An 11-year-old Polynesian male presents with 4 days of fever up to 39 degrees (102.2 degrees F), joint pain and swelling, along with shortness of breath. The fever comes and goes at random times of the day. Two days ago, his right knee was painful and swollen, but today it has improved. The joints involved today include the right ankle and left knee. They are very tender, painful, and swollen. The shortness of breath occurs with walking, but he is now unable to walk because of the joint pain. He also has some shortness of breath when lying down as he is trying to sleep.
Exam: VS T 38.2, P 160, RR 32, BP 100/60, oxygen saturation 94% in room air. He is tired appearing with tachypnea and tachycardia. HEENT: Enlarged, erythematosus tonsils with exudates. Lungs are clear but with tachypnea. Heart sounds are tachycardic with a 3/6 holosystolic murmur heard at the apex radiating into the axilla. No gallops are heard. His PMI is prominent (size of silver dollar) at the 7th intercostal space in the mid-axillary line. His abdomen is soft with normoactive bowel sounds. His liver edge is 6 to 7 cm below the right costal margin. His left knee is swollen and extremely tender with warmth. His range of motion is very painful but can flex his knee 30 degrees passively. His right ankle is very swollen and warm. He has limited and painful subtalar motion. Both his knee and ankle are very tender even to touch. Neuro: No abnormal movements of arms, hands, or tongue are noted. He is unable to walk due to pain.
Clinical course: He is admitted to the hospital. Initial laboratory work includes an erythrocyte sedimentation rate of 110 mm/hr, a CRP of 9.5 mg/dL, and a chest X-ray with cardiomegaly present. EKG reveals a prolonged PR interval. ASO titer is 754 and a multi-enzyme streptococcal serology test is positive at 1:600. The diagnosis of acute rheumatic fever is made and he is initially started on naproxen therapy at 12 mg/kg/day. His arthritis improves dramatically. An echocardiogram confirms severe mitral insufficiency, left ventricular dilation, and left atrial enlargement. Due to the significant cardiac disease with elements of congestive heart failure he is switched to 40 mg of prednisone daily and improves. His heart size decreases over the next 2 weeks, and when it normalizes, he is switched back to naproxen with a taper of his prednisone for a total treatment duration of 8 weeks while his ESR normalizes. His murmur persists. He is started on intramuscular benzathine penicillin G, which is given every 4 weeks for streptococcal prophylaxis. Cardiology recommends additional antibiotics for dental procedures to reduce his risk of bacterial endocarditis.
The terms of acute rheumatic fever (ARF) and rheumatic heart disease (RHD) are sometimes confused. Proper use of these terms requires some knowledge of the disease entities even though their pathogenesis and relation to Group A streptococci (GAS) infection are nearly identical. ARF is usually used to describe the initial or acute onset of the disease. In our case, this being the first initial presentation of the disease, it would be correct to call this ARF. The case fulfills modified Jones criteria. However, as time goes on it is found that this child has a persistence of the murmur. He also had severe carditis which caused his acute congestive heart failure, as manifestations of ARF, but he subsequently develops chronic heart disease as a sequela of the ARF valvulitis that results in valvular scarring and subsequent chronic RHD. While the initial acute valvulitis typically results in valvular insufficiency, the subsequent valvular scarring often results in valvular stenosis or a combination of the two. RHD implies there has been significant valvulitis, enough to cause chronic valvular scarring (1). This child is at an increased risk of requiring a valve replacement in the future, especially if he develops another episode of ARF, which requires great emphasis on him receiving long term penicillin prophylaxis, to prevent him from group A streptococcal (GAS) infection and possible ARF recurrence and worsening RHD.
The study of ARF and RHD parallels the history of modern medicine. At one time in the early 1900s children filled the beds of hospitals dedicated to treat only ARF. The treatment at that time was simply bed rest, sometimes for up to a year. With improvements in living conditions, reduction of crowding, and industrialization, ARF incidence has steadily decreased in the United States (2). When the link to GAS was found, the usefulness of using penicillin to prevent future attacks was also established, and ARF incidence decreased further.
However, certain areas of the country and large parts of the under-developed world, including Oceania (Australia, Melanesia, Micronesia, Polynesia), central Sub-Saharan Africa, and South Asia, still experience many cases of ARF (3). In the United States, there remains a high incidence of ARF in Hawaii and American Samoa (4,5). In Hawaii, the ethnic groups at greatest risk are those of Polynesian heritage, with Samoan children being at greatest risk (5,6,7). The Samoan children also appear to be at greater risk of developing carditis (7). More than 75% of patients with ARF in Hawai`i, have Polynesian ethnicity within their heritage. ARF occurs most commonly among children aged 5 to 15 years (4).
