conditions.

One of the well-studied determinants of bacterial virulence is the M-protein. Streptococcal M-protein is located on the surface of the streptococcal cell and has structural homology with myosin of cardiomyocytes, as well as with other molecules: tropomyosin, keratin, laminin. It is assumed that this homology is responsible for histological changes in acute rheumatic carditis. For example, laminin, an extracellular matrix protein secreted by endothelial cells lining the heart valves, is an essential component of the valve structure. It also serves as a target for polyreactive antibodies that "recognize" M-protein, myosin, and laminin.

Of the more than 130 identified M-protein types, M-types 1, 3, 5, 6, 14, 18, 19, and 24 are associated with rheumatic fever. These M-types of group A streptococci are postulated to have rheumatogenic potential. These serotypes are usually poorly encapsulated and form large mucoid colonies rich in M-protein. These characteristics enhance tissue adhesion and resistance to host phagocytosis.

Another virulence factor is streptococcal superantigens. This is a unique group of glycoproteins that can bind class II molecules of the major histocompatibility complex to the V receptors of T lymphocytes, simulating antigen binding. Thus, T cells become susceptible to antigen-nonspecific and autoreactive stimulation. In the pathogenesis of rheumatic fever, some fragments of the M protein and streptococcal erythrogenic exotoxin are considered as superantigens. Streptococcal erythrogenic toxin can also act as a superantigen for B cells, leading to the production of autoreactive antibodies.

Genetic predisposition of the macroorganism is also necessary for the development of rheumatic fever. This is currently the only explanation for the fact that rheumatic fever occurs in only 0.3-3% of individuals with acute A-streptococcal pharyngitis. The concept of genetic predisposition to RF has intrigued researchers for more than 100 years. All this time, it was believed that the disease gene has an autosomal dominant pathway of transmission, an autosomal recessive one with limited penetrance, or transmission is carried out by a gene associated with the secretory status of the blood group. Interest in the genetics of ARF has increased again with the discovery of the histocompatibility complex in humans. Research results suggest that the immune response is genetically controlled, with high reactivity to the streptococcal cell wall antigen expressed through a separate recessive gene and low reactivity expressed through a separate dominant gene. Current data confirm that the genetic control of low response to streptococcal antigen is closely related to class II histocompatibility antigens. However, the relationship between susceptibility to rheumatic fever and class II HLA antigens varies greatly depending on ethnic factors. For example, DR4 is more often present in Caucasian RL patients; DR2 in Negroid patients; DR1 and DRw6 in South African patients; DR3 is more often found in Indian RL patients (who also have a low frequency of DR2); DR7 and DW53 in Brazilian patients; DQW2 in Asian patients. Most likely, these genes are located near the rheumatic fever susceptibility gene, possibly at the same locus, but are not identical to it.

Somewhat later, B-lymphocyte surface alloantigens were identified in patients with rheumatic fever; they were called D8/17 alloantigens after the clone of monoclonal antibodies with which they were isolated. According to world data, the D8/17 B-lymphocyte alloantigen is identified in 80-100% of patients with ARF and only in 6-17% of healthy individuals. The involvement of the B-lymphocyte alloantigen of patients in the pathogenesis of rheumatic fever continues to be studied. It is most likely that the predisposition to ARF is polygenic, and the D8/17 antigen may be associated with one of the genes responsible for the predisposition; the other may be the histocompatibility complex encoding DR antigens. Although there is no exact explanation, an increased number of D8/17 positive B-cells is a sign of a special risk of developing acute rheumatic fever.

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Pathogenesis of rheumatic fever

Streptococcal infection begins with the binding of bacterial surface ligands to specific receptors on host cells and the subsequent initiation of specific processes of adhesion, colonization, and invasion. Binding of bacterial surface ligands to host surface receptors is a key event in host colonization and is initiated by fibronectin and streptococcal fibronectin-binding proteins. Streptococcal lipoteichoic acid and M-protein also play an important role in bacterial adhesion. The host responds to streptococcal infection by opsonization and phagocytosis. Streptococcal infection in a genetically susceptible organism under appropriate environmental conditions leads to activation of T- and B-lymphocytes by streptococcal antigens and superantigens, which in turn promotes the production of cytokines and antibodies directed against streptococcal N-acetyl-beta-D-glucose (carbohydrate) and myosin.

