Rheumatic Fever

N C Joshi
Consultant Pediatrician, Nanavati Hospital, Mumbai, India
First Created: 01/24/2001 

Introduction

Rheumatic Fever is an abnormal, delayed, often-recurrent probably autoimmune reaction to Group A b hemolytic streptococcal pharyngitis involving joints, skin, brain, serous surfaces, and heart valves. If it would not have involved valves, the disease would have been of little practical consequence. Whatever be the theory of its pathogenesis, few facts have not been explained by any of the theories:

  • It is predominantly but not exclusively, a disease of socially and economically disadvantaged population.

  • It is a sequela of post-streptococcal (beta-hemolytic) pharyngitis and occurs only in 3% of infected individuals.

  • It does not follow non-pharyngeal streptococcal infection.

  • It is virtually unknown in infants before 2nd birthday and rare are small children.

  • There has been a familial tendency.

The relative decrease in the incidence of acute rheumatic fever and its cardiac sequelae in the western world have led many of the young physicians in the west to consider the disease "as a thing of the past". But it is somewhat erroneous since even in the United States and Western Europe, rheumatic fever maintains its position as one of the leading causes of acquired heart disease in children. Amongst the world population from developing countries, rheumatic fever can be looked upon as a devastating public health problem. The recent decline of morbidity and mortality from the disease in the west commenced before the event of antibiotics, possibly because of improvement in socioeconomic conditions or other unknown factors. In the developing world where socioeconomic are far from being ideal, one is obliged to take a critical look at the rheumatic fever. It is equally important to maintain an equal curious eye on the disease in the west since the return of the disease may again occur in the west if resistance to penicillin appears amongst streptococci or if other unknown factors prevail.

It is with this thought in mind that despite the present discrepancies in incidence, prevalence, morbidity, and mortality of the disease in different parts of the world, physicians everywhere must remember the memorable quotations of Dr. T. B. Jones, "The exact incidence of the disease or the decrease in the incidence or in severity, seems of less importance than the need to gain further knowledge of how and why human beings develop rheumatic fever. So long as surgeons find mitral valve stenosis requiring valvotomy or children continue to die of rheumatic fever and rheumatic heart disease, the problem exists. Rheumatic fever is and will remain with us until new knowledge and better preventive or therapeutic agents become available".

This brief review deals with the pathogenesis of the disease and a few new thoughts are introduced.

Pathogenesis of Rheumatic Fever

For rheumatic fever to develop there are at least four absolute requirements:

  • Group A beta hemolytic streptococci

  • Susceptible host

  • Persistent of organism

  • Upper respiratory tract as the site of infection

Group A beta hemolytic streptococci

They are a complex group of organisms with respect to their extracellular products and their intracellular structure. The streptococcal cell wall consists of three layers: the outer layer formed by protein antigens, the middle layer containing group-specific carbohydrates, and an inner mucopeptide layer. The organism has a nonantigenic hyaluronate capsule, which does not play a significant role in its virulence. The protein layer contains three proteins - M, J, and R proteins. The M protein antigen stimulates the production of type-specific antibodies and is an immunologically distinct protein. It is the formation of these antibodies that constitutes the basis for the development of anti-streptococcal vaccines.

On the basis of polysaccharides in the middle layer of streptococcal walls, b hemolytic streptococci are divided into serologically distinct groups A, B, C, D, etc. Certain members of Group A are definitely involved in the pathogenesis of acute rheumatic fever which is called rheumatogenic strains.

The inner layer of the cell wall, which contains peptidoglycan, has been shown to produce subcutaneous nodules in rabbits, resembling these of acute rheumatic fever in human beings. The group A streptococci secrete 20 extracellular toxins and enzymes such as Streptolysin O and S, erythrogenic toxins, etc. Streptolysin O is lethal when injected intravenously to experimental animals and causes myocardial damage and electrocardiographic changes. It is a potent antigen and causes antibody response in 80% of individuals following an untreated upper respiratory tract infection with Group A b hemolytic streptococci. The response occurs in a week, reaches its peak in 3 - 5 weeks, and subsides in 4 - 6 months. For both initial and recurrent attacks, the risk of developing rheumatic fever after an untreated streptococcal upper respiratory tract infection increases with an increase in ASO response.

