Clinical Evaluation and Diagnosis of Acute Rheumatic Fever





Introduction


The diagnosis of acute rheumatic fever (ARF) relies on a combination of clinical evaluation and laboratory studies. Diagnosis is usually made using the clinical criteria first formulated by T. Duckett Jones in 1944, which have subsequently undergone multiple modifications, most recently in 2015.


Acute fever and arthritis characterize the usual presentation of the disease, although in many patients it may not be acute, rheumatic, or febrile. Carditis and neurological manifestations may also be present or may emerge several months after the initial group A streptococcal (GAS) infection. Although the fleeting arthritis resolves without lasting damage, rheumatic carditis has a destructive effect on the heart valves, leading to the only chronic sequela of consequence in ARF: rheumatic heart disease (RHD). Severe RHD is associated with a number of important complications, including heart failure, stroke, atrial fibrillation, and infective endocarditis. The French physician Ernst-Charles Lasègue succinctly encapsulated the most important elements of ARF in 1884 when he said that “Pathologists have long known that rheumatic fever licks at the joints, but bites at the heart.”


Although the Jones criteria have stood the test of time, the diagnostic process has not stood still. Marked shifts in ARF epidemiology, advances in echocardiography, and evidence that some clinical manifestations, such as joint involvement, are more variable than previously thought have all contributed to a significantly revised diagnostic landscape. In particular, the emergence of color-Doppler echocardiography in the 1990s led to a renaissance of new thinking in the subsequent 2 decades, highlighting the limitations of auscultation. National diagnostic guidelines from regions of the world where ARF remains endemic emerged, spearheading the development of new diagnostic standards that form the basis for how we think about ARF diagnosis in the 21st century. However, much work still lies ahead, particularly as we seek to bridge the gap between high RHD prevalence and low ARF incidence. New research is underway applying systems biology and genomics approaches to identify biological markers that could potentially allow for a precise and rapid diagnosis of ARF; either the holy grail is a single laboratory test for the diagnosis of ARF or at least an improvement to the Jones Criteria. Another advantage to these studies is that they will shine light on the immunological perturbations occurring in ARF, paving the way for clinical trials of immunotherapeutic agents that may ameliorate the cardiac valvular damage and prevent RHD.


This chapter will describe the detail of the clinical and laboratory manifestations of ARF. As alluded to above, there are many atypical scenarios and presentations. With this information, the reader can better understand the details of the diagnostic criteria and definitions in the second part of the chapter.


Clinical Evaluation of Acute Rheumatic Fever


Careful diagnostic work-up is essential to make the diagnosis while excluding other etiologies. This may take some time. The importance of an accurate diagnosis of ARF is clear: overdiagnosis will expose the patient to the morbidity of lengthy treatment with 3-4 weekly penicillin injections, as well as potential harm from not being treated for their actual diagnosis; under diagnosis results in a missed opportunity for secondary prophylaxis, which in turn can lead to recurrent ARF and progressive RHD, with significant morbidity and early mortality.


Risk Factors for Acute Rheumatic Fever


The clinical utility of any diagnostic criteria is dependent on the individual’s pretest probability of having the disease and the background disease prevalence; careful consideration of any existing risk factors is therefore important when considering a diagnosis of ARF. The major established risk factors for ARF include frequency of exposure to GAS infection (throat and probably skin), age (the major period of vulnerability for ARF is between ages 4 and 20 years), host genetic factors (ARF is highly heritable but mechanisms are poorly understood), and poverty and social deprivation (leading to risk factors including poor quality housing and household crowding, malnutrition, and low utilization of and access to healthcare). These risk factors are discussed in detail in Chapter 1 , and the clinical features of GAS infection are discussed in Chapter 10 .


Without GAS there would be no ARF. In other words, exposure to GAS infection is essential for developing ARF. GAS pharyngitis has, until recently, been the only accepted cause of ARF, although contemporary epidemiological evidence suggests an association between GAS impetigo and ARF. Many cases of GAS pharyngitis may be asymptomatic or cause only a mild sore throat. Older children and young adults are more likely to remember the pharyngitis (up to approximately 70% of patients) compared to young children (approximately 20% of patients), who therefore merit a higher index of suspicion when presenting with signs or symptoms consistent with ARF.


Clinical Features of Acute Rheumatic Fever


Following the initial GAS infection, there is usually a latency period during which the patient appears well before developing symptoms of ARF. This latency period, which is the same for initial as it is for recurrent attacks, averages 19 days in duration with a range usually of 1–5 weeks, although this may be significantly longer (up to 8 months) in those patients who develop isolated Sydenham chorea or indolent carditis.


