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INTRODUCTION
Background: Rheumatic
fever causes chronic progressive damage to the heart and its valves. Until
1960, it was a leading cause of death in children and a common cause of
structural heart disease. The disease has been known for many centuries.
Baillou (1538-1616) first distinguished acute arthritis from gout.
Sydenham (1624-1668) described chorea but did not associate it with acute
rheumatic fever (ARF). In 1812, Charles Wells associated rheumatism with
carditis and provided the first description of the subcutaneous nodules.
In 1836, Jean-Baptiste Bouillaud and, in 1889, Walter Cheadle published
classic works on the subject.
The association between sore throat and rheumatic fever was not made
until 1880. The connection with scarlet fever was made in the early 1900s.
In 1944, the Jones criteria were formulated to assist disease
identification. These criteria, with some modification, remain in use
today. The introduction of antibiotics in the late 1940s allowed for the
development of treatment and preventive strategies. The dramatic decline
in the incidence of rheumatic fever is thought to be largely owing to
antibiotic treatment of streptococcal infection.
Pathophysiology: ARF is a sequela of a previous group
A streptococcal infection, usually of the upper respiratory tract. One
beta-streptococcal serotype (eg, M types 3, 5, 18, 19, 24) is linked
directly to ARF.
The disease involves the heart, joints, central nervous system (CNS),
skin, and subcutaneous tissues. It is characterized by an exudative and
proliferative inflammatory lesion of the connective tissue, especially
that of the heart, joints, blood vessels, and subcutaneous tissue.
Frequency:
- In the US: Disease prevalence in the US is a
function of socioeconomic status, with higher frequency in areas of
crowding. The US had experienced a resurgence of rheumatic fever in the
last 2 decades with many of the reported cases involving persons in
upper socioeconomic groups. The reason for this disparity is unclear but
may be caused by the emergence of more virulent strains of group A
streptococci. The overall incidence has been declining in developed
nations.
Frequency of streptococcal infection and virulence of the bacterial
strain determine the incidence of rheumatic fever in the population.
As a sequela of beta-streptococcal exposure, ARF occurs during school
years when streptococcal pharyngitis is most prevalent. Similarly,
prevalence is higher in the colder months of the year when streptococcal
pharyngitis is most likely to occur.
Mortality/Morbidity: Morbidity from ARF is directly
proportional to the rate of streptococcal infections. Infections that are
not treated adequately are most likely to cause the major sequelae noted
in the list of Jones
criteria. Morbidity also is related to the care that the patient
receives.
- The mortality rate has declined steadily over the last 3 decades. A
partial explanation for the decrease in mortality rate may be the
increase in antibiotic use. In developing nations and lower
socioeconomic areas where rheumatic fever is more prevalent, ARF is a
major cause of death and disability in children and adolescents.
- Cardiac involvement is the major cause of long-term morbidity.
Valvular vegetations (endocarditis) are the cause of mitral valve
regurgitation, the end result being LV dilation and CHF. Myocarditis is
present, but not the cause of heart failure.
- Migratory polyarthritis occurs early in the disease course and is a
common complaint for patients with rheumatic fever. Joint involvement
ranges from arthralgia without objective findings to overt arthritis
with warmth, swelling, redness, and exquisite tenderness. The larger
joints are involved most frequently, such as the knees, ankles, elbows,
and wrists. An inverse relationship between severity of joint
involvement and risk of carditis appears to exist.
- In approximately 75% of cases, the acute attack lasts only 6 weeks.
- Ninety percent of cases resolve in 12 weeks or less.
- Fewer than 5% of patients have symptoms that persist for 6 months or
more.
Sex: No sex predilection exists, except that mitral
valve prolapse and Sydenham chorea occur more often in females than in
males.
Age: Although individuals of any age group may be
affected, most cases are reported in persons aged 5-15 years.
CLINICAL
History:
- ARF is associated with 2 distinct patterns of presentation.
- The first pattern of presentation is sudden onset. It typically
begins as polyarthritis 2-6 weeks after streptococcal pharyngitis, and
it usually is characterized by fever and toxicity.
- If the initial abnormality is mild carditis, ARF may be insidious
or subclinical.
- Age at onset influences the order of complications. Younger children
tend to develop carditis first, while older patients tend to develop
arthritis first.
Physical:
- Diagnosis of ARF requires a high index of suspicion.
- Guidelines of diagnosis used by the American Heart Association
include major and minor criteria (ie, modified Jones
criteria). In addition to evidence of a previous streptococcal
infection, the diagnosis requires 2 major Jones criteria or 1 major plus
2 minor Jones criteria.