Susceptible host

A susceptible host who develops rheumatic fever following an untreated upper respiratory tract streptococcal infection can be rendered susceptible by his genetic inheritance possibly influenced by his immune mechanism. Our knowledge regarding the genetic factors in rheumatic fever is rather incomplete. Although a consistent genetic pattern has not been discovered, there are some suggestions as to an occasional transmission of susceptibility by a recessive autosomal gene. Based on the present evidence it is believed that an inherited susceptibility with limited penetrance makes an individual susceptible to rheumatic fever.

In recent years, more attention has been paid to rheumatic fever as being an autoimmune disease. By the use of immunofluorescent techniques, Group A streptococci and human myocardial fibers have been shown to have common cross-reactive antigens. The cross-reactive antigens are similar in some chemical features to the streptococcal M proteins.

The effect of socioeconomic factors on the prevalence of rheumatic fever has been known and it is well accepted that acute rheumatic fever is a disease of the indigent. Unfavorable socioeconomic conditions and crowding within homes lead to increased transmission of streptococcal infections, thus exposing the susceptible individuals to the organism. Lack of medical facilities or improper treatment of such infections is a factor that would contribute to the development of rheumatic fever.

Persistence of organism

The persistence of living streptococci has been considered to be an important factor in the pathogenesis of rheumatic fever. It has been shown that rheumatic fever can be prevented by the administration of penicillin as late as nine days after streptococcal pharyngitis. It seems imperative that for a rheumatic fever to develop the streptococci must persist for a certain period of time.

Site of Infection

An important, constant, and neglected facet in the pathogenesis of rheumatic fever is the necessity that the initiating streptococcal infection should take place in the upper respiratory tract. It has been shown that the cholesterol and lipid extract of skin inhibit both hemolytic activity and the autogenic of streptolysin O. This could explain why impetigo does not lead to rheumatic fever.

The role of viruses in rheumatic fever is not at all clear. It is possible that viruses may be activated by streptococcus or vice versa.

Presentation

After a latent period of 1-5 weeks, the clinical manifestations of rheumatic fever becomes manifest. Certain manifestations have been designated as major manifestations & include carditis, arthritis, chorea, subcutaneous nodules & erythema marginatum. Other nonpathognomic signs & symptoms are called minor manifestations. The laboratory signs are included in this category.

Major Manifestations

Carditis

It has always been the first & most important element to be considered in establishing the diagnosis of rheumatic fever since it may result in the only significant sequelae of the disease. Carditis is the rheumatic inflammatory process, which involves the endocardium, myocardium &pericardium. The incidence of carditis in rheumatic fever in developing parts of the world has been reported to be much higher varying from 64% to 80% compared to West (40-51%).

The confirmation of carditis during the initial attack of rheumatic fever solely depends upon auscultatory recognition of mitral and/or aortic valvar incompetence.

The pan systolic murmur of high frequency [because of high systolic pressure gradient between the Left ventricle (LV) & Left atrium (LA) more than 100 mm Hg] begins with the first heart sound & as the pressure gradient persists after aortic closure, murmur is detected beyond 2nd heart sound. The murmur is heard at the apex &extends towards the axilla because it is the LV which transmits vibratory activity generated by the turbulent regurgitant flow to the chest wall. The murmur occasionally can propagate to the sternal border due to the predominant involvement of the posterior leaflet. This classical description may not be present if the murmur is soft & then is better detected in the left lateral position during full expiration.

In addition, an often apical mid-diastolic murmur is heard, due to the additional volume of blood in the left atrium contributed by regurgitant flow across the mitral valve. This murmur originally was described by Dr. Carry Coombs of Bristol in 1924. This murmur is only heard in the presence of mitral regurgitation & is low pitched as turbulence is caused by the increased flow without a pressure gradient. The mid-diastolic murmur as an isolated murmur would never be present as an isolated finding with the initial attack of rheumatic carditis but maybe the earliest manifestation of mitral stenosis.

Rarely a basal diastolic murmur of aortic regurgitation can be encountered in the first attack of acute rheumatic fever.

Myocarditis: Myocarditis in the absence of valvulitis is never rheumatic in origin. Myocardial involvement in acute rheumatic carditis unequivocally does exist but it is not significant from a clinical standpoint of view except for its probable role in mitral annulus dilation and it may lead to congestive heart failure. There is no way to prove the presence of myocarditis except cardiomegaly on an X-ray chest. Even myocardial biopsy has not shown to confirm the presence of myocardial involvement.

