PEDIATRIC RHEUMATOLOGY FOR THE GENERALIST
Fever: A Pediatric Rheumatologist’s
Perspective
Lynn Punaro
Department of Pediatrics,
Key Words: Fever, Arthritis, Rheumatic Disease, Fevers of Unknown Origin (FUOs)
Correspondence to:
Marilyn Punaro, MD
Texas Scottish Rite Hospital
2222 Welborn
Dallas, TX 75219
Phone: 214-559-7855 fax: 214-559-7835
Email:
mpunaro@tsrh.org
Abstract
Unexplained fever is one of the most common conditions evaluated by the pediatric
rheumatologist. Indeed, fever is the predominant symptom of certain rheumatic
diseases, and 5-20% of fevers of unknown origin (FUOs)
are caused by collagen vascular diseases (1-5).
Arthritis is simply the presence of swelling in a joint. Like fever, it
is a non-specific finding. The presence of arthritis narrows the differential
diagnosis of an unexplained fever, but the list of potential etiologies is
still extensive. While an exhaustive review of this topic is beyond the scope
of a single article, a systematic approach to diagnosis of the child with fever
and arthritis is presented, including a discussion of the more common
conditions resulting in these symptoms.
The approach is based on a thorough history and physical exam, combined
with an understanding of the clinical presentation of rheumatic diseases, and
the recognition of patterns of signs and symptoms that guide in the selection
and evaluation of laboratory tests, and ultimately in establishing the
diagnosis.
Conditions that mimic a collagen vascular disease (see Diagnostic Considerations #1)
Most large case series of FUOs
divide the causative diagnoses into four major disease categories: infections,
malignancies, collagen vascular diseases, and miscellaneous. When evaluating an unexplained fever in the
context of symptoms suggestive of a collagen vascular disease, it is still
necessary to systematically consider diagnoses for all four disease
categories. It is well known that some
rheumatic diseases can mimic other conditions; and the reverse is also
true. One of the more difficult problems
facing the rheumatologist is the distinction between conditions that mimic a
rheumatic disorder and that may require prompt and specific treatment such as
antibiotics, and actual collagen vascular diseases that require immunosuppression.
Some rheumatic disorders will evolve over weeks or even months before a
definitive diagnosis can be established; some remain both clinical diagnoses as
well as diagnoses of exclusion. Thus, it is important to first consider other
possible etiologies.
Infection
Infections represent the most frequent cause of
fever in children (1-5). A thorough
search for infectious etiologies which include cultures of blood and urine as
well as any additional testing indicated by the history or physical examination
should be conducted prior to consulting the rheumatologist. Musculoskeletal complaints associated with
active infection usually occur in three settings (6): 1) localized infection of
a joint or bone, 2) arthritis occurring as a manifestation of a systemic
infection, or 3) arthritis following an acute infection as the result of
immunologic cross-reactivity to an epitope present on the infecting organism.
Localized Infection.
A single joint with the acute onset of
unexplained pain and swelling in a febrile patient must be considered a septic
joint until proven otherwise. Typically,
the fever pattern is high grade, between 100-104 F, (37.8- 40 C), consistent
with a closed space bacterial infection (6). The involved joint is usually
warm, swollen, sometimes erythematous and very
painful to palpation and range of motion testing. Septic arthritis most
commonly affects the knees, hips, ankles or elbows and is usually monoarticular, but can involve several joints (7). Septic
arthritis may be a component of a more systemic infection; therefore, blood
cultures should be drawn in all patients. Cultures of other sites may also be
indicated. Prompt aspiration and evaluation of the synovial
fluid for infection is essential since considerable morbidity is associated
with a delay in treatment.
Fever associated with bone pain should suggest osteomyelitis, which may be associated with a septic joint
or arise as an isolated condition. A prior history of trauma is present in some
patients. Typically the infection is located in the metaphysis
and pressure over the affected area elicits pain. Two thirds of patients have
involvement of the lower extremity (8).