The clinical profile of ARF is similar in all settings. The features that most often characterize ARF have been divided into major manifestations and minor manifestations. Clinical presentation may involve one or more of these manifestations, which can occur at various different points over the course of the illness: the mode of presentation can therefore be extremely variable ( Box 3.1 ). Although classical descriptions involve severe symptoms, particularly with joint pain and high fever, in some patients an episode may be asymptomatic or be so minor, resolving without intervention or with antiinflammatory medication, that affected individuals do not seek medical attention.



Box 3.1

Modes of Presentation of Acute Rheumatic Fever

RHD rheumatic heart disease; ARF acute rheumatic fever


Acute presentations




  • Arthritis



  • Carditis



Subacute presentations




  • Sydenham chorea



  • Indolent carditis



Presentation with RHD


A large proportion of all ARF and RHD patients present with chronic RHD (40%–70% of cohort reports—see Chapter 5, Chapter 6 ). Such patients have no known history or symptoms suggestive of ARF. This scenario is more common in poorer environments, where sequelae of RHD such as heart failure, stroke, infective endocarditis, and atrial fibrillation may be the first presentation of ARF or RHD.



Major Manifestations


There are five major manifestations of ARF: joint symptoms (arthritis and arthralgia), carditis, chorea, and the skin manifestations erythema marginatum and subcutaneous nodules. These are termed “major” because they are relatively specific for ARF, although none is 100% specific.


Joint symptoms (arthritis and arthralgia)


Joint involvement is typically the presenting symptom of ARF. It is also the most common major manifestation, occurring in upwards of 75% of patients overall, affecting almost all young adults, most teenagers (82%), and children (66%). Joint involvement may qualify as a major manifestation or minor manifestation (see Diagnosis section).


Rheumatic joint involvement is notoriously variable, ranging from the classic migratory polyarthritis of large joints, to monoarthritis, polyarthralgia, and monoarthralgia. In the context of ARF, involvement of two or more joints is defined as polyarthritis. When joint symptoms are the sole major manifestation, the diagnosis of ARF may be problematic. Nevertheless, in patients from medium- to high-risk populations, ARF should always be included in the differential diagnosis of children and young adults presenting with arthritis and/or arthralgia.


The key to diagnosis is a detailed history and examination. It may take some time for the joint involvement to fully manifest (e.g., a monoarthritis on presentation may evolve into a polyarthritis several days later). Joint pain in ARF is usually asymmetrical, with a predilection for large joints including the knees, ankles, hips, elbows, and wrists (the leg joints are usually affected first). The small joints of the hands, feet, and spine are occasionally involved in ARF.


Rheumatic arthritis is usually extremely painful, often limiting movement and is often out of proportion to objective local signs of inflammation such as joint swelling, erythema, and increased temperature. Any child who refuses to put any weight on the affected limb is however a “red flag” for serious illness, such as infection (e.g., septic arthritis) or malignancy (e.g., leukemia)—see Differential Diagnosis. A history of inability to walk due to hip pain is regarded by some guidelines as arthritis, even if the signs of arthritis have resolved. The joint inflammation is characteristically transient, quickly disappearing from each joint often over a period of hours or just a few days and then appearing in another joint. Classically, multiple joints are often affected in quick succession, termed migratory arthritis. If subsequent joints are involved while preceding ones are still inflamed this can be termed “additive” polyarthritis, although this pattern is less specific to ARF than migratory polyarthritis. Joint involvement may number 6–16 in untreated patients.


Polyarthralgia, although very common and highly nonspecific in low-risk populations, is considered a major manifestation in high-risk populations where it is more specific for ARF. The same applies to monoarthritis and monoarthralgia, which are both common manifestations of ARF in these populations. For example, aseptic monoarthritis was a major manifestation in 19% of high-risk children in Australia. It is important however to first exclude septic arthritis in those who present with monoarthritis before diagnosing ARF. Close liaison with orthopedic colleagues may be necessary. The synovial fluid white cell count in joints affected by ARF contains 10,000–100,000 white blood cells/mm 3 (mostly neutrophils), while a count of >100,000 cells/mm 3 significantly increases the likelihood of the diagnosis of septic arthritis. Other findings on synovial fluid analysis in rheumatic arthritis include a protein concentration of approximately 4 g/dL, normal glucose levels, and presence of a mucin clot.