Pericarditis

As with myocarditis in acute rheumatic fever, pericarditis is never encountered in the absence of valvar involvement. The precordial pain of pericarditis automatically directs attention to the heart but from a practical standpoint, it is not hemodynamically significant and never causes cardiac tamponade.

The onset of carditis in the majority of children older than 6 years of age is rather abrupt and 76% of the cases occur during the first week. In children younger than 6 years the onset of carditis is often insidious and it may take several weeks until an unequivocal diagnosis can be made. During this period children are chronically ill with low-grade fever and pain in joints. The incidence and severity of carditis in this group are often greater.

Polyarthritis

Polyarthritis has always been the "Achilles heel" of Jone's criteria. The list of disorders that can mimic rheumatic polyarthritis includes juvenile rheumatoid arthritis, post-viral arthritis, and systemic lupus. At the onset of polyarthritis, a given diagnosis is difficult to establish.

Rheumatic arthritis can be present with a wide range of severity and duration. The pain can be so severe that the patient may refuse to walk and will scream with pain when hardly touched, even by bed clothing. On the other hand, pain may be so mild that it is often not recalled a week later. The pain can last less than 24 hours or recur off and on for weeks.

Rheumatic arthritis is a migrating polyarthritis and the involvement of a single joint is extremely unusual. It usually involves larger joints- knees, ankles, elbow, and wrist joints. Characteristically the pain far exceeds the objective findings which may well be the reason Dr. Jones originally chose polyarthralgia rather than polyarthritis as a major manifestation. The 1955 modification which Dr. Jones personally endorsed has required only minimal objective findings to establish the presence of arthritis. Limitations of voluntary motion and tenderness to touch are acceptable and both are usually present. Though Feinstein described rheumatic joints as typically red, hot, or swollen, this is not usually seen. Redness is uncommon and when present with rheumatic arthritis- usually only a small area of mild erythema is encountered. Any joint that is markedly inflamed and swollen should be considered septic. If this is associated with pericarditis the first consideration should be that it is infectious mandating immediate confirmation and intervention. If a patient fails to respond to aspirin on a dosage of 100 mg/kg within 48 hours, one can exclude rheumatic arthritis.

There is a lower incidence of carditis in patients with classical sever migratory polyarthritis as compared to those who have milder joint manifestation.

Arthralgia is an extremely common complaint in all patients with rheumatic fever especially during recurrence and is probably neglected because of its nonspecific nature. Nevertheless, it does at times precede severe carditis and deserves better recognition.

Chorea (Sydenham chorea)

This is a late manifestation of acute rheumatic fever whose incidence has apparently shown a decline. Earlier reports showed an incidence of 52% as against 15-20% in the more recent surveys. This is of interest since, in areas where rheumatic fever is still a common affliction, the incidence of chorea is equal to the west where the disease has shown a decline.

The latent period of chorea varies from 1 to 6 months. It is more common in females and is characterized by non-repetitive, purposeless involuntary movement often associated with muscle weakness signs of incoordination, Nervous milking grip, positive pronator sign, hanging knee jerk, alternating contraction & relaxation of pupils, and emotional instability. It may be associated with carditis but laboratory signs of rheumatic activity have usually subsided.

Erythema marginatum and subcutaneous nodules

Although erythema marginatum has been traditionally regarded as a major manifestation of acute rheumatic fever - its validity is indeed questionable because of the following facts

It is an uncommon finding. It cannot be correlated with other signs of rheumatic activity. It is nonspecific and can occur with drug reactions, glomerulonephritis, and sometimes without apparent reason. It is however often associated with carditis and in such instance, it serves to confirm the diagnosis of rheumatic fever. If seen as an isolated finding it can by no means serve as evidence of acute rheumatic fever. It is an irregular circinate evanescent red rash with a normal central stain without an itch.

Subcutaneous nodules are late and relatively uncommon manifestations of an active rheumatic fever and are almost always associated with severe carditis. These appear on wrist, elbow, knees, ankles, and skull.

The inclusion of these two signs as major manifestations of acute rheumatic fever independent of other major manifestations is thus somewhat erroneous and it is preferable to designate them as secondary major manifestations of acute rheumatic fever.