Damage to the valvular endothelium by anticarbohydrate antibodies is thought to result in increased production of adhesion molecules and an influx of activated CD4+ and CD8+ T cells. Disruption of the integrity of the valvular endothelium results in exposure of subendothelial structures (vimentin, laminin, and valvular interstitial cells), which contributes to the development of a “chain reaction” of valvular destruction. After involvement of the valve leaflets in the inflammatory process, newly formed microvessels infiltrate the valvular endothelium with T cells, maintaining the process of valve destruction. The presence of T cell infiltration even in old mineralized lesions is an indicator of disease persistence and progression of valve damage. Under the influence of proinflammatory cytokines, valvular interstitial cells and other valvular components lead to “abnormal restoration” of the valve.

The pathogenetic mechanism described above is the most likely, but to date there is no direct and convincing evidence of the pathogenetic role of cross-reacting antibodies in vivo and there is no suitable animal model for studying rheumatic fever.

In 2000-2002, the European Society of Cardiology published data on the possible trigger role of viruses and heat stress proteins in the formation of relapses of rheumatic fever and rheumatic carditis, but this theory still requires further study.

Thus, the basis of modern concepts of rheumatic fever is the recognition of the etiological role of GABHS and hereditary predisposition to the disease, which is realized by an anomaly of the body's immune response.

Symptoms of Rheumatic Fever

Rheumatic fever occurs in attacks. In 70% of patients, the rheumatic attack subsides, according to clinical and laboratory data, within 8-12 weeks, in 90-95% - 12-16 weeks, and only in 5% of patients the attack continues for more than 6 months, i.e. it takes a protracted or chronic course. In other words, in most cases the rheumatic process has a cyclical course, and the attack ends on average within 16 weeks.

In more than half of cases, patients complain of shortness of breath, irregular heartbeats, palpitations, which occur against the background of general symptoms of rheumatic fever: rapid fatigue, lethargy, sweating, increased body temperature. Adults may experience pain in the heart area of an unspecified nature.

Rheumatic heart disease, rheumatoid arthritis, chorea, erythema annulare, and subcutaneous nodules are major diagnostic features of acute rheumatic fever.

Subcutaneous nodules and erythema annulare

Subcutaneous nodules and erythema annulare are rare manifestations of rheumatic fever, occurring in less than 10% of cases.

Subcutaneous nodules are round, dense, easily displaced, painless formations measuring from 0.5 to 2 cm, most often localized on the extensor surfaces of the elbow, knee and other joints, in the occipital region and along the tendon sheaths, extremely rarely occur during the first attack of rheumatic fever. The number of nodules varies from one to several dozen, but usually there are 3-4 of them. It is believed that they are easier to palpate than to see. They persist from several days to 1-2 weeks, less often - more than a month. Subcutaneous nodules are almost always associated with cardiac involvement and are found more often in patients with severe carditis.

Erythema annulare is a transient, annular macule with a pale center, usually occurring on the trunk, neck, and proximal extremities. Erythema annulare is never localized to the face. Because of the fleeting nature of the changes and the absence of associated symptoms, erythema annulare may be missed unless specifically sought, especially in dark-skinned patients. Individual lesions may appear and disappear within minutes or hours, sometimes changing shape before the examiner's eyes, merging with adjacent lesions to form complex structures (hence, they are described in some sources as "cigarette smoke rings"). Erythema annulare usually appears at the onset of rheumatic fever, but it may persist or recur for months or even years, persisting after other manifestations of the disease have subsided; it is not affected by anti-inflammatory treatment. This cutaneous phenomenon is associated with carditis, but, unlike subcutaneous nodules, it is not necessarily severe. Nodules and annular erythema are often combined.

Erythema annulare is not unique to rheumatic fever and has also been described in sepsis, drug allergies, glomerulonephritis, and in children with no known illness. It must be distinguished from erythema toxicum in febrile patients and the rash of juvenile idiopathic arthritis. The erythema annulare of Lyme disease (erythema chronicum migrans) may also resemble the erythema annulare of rheumatic fever.