Aspirin, naproxen, ibuprofen and other NSAIDs, and corticosteroids often produce a dramatic improvement in joint symptoms. The arthritis of ARF is so responsive to NSAIDs that rapid resolution is strongly supportive of the diagnosis of ARF. Conversely, if there is no improvement within 72 h of starting antiinflammatories, an alternative diagnosis should be considered. In patients who present with monoarthritis or monoarthralgia, it is important to withhold NSAIDs, instead using paracetamol or codeine for pain relief, to prevent masking any evolution of joint symptoms. NSAIDs can be commenced once a second joint is involved, and the diagnosis is clear. Monoarthritis is now accepted as a major manifestation of ARF whether or not NSAIDs have been prescribed. The indiscriminate use of NSAIDs in some low- and middle-income countries (LMICs) may in part be responsible for the apparent fall in incidence of ARF in these populations.


There is no evidence that temporarily withholding antiinflammatory therapy leads to worse outcomes. The only long-term sequela of rheumatic arthritis is Jaccoud arthropathy, although this is very rare. Originally thought to be associated only with ARF, Jaccoud arthropathy has since been shown to also occur with systemic lupus erythematosus (SLE), Sjögren syndrome, scleroderma, dermatomyositis, psoriatic arthritis, vasculitis, and ankylosing spondylitis.


An episode of ARF lasts for approximately 3 months on average when unaltered by antiinflammatory medication. In most treated patients, the polyarthritis is severe for less than 1 week in two-thirds of cases and continues for another 1–2 weeks in the remainder before resolving completely. Symptoms persisting beyond 4 weeks should trigger a search for alternative pathologies, including juvenile idiopathic arthritis or SLE. Chronic ARF occurs in fewer than 5% of cases and is defined as the presence of active symptoms for more than 6 months.


Carditis


Rheumatic carditis is the most important prognostic factor in ARF because carditis can evolve to chronic RHD. Depending on whether the diagnosis is made based on clinical assessment alone, or combined with echocardiography, the incidence of carditis during an initial attack of ARF ranges from 40% to 91%. In the 1951 Bland and Duckett review of 1000 patients with ARF, 65% were diagnosed with carditis and in the 1987 outbreak of ARF in Utah in the United States, 91% had carditis when clinical examination was combined with echocardiographic evaluation. More recent studies that report both clinical and subclinical carditis show similar rates of carditis: for example, 85% of 66 children with definite or probable ARF had carditis. In general, the younger the patient the higher the incidence of carditis during an episode of ARF.


Carditis can be found at presentation along with fever and arthritis although it often appears within 2–4 weeks of the acute illness, highlighting the importance of repeatedly examining the patient after initial presentation. The clinical findings of rheumatic carditis can be variable, ranging in severity from mild subclinical involvement (up to 53%) to severe carditis (20%), leading to acute heart failure. Death is also a rare but well-described complication of the acute illness. In most of those who present with ARF for the first time, however, carditis tends not to be severe: a New Zealand study of true first episodes of ARF found that severe carditis occurred in <10% of such patients. In those with recurrent ARF, carditis almost invariably recurs if the initial episode involved the heart, and with each episode the cumulative heart valve damage can worsen. Internationally, acute carditis on chronic RHD may be as common as a true first episode of ARF. However, this chapter focuses on first episodes of ARF not chronic RHD.


Rheumatic carditis may involve all layers of the heart, including the pericardium (pericarditis), myocardium (myocarditis), and endocardium (endocarditis), hence some descriptions of rheumatic carditis use the term “pancarditis.” It is worth emphasizing that the endocarditis part of rheumatic carditis is inflammatory and not infective in origin and is characterized by inflammation of the left-sided heart valves, leading to acute or subacute valvular regurgitation (valvulitis). Given that the term endocarditis is potentially confusing in this context, it should be avoided and valvulitis used instead.


Pericarditis and myocarditis rarely, if ever, occur without concomitant valvulitis. Therefore, a diagnosis of rheumatic carditis should be reevaluated if clinical features of pericarditis or myocarditis occur in the absence of valvulitis.


Infrequently, carditis can also develop more subtly over several months after the GAS infection (known as indolent (insidious onset) carditis), and may be the only presenting feature of ARF. Indolent carditis is characterized by a subacute illness of several weeks or months with severe cardiac involvement and little or no joint symptoms. The presentation is with subacute heart failure in many cases. Younger children may have cardiac cachexia with weight loss. In those patients with severe heart failure, heart valve surgery may be contraindicated due to severely impaired left ventricular function, with heart transplantation the only surgical option.