Fever associated with gait abnormalities and hip or groin pain may
represent pelvic osteomyelitis (9). Bone scans,
although non-specific, may be useful in localizing the infection, especially if
the axial skeleton is involved. Biopsy and culture of bone is necessary to
accurately identify an organism.
Recurrent episodes of culture negative osteomyelitis
with fever and lytic bone lesions may represent
chronic recurrent multifocal osteomyelitis
(CRMO), a benign idiopathic inflammatory condition.(10)
Systemic Infection
Gonococcal arthritis usually occurs in the context of a
systemic illness manifested by fever, chills, rash and arthritis. It occurs most commonly in adolescent girls
during or just after menstruation. The arthritis is initially migratory and may
result in a purulent arthritis in several joints. Wrist involvement with
associated tenosynovitis is characteristic as it is a
sparse vesiculopustular rash. Most patients deny
genitourinary symptoms. Cultures of both blood and synovial
fluid may be negative, so it is important to culture multiple sites including
the vesicle, genital tract, rectum, and pharynx. Prompt response to antibiotic
therapy is typical (11).
In endemic areas, Lyme
disease should be considered in patients with fever, flu-like symptoms and
migratory arthralgia or arthritis, especially if
followed by an erythema chronicum
migrans rash (12, 13). False positive results are common with the
enzyme-immunoassay, so clinical characteristics consistent with Lyme and a confirmatory Western blot are important in
establishing this diagnosis.
Rare in
Bartonella (cat scratch disease) can also mimic a collagen
vascular disease. Cases of arthritis and myositis
associated with fever have been reported in several children (16, 17).
Although many viruses cause arthralgia
with fever, true viral arthritis is relatively rare. The most common organisms associated with
viral arthritis are parvovirus B-19, rubella and hepatitis B. Viral arthritis is generally migratory,
self-limited and non-deforming, although the arthritis associated with
parvovirus can last for months in some cases. HIV has been associated with a
variety of rheumatic syndromes including reactive arthritis, Reiter’s, and psoriasiform arthritis in adults, but appears to be much
less common in children (6, 11).
Post-Infectious Causes.
Arthritis is the most common major
manifestation of Acute Rheumatic Fever (ARF), occurring in approximately 70% of
patients (7). ARF should be considered
in the diagnosis of any acute onset arthritis associated with fever. Initially, the arthritis of ARF may resemble
a septic joint. Typically a single large joint such as a knee, ankle, elbow or
wrist becomes acutely painful, red, warm, and swollen. Pain is the predominant symptom. As that
joint spontaneously improves over hours to a week, a different joint becomes
involved. The arthritis then follows a migratory and often additive pattern (6). Fever occurs in most patients, but is
variable in duration and intensity (18).
Many patients will recall a pharyngitis two or
three weeks prior to the onset of the arthritis. The most feared complication
of ARF is rheumatic heart disease; this underscores the importance of a
complete physical exam in any patient with fever and arthritis. The detection
of a new cardiac murmur may provide the clue that allows the diagnosis of an
acutely swollen knee. Diagnosis is based on clinical criteria, and the demonstration
of prior streptococcal infection is required.
Not all children developing articular
symptoms and fever after a Group A streptococcal infection will fulfill the
modified Jones criteria for the diagnosis of acute rheumatic fever. Post streptococcal reactive arthritis is
characterized by a shorter latency period (<10 days) after strep infection
then ARF, as well as a distinctive non-migratory, persistent arthritis which is
poorly responsive to salicylates or non-steroidal
inflammatory medications. The need for
penicillin prophylaxis in this group is controversial. (19)
Reactive arthritis refers to an inflammatory
arthritis that appears to be secondary to an immunologic response to infection,
typically of the gastrointestinal or genitourinary tract. The presence of a certain genetic background,
specifically the haplotype HLA-B27, increases the
likelihood of developing this condition.