Clinical minor criteria for rheumatic fever

Arthralgia and fever are designated as "minor" clinical manifestations of rheumatic fever in the diagnostic criteria of T. Jones not because they are less common than the five major criteria, but because they have lower diagnostic specificity. Fever is observed at the beginning of almost all rheumatic attacks and is usually 38.4-40 C. As a rule, there are fluctuations during the day, but there is no characteristic temperature curve. Children who have only mild carditis without arthritis may have a subfebrile temperature, and patients with "pure" chorea are afebrile. Fever rarely persists for more than a few weeks. Arthralgia without objective changes is often found in rheumatic fever. Pain usually occurs in large joints and can be insignificant or very strong (up to the impossibility of movement), it can persist from several days to weeks, changing in intensity.

Although abdominal pain and nosebleeds are noted in approximately 5% of patients with LC, they are not considered part of the T. Jones criteria due to the lack of specificity of these symptoms. However, they may be clinically significant, since they appear several hours or days before the development of major manifestations of LC, abdominal pain is usually localized in the epigastrium or periumbilical region, may be accompanied by symptoms of muscular guarding and often simulates various acute diseases of the abdominal organs.

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Clinical observation

Patient S., 43 years old, was consulted at the Moscow City Rheumatology Center on January 20, 2008, where she was referred from the city clinic to clarify the diagnosis.

During examination, she complained of general weakness, sweating, rapid fatigue, and shortness of breath during physical exertion. In December 2007, she suffered from acute pharyngitis, for which she did not receive antibacterial treatment. After 3-4 weeks, shortness of breath and palpitations during light physical exertion, pain in the precordial region of various nature, an increase in body temperature to 37.2 C, and an increase in ESR to 30 mm/h appeared.

It is also known from the anamnesis that since childhood he has been under the supervision of a cardiologist for primary mitral valve prolapse; a mid-diastolic click and late-systolic murmur over the apex were constantly heard during auscultation of the heart. Over the past month, the cardiologist noted an increase in systolic murmur with the acquisition of a pan-systolic sound, which became the basis for suspecting ARF and referring him for consultation to the rheumatology center.

Objectively: the skin is of normal color, nutrition is normal. There is no peripheral edema. The tonsils are hypertrophied, loosened. Vesicular breathing in the lungs, no wheezing. The boundaries of relative cardiac dullness are not expanded. Weakening of the first heart sound above the apex, pansystolic murmur radiating to the left axillary region and interscapular region of the 5th grade, as well as systolic murmur above the tricuspid valve and the pulmonary artery valve of the 3rd grade are heard. Extrasystole. HR is 92 beats per minute, BP is 130/70 mm Hg. The abdomen is soft and painless on palpation. Percussion reveals that the liver and spleen are not enlarged.

Clinical blood test from 01/16/08: Hb ~ 118 g/l, leukocytes - 9.4x10 ⁹ /l, ESR - 30 mm/h

General urine analysis from 16.01.08 without pathological changes. In the immunological blood analysis from 16.01.08: C-reactive protein - 24 mg/l, antistreptolysin-O - 600 U.

The ECG shows a normal position of the electrical axis of the heart, sinus rhythm, heart rate - 70 per minute, isolated atrial extrasystoles, PQ - 0.14 s, QRS - 0.09 s.

Doppler echocardiography of 20.01.08 showed both mitral valve leaflets prolapsing into the left atrium, marginal thickening of the anterior leaflet, their movements in antiphase. Fibrous ring - 30 mm, orifice size 39x27 mm, peak gradient - 5.8 mmHg, grade 3 mitral regurgitation. Left atrium 44 mm, left ventricular dilation: end-diastolic dimension (EDD) - 59 mm, end-systolic dimension (ESD) - 38 mm, end-diastolic volume (EDV) - 173 ml, end-systolic volume (ESV) - 62 ml, stroke volume - 11 ml, ejection fraction (EF) - 64%. Aorta 28 mm, unchanged. The aortic valve is tricuspid, with slight marginal thickening of the cusps, the fibrous ring is 24 mm, and the peak pressure gradient is 4 mm Hg. The right atrium is 48 mm, the right ventricle is slightly dilated (equal to the left in volume), the calculated pressure is 22 mm Hg. The pulmonary artery is moderately dilated, the pulmonary valve is unchanged, the fibrous ring is 29 mm, the systolic pressure gradient on the pulmonary artery valve is 3 mm Hg, there is no regurgitation. The tricuspid valve is prolapsed, the fibrous ring is 30 mm, and the 1st degree of regurgitation. Conclusion: prolapse of both mitral valve cusps, marginal thickening of the mitral and aortic valve cusps, grade 3 mitral regurgitation, grade 1 tricuspid regurgitation, and dilation of the heart cavities.