- Carditis: This occurs in as many as 40% of patients and may
include cardiomegaly, new murmur, congestive heart failure, and
pericarditis, with or without a rub and valvular disease.
- Migratory polyarthritis: This condition occurs in 75% of cases and
is polyarticular, fleeting, and involves the large joints.
- Subcutaneous nodules (ie, Aschoff bodies): These nodules occur in
10% of patients and are edematous, fragmented collagen fibers. They
are firm, painless nodules on the extensor surfaces of the wrists,
elbows, and knees.
- Erythema marginatum: This condition occurs in about 5% of cases.
The rash is serpiginous and long lasting.
- Chorea (also known as Sydenham chorea and "St Vitus dance"): This
characteristic movement disorder occurs in 5-10% of cases. Sydenham
chorea consists of rapid, purposeless movements of the face and upper
extremities. Onset may be delayed for several months and may cease
when the patient is asleep.
- Clinical findings include arthralgia, fever and previous history
of ARF
- Laboratory findings include elevated acute phase reactants (eg,
erythrocyte sedimentation rate, C reactive protein), a prolonged PR
interval, and supporting evidence of antecedent group A streptococcal
infections (ie, positive throat culture or rapid streptococcal screen
and an elevated or rising streptococcal antibody titer).
Causes:
- ARF has been linked definitely with a preceding streptococcal
infection, usually of the upper respiratory tract.
- Although streptococcal skin infections also are extremely common,
they have not been linked with ARF. Note the suggestion by McDonald et
al that pyoderma may be the cause in Aboriginal populations of
Australia.
DIFFERENTIALS
Aortic Regurgitation
Atrial Fibrillation
Endocarditis
Huntington Chorea
Mitral Regurgitation
Mitral Stenosis
Myocarditis
Pediatrics, Kawasaki Disease
Pediatrics, Scarlet Fever
Scarlet Fever
Other Problems to be Considered:
Leukemia
Juvenile rheumatoid arthritis
WORKUP
Lab Studies:
- No specific confirmatory laboratory tests exist. However, several
laboratory findings indicate continuing rheumatic inflammation. Some are
part of the Jones minor criteria.
- Streptococcal antibody tests disclose preceding streptococcal
infection.
- Isolate group A streptococci via throat culture.
- Acute phase reactants (eg, erythrocyte sedimentation rate [ESR],
C-reactive protein [CRP] in serum and leukocytosis) may show an increase
in serum complement, mucoproteins, alpha-2, and gamma globulins. Anemia
usually is caused by suppression of erythropoiesis.
- PR interval prolongation is present in approximately 25% of all
cases and is neither specific to nor diagnostic of ARF.
- Troponins have not been shown to be helpful in making the diagnosis
since ischemia and necrosis are not the major cardiac problems.
Imaging Studies:
- Echocardiography may be helpful in establishing carditis.
- Synovial fluid analysis may demonstrate an elevated white blood cell
count with no crystals or organisms.
TREATMENT
Emergency Department Care:
- The emergency medicine physician's primary responsibilities are to
suspect the diagnosis and to treat complications.
- Consider early administration of antibiotics.
- ARF usually is preventable if antibiotics are initiated within 9
days of the onset of streptococcal infection. The Infectious Disease
Society of America recommends that the diagnosis of GABHS infection be
confirmed. In children and adolescents, a negative rapid antigen test
(strep screen) result should be followed by culture unless the physician
has determined that in his or her own practice the rapid antigen test is
comparable to a throat culture. Because of the low incidence of ARF in
adults a negative, properly performed rapid antigen test is considered
acceptable evidence that streptococcal infection is not present.
- The best approach to treating the patient with pharyngitis is beyond
the scope of this discussion.
Consultations: Because of the many clinical features
of ARF, consider consulting a cardiologist, a rheumatologist, and a
neurologist.
- Carditis is not only a major clinical finding, but it also is the
cause of much of the disability.
- Arthritis is one of the major manifestations.
- Movement disorders associated with ARF may be difficult to
differentiate from those of other clinical problems.
MEDICATION
Medical therapy involves the following 5
areas:
- Treat group A streptococcal infection regardless of organism
detection.
- Steroids and salicylates are useful in the control of pain and
inflammation. The nonsteroidal anti-inflammatory drug (NSAID) naproxen
has also been studied. It is effective and may be easier to use than
aspirin.
- Heart failure may require digitalis.
- Administer prophylaxis to patients who have developed ARF. Patients
with ARF should receive prophylaxis against future GABHS infections.