To accurately diagnosis ARF, one should adhere to the 2015 American Heart Association (AHA) modified Jones criteria (8). The last modification includes the use of echocardiography to identify subclinical carditis as a major criterion. Diagnostic criteria are newly stratified for high and low-risk populations to avoid underdiagnosis and overdiagnosis, respectfully. These criteria were developed to accurately diagnose ARF. If the criteria are not used, and the patient is misdiagnosed, this subjects the patient to needless penicillin injections for years. It is sometimes difficult for ARF patients to get life insurance and medical insurance later, due to the implications of the cardiac disease. Therefore, the diagnosis must fulfill the modified Jones criteria.
Table 1 describes the modified Jones criteria categorized into major and minor criteria. Note that they are different for low and high risk populations. A major criterion is more specific to ARF than the minor criteria. If a child has two major criteria, this fulfills the Jones criteria for the initial diagnosis, as long as they have some evidence of previous GAS infection. On the other hand, if there is evidence of only one major criterion, two additional minor criteria are required to fulfill the Jones criteria, along with evidence of GAS. Since the minor criteria are less specific for the diagnosis of ARF, the diagnosis of ARF cannot be made with just minor criteria. The diagnosis of recurrent ARF requires one of the following: 2 major criteria, 1 major and 2 minor criteria, or 3 minor criteria. The symptoms may be dampened by giving aspirin or other non-steroidal anti-inflammatory medications too early, thus not allowing the manifestations to fully develop.
Table 1. Summary of American Heart Association 2015 Jones Criteria (8)
| Low risk population | High risk population
| Definition
| Annual ARF incidence <2 per 100,000 school-aged children or all-age prevalence of RHD <= 1 per 1,000 | Not low risk |
Major criteria
| - Chorea - Erythema marginatum - Subcutaneous nodules - Polyarthritis | - Monoarthritis or ploy arthritis and /or polyarthralgia |
Minor criteria
| - Polyarthralgia | - Monoarthralgia |
- Fever (<= 38.5 deg C) | - Fever (<= 38.5 deg C) |
- ESR <= 60 mm/hr and/or CRP <=3.0 mg/dL | - ESR <= 30 mm/hr and/or CRP <=3.0 mg/dL |
| |||||||
In addition to Jones criteria, the diagnosis of ARF also requires evidence of preceding GAS infection (positive ASO titer, other streptococcal serology, positive GAS throat culture). The multienzyme streptococcal serology test known as “Streptozyme” is no longer available.
The incidence of major criteria present upon initial ARF diagnosis are carditis (50-80%), arthritis (35-70%), chorea (10-30%), subcutaneous nodules (0-10%), and erythema marginatum (<6%) (9–15). Prolonged PR interval (first degree atrioventricular block) can only be considered a minor criterion if carditis is not a major criterion. Joint manifestations (arthritis and arthralgia) can only be considered either major or minor criteria, but not both in the same patient. Polyarthritis is classically migratory in that a joint can be affected, then as it resolves, a different joint becomes inflamed. Clinically distinguishing arthritis from arthralgia can be difficult. Arthralgia is typically a subject sense of pain or discomfort in a joint, while arthritis more classically has objective findings such as swelling, redness, diminished range of motion, painful range of motion, and/or tenderness on palpation (mostly for minimally-mobile joints such as the carpal or tarsal joints).
The presence of a new murmur due to cardiac disease (i.e., carditis) is always sought on physical exam of a child that presents with symptoms suggestive of ARF. A very careful cardiac examination should include a description of the PMI and its location (for evidence of congestive heart failure). Our case had an enlarged and laterally displaced PMI indicating cardiomegaly. The enlarged liver provides further evidence of congestive heart failure. These findings are important to note, especially in a child with possible symptoms of orthopnea or paroxysmal nocturnal dyspnea (PND). Congestive heart failure is a severe form of carditis in ARF, and is managed more aggressively, often needing corticosteroids, diuretics, vasodilator therapy, digoxin, and occasionally inotropic agents (16).