These patients may present with fever, weight loss, arthralgia,
myalgia, and arthritis several weeks after an
infection with Shigella, Salmonella, Yersinia, Campylobacter or Chlamydia. Other common symptoms
include mucocutaneous involvement such as oral or
genital ulcers, and ocular inflammation (11).
Reiter’s syndrome, one possible presentation of reactive arthritis, is
the triad of arthritis, conjunctivitis, and urethritis.
Patients usually have low-grade fever, and involvement of a few lower extremity
large joints in an asymmetric pattern, although multiple small joint
involvement can occur. Enthesitis and dactylitis also may be present. Most patients resolve
within a few months, but some will have recurrent episodes and may evolve into
a chronic spondyloarthropathy (7).
Malignancy
As
with infection, malignancy must always be considered in the differential
diagnosis of fever with musculoskeletal complaints. In leukemia, the fever is usually low grade,
although as many as 30% of children will have high fevers (20). The arthritis
typically involves fewer than 5 joints, and may be migratory or transient. Pain
is typically out of proportion to the swelling. Other features that suggest
malignancy are non-articular bone pain, back pain,
and night sweats (20, 21). The initial CBC may be normal in these patients, but
a discordant ESR and platelet count (i.e., highly elevated ESR with a normal
platelet count) may be present. Elevated
uric acid or lactic dehydrogenase levels are also
suggestive (22).
Inflammatory bowel disease
The presence of overlapping symptoms may make it difficult
to distinguish the initial presentation of inflammatory bowel disease (IBD)
from that of a collagen vascular disease.
Patients often display non-specific signs of inflammation such as fever,
weight loss, anemia and elevated acute phase reactants. Arthritis is a common
extra intestinal manifestation occurring in 10-20% of patients, and may precede
the onset of gastrointestinal symptoms (7). Usually the arthritis is episodic,
lasting a period of weeks, and is most commonly oligoarticular,
involving the large joints of the lower extremity (23, 24). Other extra-intestinal features suggestive of
IBD include uveitis, erythema
nodosum, pyoderma gangrenosum, and oral or perianal
ulcers (23). A detailed history of
gastrointestinal symptoms is very important in this context and if negative,
may need to be reassessed over time. Diagnosis is based on consistent clinical
features in conjunction with compatible endoscopic
and radiographic findings.
Collagen vascular diseases (see Diagnostic
Considerations #2)
The most common collagen vascular diseases cited
in pediatric FUO case series are systemic onset juvenile arthritis (SOJA) and
systemic lupus erythematosus (SLE) (1-5). As with most collagen vascular diseases,
diagnosis for these conditions is based on a set of criteria rather than a
single definitive test. In rheumatic
diseases, any single piece of information is almost never diagnostic. Serologic testing is very non-specific, and
must be interpreted with caution since the likelihood of false-positive results
is extremely high, unless tests are ordered in the context of symptoms
suggestive of a specific
disorder. A complete history, a thorough
and skilled physical examination, and familiarity with and recognition of rheumatic
disease patterns are essential in the diagnosis of collagen vascular
diseases. Close clinical follow-up and
re-evaluation are sometimes necessary to establish a diagnosis.
Systemic onset juvenile idiopathic
arthritis
Systemic onset juvenile arthritis is the collagen
vascular disease most likely to present as an FUO. In 4 large pediatric FUO reviews, systemic
onset juvenile arthritis represented over half of all patients with collagen
vascular disease presenting as fever (1-4).
Indeed, high spiking fever is the predominant symptom seen in of this
type of onset. Characteristically the fever is high grade, reaching 39 C,
(102.2 F), or higher once or twice daily before returning to baseline. Spikes
of fever often occur in the afternoon or evening. This quotidian fever pattern
is quite distinct from the usual more hectic fever seen in most infectious
conditions which has less predictable spikes and which may not return to
baseline. During afebrile periods the child with SOJA
may appear surprisingly well. An
evanescent salmon pink macular rash frequently accompanies episodes of fever.