Rheumatic Valvulitis. Valvulitis is the sine qua non of rheumatic carditis. It manifests as mitral regurgitation (MR) or aortic regurgitation (AR), or both, either clinically by detection of a corresponding murmur ( Box 3.2 ) or subclinically by echocardiography (see next section). The mitral valve is almost always affected in rheumatic valvulitis, with the aortic valve also involved in up to one-third of cases. Isolated aortic valvulitis only occurs in 2% of patients and right-sided valvulitis only occurs in combination with the left : therefore, carditis cannot be diagnosed on the basis of right-sided regurgitation alone. It is also important to rule out volume and pressure overload from left-sided lesions before attributing even moderate tricuspid regurgitation to valvulitis. Stenotic valvular lesions do not occur as part of the acute illness but occur after the transition from rheumatic carditis to the chronic valvular changes that define RHD, which evolve over months to years following one or more episodes of ARF.



Box 3.2

Cardiac Examination in Rheumatic Valvulitis.

ARF acute rheumatic fever; RHD rheumatic heart disease; MR mitral regurgitation; AMVL anterior mitral valve leaflet; PMVL posterior mitral valve leaflet


It is important to remember that clinical findings associated with acute valve regurgitation (e.g., in the setting of ARF) often differ significantly from those findings in chronic valve regurgitation (e.g., in setting of RHD)


Mitral Regurgitation . On palpation, the arterial pulse may be rapid and of low amplitude and the left ventricular impulse prominent with severe MR. On auscultation, acute MR may be detected as a blowing, pansystolic murmur that radiates to the back or axilla. It may also be short and soft, or may even be inaudible, owing to the rapid equilibration of left atrial and ventricular pressures. The murmur is best heard at the apex with the patient in the left lateral decubitus position using the diaphragm of the stethoscope. The murmur of rheumatic MR usually radiates to the axilla due to the posteriorly directed jet of MR secondary to AMVL prolapse. Less frequently, isolated PMVL prolapse occurs leading to an anteriorly directed jet of MR and this murmur is loudest at the lower left sternal edge. The most reliable auscultatory finding indicating a high regurgitant volume (severe MR) and left ventricular volume overload is a left-sided S3 gallop.


Carey Coombs Murmur. This middiastolic murmur is indicative of severe MR and is caused by increased blood flow across the mitral valve as a result of the high regurgitant volume. It is typically a short, middiastolic rumble and can be differentiated from the murmur of mitral stenosis by absence of an opening snap.


Aortic Regurgitation. On palpation, the typical signs of chronic aortic regurgitation, indicative of a hyperdynamic circulation, may be absent in acute aortic regurgitation. On auscultation, there is an early diastolic murmur best heart at the left sternal border that is low-pitched, quiet, and short (or sometimes inaudible in very severe regurgitation), due to rapid equilibration of aortic and left ventricular diastolic pressures. The murmur may be accentuated by asking the patient to sit up and lean forward while holding their breath after expiration. AR may also be difficult to define in the presence of tachycardia.



In addition to acute/subacute valvular regurgitation, cardiomegaly and heart failure make up the three most common clinical manifestations of valvulitis. Each of these features can be used to assess the severity of rheumatic carditis ( Table 3.1 ), which helps guide appropriate medical and surgical management and determine the duration of secondary prophylaxis in the long term. In patients with both right- and left-sided lesions, diagnostic severity is determined by the left-sided lesion.



Table 3.1

Grading the Severity of Rheumatic Carditis.

Reproduced with permission from New Zealand Heart Foundation
















Severity Clinical Features
Mild carditis Mild mitral and/or aortic regurgitation clinically a and/or by echocardiography (see Table 3.6 for minimal echocardiographic criteria)
No clinical evidence of heart failure and no cardiac chamber enlargement on echocardiography, CXR, or ECG
Moderate carditis Any mitral or aortic valve lesion of moderate severity on clinical examination a or cardiac chamber enlargement seen on echocardiogram or any mitral or aortic valve lesion graded as moderate on echocardiogram


  • mitral regurgitation: Broad high-intensity proximal jet filling half the left atrium or a lesser volume high-intensity jet producing prominent blunting of pulmonary venous inflow



  • aortic regurgitation: The diameter of the regurgitant jet is 15%–30% of the diameter of the left ventricular outflow tract with flow reversal of the upper descending aorta

Severe carditis Any impending or previous cardiac surgery or any valve lesion graded as severe on clinical examination a or any valve lesion associated with significant cardiomegaly or heart failure or any valve lesion graded as severe on echocardiogram


  • In children: Abnormal regurgitant color and Doppler flow pattern in pulmonary veins (mitral regurgitation) and Doppler reversal in the lower descending aorta (severe aortic regurgitation)



  • In adults: Doppler flow reversal in the pulmonary veins (severe MR) or abdominal aorta (for severe AR) are specific, if present, but can be more difficult to detect and their absence does not exclude severe regurgitation if not detected.