Available regimens include benzathine penicillin G 1.2 million U IM
every month, penicillin V 200,000 U or 250 mg PO bid, or erythromycin
250 mg PO bid. Most authorities suggest that prophylaxis be given for 5
years. For those who have rheumatic carditis, some authorities suggest
life-long prophylaxis.
- Haloperidol may be helpful in controlling chorea.
Drug Category: Antimicrobials -- Because
of the direct link between ARF and group A beta-streptococcal infection,
the first step in treatment is the eradication of the organism.
Drug Name
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Penicillin G benzathine (Bicillin
LA) -- Interferes with synthesis of cell wall mucopeptide during
active multiplication resulting in bactericidal activity against
susceptible bacteria.
Because of its prolonged blood level,
several authors believe this to be the DOC. Others prefer daily
injections.
| Adult Dose |
2.4 million U IM once
|
| Pediatric Dose |
Infants and children <30 lb:
600,000 U IM once
Children 30-60 lb: 900,000 to 1.2 million U
IM once
| Contraindications |
Documented hypersensitivity
|
| Interactions |
Probenecid can increase penicillin
effectiveness by decreasing its clearance; coadministration of
tetracyclines can decrease penicillin effectiveness
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| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Caution in impaired renal
function | | |
Drug Name
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Penicillin G procaine
(Crysticillin, Wycillin) -- Long-acting parenteral penicillin (IM
only) indicated in the treatment of moderately severe infections
caused by penicillin G-sensitive microorganisms.
Some prefer
10-d therapy.
Administer by deep IM injection only into the
upper outer quadrant of the buttock. In infants and small children,
the midlateral aspect of the thigh may be the best site for
administration.
| Adult Dose |
2.4 million U IM once
|
| Pediatric Dose |
Infants and children <30 lb:
600,000 U IM
Children 30-60 lb: 900,000 to 1.2 million U IM
| Contraindications |
Documented hypersensitivity
|
| Interactions |
Increases risk of bleeding when
administered concurrently with warfarin; ethacrynic acid, aspirin,
indomethacin, and furosemide may compete with penicillin G for renal
tubular secretion increasing penicillin serum concentrations
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Never use IV route to administer
penicillin G procaine; administer >10 d to eliminate organism and
prevent complications, such as endocarditis and rheumatic fever;
perform cultures after treatment to confirm streptococci
eradication | | |
Drug Name
|
Penicillin VK (Beepen-VK,
Betapen-VK, Robicillin VK, Veetids) -- Inhibits the biosynthesis of
the cell-wall mucopeptide and is effective during the stage of
active multiplication. Inadequate concentrations may produce only
bacteriostatic effects. Penicillin VK is the oral alternative for
the treatment of rheumatic fever.
|
| Adult Dose |
500 mg PO q6h for 10 d
|
| Pediatric Dose |
<12 years: 25-50 mg/kg/d PO
divided tid/qid; not to exceed 3 g/d
>12 years: Administer
as in adults
| Contraindications |
Documented hypersensitivity
|
| Interactions |
Probenecid may increase
effectiveness by decreasing clearance; tetracyclines are
bacteriostatic, causing a decrease in the effectiveness of
penicillins when administered concurrently
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Caution in renal
impairment | |
Drug Name
|
Erythromycin (EES, E-Mycin,
Ery-Tab, Erythrocin) -- DOC for patients allergic to penicillin;
inhibits RNA-dependent protein synthesis, possibly by stimulating
the dissociation of peptidyl t-RNA from ribosomes, which inhibits
bacterial growth.
In children, age, weight, and the severity
of infection determine the proper dosage. When bid dosing is
desired, one-half the daily dose may be administered q12h. For more
severe infections, the dose may be doubled.
| Adult Dose |
1 g/d PO divided bid for 10 d
|
| Pediatric Dose |
30-50 mg/kg/d PO divided bid
|
| Contraindications |
Documented hypersensitivity;
hepatic impairment
|
| Interactions |
Coadministration may increase
toxicity of theophylline, digoxin, carbamazepine, and cyclosporine;
may potentiate anticoagulant effects of warfarin; coadministration
with lovastatin and simvastatin, increases risk of rhabdomyolysis
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Caution in liver disease; estolate
formulation may cause cholestatic jaundice; GI adverse effects are
common (give doses pc); discontinue use if nausea, vomiting,
malaise, abdominal colic, or fever occur | | Drug Category: Glucocorticoids -- Possess
anti-inflammatory (ie, glucocorticoid) and salt retaining (ie,
mineralocorticoid) properties. Glucocorticoids cause profound and varied
metabolic effects. In addition, these agents modify the body's immune
response to diverse stimuli.
