At a Glance

Acute rheumatic fever (ARF) is a noninfective autoimmune sequelae of pharyngitis caused by group A beta-hemolytic streptococcus. ARF mainly affects children 6-15 years of age. Symptoms usually appear 2-3 weeks after the initial infection. This latent period is rarely shorter than 1 week or longer than 5 weeks.

ARF symptoms very between individuals, as symptoms may occur alone or in various combinations and may change during the course of the disease. Some symptoms are nonspecific, such as fever, fatigue, malaise, abdominal pain, and epistaxis, whereas others indicate involvement of the joints, heart, skin, and central nervous system.

A significant number of patients complain about painful and tender joints. On inspection, the joints are usually red, hot, and swollen. The inflammation is usually symmetrical and restricted to large joints (most often the wrists, elbows, knees, and ankles; less often the feet, hands, shoulders, and hips). Arthritis seen in ARF is usually acute and severe. The pain typically moves from 1 joint to another. However, multiple joints may be inflamed simultaneously, causing a more additive than migratory pattern.

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Symptoms of cardiac involvement include sensations of rapid, fluttering, or pounding heartbeats (palpitations); chest pain; shortness of breath (dyspnea on exertion, paroxysmal nocturnal dyspnea, and/or orthopnea); and cough.

The skin is often affected, as well. There is frequently a flat or slightly raided, nonpruritic, painless rash with ragged edge (erythema marginatum). Skin eruptions occur most frequently on the trunk and upper part of the arms or legs and have a ring-shaped or snake-like appearance that is much easier to detect in fair-skinned patients. The face is typically spared. The rash migrates from central areas to periphery and has well-defined borders.

Small nodules can be found beneath the skin and are rarely recognized by the patient. These nodules are usually located over bones or tendons and are painless and firm. The overlying skin is not inflamed and can usually be moved over the nodules.

ARF patients often have symptoms of Sydenham’s chorea (St. Vitus’ dance), manifested by jerky, abrupt, purposeless, nonrhythmic, uncontrollable body movements in hands, feet, and face. Symptoms are more marked on 1 side and cease during sleep. There are also episodes of emotional instability, such as crying or inappropriate laughing. Sydenham’s chorea is very rarely present in adults and is more common in females. If it is the only manifestation of ARF, and its presence is diagnostic.

Very helpful is a previous history of pharyngitis or scarlet fever. Patientsdo not always recollect having a sore throat 2-4 weeks prior to theonset of symptoms, particularly small children. Therefore, youngchildren who present with signs and symptoms of AFR in the absence of aprevious history of pharyngitis merit full ARF work-up.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Thereare no specific laboratory tests that can, by themselves, establish thediagnosis of ARF. When evaluating a patient for ARF, it is necessary tolook for evidence of previous streptococcal infection.

Acute phase reactants C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are usually elevated at the onset of ARF. They are nonspecific, but they may be useful in monitoring disease activity. ARF is an inflammatory condition; therefore, acute-phase reactants will typically be increased during the active phase and suppressed by treatment. CRP or ESR is useful in monitoring therapeutic effectiveness; a normal test obtained a few weeks after discontinuing antirheumatic therapy suggests the illness has ended, unless chorea appears. In cases in which a patient has carditis consistent with the diagnosis of ARF, the disease activity is gauged by the ESR, which is nearly always greater than 40 mm/hr (in the absence of heart failure) or by the presence of CRP.

Tests that determine preceding streptococcal infection include rapid streptococcal antigen detection tests, throat culture, and anti-streptococcal antibody tests.

Rapid streptococcal antigen detection tests are highly specific but not very sensitive. A positive rapid antigen test confirms a streptococcal infection, whereas a negative test requires a confirmatory throat culture.

It is typically necessary to obtain 2-3 throat cultures for group A streptococci. The sensitivity of throat culture, as evidence of recent streptococcal infection, is 25-40%. Throat cultures are usually negative by the time rheumatic fever appears; nevertheless, an attempt should be made to isolate the organism.

Anti-streptococcal antibody tests usually reach peak titers at the time of onset of ARF and are more useful, since they indicate active infection, rather than a carrier state; serologic examination for three or more streptococcal antibodies considerably increases the chances for confirming a previous streptococcal infection.

The most commonly used anti-streptococcal antibody test is anti-streptolysin O titer (ASO). At least 80% of patients with ARF have an elevated ASO titer at presentation (adults have >240 Todd U, and children have >320 Todd U). The titer can be elevated at presentation; however, it is more convincing to demonstrate an increase in titer from the acute to convalescent phase. After streptococcal pharyngitis, the antibody response peaks at about 4-5 weeks, which is usually during the second or third week of rheumatic fever, depending on how early it is detected. Therefore, it is useful to take one serum specimen when the diagnosis of ARF is first suspected and another 2 weeks later for comparison. Antibody titers fall off rapidly in the next several months and reach a slower decline after 6 months. Titers cannot be used as a measure of rheumatic activity.

If ASO is negative, than testing for other anti-streptococcal antibodies, such as antideoxyribonuclease B (anti-DNase B), antistreptokinase, and antihyaluronidase (AH), is necessary. These antibodies target extracellular products produced by streptococci. Testing for more than one antibody increases the likelihood of detecting evidence of previous streptococcal infection. The sensitivity of elevated ASO titers, together with elevated anti-DNase B or antihyaluronidase, is 90%. If initial ASO and anti-DNase B titers are not confirmatory, they need to be repeated 10-14 days later. In the isolated form of Sydenham’s chorea, which may occur months after the inciting infection, or indolent rheumatic heart disease, laboratory evidence of a preceding streptococcal infection may never be found.

Other helpful tests include complete blood count (CBC), blood culture, synovial fluid analysis, and determination of serum complement levels. During ARF, CBC shows evidence of leukocytosis and presence of a mild normochromic normocytic anemia typical of chronic inflammation. Suppressing the inflammation usually improves the anemia. Blood cultures are obtained if the patient is febrile to help rule out infective endocarditis, bacteremia, and disseminated gonococcal infection. Synovial fluid analysis reveals a sterile inflammatory reaction, usually with fewer than 20,000 cells/µL (mainly granulocytes) and no presence of crystals. Patients with ARF have minimal changes in serum levels of complement compared to healthy individuals. By contract, patients with other forms of inflammatory arthritis, or with acute post-streptococcal glomerulonephritis, have decreased serum levels of complement components (C1q, C3, C4).

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Childrenwithout ARF may have an isolated positive ASO titer. Up to 30% ofasymptomatic elementary school age children commonly have titers of200-300 Todd units per mL. Isolated positive ASO titers can also befound in patients with certain related diseases, such as rheumatoidarthritis and Takayasu arteritis. Therefore, rising ASO titers should becombined with a careful clinical evaluation and the discovery of otherantistreptococcal antibodies to support the diagnosis of ARF.

Theantibody tests must be interpreted with caution in areas with highrates of streptococcal infection and ARF, as relatively high titers arecommonly encountered in the population. These tests are of greaterutility in areas with lower prevalence (e.g., most Western countries).

What Lab Results Are Absolutely Confirmatory?

There are no absolutely confirmatory laboratory results for ARF. Although abnormal laboratory results indicating elevated acute phase reactants (leukocytosis, ESR, CRP) and presence of recent streptococcal infection (increased ASO or other streptococcal antibodies, positive throat culture for Group A beta-hemolytic streptococci, positive rapid direct Group A strep antigen test) are important criteria in the diagnosis of ARF according to the modified Jones criteria, they are not diagnostic per se.