CXR chest X-ray; ECG electrocardiogram; MR mitral regurgitation; AR aortic regurgitation

a Clinical evaluation of the severity of valve lesions in discussed in detail in Chapter 5



Valvulitis may not always be evident at presentation. Those who do subsequently go on to develop valvulitis usually do so within 2 weeks or, at the latest, within 4 weeks. Therefore, if the initial echocardiogram is negative or equivocal, a second echocardiogram should be performed within 2–4 weeks of presentation to confidently exclude rheumatic valvulitis.


Subclinical carditis. Echocardiographic-based studies over the last 20 years have also revealed that a considerable number of patients with rheumatic valvulitis (up to 53%) do not have a murmur. This has given rise to the term subclinical carditis , which refers exclusively to the circumstance where a patient is found to have pathological MR and/or AR on echocardiography but where classic auscultatory findings are not present or are not recognized by the examining clinician.


The clinical course of subclinical carditis is similar to mild carditis detected by a murmur. A 2007 meta-analysis that included 23 studies from around the world showed that echocardiographic findings persisted or progressed in 44.7% of patients diagnosed with subclinical carditis. Therefore, although a murmur remains an important manifestation of valvulitis, it is no longer the only means of diagnosing carditis: both clinical and subclinical carditis are now considered a major criterion of ARF by the American Heart Association in both low- and moderate-to-high-risk settings (see Diagnosis of Acute Rheumatic Fever).


Pericarditis. Acute pericarditis often appears 7–10 days after the initial fever and arthritis and occurs in approximately 15% of patients. Pericarditis should be suspected if the patient complains of chest pain or is found to have a friction rub or muffled heart sounds. The friction rub can mask cardiac murmurs. The early ECG changes that often characterize pericarditis (i.e., diffuse concave upward ST elevation with upright T waves and PR segment depression) are usually absent in rheumatic pericarditis.


The chest pain is usually precordial or retrosternal and may radiate to involve the trapezius ridge (bottom portion of the scapula), neck, left shoulder, or left arm. The chest pain is typically exacerbated on lying down or during inspiration and relieved by sitting up and bending forward. Rheumatic pericarditis may result in a pericardial effusion, which is usually small to moderate in size and only very rarely leads to cardiac tamponade (see Chapter 16 ). Constrictive pericarditis is also a very rare complication of ARF.


Myocarditis. Rheumatic myocarditis is often asymptomatic. Different from many other forms of myocarditis, rheumatic myocarditis does not lead to impaired ventricular function in the absence of valvulitis and does not produce elevated serum cardiac troponins. Instead, the left ventricular enlargement and systolic dysfunction associated with severe carditis is secondary to volume overload from acute valve dysfunction. If troponins are elevated, this should raise suspicion of an alternative diagnosis such as viral myocarditis (see Differential Diagnosis (later) and Chapter 16 ).


Chorea


Rheumatic chorea, also known as Sydenham chorea or St Vitus’ dance, is characterized by purposeless, involuntary movements of the trunk or extremities. Chorea is a neuropsychiatric disorder that occurs in 10%–30% of patients who have had ARF. It is the most common form of acquired chorea in childhood (accounting for up to 96% of cases), most commonly occurring in those aged between 5 and 13 years and is rare after the age of 20 years. Females are more frequently affected than males by a ratio of 2:1.


Sydenham chorea has the longest latency period of all ARF manifestations, presenting 1–8 months after the initial GAS infection. As a consequence, it only features as part of the acute illness in 5%–10% of patients, where it may be associated with other disease manifestations, although joint symptoms and chorea seldom occur simultaneously due to disparities in their respective latency periods. In other patients, it may be the only manifestation of ARF, developing several weeks to months after the acute illness when other features of the disease have typically disappeared. For this reason, chorea is considered a stand-alone criterion for establishing the diagnosis of ARF, but only when other differential diagnoses have been excluded. Sydenham chorea is also commonly associated with carditis (28%–63% of cases), regardless of the presence of cardiac murmurs. As with all patients suspected of having ARF, echocardiography should therefore be performed and the finding of subclinical carditis by echocardiography will support the diagnosis of chorea as a manifestation of ARF.


