PAMELA A. MAZZEO
HISTORY OF PRESENT ILLNESS
A 9-year-old active young boy presented to his pediatrician with left ankle pain of approximately 5 days duration. The boy’s mother reported that he had complained of various muscle injuries over the last month. Three weeks prior to presentation, he had begun limping, which he had attributed to having hurt his right hip while playing basketball. After a few days of “taking it easy,” he reported complete resolution. Shortly thereafter, the boy had complained of left elbow pain, and his mother speculated that the injury had occurred while he was wrestling with his older brother. He received ibuprofen and after a few days of treatment was able to play video games without discomfort. Just over the past few days, the mother had noted the boy limping again, but he had denied any problems until the coach of his indoor soccer team sat him for the first time all season. The boy confessed that his left ankle had been hurting him, but he had not wanted to miss any games. The coach had called the boy’s mother and told her he was not allowed back to practice until the doctor had checked him over.
The boy described the hip and elbow symptoms as vague pains, which worsened with movement of the specific limbs. He denied having had swelling or redness of the elbow or hip when they were bothering him, but he thought that his ankle was a “little puffy” now.
The mother reported that he had felt warm on occasion and that he had not been eating well. She felt that he had lost weight and she had found his sheets damp a few mornings when she woke him for school. The boy denied headache, rash, sore throat, nausea, vomiting, diarrhea, palpitations, or fatigue, and he asked if he could still make it to practice scheduled for later that day.
The patient had received all required immunizations and, aside from a broken nose from a stray softball 3 years earlier, he had no significant medical history. He had never required any regularly scheduled medications. He had no known medication allergies.
The boy’s family history was significant for migraine headaches in his mother and maternal grandmother and Trisomy 21 in his youngest brother. There was no family history of arthritis or malignancy. His travel had been limited to 2 weeks at the New Jersey shore over the summer and 1 month of “sleep away” camp in northeastern Pennsylvania.
T 38.6°C; HR 112 bpm; BP 112/60 mmHg; RR 18/min
The boy’s weight was in the 60th percentile but was down 3 kg from his preparticipation physical examination 4 months earlier. His height was in the 75th percentile, up by 1 cm from earlier measurements.
The patient was a cooperative male in no acute distress. He was slender and his clothes hung loosely from his frame. Eyes, nose, ears, and oropharynx were not inflamed. His tonsils were 3+ and symmetric without erythema or exudates. His neck was supple with only shotty anterior cervical adenopathy. His thyroid was not enlarged. His lungs were clear with good aeration. His heart had a regular rhythm but was tachycardic with a soft systolic murmur at the apex, which was audible throughout systole. His abdomen was soft, nontender, and nondistended with no hepatosplenomegaly. The left ankle demonstrated a small effusion with increased warmth and mild erythema. There was exquisite pain with active and passive range of motion and with gentle palpation of the joint. All other joints were normal on examination. There was no rash.
A complete blood count revealed a white blood cell count of 12 200 cells/mm3 (74% neutrophils, 20% lymphocytes, 5% monocytes, 1% eosinophils); a hemoglobin of 9.5 g/dL; and a platelet count of 556 000/mm3. A basic metabolic panel was normal, but inflammatory markers were elevated, with an erythrocyte sedimentation rate of 120 mm/h and a C-reactive protein of 8.3 mg/dL. A rapid streptococcal antigen test and culture of his throat were both negative. Radiographs of both ankles were normal.
COURSE OF ILLNESS
The patient was treated with doxycycline for presumed Lyme arthritis. He also received regularly scheduled naproxen with good symptomatic relief of his joint pain. Several days later, the Lyme antibody titers by Western blot were negative. An electrocardiogram (ECG) suggested another possible etiology (Figure 5-7). Additional testing confirmed the diagnosis, which mandated definitive ongoing treatment.
FIGURE 5-7. An electrocardiogram.
DISCUSSION CASE 5-6
This previously healthy young man presented with a 1-month history of joint pains, with true arthritis of the ankle demonstrated at the office visit. The arthritis involved relatively large joints affected in a nonsimultaneous sequence. This pattern is referred to as a migratory pattern, where new joint inflammation occurs after previous joint inflammation resolves. The fever, weight loss, elevated inflammatory markers, and mild anemia were also noteworthy and suggested an infectious, rheumatologic, or malignant process.