The rash is most frequently seen on the trunk and proximal extremities. It
exhibits the Koebner phenomenon, and may be pruritic. Patients may also have hepatosplenomegaly,
lymphadenopathy, or pericarditis
(8). Uveitis
is rare in systemic onset juvenile arthritis, and its presence should prompt a
review of other possible etiologies, including sarcoidosis
or Chronic Infantile Neurologic Cutaneous
and Articular syndrome (CINCA) /Neonatal Onset
Multi-system Inflammatory disease (NOMID). (25). The arthritis that allows the
definitive diagnosis of SOJA may be present at onset, but can take months and
even years to evolve (7).
Systemic onset juvenile arthritis
cannot be diagnosed by serologic means and remains both a clinical diagnosis
and a diagnosis of exclusion. Typical laboratory results (leukocytosis
with a neutrophilic shift, anemia, thrombocytosis, and highly elevated erythrocyte
sedimentation rate) reflect the systemic inflammation, but are non-specific.
Rheumatoid factor and antinuclear antibody tests are usually negative. If the patient has atypical features, it is
extremely important to pursue differential diagnosis including infectious
etiologies, acute rheumatic fever, malignancy, and other forms of collagen
vascular disease, particularly vasculitis.
Fever is unusual in other forms of
juvenile idiopathic arthritis, although polyarticular
onset patients may have low-grade fever.
Systemic lupus erythematosus
The majority of lupus patients will experience
fever and other constitutional symptoms, especially at onset. The fever of
active lupus is typically mild to moderate, 99.5-101.5 F, (37–38.6 C), and can be either persistent or
intermittent. Occasionally fevers can be high grade, 102-105 F, (39- 40.6 C),
and rarely SLE may present as an FUO (6). Systemic lupus is much more common in
girls and has a peak childhood onset between 11-15 years. It is rare below the
age of 5 years (26). The clinical manifestations of lupus are protean. Although
SLE can present with a single affected organ system, multisystem
disease is more characteristic and is one of the features that should suggest
this diagnosis. Most children will have cutaneous findings with approximately half exhibiting a malar erythema. Photosensitivity, alopecia, and oral ulcers
are also seen. Arthritis and arthralgia are common
(26, 27). The arthritis can be transient, migratory or persistent, and is
usually painful. Small joints of the hand, wrists with an accompanying tenosynovitis, elbows, shoulders, knees and ankles are the
most commonly involved joints (7). Nephritis is more common in children with
SLE than in adults, involving at least 80% of patients, usually early in the
course. CNS disease is another major
source of morbidity and mortality in lupus (26). Its manifestations vary widely, ranging from
psychosis and seizures to cerebrovascular accidents
and headaches. Serositis, Raynaud’s,
hepatosplenomegaly, myositis,
and lymphadenopathy are also seen.
The diagnosis of SLE is clinical with
confirmatory lab tests. The importance of having a clinical picture consistent
with lupus prior to drawing immunologic serology must be emphasized. The yield of serologic tests such as ANA,
rheumatoid factor, Anti-Neutrophil Cytoplasmic Antibodies (ANCA), Extractable Nuclear Antigen
(ENA), and antibody to double-stranded DNA is relatively low, and false
positive results are common, unless the tests are drawn in a context of
symptoms suggestive of a specific disorder (28). However, having said this,
laboratory testing is essential in the diagnosis of SLE.
Routine
laboratory tests such as the CBC and urinalysis are usually abnormal and may
suggest the diagnosis with findings of leucopoenia, lymphopenia,
anemia, thrombocytopenia, proteinuria, hematuria, or red blood cell casts. A positive ANA is the hallmark of SLE, and is
present in virtually all active patients (7).
A negative ANA indicates that the diagnosis of SLE is very unlikely.