Taking into account the connection between the deterioration of the patient's condition and previous acute pharyngitis and evidence of previous A-streptococcal infection (detection of an elevated antistreptolysin-O titer), an increase in the existing systolic murmur above the apex of the heart, as well as cardiomegaly detected by echocardiography, an increase in the level of C-reactive protein and an increase in ESR, the following diagnosis was made: "Acute rheumatic fever: moderate carditis (mitral and aortic valvulitis). Mitral regurgitation grade 3. Tricuspid regurgitation grade 1. Supraventricular extrasystole. HF stage 1, FC II."

The patient was hospitalized in City Clinical Hospital #52, where she was treated for streptococcal infection with amoxicillin at a dose of 1500 mg/day for 10 days, diclofenac at a dose of 100 mg/day for 14 days, and strict bed rest was observed for 2 weeks with subsequent expansion of the exercise regimen. The patient's condition improved, the heart size decreased. At the time of discharge from the hospital for outpatient follow-up care, the patient had no complaints. Blood tests showed ESR of 7 mm/h, C-reactive protein of 5 mg/l, and antistreptolysin-O of less than 250 U. Secondary prophylaxis of rheumatic fever was initiated with benzathine benzylpenicillin at a dose of 2.4 million U intramuscularly once every 4 weeks, which was recommended to be carried out for the next 10 years.

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Classification of rheumatic fever

Currently, the Russian Federation has adopted a national classification of rheumatic fever.

Classification of rheumatic fever (APR, 2003)

Clinical variants	Clinical symptoms		Exodus	Stages of circulatory failure (CF)
	Main	Additional		SWR*	NYHA**
Acute rheumatic fever Recurrent rheumatic fever	Carditis Arthritis Chorea Erythema annulare	Fever Arthralgia Abdominal syndrome Serositis	Recovery Rheumatic heart disease without heart defect*** heart defect****	0	0
				I	I
				IIA	II
				IIB	III
				III	IV

• * According to the classification of N.D. Strazhesko and V.Kh. Vasilenko.
• ** Functional class of heart failure according to the New York classification.
• *** It is possible to have post-inflammatory marginal fibrosis of the valve leaflets without regurgitation, which is clarified using echocardiography.
• **** In the presence of a “first detected heart defect”, it is necessary, if possible, to exclude other causes of its formation (infective endocarditis, primary antiphospholipid syndrome, calcification of valves of degenerative genesis, etc.).

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Diagnosis of rheumatic fever

In the anamnesis of patients with suspected rheumatic carditis, it is necessary to describe in detail the family and sexual anamnesis for the presence of rheumatic fever in close relatives and documented confirmation of this diagnosis, as well as to establish the presence or absence of documented tonsillopharyngitis, scarlet fever, otitis, rhinitis, lymphadenitis of the anterior cervical lymph nodes over the past 2-3 weeks. The presence of risk factors should also be taken into account:

• hereditary predisposition (detection of the specific B-lymphocyte antigen D8/17, as well as a high prevalence of class II antigens of the HLA system);
• "vulnerable" age;
• overcrowding;
• unsatisfactory housing and sanitary and hygienic living conditions (small living space, large families);
• low level of medical care,

Currently, in accordance with WHO recommendations, the diagnostic criteria for rheumatic fever by T. Jones, revised in 2004, are used as international criteria.