Minor Manifestations

Clinical manifestations

Fever: It is usually present during the first week to ten days of rheumatic fever and is rarely above 39 0 C. If the patient's temperature elevation persistently exceeds 390 C, other cause should be sought. In particular, in the presence of rheumatic heart disease superimposed infective endocarditis should be the first consideration.

Arthralgia: Arthralgia is an extremely common complaint in rheumatic fever. It commonly precedes an acute attack of carditis.

Laboratory minor manifestations

Laboratory data which can be helpful in the diagnosis of acute rheumatic fever are of two kinds:

  • Evidence of Streptococcal infection

  • Tests for the presence of rheumatic activity

The proof of streptococcal infection can be based on:
A positive throat culture for group A beta-hemolytic Streptococcus. Although old literature quotes throat culture to be positive in 25%, with the common use of antibiotics in almost every febrile child this figure is nowadays hardly ever attained.

The most useful and practical test for detecting a preceding streptococcal infection is a rise in antistreptolysin O titer. The rise occurs in a week, reaches a peak in 3-5 weeks, and subsides in 2-6 months. It can be detected in about 80% of cases of acute rheumatic fever because it remains elevated far longer than other signs.

It must be understood that a low ASO titer does not exclude the diagnosis of rheumatic fever if other criteria are fulfilled and on the other hand, too much reliance on a solely elevated ASO titer can result in unnecessary treatment.

Role of Echocardiography

Echocardiography is the only new diagnostic tool, which significantly contributes to confirming the presence of rheumatic carditis.

Initially, echocardiography was used to differentiate the murmur of mitral regurgitation from systolic murmur caused by VSD, obstructive cardiomyopathy, and mitral valve prolapse. It is now established that more than leaflet edema, the mitral annular dilation, and secondary chordal elongation permits the apical portion of the anterior leaflet to prolapse back into the left atrium resulting in a characteristic jet of regurgitant flow that passes over the posterior leaflet striking on the posterior left atrial wall.

Recent experience suggests that silent mitral regurgitation can be demonstrated by doppler evaluation in patients presenting with isolated rheumatic polyarthritis. Silent but pathologic mitral regurgitation that cannot be heard can be differentiated from physiologic if:

  • Regurgitant flow is holosystolic

  • Regurgitant flow should extend back to left-atrial wall

  • Regurgitant flow should have mosaic pattern on color flow

  • Regurgitant flow should be confirmed in more than one plane

There now appears to be enough experience to add echocardiographic demonstration of silent-valve regurgitation as an additional minor manifestation. It is also important to demonstrate this echocardiographic evidence of pathologic regurgitation in patients presenting with polyarthritis to decide about future penicillin prophylaxis.

Test For Presence of Rheumatic Activity

Erythrocyte sedimentation rate

The elevation of ESR is due to an increase in plasma fibrinogen secondary to inflammation. The magnitude of elevation of ESR is often directly proportional to the severity of the disease except in patients with heart failure whose liver may not produce enough fibrinogen.

Elevation of ESR is a fairly good index of rheumatic activity. ESR remains elevated for about 4-8 weeks and it may remain high in severe carditis. Also, it may remain high longer in the presence of anemia. ESR is useful in deciding how long a child should remain in bed or when to modify suppressive therapy.

C-reactive protein

It is not usually present in the blood. It appears promptly in the course of any inflammatory reaction. It becomes normal much more readily than ESR and is a helpful adjunct in proving rheumatic activity because of its transient nature and rapid disappearance from the blood. ESR is preferable to CRP especially for the follow up of rheumatic activity. CRP is not influenced by anemia or CHF so, in the presence of other criteria and normal ESR, CRP is a good indication of the rheumatic process. But in the absence of other criteria, normal ESR and elevated CRP suggest non-rheumatic etiology.

Leukocyte changes

are of little help in rheumatic fever due to its variability.

Electrocardiogram in rheumatic fever

The most characteristic feature in acute rheumatic fever is conduction disturbances most commonly in the form of a 1st-degree heart block (a prolonged PR interval) which occurs in 24 - 40%. Dr. Jones in 1944 recommended repeat tracings to demonstrate a variation in atrioventricular conduction which is more valuable. The PR interval usually returns to normal after the disease becomes inactive and it can occur with or without carditis. In acute rheumatic pericarditis, ST elevation or inversion is present.