Drug Name
|
Prednisone (Deltasone) -- Patients
with carditis require prednisone instead of aspirin. The goal is to
decrease myocardial inflammation.
Useful in treatment of
inflammatory and autoimmune disorders. Reversing increased capillary
permeability and suppressing PMN activity may decrease inflammation.
| Adult Dose |
60-80 mg/d PO
|
| Pediatric Dose |
2 mg/kg/d PO
|
| Contraindications |
Documented hypersensitivity; viral,
fungal, or tubercular skin infections
|
| Interactions |
Coadministration with estrogens may
decrease clearance; concurrent use with digoxin, may cause digitalis
toxicity secondary to hypokalemia; phenobarbital, phenytoin, and
rifampin may increase metabolism of glucocorticoids (consider
increasing maintenance dose); monitor for hypokalemia with
coadministration of diuretics
|
| Pregnancy |
B - Usually safe but benefits must
outweigh the risks.
|
| Precautions |
Abrupt discontinuation of
glucocorticoids may cause adrenal crisis; hyperglycemia, edema,
osteonecrosis, myopathy, peptic ulcer disease, hypokalemia,
osteoporosis, euphoria, psychosis, myasthenia gravis, growth
suppression, and infections may occur with glucocorticoid
use | | Drug Category: Neuroleptic
agents -- May help to control the chorea associated with ARF.
Drug Name
|
Haloperidol (Haldol) -- A dopamine
receptor blocker useful in the treatment of irregular spasmodic
movements of limbs or facial muscles.
|
| Adult Dose |
0.5-2 mg PO bid/tid
|
| Pediatric Dose |
<3 years: Not
established
3-12 years: 0.05 mg/kg/d or 0.25-0.5 mg/d
bid/tid; increase by 0.25-0.5 mg q5-7d
Maintenance dose:
0.05-0.15 mg/kg/d bid/tid; not to exceed 0.15 mg/kg/d
>12
years: Administer as in adults
| Contraindications |
Documented hypersensitivity;
narrow-angle glaucoma; bone marrow suppression; severe cardiac and
liver disease; severe hypotension; subcortical brain damage
|
| Interactions |
May increase tricyclic
antidepressant serum-concentrations and hypotensive action of
antihypertensive agents; phenobarbital or carbamazepine may decrease
effects; coadministration with anticholinergics may increase
intraocular pressure; encephalopathy-like syndrome associated with
concurrent administration of lithium and haloperidol
|
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Severe neurotoxicity manifesting as
rigidity, or inability to walk or talk may occur in patients with
thyrotoxicosis also receiving antipsychotics; if IV/IM, watch for
hypotension; caution in CNS depression or cardiac disease; if
history of seizures, benefits must outweigh risks; significant
increase in body temperature may indicate intolerance to
antipsychotics (discontinue if this occurs) | | Drug Category: Inotropic agents -- Some believe
that digoxin may be helpful in congestive heart failure.
Drug Name
|
Digoxin (Lanoxin) -- Cardiac
glycoside with direct inotropic effects and indirect effects on the
cardiovascular system.
Effects on the myocardium involve a
direct action on cardiac muscle that increases myocardial systolic
contractions and indirect actions that result in increased carotid
sinus nerve activity and enhanced sympathetic withdrawal for any
given increase in mean arterial pressure.
| Adult Dose |
0.125-0.375 mg PO qd
|
| Pediatric Dose |
Digitalizing dose:
2-5
years: 30-40 mcg/kg PO
5-10 years: 20-35 mcg/kg
PO
>10 years: 10-15 mcg/kg PO
Maintenance dose:
25-35% of PO loading dose
| Contraindications |
Documented hypersensitivity;
beriberi heart disease; idiopathic hypertrophic subaortic stenosis;
constrictive pericarditis; carotid sinus syndrome
|
| Interactions |
Medications that may increase
digoxin levels include alprazolam, benzodiazepines, bepridil,
captopril, cyclosporine, propafenone, propantheline, quinidine,
diltiazem, aminoglycosides, oral amiodarone, anticholinergics,
diphenoxylate, erythromycin, felodipine, flecainide,
hydroxychloroquine, itraconazole, nifedipine, omeprazole, quinine,
ibuprofen, indomethacin, esmolol, tetracycline, tolbutamide, and
verapamil; medications that may decrease serum digoxin levels
include aminoglutethimide, antihistamines, cholestyramine, neomycin,
penicillamine, aminoglycosides, oral colestipol, hydantoins,
hypoglycemic agents, antineoplastic treatment combinations
(including carmustine, bleomycin, methotrexate, cytarabine,
doxorubicin, cyclophosphamide, vincristine, procarbazine), aluminum
or magnesium antacids, rifampin, sucralfate, sulfasalazine,
barbiturates, kaolin/pectin, and aminosalicylic acid
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| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Hypokalemia may reduce positive
inotropic effect of digitalis; IV calcium may produce arrhythmias in
digitalized patients; hypercalcemia predisposes patient to digitalis
toxicity, and hypocalcemia can make digoxin ineffective until serum
calcium levels are within reference range; magnesium replacement
therapy must be instituted in patients with hypomagnesemia to
prevent digitalis toxicity; patients diagnosed with incomplete AV
block may progress to complete block when treated with digoxin;
exercise caution in hypothyroidism, hypoxia, and acute
myocarditis | | | Drug Category:
Anti-inflammatory agents -- Reduce the inflammation
associated with the disease process. Joints and heart are the targets.