Sydenham chorea is characterized by chorea (involuntary, brief, jerky, uncoordinated movements of the limbs and face), hypotonia (which may be diffuse), emotional liability, and psychiatric manifestations. The caudate nucleus in the basal ganglia is involved and so there is no pyramidal tract or sensory involvement. Symptoms are often bilateral, although are frequently more marked on one side and are unilateral (hemichorea) in 20%–30% of cases. Movements are accentuated by purposeful movement, excitement, and emotional stress, and disappear during sleep. Sometimes the movements are subtle and intermittent and might only be observed after a short period of observation. In severe cases, the chorea may impair the ability to eat and increase the risk of injury, requiring medication (see Chapter 4 , Management of Acute Rheumatic Fever).


Speech can be explosive and dysarthric and the individual often has trouble counting rapidly. The tongue is sometimes said to resemble a “bag of worms” on inspection and some patients may demonstrate motor impersistence, involuntarily withdrawing the tongue when asked to protrude it for 30 s (known as a “darting tongue”). Facial involvement often leads to erratic movements that resemble grimaces, grins, and frowns. The handwriting can be clumsy and is a good objective means of monitoring the course of the disease. When examining the hands, there are three specific signs to look for:



  • 1.

    Milkmaid’s grip: when asked to grip the physician’s fingers, the patient is unable to maintain grip, resulting in rhythmic squeezing and is another manifestation of motor impersistence


  • 2.

    Spooning sign: flexion of the wrists and extension of the fingers when the hands are extended


  • 3.

    Pronator sign: the arms and palms turn outwards (pronate) when the arm is held above the head



Psychiatric and cognitive disorders, such as attention deficit hyperactivity disorder and anxiety, are also commonly associated with Sydenham chorea and early recognition of these symptoms may aid in the management of the disorder. Mental status however is usually normal and a confusional state suggests an alternative diagnosis, such as encephalitis.


Restlessness and abnormal behavior, such as easy crying and irritability and inappropriate laughing are also observed. In rare cases, patients may develop a transient psychosis, which can present many years after the initial onset of chorea symptoms. Not unsurprisingly, there is often a high burden of distress for the patient and their family, with missed school days and poor school performance, or self-isolation due to embarrassment, causing a significant reduction in functionality. However, no cases of permanent serious neurological deficits have been observed.


The manifestations of chorea may also wax and wane over its course, often during times of intercurrent illness and stress. It usually resolves gradually and the median duration of symptoms is 12–15 weeks, although rarely symptoms may last 2–3 years. Of all the ARF manifestations, chorea is one most likely to recur, doing so in 15%–30% of cases and usually within 2–3 years. In most patients, recurrence is usually due to a repeat GAS infection. Some recurrences may occur despite faithful adherence to penicillin prophylaxis, while other episodes may be seen with pregnancy (chorea gravidarum) or the oral contraceptive pill, suggesting a relation to hormonal factors.


Erythema Marginatum


Erythema marginatum is usually an evanescent, pink rash seen with pale centers and rounded or serpiginous margins. This is a rare and difficult to detect manifestation, particularly in dark-skinned patients, hence careful inspection is required. Although estimates vary, it is usually observed in <6% of patients with ARF. When present, it usually occurs early in the course of the illness but may also occur during recovery. It may also persist or recur after all other manifestations have resolved. It rarely occurs in isolation and is usually associated with carditis. Therefore, ARF should almost never be diagnosed on the basis of erythema marginatum alone without the presence of other major criteria.


It is a distinctive rash and is neither painful nor pruritic. It appears as bright pink, slightly raised macules or papules that blanch under pressure. They are seen initially on the trunk and proximal ends of the extremities and never on the face. The lesions begin as a macule and expand centrifugally with central clearing ( Fig. 3.1 ). Rapid migration (up to 2–10 mm in 12 h) is a characteristic feature of this rash and this movement can be documented with the use of ink markers on the skin ( Fig. 3.2 ). The macules may be oval, ring, or crescentic shaped and the outer edge of the lesions is usually sharp whereas the inner edge is diffuse. The macules can fuse and coalesce to form a serpiginous pattern, and when circular, the rash is known as erythema annulare. It should not be confused with the circinate (circular) rash of Lyme disease, erythema chronicum migrans.




Fig. 3.1


Erythema marginatum in acute rheumatic fever demonstrating the characteristic pink rash with pale centres. Some of the margins are rounded while others are serpiginous.