Anti-DNA antibodies are present in most patients and are quite specific. A
whole host of other autoantibodies, including
rheumatoid factor and antiphospholipid antibodies may
be present. Other tests that should
suggest the diagnosis are coagulation abnormalities, and depressed complement
levels.
Other systemic connective tissue diseases
Fever is present to some degree in the onset of juvenile
dermatomyositis (JDM) in about two thirds of patients, but rarely dominates the
clinical picture (29). Muscle weakness
and pain are usually present, but if not specifically sought, may be missed,
particularly in a younger child in whom these symptoms may be misinterpreted as
clinginess or irritability. Fortunately, most children with inflammatory myositis will exhibit typical rash: heliotrope, Gottron’s and periungal erythema. Periorbital, facial, or more generalized subcutaneous edema
without proteinuria should also suggest this
diagnosis. Elevation of transaminases without
evidence of liver disease should prompt assessment of muscle enzymes. It is
best to check a panel of muscle enzymes (CPK, aldolase,
LDH, AST and ALT) since any one enzyme may be normal in the presence of active myositis (30). Diagnosis is based on a combination of
clinical and laboratory findings.
Mixed connective tissue disease (MCTD) is
characterized by the clinical features of rheumatoid arthritis, scleroderma,
SLE, and dermatomyositis and a positive antibody titer to the ribonuclear protein (RNP) component of extractable nuclear
antigen (ENA). Fever is common at onset and MCTD has been reported as a cause
of FUO (6).
Vasculitis (see Diagnostic Considerations #3)
Vasculitis is relatively rare. Nevertheless, it is very important to consider
it in the differential diagnosis of unexplained fever, since failure to
diagnose and treat vasculitis in a timely manner may
have catastrophic consequences for the patient.
Invasive procedures such as angiography or biopsy may be required to
establish the diagnosis in some types of vasculitis,
so pattern recognition is especially important to guide investigations.
The most common
childhood vasculitis that presents with fever is
Kawasaki Disease (KD). This condition
occurs primarily in young children with 80% of cases presenting under the age
of 4 years. Fever is a predominant
feature and is required for diagnosis. It is typically present at onset, high
grade, >39 C (>102.2 F), and remittent.
Untreated, the fever usually lasts1-2 weeks, but may persist up to a
month. Rarely, persistent fever may be almost the sole manifestation of KD,
with diagnosis later revealed by the finding of coronary aneurysms on
echocardiography (31). Other symptoms
typically seen during the initial stages of illness include bilateral conjunctival injection without exudate,
often associated with an anterior uveitis, dry
swollen cracked lips, erythema of the oral cavity,
and a strawberry tongue. The child’s
hands and feet become diffusely swollen, painful and erythematous
on the palms and soles followed several weeks later by periungal
desquamation. Rashes on the trunk, often in the perineal
area, can be maculopapular, scarletinaform
or erythema multiforme. The adenopathy of
KD is typically a solitary node >1.5 cm in the anterior cervical chain.
Other characteristic features include extreme irritability, aseptic meningitis,
diarrhea, and otitis media (31). Arthralgia, myalgia, and more rarely arthritis can occur. The arthritis
usually develops during the second week of illness and involves the large
joints of the lower extremity. Small
joints in the hand may also be involved, but are difficult to distinguish from
the edema in the digits (7).
Lab findings reveal systemic inflammation, but
are nonspecific. The acute phase is
characterized by a leukocytosis with a neutrophilic predominance, mild anemia, and elevated acute
phase reactants. Mildly elevated liver enzymes and a sterile pyuria can also be seen. Thrombocytosis
typically develops in the second week (7).
Antinuclear antibody tests and rheumatoid factors are negative.
Diagnosis is based on clinical
criteria. The differential diagnosis includes a variety of infections, toxic drug
reactions, systemic onset juvenile arthritis and polyarteritis
nodosa (31).