More often, the carditis of ARF is not quite this severe, but can be problematic. The most common valve involved is the mitral valve. The second most common valve involved is the aortic valve. Auscultation of classic mitral insufficiency reveals a holosystolic murmur heard at the apex which radiates to the axilla. There are very few cardiac lesions that can be heard in the axilla. Besides mitral insufficiency, a ventricular septic defect could be heard in the axilla, but this murmur is usually heard all over the precordium and it should have been heard long before the acute rheumatic fever. The murmur of aortic insufficiency is a diastolic murmur (difficult to hear) that is usually heard best at the upper left sternal border. There is often a decrescendo component to this murmur that is sometimes very high pitched. One should also listen for a rub which would indicate pericarditis and a gallop for evidence of congestive heart failure.
The initial valvulitis of ARF results in valvular insufficiency. Subsequently as RHD develops, if enough inflammation has occurred on the valve leaflets of the mitral valve, the leaflets may scar and become adherent to each other, resulting in mitral stenosis (usually seen late in the patient's course, sometimes after repeated episodes of ARF). The murmur of mitral stenosis is a diastolic murmur, although it is described as occurring in mid-diastole, rather than later in diastole like aortic insufficiency. Similarly, aortic stenosis may subsequently result from initial aortic insufficiency.
Arthritis is a common major criterion in ARF. Previously, the arthritis had to be migratory and involving multiple joints (polyarthritis) to fulfill the major criteria, but the migratory and widespread pattern are no longer required in high-risk populations (8,17). Nevertheless, migratory polyarthritis is a typical joint manifestation of ARF. Usually, one joint becomes involved and over a few days resolves, then another joint(s) becomes involved as demonstrated in our case. Occasionally, the first joint does not resolve completely by the time the second joint becomes involved. This is termed "additive arthritis" and also fulfills a diagnosis of migrating polyarthritis. If arthritis is present, you cannot use the minor criteria of "arthralgias" as virtually all the children with arthritis from ARF have a significant amount of pain. The most common joints involved are large joints, usually those that bear weight. Knees and ankles are most often involved, although elbows and wrists can also be involved. Metatarsophalangeal joints can be involved, and one can screen for their involvement by squeezing them together, across the foot, and eliciting pain. The joint pain of ARF is typically very severe even if the visual findings are not very impressive. Merely touching the joint often elicits severe pain. Lower extremity joint involvement renders these patients non-ambulatory.
The other major criteria describe manifestations that are less often seen in ARF. Chorea is the more common of these three and is often difficult to diagnose. It is also known as Sydenham's chorea or St. Vitus dance and causes purposeless and involuntary movements. The hands and tongue are often involved. Parents may also notice the child having mood swings or just "not acting right". Emotional lability is often seen with this manifestation of chorea. Occasionally, chorea occurs so late in the illness that the laboratory tests including ASO titers, ESR, and CRP titers may all be normal. Thus, chorea is often termed a "subacute" phenomenon of rheumatic fever (as opposed to acute rheumatic fever). Despite this lack of evidence of inflammation, these patients can develop cardiac disease. Typically, chorea is not present while sleeping. Chorea usually resolves with time. Of note, Sydenham’s chorea is well established as a major criterion in rheumatic fever and its pathogenesis is undisputed; however, it is interesting that this is a neuropsychiatric consequence of a GAS infection. Compare this to PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) that is less well established, mostly because it is newer, yet its relationship to GAS infections is similarly autoimmune as in Sydenham’s chorea.
Both subcutaneous nodules and erythema marginatum are less common in ARF, but if they are seen, there is a greater chance of the patient developing carditis. The nodules are usually firm, painless, and small being <0.5 cm in diameter. They are located over areas that tend to be more prominent and rub against surfaces causing microtrauma. For example, they can be located at the tips of the elbows, around the joints, and the bony prominences of the spinal column. Erythema marginatum is a rash usually present over the trunk, and almost never seen over the face. The erythema is described as an evanescent pink eruption with irregular but well-demarcated borders. Individual lesions usually last for hours and then disappear, which is why it seen so infrequently. It is worthwhile to spend some time looking for nodules and rash as their presence heralds severe carditis and warrants a careful cardiac exam (15).