Infectious etiologies of arthritis include primary infection of a joint space or infection of bone or soft tissue in close proximity to a joint, with or without direct communication of the infection with the joint. These are more likely to involve a single site, but multifocal infections can be seen with ongoing or intermittent bacteremia leading to multiple hematogenously seeded sites. When more than one joint is involved, postinfectious arthritis should be considered. These inflammatory joint reactions are sequelae of preceding infections, and are usually considered to be sterile and mediated through an immune response. Epstein-Barr and parvovirus B19 are among the common viral agents associated with this reaction, and meningococcus and Group A beta-hemolytic streptococcus are notorious bacterial causes for this phenomenon.
Arthritis characterizes late stage Lyme disease and develops 6-12 weeks after the tick bite. Large joints, especially the knees, are involved, and the recurrence of arthritis mimics a migratory pattern. Each bout of arthritis lasts 1-2 weeks but may become prolonged if left untreated. The involved joint often appears remarkably swollen, with little or no erythema, and ambulation is often maintained despite impressive effusion in the involved lower extremity joint. Carditis, presenting as heart block, can also complicate the picture but is more common in the early disseminated stage of the disease, which occurs a few weeks to months after infection.
The involvement of multiple joints and stigmata of acute inflammation make rheumatologic conditions an important consideration. Systemic-onset juvenile idiopathic arthritis can present initially with or without arthritis, but chronic arthritis of at least 6 weeks’ duration is required for diagnosis. Systemic lupus erythematosus most often presents with joint involvement with constitutional complaints of fatigue, weight loss, fever, and a typical rash, and there is nearly always an elevation in the antinuclear antibody (ANA) titer. Progressive muscle weakness is characteristic of dermatomyositis, which may present with extremity complaints and, infrequently, true arthritis. Back pain eventually develops in ankylosing spondylitis, which is much more common in boys than in girls and is associated with HLA-B27 in 9 of 10 cases. Mixed connective tissue diseases may have overlapping features with many of these conditions, but the arthritis often involves small joints. Vasculitis syndromes may also present with arthritis, with Henoch-Schönlein purpura being the most common vasculitis of children. The characteristic palpable petechial or purpuric rash, especially evident in the lower extremities, in the absence of thrombocytopenia, is key in the diagnosis of this IgA-mediated vasculitis. Other inflammatory conditions, including Crohn disease, ulcerative colitis, Reiter syndrome, Behçet disease, or Sjögren syndrome, may also present with arthritis, constitutional symptoms, and elevated erythrocyte sedimentation rate, but other features of the illnesses are usually present, or eventually manifest themselves.
Joint or extremity pain, with fever and weight loss, can certainly raise the suspicion of a malignancy. True arthritis (joint effusion, warmth, erythema, and pain with range of motion) is not a typical presentation of musculoskeletal tumors but may be part of a paraneoplastic syndrome with reactive arthritis. Disseminated malignancies, such as neuroblastoma or leukemia, may also involve joints or the skeletal system through direct bony destruction in close proximity to a joint. Abnormalities may or may not be detected by plain radiographs of the involved limb.
The ECG revealed a ventricular rate of 110 bpm, sinus arrhythmia, first-degree atrioventricular block (P-R interval = 0.2 seconds), and a Mobitz II atrioventricular block (occasional atrial beats not conducted to the ventricle) (Figure 5-7). Echocardiogram revealed mild aortic insufficiency and moderate mitral regurgitation. The antinuclear antibody titers were less than 1:40. Anti-streptolysin-O titers and anti-DNase B titers were positive at 1:1955 and 1:680, respectively. These findings confirmed the diagnosis of acute rheumatic fever (ARF).
The negative Lyme serology and the elevated titers to streptococcal antigens make acute rheumatic fever (ARF) an important diagnostic consideration in this case. The Jones criteria are used to make the diagnosis (Table 5-8).
TABLE 5-8. The Jones criteria for diagnosis of an initial attack of rheumatic fever.
Two major or one major plus two minor criteria, along with evidence of preceding group A beta-hemolytic streptococcal (GABHS) infection, make the diagnosis of acute rheumatic fever (ARF) highly probable. This young boy demonstrated several features of this disease, including auscultatory evidence of valvular heart disease and a migratory polyarthritis (two major criteria), as well as fever, prologation of the PR interval on ECG, and elevated ESR and CRP (three minor criteria). Echocardiography revealed mild aortic valvular insufficiency and moderate mitral valve regurgitation with thickening of the mitral valve.