Diagnostic criteria for rheumatic fever

Big criteria		Minor criteria				Evidence of prior streptococcal A infection
Carditis Migratory polyarthritis Sydenham's chorea (minor chorea) Annular erythema Subcutaneous rheumatic nodules		Clinical: arthralgia, fever Laboratory: increased levels of acute phase reactants - ESR, C-reactive protein Prolongation of the PQ interval on the ECG				Positive streptococcal A-type throat culture or positive rapid streptococcal A-type antigen test Elevated or rising streptococcal antibody titers

Confirmation of a primary attack of the disease requires the major and minor criteria of rheumatic fever, laboratory abnormalities, and evidence of a previous streptococcal infection according to the 2004 WHO recommendations. In the context of a previous streptococcal infection, two major criteria or a combination of one major and two minor criteria are sufficient to diagnose ARF. The diagnosis of recurrent rheumatic fever in a patient with established RHD can be made on the basis of the minor criteria in combination with evidence of a recent streptococcal infection.

Diagnostic criteria for rheumatic fever and rheumatic heart disease (WHO, 2004, based on the revised criteria of T. Jones)

Diagnostic categories	Criteria
0RL (a) Recurrent attacks of rheumatic fever in patients without established RHD (i) Recurrent attacks of rheumatic fever in patients with established RHD Rheumatic chorea; latent rheumatic carditis (i)	Two major or one major and two minor criteria + evidence of previous group A streptococcal infection Two major or one major and two minor criteria + evidence of previous group A streptococcal infection Two minor criteria + evidence of previous group A streptococcal infection (c) No other major criteria or evidence of group A streptococcal infection required

(a) - Patients may have polyarthritis (or only polyarthralgia or monoarthritis) and several (3 or more) other minor manifestations, as well as evidence of recent GABHS infection. Some of these cases may subsequently progress to LC. They may be considered as cases of "possible LC" (if other diagnoses are excluded). In these cases, regular secondary prophylaxis is recommended. Such patients should be observed and have regular cardiac examinations. This cautious approach is especially important in patients of "vulnerable" age.

(b) - Infective endocarditis must be excluded.

(c) - Some patients with recurrent attacks may not fully meet these criteria.

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Laboratory diagnostics of rheumatic fever

In the presence of rheumatic fever in the active phase, a blood test reveals an increase in non-specific “acute phase indicators”, which include:

• neutrophilic leukocytosis (no more than 12,000-15,000);
• dysproteinemia with increased levels of a-2 and gamma globulins;
• increased ESR (already in the first days of the disease);
• increased levels of C-reactive protein (from the first days of the disease).

Bacteriological examination of a throat swab allows detection of GABHS, but does not differentiate between active infection and streptococcal carriage.

Evidence of a recently suffered streptococcal infection is an increase in the titers of streptococcal antibodies determined in paired sera, which is observed during the first month from the onset of the disease, usually persists for 3 months, and normalizes after 4-6 months.

Normal, borderline and high streptococcal antibody levels

Antibodies	Titers, U/ml
	Normal	Border	Tall
ASL-0	<250	313-500	>625
ASG	<250	330-500	>625
ASK	<200	300-500	>600
ADNK-8	<600	800-1200	>1200

Instrumental diagnostics of rheumatic fever

An ECG examination may reveal rhythm and conduction disturbances: transient atrioventricular block (prolongation of PQ) of the 1st, less often 2nd degree, extrasystole, changes in the T wave in the form of a decrease in its amplitude up to the appearance of negative waves. The above ECG changes are characterized by instability and quickly disappear during treatment.

Phonocardiographic examination helps to clarify cardiac auscultation data and can be used to objectify changes in tones and noises during dynamic observation.

Chest X-ray is performed to determine cardiomegaly and signs of congestion in the pulmonary circulation.

EchoCG criteria for mitral valve endocarditis are:

• club-shaped marginal thickening of the mitral valve;
• hypokinesia of the posterior mitral valve;
• mitral regurgitation;
• transient doming of the anterior mitral leaflet during diastolic flexure.

Rheumatic endocarditis of the aortic valve is characterized by:

• marginal thickening of the valve leaflets;
• transient valve prolapse;
• aortic regurgitation.

It should be remembered that isolated aortic valve damage without mitral regurgitation noise is not characteristic of acute rheumatic carditis, but does not exclude its presence.

Example of diagnosis formulation

• Acute rheumatic fever: moderate carditis (mitral valvulitis), grade I MR, migratory polyarthritis. NC 0, 0 FC.
• Acute rheumatic fever: mild carditis, chorea. NC 0, 0 FC.
• Recurrent rheumatic fever: carditis, severe RHD: combined mitral heart disease: mild mitral valve insufficiency, mild left atrioventricular stenosis. NC IIA, FC II.