Rheumatic Fever - Diagnosis

The diagnosis of rheumatic fever in the presence of characteristic clinical and laboratory findings is straightforward in the majority of cases. In clinical practice, however, many borderline cases are encountered leading to overdiagnosis or misdiagnosis and unnecessary treatment and precautions, which can be harmful. The Jones criteria originally diagnosed and subsequently revised in 1965 are useful guides to the diagnosis of rheumatic fever in most cases. According to Jones criteria, 1 major and 2 minor or 2 major criteria plus evidence of preceding streptococcal infection are required to establish the diagnosis of rheumatic fever.

The shortcomings of Jones criteria are as follows:

  • Mild attack of rheumatic fever may not meet the criteria

  • Other clinical pictures such as those of rheumatoid arthritis may at times meet the criteria

  • Subcutaneous nodules and erythema marginatum although diagnostic are quite rare and secondary in importance and alone neither one can serve as fully convincing evidence for the disease. The inclusion of these criteria as major manifestations may be confusing particularly to students and it is preferable to designate them as secondary major manifestation.

  • Arthralgia is an extremely common prodromal sign in almost all patients who develop carditis. If carditis develops early, there is no diagnostic problem but at least 25% of patients who develop carditis; arthralgia, and low-grade fever are present a few weeks prior. In a retrospective study of patients with carditis, at least one third were found to have a history of arthralgic episodes before the diagnosis of rheumatic fever was made. It is possible that such cases have had mild attacks of rheumatic fever, which have escaped attention and have developed carditis in subsequent attacks. It is well known that attacks of rheumatic fever resemble one another but this observation was based on cases in whom the first attack had been diagnosed. No information is as yet available to indicate that major attacks of rheumatic fever may at times be preceded by minor attacks. Our data at B.J Wadia hospital suggest that such a state may indeed exist and a different approach to the Jones criteria may be needed.

Due to the diversity of clinical manifestations of rheumatic fever one can parallel the spectrum of the diseases to a shooting target. When the diseases manifest itself fully it hits the center of the board and the manifestations are carditis, polyarthritis, and chorea. Simultaneously with the first two, subcutaneous nodules and erythema marginatum may appear, both of which are of secondary importance. The disease may hit the periphery of the target. It is the periphery that does not contain the major manifestation. On future attacks, the center may again be hit. Most important is recognizing the patients in the periphery and protecting them from future full-blown attacks of the diseases. The patient in the periphery can be divided into three groups:

  • Children who complain of significant arthralgia without a high ASO titer or ESR. Such patients should follow all the instructions for full protection against streptococcal infections that must be given.

  • Children with arthralgia with raised ASO titer and normal ESR. These patients may be in the recovery phase of mild rheumatic fever. They must again be followed as the potential risks.

  • Children with arthralgia with high ASO titer and ESR. Such patients probably suffered from mild rheumatic fever. Prophylaxis and even a short course of aspirin treatment are indicated.

All 3 groups must have a throat culture and should be treated accordingly. If prophylaxis is decided to be given- a period of 6 months to one year would suffice followed by insuring further protection against streptococcal infections.

Aims of Treatment

  • Eradication of initiating streptococcal infection by a therapeutic course of penicillin.

  • Treatment of acute carditis

  • Treatment of extracardiac manifestations

  • Specific treatment of congestive cardiac failure

Eradication of initiating streptococcal infection by a therapeutic course of penicillin

: The patient with an acute rheumatic fever with whatever manifestations should be given a therapeutic course of antibiotics to eradicate residual streptococci which may be difficult to isolate.

A ten-day course of oral penicillin or Inj Benzathine penicillin in single IM injection 1,20,000 IU in children above 60 kg and 600,000 IU in children below 60 kg. If the patient is sensitive to penicillin - oral erythromycin 20 mg/kg/day in three divided doses can be given for 10 days. Tetracyclines and sulphonamides are not used.

Bed rest:

The recommended duration and strictness of bed rest is variable. The reason for bed rest is to reduce cardiac work and to avoid the use of involved joints.

  • In those patients with only arthritis 3 weeks, bed rest is advised. Generally, patients with polyarthritis or arthralgia become asymptomatic by 2nd or 3rd week, and also if at all carditis is going to develop it develops within 3 weeks. After three weeks, the ambulatory bed rest is given.