Response to aspirin and other NSAIDs is typical and, perhaps, a diagnostic clue. Children given aspirin for the arthritis of ARF have responded so well as to go from bed-ridden to running down the halls within hours of the first dose. In the current day, the liberal use of ibuprofen for fever or analgesia may obscure the classic migratory pattern of arthritis in ARF due to the symptomatic relief this agent may provide.
INCIDENCE AND ETIOLOGY
Although ARF remains an important cause of cardiovascular disease worldwide, the incidence of ARF has been decreasing since the early 1900s in developed nations. Regional outbreaks occurred throughout the United States in the 1980s and 1990s, and this resurgence may have been related to the increased prevalence of strains of GABHS thought to be more “rheumatogenic.”
Populations at greatest risk for ARF mirror the populations with increased incidence of GABHS pharyngitis: ages 5-15 years and older individuals in close living quarters, such as military recruits. In developing countries and in the United States in the early 1900s, poorer socioeconomic communities had higher rates of GABHS pharyngitis and ARF. However, more recent outbreaks of ARF in the United States occurred predominantly in suburban and rural middle-class communities, as well as among military recruits.
The pathogenesis of ARF is not completely understood; however, evidence increasingly points to the contribution of molecular mimicry, in which antibodies directed at GABHS cross-react with host antigens. Strains of GABHS that cause impetigo do not appear to be an important cause of ARF. Genetic susceptibility may also play a role in disease development. Recurrent disease with subsequent episodes of GABHS pharyngitis is common and, for this reason, secondary prevention is an important feature of disease management.
Acute rheumatic fever is a nonsuppurative sequela of GABHS pharyngitis. The symptoms begin approximately 2-4 weeks following throat infection; however, in many cases, a sore throat is not reported, even in retrospect. GABHS infections that do not include pharyngitis are not initiators of acute rheumatic fever.
Approximately 80% of patients present with arthritis, typically a migratory polyarthritis with predilection for large joints. In contrast to Lyme arthritis, the subjective pain of ARF arthritis often is much more severe than the objective findings visible to the examiner. Analysis of fluid from an acutely inflamed joint reveals an elevated white count in the range of 20 000-40 000 cells/mm3 with a neutrophil predominance.
Carditis can involve any part of the heart, but the most typical is an endocardial process with particular affinity for the mitral and aortic valves. Acutely, the valves demonstrate insufficiency, but the lesions progress to stenosis over time. Involvement of the myocardium can be seen, especially with the more severe presentations of congestive heart failure. Pericarditis and epicarditis can also complicate the picture but rarely occur in isolation. Carditis develops in approximately half of patients but has been reported in up to 80% of patients in the more recent US outbreaks. Clinical signs accepted for evidence of carditis include appropriate murmurs, cardiomegaly, congestive heart failure, or pericardial friction rub. The most recent update of the Jones criteria (1992) does not consider echocardiographic evidence of valvulitis without auscultatory findings to be sufficient to establish the presence of carditis for ARF.
Erythema marginatum and subcutaneous nodules are seen infrequently. When erythema marginatum is fully developed, it has an indistinct serpiginous red border with central clearing and is nonpruritic. It is specific for ARF, but its usefulness is limited by the fact that the rash is evanescent and is present in less than 10% of patients. Subcutaneous nodules are usually a late finding of ARF and may correlate with more severe or prolonged carditis. The lesions are pea-sized, nontender, and tend to be located over extensor tendons at the elbows or knees or the Achilles tendon.
Sydenham chorea is a late manifestation of ARF and can present after resolution of the other features or in isolation if the other features were never clinically apparent. This movement disorder may start with subtle deteriorations of handwriting before evolving into the involuntary, uncontrollable, and purposeless choreiform movements. Due to the late onset of this feature, the presence of Sydenham chorea alone can be considered diagnostic of ARF if other causes of chorea have been excluded.