When evaluating a child with acute onset arthritis, the differential diagnosis can be quite overwhelming. Certain elements of the history and physical can help lead to the correct diagnosis. In ARF, the modified Jones criteria are very helpful, but there are other findings which can also help confirm your suspicion of ARF. For example, you should be able to describe the type of arthritis you are observing. Are the joints swollen and without much tenderness, but very stiff in the morning which are more typical of Juvenile Idiopathic Arthritis (JIA)? Are the effusions rather bland and non-tender lasting for a few days as they are in Systemic Lupus Erythematosus (SLE)? Is the joint so tender and swollen it cannot be moved even a few degrees as is seen in a septic joint? In ARF the joints are usually somewhere between these extremes of pain/tenderness. They can be very painful, yet if you do not move them, the child is still fairly comfortable. In a septic joint, the child usually has pain even at rest. The classic ARF joint is very warm, only sometimes erythematosus, and very tender. Even the weight of the bedsheet can cause pain, and this finding is sometimes called the "bedsheet sign". The tenderness is almost hyper-esthetic, with light pressure causing pain.
To simplify the treatment of ARF, we will separate the regimen into (1) eradication of GAS, (2) acute management of the inflammatory condition, and (3) prevention of recurrent episodes via antibiotic prophylaxis. With any good treatment plan, medical jargon should be avoided or translated for the parents to help with understanding and compliance issues. This is especially important when dealing with a long-term treatment like monthly benzathine penicillin G injections.
When a patient is diagnosed with ARF, they should be started on antibiotics for GAS eradication, even if pharyngitis symptoms are not present or GAS is not identified in the culture (18). Options include IM long acting benzathine penicillin, oral penicillin V, cephalexin, or azithromycin (19), although cephalexin is unnecessarily broad, and there is increasing GAS resistance to macrolides.
The acute arthritis of ARF will typically respond dramatically to NSAIDs, often within hours. High-dose salicylates (aspirin) were previously the first-line for treatment of acute arthritis; however, naproxen and ibuprofen have less GI toxicity than aspirin and have effectively treated ARF arthritis in controlled trials (20–22). Thus, naproxen or ibuprofen are preferred over high-dose aspirin (19). There is much less of a risk of developing Reyes syndrome with ibuprofen or naproxyn therapy also. The naproxen dose for children is 10-15 mg/kg/day orally BID, up to 1,000 mg daily. The ibuprofen dose is 5-10 mg/kg orally TID, up to 2,400 mg daily. The aspirin dose is 50-60 mg/kg/day divided into 4-5 doses and can be escalated to maximum 80-100 mg/kg/day divided into 4-5 doses. Maximum doses of aspirin should be kept under 4 grams per day. Due to Reye syndrome risk, aspirin should be avoided in children with intercurrent viral illness. Monitor salicylate levels and liver function tests while on aspirin. Be very careful with ARF patients who have some elevation in liver function tests prior to being put on aspirin since a low-grade inflammatory hepatitis can be seen in ARF; the aspirin could aggravate this problem (23). The treatment duration is usually 1 to 2 weeks or until the patient is pain free with improved ESR and CRP (19). If it is stopped too early, the arthritis usually returns.
If the carditis is mild and the child is asymptomatic from a cardiovascular standpoint, then no additional therapy is given. However, if there is evidence of severe carditis, then corticosteroids are indicated. Severe carditis is manifested by evidence of congestive heart failure (e.g., gallop rhythm, cardiomegaly, etc.) or severe myocardial disease (e.g., two valve disease or a new or a worsening arrhythmia). Close follow-up and evaluation by the cardiology service is warranted. Repeat echocardiograms will be needed. Corticosteroids are indicated for severe carditis under the direction of a cardiologist. Prednisone is usually given for 1 to 3 weeks followed by NSAIDS while the corticosteroids are tapered (19).
Some RHD patients will develop an indolent flare-up of their cardiac disease which occurs long after their first episode of ARF. These patients are extremely challenging. During this indolent flare-up, they develop no fever or arthritis, but just present with worsening cardiac disease. Sometimes, this is found on repeat echocardiograms, or by symptomatic CHF returning without other warning signs of a recurrence of rheumatic fever. Often increases in the ESR, CRP, and/or ASO titer are seen, indicating a sub-clinical case of GAS infection leading to the recurrence of the immune reaction in ARF. These patients may respond to another course of corticosteroids. This underscores the importance of close follow up by the cardiology service.
Chorea is generally self-limited and does not require acute treatment. Patients with severe chorea may be treated with chorea-suppressing medications and corticosteroids. The nodules and rash are temporary and do not require treatment (19).