Drug Name
|
Aspirin (Ascriptin, Bayer Buffered
Aspirin, Ecotrin) -- Treats mild to moderate pain. Inhibits
prostaglandin synthesis, which prevents formation of
platelet-aggregating thromboxane A2.
|
| Adult Dose |
6-8 g/d PO for 2 mo or until ESR
has returned to normal
|
| Pediatric Dose |
80-100 mg/kg/d PO for 2 mo or until
ESR has returned to normal
|
| Contraindications |
Documented hypersensitivity; liver
damage, hypoprothrombinemia, vitamin K deficiency, bleeding
disorders, asthma; because of association with Reye syndrome, do not
use in children (<16 y) with flu
|
| Interactions |
Effects may decrease with antacids
and urinary alkalinizers; corticosteroids decrease salicylate serum
levels; additive hypoprothrombinemic effects and increased bleeding
time may occur with coadministration of anticoagulants; may
antagonize uricosuric effects of probenecid and increase toxicity of
phenytoin and valproic acid; doses >2 g/d may potentiate glucose
lowering effect of sulfonylurea drugs
|
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Pregnancy category D if full dose
given during third trimester; may cause transient decrease in renal
function and aggravate chronic kidney disease; avoid use in patients
with severe anemia, with history of blood coagulation defects, or
taking anticoagulants |
Drug Name
|
Naproxen (Anaprox, Naprelan,
Naprosyn) -- For relief of mild to moderate pain; inhibits
inflammatory reactions and pain by decreasing activity of
cyclo-oxygenase, which is responsible for prostaglandin
synthesis.
NSAIDs decrease intraglomerular pressure and
decrease proteinuria.
| Adult Dose |
250-500 mg PO bid; may increase to
1.5 g/d for limited periods
|
| Pediatric Dose |
<2 years: Not
established
>2 years: 2.5 mg/kg/dose PO; not to exceed 10
mg/kg/d
| Contraindications |
Documented hypersensitivity; peptic
ulcer disease; recent GI bleeding or perforation; renal
insufficiency
|
| Interactions |
Coadministration with aspirin
increases risk of inducing serious NSAID-related side effects;
probenecid may increase concentrations and, possibly, toxicity of
NSAIDs; may decrease effect of hydralazine, captopril, and
beta-blockers; may decrease diuretic effects of furosemide and
thiazides; may increase PT when taking anticoagulants (instruct
patients to watch for signs of bleeding); may increase risk of
methotrexate toxicity; phenytoin levels may be increased when
administered concurrently
|
| Pregnancy |
C - Safety for use during pregnancy
has not been established.
|
| Precautions |
Pregnancy category D in third
trimester; acute renal insufficiency, interstitial nephritis,
hyperkalemia, hyponatremia, and renal papillary necrosis may occur;
patients with preexisting renal disease or compromised renal
perfusion risk acute renal failure; leukopenia occurs rarely, is
transient, and usually returns to normal during therapy; persistent
leukopenia, granulocytopenia, or thrombocytopenia warrants further
evaluation and may require discontinuation of drug | | |
FOLLOW-UP
Complications:
- Congestive heart failure (CHF)
Prognosis:
- Sequelae are limited to the heart and are dependent upon the
severity of the carditis during the acute attack.
MISCELLANEOUS
Medical/Legal Pitfalls:
- Diagnosis of acute rheumatic fever usually is evident if considered
in the differential of a child with suggestive signs and symptoms. The
primary medicolegal pitfall is not making the diagnosis in a timely
fashion. Failure to diagnose translates into failure to treat.
Complications may occur in any patient but are much more likely if
treatment is delayed.
- Concern also arises over failure to recognize and treat a
streptococcal infection that eventually leads to ARF.
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