Some of the minor criteria for ARF overlap with some of the major criteria. Arthralgias, painful joints without objective findings of arthritis, should be considered only if arthritis is not used as a major criterion. However, PR prolongation by ECG can be considered in addition to ausculta-tory evidence of carditis. The ESR and CRP are significantly elevated with the acute illness, with ESR usually greater than 50 mm/h and often approaching or exceeding 100 mm/h. The fever has no characteristic pattern but usually resolves in 3 weeks, even without treatment.
Other clinical findings of ARF are less specific but are often part of the clinical picture (Table 5-9).
TABLE 5-9. Features associated with acute rheumatic fever.
Establishing the diagnosis of ARF involves assessing for the presence of major and minor criteria, documenting a preceding GABHS infection, and excluding disorders that mimic ARF.
Jones criteria. The five major criteria have been discussed in the preceding section. Evaluation for the minor criteria includes clinical assessment (fever, arthralgias), laboratory assessment (ESR, CRP), and evidence of atrioventricular conduction delay by electrocardiogram (PR interval prolongation).
Evidence of preceding GABHS infection. This can be obtained by:
1. Throat swab yielding a positive antigen (rapid test) or culture for GABHS at the time of presentation or documented in the preceding weeks. Most patients do not demonstrate a positive throat swab when presenting with ARF, having cleared the infection during the latent period. Furthermore, a positive throat swab at the time of ARF presentation may represent colonization, which does not necessarily indicate preceding GABHS pharyngitis.
2. History of scarlet fever in the preceding weeks. Scarlet fever does not occur during the presentation of ARF but is sufficiently specific for GABHS infection that it can serve as evidence of preceding infection.
3. Elevated serum GABHS antibodies (antistreptolysin O, antiDNAase B, antihyaluronidase, antistreptokinase). A commercial agglutination assay that tests for several streptococcal antigens is rapid and widely available but is less standardized and less reproducible than quantitative titers of specific antibodies. Quantitative ASO is positive in 80% of patients with ARF; when three antibodies are tested quantitatively, at least one will be elevated in 95% of ARF patients.
Excluding disorders that mimic ARF. When joint pain is the salient complaint, the differential diagnosis for ARF includes septic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, Lyme disease, postinfectious reactive arthritis, serum sickness, and malignancies. When carditis is the main manifestation, infective endocarditis and viral myocarditis/pericarditis should be considered.
TREATMENT AND PREVENTION
There are three distinct aspects to the treatment of ARF: eradication of the GABHS, secondary prophylaxis, and treatment of the ARF manifestations.
Eradication. At the time of ARF diagnosis, patients require treatment for acute streptococcal pharyngitis, regardless of the results of a throat culture or rapid antigen test. The treatment is not thought to alter the course of the active ARF illness but to remove the inciting agent. The recommended regimen is the same as that for streptococcal pharyngitis: 10 days of oral penicillin V or amoxicillin, or a single intramuscular dose of benzathine penicillin G. After completion of this therapeutic regimen, secondary prophylaxis is begun.
Secondary prophylaxis. Recurrence of ARF from a subsequent GABHS infection is a well-recognized phenomenon, and the degree of cardiac involvement increases with each episode of ARF. Asymptomatic as well as symptomatic GABHS throat infections can cause recurrences of ARF; therefore, prevention of these infections is vital, and continuous antibiotic prophylaxis is necessary for all patients with ARF. The American Heart Association (AHA) provides guidelines regarding choice of antibiotic, route and schedule of administration, and duration of prophylaxis. The risk for recurrence is greatest within the first 5 years after the initial attack; however, in some cases, lifelong prophylaxis may be indicated.
The AHA has also provided guidelines for which patients are at highest risk of bacterial endocarditis and should receive antibiotic prophylaxis against infective endocarditis (e.g., during dental procedures, cystoscopy, and intestinal surgery). Not all patients with rheumatic heart disease will warrant infective endocarditis prophylaxis, but those with certain conditions, as delineated in the guidelines, should be treated with a short course of additional antibiotics in accordance with the AHA’s recommendations.
Treatment of the ARF manifestations. Antiinflammatory medications, such as aspirin, are effective in the treatment for the carditis and arthritis symptoms of ARF. Aspirin is highly effective for the symptomatic treatment of the arthritis of ARF, and failure to respond to this therapy should bring the diagnosis of ARF into question. Congestive heart failure is managed medically, with diuretics and inotropic support, or surgically, with valve repair or replacement, as indicated by the severity of the symptoms.
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