Antibiotic prophylaxis against GAS infection is utilized to prevent a recurrence of ARF, and thus prevent further damage to the valves. Long term prophylaxis needs to be carefully described to the parent and child. Many of the families do not understand why the child needs penicillin injections when they feel fine following the episode of ARF. Many mistakenly think the injections are for the arthritis and therefore do not comply with this regimen once the arthritis has resolved. It should be noted that benzathine penicillin G (also known as long acting Bicillin or LA Bicillin) is an opaque white paste. Injecting benzathine penicillin is painful and because it is opaque, there is some risk of intravascular injection (drawing back the syringe does not fill the syringe with visible blood). It is also expensive; however, the alternative of daily oral penicillin has an extremely low likelihood of successful long term prophylaxis; leaving clinicians and patients with benzathine penicillin injections as the most reliable means of streptococcal prophylaxis.
For prophylaxis of recurrent ARF, children require benzathine penicillin G injections as long as they are at greatest risk of contracting GAS infection, which means at least until adulthood; some require it for their lifetime. Injections should be given every 4 weeks or every 3 weeks in high incidence populations (18). Even though Hawaii is a high incidence population, we recommend that our patients receive it every 4 weeks, partly due to compliance concerns. With every 3 weeks it is difficult for families to remember when to get their injection, and this has an increased negative effect on compliance. In penicillin allergic patients, the only option is to utilize non-penicillin oral antibiotics.
It is important to counsel families on the importance of preventing bacterial endocarditis from occurring in RHD patients. Like children with other cardiac malformations, once a child is diagnosed with RHD, they are at similar risk of developing bacterial endocarditis. Antibiotics for prophylaxis against alpha-hemolytic viridans streptococci valvular infection is important prior to and following any dental or gastrointestinal procedure. These recommendations can be found in the AAP Redbook.
The development of persistent cardiac disease is dependent on the amount of inflammation suffered by the cardiac structures during the acute period of disease and by the number of recurrences. Each recurrence will cause increased damage to valvular components and an increased likelihood of mitral stenosis and/or aortic stenosis, and the need for valve replacement. The global mortality from ARF and RHD was 4.4 to 5.1 deaths per 100,000 in 2015 (3). In Australia, 27% of children develop RHD within 1 year of initial ARF presentation and 52% develop RHD within 10 years of initial ARF presentation (19).
The diagnosis of ARF can be challenging and difficult to make. However, the modified Jones criteria can be extremely helpful in assisting the clinician in this process. It is important to verify the development of the major criteria before starting treatment, because treating too early may stop migration of the arthritis and make fulfilling Jones criteria more difficult. Without fulfilling Jones criteria, it is difficult to justify long term penicillin prophylaxis, which may last decades, to patients and their families.
Questions
1. You are seeing a child from American Samoa who develops a painful, swollen right knee after developing a streptococcal pharyngitis a month prior. Which of the following correctly describes the Jones criteria in this patient?
a. You have one major and one minor criteria in this child
b. You have one minor criteria
c. You have monoarticular arthritis as a major criterion
2. What does mitral insufficiency sound like on auscultation?
a. Holosystolic murmur heard at the apex which radiates to the axilla
b. Holosystolic murmur heard all over the precordium
c. Systolic, soft, musical murmur heard at the lower left sternal border
d. Diastolic murmur occurring in mid-diastole heart at the apex
e. Diastolic, decrescendo murmur heard at the upper left sternal border
3. What does aortic insufficiency sound like on auscultation?
a. Holosystolic murmur heard at the apex which radiates to the axilla
b. Holosystolic murmur heard all over the precordium
c. Systolic, soft, musical murmur heard at the lower left sternal border
d. Diastolic murmur occurring in mid-diastole heart at the apex
e. Diastolic, decrescendo murmur heard at the upper left sternal border
4. How does mitral stenosis result from acute rheumatic fever when the patient initially presents with mitral insufficiency?
a. Calcification of mitral valve
b. Fibrotic thickening (scarring) of mitral valve leaflets
c. Congenital valve malformation
d. Bacterial endocarditis
5. An 8-year-old child develops acute rheumatic fever with acute arthritis. Which of the following statements is true?
a. Aspirin should always be used in children with ARF, regardless of viral illness status
b. High-dose aspirin is the preferred first-line treatment for ARF arthritis
c. Naproxen and ibuprofen are preferred over aspirin for treating ARF arthritis because they have less gastrointestinal toxicity and lower risk of Reye syndrome
d. NSAIDs are ineffective in treating ARF arthritis, and corticosteroids should be used instead
References
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Answers to questions
1.c, 2.a, 3.e, 4.b, 5.c