Courtesy of Professor Mike South, Royal Children’s Hospital, Melbourne; used with permission.



Fig. 3.2


Erythema marginatum demonstrating rapid migration: the pen mark shows the location of the rash around 60 min earlier.

Courtesy of Professor Mike South, Royal Children’s Hospital, Melbourne; used with permission.


The rash may be characteristically evanescent, disappearing over a matter of hours and reappearing intermittently over the course of weeks, months, or even years; some lesions may appear and then disappear before the examiner’s eyes, appearing like “smoke rings” beneath the skin. It may be more apparent or reappear after a warm shower or bath and it is not affected by antiinflammatory medication.


Subcutaneous Nodules


Similar to erythema marginatum, these are also rare, occurring in less than 2% of patients with ARF. When present, they are highly specific for ARF but, similar to erythema marginatum, they rarely appear as a sole manifestation of the illness and should be accompanied by additional major criteria to establish a diagnosis of ARF. They are strongly associated with severe carditis and usually appear 1–2 weeks after the illness starts, lasting usually 1–2 weeks but rarely longer than a month.


The nodules are firm, round, painless, and freely mobile, usually 0.5–2.0 cm in diameter and are typically located over extensor surfaces (near bony prominences or tendons) of the elbows, wrists, knees, ankles, Achilles tendon, occiput, and the spinous processes of the thoracic and lumbar vertebrae ( Fig. 3.3 ). The overlying skin is not inflamed. They are usually symmetrical and occur in crops of up to 12, but the average number is 3–4. The nodules of ARF may resemble those seen in rheumatoid arthritis, although the former are smaller and shorter lived. Although nodules most commonly occur on the elbow in both conditions, ARF nodules occur more commonly on the olecranon whereas rheumatoid nodules tend to be found 3–4 cm distally.




Fig. 3.3


Subcutaneous nodules in acute rheumatic fever located over the bony prominence of the extensor surface of the elbow.

Reproduced with permission from Beerman LB et al.


Minor Manifestations


The four minor manifestations used in the diagnosis of ARF are as follows: fever, arthralgia, elevated acute phase reactants (erythrocyte sedimentation rate, C-reactive protein, and white cell count), and first-degree heart block.


Fever


Most episodes of ARF are accompanied by fever (>90% of cases), unless the patient has taken antipyretics or presents with subacute or late-presenting manifestations, such as Sydenham chorea or indolent carditis. The fever may rise as high as 40°C, although there is no characteristic pattern and diurnal variations are common. Similar to arthritis and arthralgia, fever should respond rapidly to antiinflammatory treatment, usually decreasing within 1 week and rarely lasting more than 4 weeks. Documented fever before admission is also acceptable as a minor criterion, particularly if the patient has taken NSAIDs or paracetamol, which may suppress the fever.


Arthralgia


It is important to differentiate arthralgia from arthritis. In patients with ARF, several joints (polyarthralgia) are usually affected, although monoarthralgia may also be seen. Rheumatic polyarthralgia usually affects joints in the same pattern as rheumatic polyarthritis: that is, it is migratory, asymmetrical, and predominantly affects the large joints. If this pattern is not observed, alternative diagnoses should be considered. It is worth remembering that polyarthralgia and monoarthralgia are common in many other rheumatological and nonrheumatological disorders.


Elevated Acute Phase Reactants


Most guidelines, including the Jones criteria, recommend measuring the erythrocyte sedimentation rate (ESR) and/or the C-reactive protein (CRP) as part of the diagnostic work-up of ARF. The WHO diagnostic criteria differ slightly and recommend ESR and peripheral white blood cell (WBC) count. The ESR and CRP are usually elevated in patients presenting with ARF (except in those with isolated Sydenham chorea), whereas Australian data showed that the WBC count is elevated (>15 × 10 9 /L) in only 25% of patients during an acute episode and is therefore much less sensitive for inflammation.


The magnitude of the ESR is proportional to the degree of the inflammatory response. Most episodes of ARF produce an ESR >60 mm/h, although antiinflammatories can reduce this figure. If there is concomitant heart failure, the ESR may also be decreased whereas the CRP may be elevated. The CRP is a direct measure of inflammation and typically rises and falls before the ESR (an indirect measure of inflammation) and thus may be a more precise reflection of the patient’s rheumatic activity. The ESR might remain elevated for 3–6 months following recovery and chronic elevation (>6 months) is occasionally seen but poorly understood.