Treatment of rheumatic fever

The main goal of rheumatic fever treatment is the eradication of beta-hemolytic streptococcus from the nasopharynx, as well as suppression of the activity of the rheumatic process and prevention of severe disabling complications of rheumatic fever (RHD with heart disease).

All patients with suspected acute rheumatic fever should be hospitalized for diagnosis and treatment.

Drug treatment of rheumatic fever

From the moment rheumatic fever is established, treatment with penicillins is prescribed to ensure the removal of BGS from the nasopharynx. Of the penicillins, benzathine benzylpenicillin or phenoxymethylpenicillin are most often used. The recommended daily doses of benzathine benzylpenicillin are: for children - 400,000-600,000 IU, for adults - 1.2-2.4 million IU intramuscularly once. Phenoxymethylpenicillin is recommended for adults at 500 mg orally 3 times a day for 10 days.

Treatment algorithm for streptococcal pharyngitis:

• Phenoxymethylpenicillin (Ospen 750) 1.5 g/day, 10 days: 500 mg (tablets) 3 times a day orally or 750,000 IU/5 ml (syrup) 2 times a day.
• Amoxicillin 1.5 g/day, 10 days: - 500 thousand (tablets) 2-3 times a day orally, regardless of food intake.
• Benzathine benzylpenicillin 1.2-2.4 million units intramuscularly once. It is advisable to prescribe for:
  • questionable patient compliance with regard to oral antibiotic intake;
  • the presence of rheumatic fever in the patient's medical history or in close relatives;
  • unfavorable social and living conditions;
  • outbreaks of A-streptococcal infection in preschool institutions, schools, boarding schools, colleges, military units, etc.
• Cephalexin - 10 days: - 500 mg 2 times a day orally.
• In case of intolerance to ß-lactam antibiotics - macrolides - 10 days (including azithromycin - 5 days).
• In case of intolerance to ß-lactam antibiotics and macrolides - clindamycin 300 mg 2 times a day orally, with plenty of water, for 10 days.

Penicillins should always be considered as the drugs of choice in the treatment of ARF, except in cases of individual intolerance, when macrolides or lincosamides are prescribed. Of the macrolides, erythromycin is most often used at 250 mg orally 4 times a day.

Patients with intolerance to both ß-lactams and macrolides are prescribed lincosanides, in particular lipcomycin 0.5 g orally 3 times a day (10 days).

When studying the long-term prognosis of rheumatic fever and analyzing the frequency of heart defects during the year after the attack, according to the Cochrane review, no reliable effect of anti-inflammatory treatment was found. However, the conclusion made about the ineffectiveness of this effect is not sufficiently substantiated, since in the meta-analysis of eight studies cited by the authors, most of them were from the 50-60s. XX o. These works lacked the most important principles of high-quality clinical practice, such as the principle of randomization. In this regard, the authors of the meta-analysis consider it necessary to conduct multicenter randomized placebo-controlled studies to study the effectiveness of anti-inflammatory effects in rheumatic carditis.

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Prevention of rheumatic fever

The goal of prevention is to prevent relapse of rheumatic fever. Relapses are most common within 5 years after the first attack. Although the number of relapses decreases with increasing age of the patient, they can develop at any time.

Primary prevention of rheumatic fever includes a number of strategic aspects:

• diagnosis of streptococcal infection;
• treatment of streptococcal infection;
• streptococcal immunization;
• socio-economic activities;
• development of methods for predicting the disease.

Secondary prevention is a set of measures aimed at preventing acute respiratory streptococcal infection in patients who have suffered a rheumatic attack.

Prevention of relapse of rheumatic fever should be prescribed immediately in hospital after completion of 10-day treatment with penicillins (macrolides, lincosamides). The classic parenteral regimen is benzathine benzylpenicillin 1.2-2.4 million units intramuscularly once every 3-4 weeks. In case of allergy to penicillins, erythromycin 250 mg can be used twice a day.

Secondary prevention of rheumatic fever

Preparation		Dosage
Benzagina benzylpenicillium		1.2-2.4 million IU every 3-4 weeks intramuscularly
For allergies to penicillins - erythromycin		250 mg 2 times a day

Patients who have undergone heart surgery for rheumatic heart disease undergo secondary prevention for life.