  • In those patients with a murmur of mitral &/or aortic regurgitant murmur but without cardiomegaly or CHF- two weeks complete bed rest and next two weeks gradual ambulatory bed rest is given.

  • In those patients with murmur and cardiomegaly without CHF, 4 weeks strict bed rest followed by 2 weeks ambulatory bed rest is given.

  • In those patients with a murmur, cardiomegaly, and CHF, strict bed rest is given until CHF is completely controlled and ambulatory bed rest is given for 4 weeks after anti-inflammatory therapy has been stopped.

Anti-inflammatory drugs

Aspirin and steroids are the two anti-inflammatory agents of choice for the treatment of acute rheumatic fever. Both drugs suppress inflammation, joint manifestations as well as acute phase reactions. There is a little or doubtful effect on erythema marginatum, subcutaneous nodules, chorea as well as on long term complications of arthritis. Aspirin is effective for arthritis but steroids are far superior to aspirin in case of severe carditis.

Use of anti-inflammatory drugs in acute rheumatic fever:


PC/C-CHF/ C-CAR
Silent carditis (Only murmur)
Arthritis
Arthralgia/ Raised ASO & ESR
Steroid zone
Steroids 
aspirin 
Aspirin zone
Analgesics with penicillin

PC - Pancarditis C-CHF - Carditis with failure C-CAR - Carditis with cardiomegaly Silent carditis - ECHO evidence only.

In the steroid zone, these conditions require definite steroid treatment.

In the aspirin zone, the use of aspirin is adequate.

In the central zone, either of the drugs can be used.

Why aspirin is not given in severe carditis?

High dosage aspirin increases O2 consumption of the myocardium and increases the workload on the heart and so precipitates CHF. It has been shown that if only aspirin is used in carditis, during the course of aspirin the patient can develop pericardial rub which never happens during the steroid course. Aspirin exerts no specific effect on the lesion of the acute rheumatic process at any site but produces excellent symptomatic relief of arthritis and fever. There is not yet proven evidence that steroids reduce the incidence and severity of residual rheumatic heart disease but there is a definite impression that death during an acute attack of carditis is prevented.

Duration of Treatment

With either drug, the duration is 6 weeks or until the patient's clinical condition improves and ESR has returned to normal. Both drugs should be given for 4 weeks and then tapered off slowly in the next 2 weeks. To avoid or minimize rebounds addition of aspirin towards the end of steroid treatment is quite useful.

Occasionally, it is necessary to continue the steroid treatment for longer periods of time especially in patients who remain in heart failure with other decongestive measures. If the patient remains in CHF beyond 3 - 4 months of steroid and other decongestive measurers one should seriously think of surgery.

In very severe CHF, methylprednisolone parenterally should be used followed by oral prednisolone.

Doses

  • Aspirin: 100-120 mg/kg/day

  • Prednisolone: 2-3 mg/kg/day (maximum 60 mg/day)

Congestive heart failure in patients who present with heart failure, digitalis, and diuretics are considered. Digitalis i.e. digoxin was previously contraindicated since some patients are extremely sensitive to glycoside. It can be used if one remains on a low dosage schedule.

Chorea - Isolated chorea is treated symptomatically since neither aspirin nor steroids have any effect on the course. The combination of phenobarbitone and chlorpromazine works well, if not haloperidol can be used.

Prophylaxis

The story of rheumatic fever does not end with the completion of anti-inflammatory treatment and normalization of acute-phase reactants. Every patient of acute rheumatic fever is a candidate for continuous prophylaxis as the risk of a recurrent attack of acute rheumatic fever continues.

The method of choice is a monthly intramuscular injection of 1.2 mega units of benzathine penicillin and at times every three weeks. In the case of genuine penicillin allergy, sulfonamides (0.5 gm/daily <25 kg and one gm daily above>25 kg) or erythromycin can be used.

The point of confusion is when to stop prophylaxis. If a patient presents with severe carditis or with recurrent episodes of Acute Rheumatic Fever, prophylaxis is considered for life. For moderate carditis, prophylaxis till 16 years and for mild or no carditis for 3 years from the last episode should be given.


Rheumatic Fever Rheumatic Fever Rheumatic Fever 01/24/2001
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