First-Degree Heart Block


First-degree heart block is observed in 20%–60% of cases of ARF. In addition to valvulitis, it is a manifestation of carditis and is due to inflammation around the atrioventricular (AV) node as a consequence of myocarditis. First-degree heart block is due to delayed conduction from the atrium to the ventricle, defined as a prolonged age-adjusted PR interval ( Table 3.2 ). It cannot be detected from history or examination alone and diagnosis is best confirmed using a 12-lead ECG, which should be performed on every patient suspected of having ARF.



Table 3.2

Upper Limits of Normal of the PR Interval.

Adapted from Park MK.
















Age (years) Duration (seconds)
3–12 0.16
12–16 0.18
≥17 0.20


First-degree heart block is almost universally benign and is occasionally a normal variant, often related to parasympathetic tone. Up to one-third of patients with uncomplicated GAS infections are also found to have first-degree heart block. In the context of rheumatic carditis, any first-degree heart block should therefore be transient to distinguish from the normal variant. A prolonged PR interval on presentation that resolves over the following days to weeks may therefore be a useful clinical sign in patients whose symptoms were equivocal for ARF. If the PR interval has not normalized after 2 weeks, it is useful to repeat the ECG again after 1–2 months.


Higher degrees of heart block and other arrhythmias are also occasionally observed in rheumatic carditis ( Fig. 3.4 ). First-degree heart block may lead to an accelerated junctional rhythm, which has been detected in 9.4%–20% of ECGs from children with ARF and may be a highly specific finding when present. Second-degree heart block (2.6%) and rarely third-degree heart block (0.6%) may also complicate ARF. Very rarely, patients with ARF may also present with syncope (1 of 508 pts ) or develop ventricular asystole, requiring temporary transvenous pacing. Interestingly, the echocardiograms of some of these patients revealed only minimal left-sided regurgitant lesions, suggesting features of myocarditis with conduction system disease may dominate in rare circumstances. Other conduction abnormalities reported in association with ARF include ventricular tachycardia, right and left bundle branch block, brady-tachyarrhythmia, and ventricular premature complexes. The larger case series reported that patients with advanced AV block or accelerated rhythm all reverted to sinus rhythm during convalescence.




Fig. 3.4


Heart block in rheumatic carditis demonstrating complete heart block early in the disease, with improvement to secondary then first-degree heart block before return to sinus rhythm.

Reproduced from Bishop W et al.


Other Clinical Manifestations of Acute Rheumatic Fever


In the original 1944 Jones criteria, epistaxis and abdominal pain were both considered minor criteria, although both were removed (due to lack of specificity) in the subsequent 1956 modification and have been absent since. However, it is important to be aware that about 5% of patients with ARF will develop these features. Particularly important is abdominal pain that can appear hours to days before the major manifestations and may mimic other acute abdominal conditions. The pain may be severe, is often epigastric or periumbilical, may be associated with guarding, and is sometimes indistinguishable from acute appendicitis.


Pulmonary manifestations (“rheumatic pneumonia”) are also observed occasionally, usually in association with carditis and, like epistaxis and abdominal pain, were a minor criterion in the original Jones criteria. The clinical spectrum varies from mild (dyspnoea and nonproductive cough) to fulminant, with a variety of radiological patterns observed, including focal consolidation, diffuse bilateral infiltrates, pleural effusion, and confluent nodular lesions. There are no specific diagnostic criteria for rheumatic pneumonia and it is likely that multiple etiologies contribute to this umbrella term, either as part of the rheumatic process (in which case steroids may help), or secondary to acute heart failure, uraemia, or intercurrent infection. Other less common clinical features include mild elevations of plasma transaminase levels and microscopic haematuria, pyuria, or proteinuria. Full blood count (FBC) may show a normochromic, normocytic anemia.


Diagnostic Investigations for Acute Rheumatic Fever


The standard investigations used in the diagnostic work-up of ARF, when available, should include: select blood tests (FBC, ESR, CRP) and ECG (discussed earlier); and laboratory confirmation of a preceding GAS infection, Chest X-ray (CXR), and echocardiography (discussed here) ( Table 3.3 ). Other nonroutine investigations may be required depending on the clinical picture and differential diagnoses being considered but typically include additional blood testing (e.g., rheumatology immunology, viral serology, ceruloplasmin levels), joint X-ray or ultrasound scan, and magnetic resonance imaging (MRI) of the brain and heart ( Table 3.4 ).


Feb 2, 2021 | Posted by in RHEUMATOLOGY | Comments Off on Clinical Evaluation and Diagnosis of Acute Rheumatic Fever
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