Duration of secondary prevention of rheumatic fever

Category of patients	Duration
RL with carditis and valve disease	At least 10 years after the last episode and at least until age 40. Sometimes lifelong prophylaxis
RL with carditis but without valvular lesions	10 years or up to 21 years
RL without carditis	5 years or up to 21 years

Prevention of infective endocarditis is indicated for all patients who have had rheumatic fever with the formation of a heart defect, in the following situations:

• dental procedures that cause bleeding;
• operations on ENT organs (tonsillectomy, adenoidectomy);
• procedures on the respiratory tract (bronchoscopy, mucosal biopsy);
• surgical interventions in the abdominal cavity, genitourinary tract, gynecological sphere.

Prognosis of rheumatic fever

Relapses of rheumatic fever are more common in childhood, adolescence and young adulthood and occur primarily in individuals who have had moderate to severe carditis, especially in cases of the development of rheumatic heart disease.

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Rheumatic fever - history of the issue

Rheumatic fever is one of the most ancient human diseases: it is mentioned in the early literature of China, India, and Egypt. The Book of Diseases by Hippocrates (460-377 BC) first described typical rheumatic arthritis: intermittent inflammation of many joints, with swelling and redness, severe pain, not life-threatening for patients and observed mainly in young people. The first use of the term "rheumatism" to describe arthritis is attributed to the 2nd-century Roman physician Galen. The term "rheumatism" comes from the Greek word "rheumatismos" and means "spreading" (throughout the body). Being an active representative of the humoral concept of the origin of various diseases, including arthritis, Galen considered these diseases to be a kind of catarrh. Galen's great authority and the slow progress of knowledge in this area contributed to the fact that Galen's understanding of the essence of the clinical picture of the disease lasted until the 17th century, when the work of Baillou (Bayou), who called himself Ballonius, appeared. The study "Liber cle Rheumatismo et pleuritiddorsal" was published posthumously by his nephew only in 1642. It contained a description of the disease. "Rheumatism is found throughout the body and is accompanied by pain, tension, heat, sweat... with arthritis, the pains are repeated at certain intervals and at certain periods."

The outstanding physician of the 17th century Sydenham, somewhat later than Baililou, clearly described rheumatic arthritis: “Most often the disease occurs in the fall and affects young and middle-aged people - in the prime of life... patients experience severe pain in the joints; this pain moves from place to place, in turn in all the joints, and finally affects one joint with redness and swelling”, Sydenham is credited with the first description and recognition of chorea as a rheumatic disease.

The first reports of heart damage in rheumatic joint diseases appeared at the end of the 18th century, but these facts were considered as a common combination of two different diseases, and not as a single disease.

The English physician Pitcairn (1788) was one of the first to recognize the connection between rheumatic fever and heart disease. Pitcairn was the first to note frequent heart disease in rheumatism. He assumed a common cause of heart and joint disease and introduced the term "rheumatism of the heart."

NI. Sokolsky and J. Bouillaud simultaneously but independently of each other established a direct organic connection between rheumatic polyarthritis and rheumatic carditis. Most scientists of that time attached primary importance to the development of endocarditis and pericarditis in rheumatism, Professor of Moscow University G.I. Sokolsky in his work “On Rheumatism of the Muscular Tissue of the Heart” (1836) identified clinical and anatomical forms of rheumatic heart disease - myocarditis, endocarditis and pericarditis, devoting special attention to rheumatic myocarditis. ßouillaud in his “Clinical Guide to Heart Disease” (Paris, 1835) and “Clinical Guide to Articular Rheumatism and the Law of Coincidence of Heart Inflammation with This Disease” (Paris, 1840) noted the high prevalence of rheumatic heart disease in the form of valvulitis and pericarditis and formulated his famous law of coincidence of rheumatic polyarthritis and heart disease.

The works of Bouillaud and G.I. Sokolsky in the history of the development of the theory of rheumatic fever had the significance of a scientific feat and became a turning point in the understanding of this disease. From a historical and scientific point of view, the definition of rheumatic fever as Sokolsky-Buillot disease is entirely justified.

In 1894, Romberg found significant infiltrates at the valve attachment site in 2 deceased patients, and numerous small connective tissue calluses in the myocardium, confirming rheumatic myocardial damage. This was later proven in the classic works of Aschoff, who described rheumatic granulomas in the myocardium in 1904. V. T. Talalaev (1929) deserves exceptional credit for studying the stages of development of the rheumatic process. “The significance of the morphological criteria of rheumatic carditis developed by Aschoff and V. T. Talalaev,” wrote A. I. Nesterov, “is so great that rheumatic granulomas are rightfully called Aschoff-Talalaev granulomas.”

Many outstanding clinicians of the 20th century devoted themselves to studying the problems of rheumatic fever and rheumatic heart disease (RHD) (Botkin S.P., Davydovsky I.V., Nesterov A.I., Strukov A.I., etc.). The studies of M.A. Skvortsov are of great importance for the clinical and anatomical characteristics of rheumatic carditis in children. In 1944, T. Jones presented the first classification of RL, which is used in an improved form to this day. However, when studying the domestic literature, it was possible to establish that 5 years before the appearance of T. Jones's work, the outstanding Soviet pediatrician A.A. Kisel described T. Jones's 5 main criteria, calling them "absolute signs of rheumatism." He claimed that "for rheumatism, absolute signs are rheumatic nodules, circular erythema, chorea, and a special form of arthritis that quickly passes from one joint to another. The presence of only one of these signs finally resolves the question of the presence of rheumatism in a child. Perhaps, the absolute signs should also include a completely unique heart lesion in rheumatism, since we do not observe a similar clinical picture in children with heart lesion from other causes. Heart lesion of rheumatic origin is characterized by constant progression of the heart defect, and often the patient does not complain of anything. This feature almost never occurs with heart lesion of other origins."

The discovery of the major histocompatibility system by the French scientist J. Dass in 1958 and the clinical development of the topic "Association of HLA with various diseases" that began in 1967 became prerequisites for studying the connection of HLA with rheumatic fever. In 1976, Academician A.I. Nesterov wrote that "modern concepts of rheumatism lack something very important, intimate, embedded, probably, in the individual features of the molecular structure of lymphocytes or the features of the individual gene pool." This statement by the largest Russian scientist, a rheumatologist with a world name, turned out to be prophetic. Since 1978, a new direction in the study of the mechanisms of predisposition to rheumatic fever has been emerging abroad and in our country.

Thanks to the work of the outstanding scientist and our teacher, Academician A.I. Nesterov, additions to the diagnostic criteria for rheumatic fever were developed, increasing their differential diagnostic significance. A thorough study of the etiology, clinical picture and diagnostics of rheumatic fever allowed A.I. Nesterov to put forward the problem of an active pathological process and develop a classification of the degrees of activity of the rheumatic process, approved at a symposium of socialist countries in 1964 and serving as the basis for creating similar classifications for other rheumatic diseases. He wrote: "Each new classification is not a fully completed system of knowledge and experience, but only a key stage in scientific progress, which, as knowledge accumulates, will be replaced by a new stage that will reveal and explain new facts and new scientific and practical horizons." Taking into account the etiological role of streptococcus in the development of rheumatic fever, an original method of bicillin-aspirin prevention of relapses of the disease was developed at the Institute of Rheumatism of the USSR Academy of Medical Sciences (State Institution “Institute of Rheumatology of the Russian Academy of Medical Sciences”), founded by Academician A.I. Nesterov.

The ideas about the nature of rheumatic fever and its clinical and anatomical forms that have developed in different countries have given rise to various designations of the disease in the historical aspect: "rheumatic fever" (rheumatic fever) by Anglo-Saxon authors, "acute articular rheumatism" (rhumatisme areiculaire aigu) or, less commonly, Bouillaud's disease (maladie de Bouillaud) by French authors, rheumatic polyarthritis or acute rheumatic fever by German authors. At present, it is generally accepted to call the disease rheumatic fever.

Today, acute rheumatic fever is one of the few rheumatic diseases whose etiology has been proven. Undoubtedly, this disease is caused by group A beta-hemolytic streptococcus (GABHS). According to the figurative expression of academician A.I. Nesterov, "without streptococcus there is neither rheumatism nor its relapses."