Not all patients with KD will fulfill the diagnostic criteria. It is
therefore important to consider this diagnosis even in incomplete or atypical
cases, since the failure to administer IVIG in a timely fashion may result in
very serious cardiac consequences.
Unfortunately, incomplete KD appears to be more common in infants, the
group with the highest risk of developing coronary aneurysms (32). Fever generally responds to treatment with
IVIG within 1-2 days (31). If the fever
recurs or persists despite IVIG, or if the presentation is atypical,
differential diagnosis must be reconsidered and the involvement of a pediatric
rheumatologist is recommended.
Other Forms of Vasculitis
The other
common form of vasculitis in childhood is Henoch-Schonlein purpura
(HSP). Although low-grade fever is not
unusual in this condition, fever is seldom a major symptom. Typically the
clinical picture is dominated by purpuric rash,
abdominal pain, arthritis, and renal involvement.
Polyarteritis nodosa is very rare,
but may present insidiously with high or low-grade fever in a remittent
pattern; arthritis, diffuse muscle pain,
abdominal pain, and cutaneous findings are common.
Other suggestive findings include nephritis, testicular pain and peripheral
neuropathy.
Fever can also be a symptom in most other forms
of vasculitis.
Microscopic polyarteritis nodosa
is characterized by pulmonary hemorrhage, a rapidly progressive pauci-immune nephritis and a perinuclear
staining pattern of antineutrophil cytoplasmic antibodies (p-ANCA) with specificity for myeloperoxidase (MPO).
In contrast, Wegener’s Granulomatosis
typically has ANCA in a cytoplasmic pattern (c-ANCA)
specific to proteinase 3 (PR3) as well as a granulomatous vasculitis of the
upper and lower respiratory tracts and a pauci-immune
nephrititis. Churg-Strauss vasculitis
typically develops after a long history of asthma and is characterized by eosinophilia, shifting pulmonary infiltrates, and neuropathy.
Takayasu’s Arteritis
is most common in young women and may have a subtle and insidious
presentation. The aorta and its major
branches are typically affected and loss of brachial pulse, and claudication of extremities may result. Hypersensitivity vasculitis
usually begins a week or two after exposure to a medication and is
characterized by rash (palpable purpura, urticaria or nodules), arthritis/arthralgia
and myalgia.
Features that suggest vasculitis
include unexplained constitutional symptoms such as fever, fatigue and weight
loss associated with skin lesions, neurologic
symptoms, pain or inflammation of the joints or muscle, hypertension and
pulmonary infiltrates or hemorrhage. Suggestive lab findings include evidence
of inflammation (leucocytosis, anemia, elevated acute
phase reactants), eosinophilia, hematuria,
and the presence of antineutrophilic cytoplasmic antibodies (ANCA) (7).
Bechet’s Disease
Bechet’s
Disease, a vasculitis of unknown etiology, was
originally described as the triad of recurrent apthous
stomatitis, genital ulcerations, and uveitis. Fever is a common symptom and Bechet’s
disease has been occasionally reported as the cause of FUO. Other clinical
features include erythema nodosum,
arthritis, neurologic involvement and pathergy (the development of a pustular
rash at the site of needle injection). Bowel disease virtually identical to
that seen in IBD can occur in Bechet’s Disease,
making the differentiation between these two conditions difficult (33,
34).
Sarcoidosis
Sarcoidosis is a rare multisystem
inflammatory disease of unknown etiology characterized by the presence of non-caseating granulomas. Age of
onset appears to affect the clinical presentation. Older children have similar
features to adult onset disease, with prominent pulmonary involvement,
especially hilar adenopathy
and lymphadenopathy, and usually have a milder course
(35). Children presenting under the age
of four more typically have the triad of uveitis,
rash, and arthritis. They often have significant fever, and may be misdiagnosed
as systemic onset juvenile arthritis. The arthritis is initially very boggy,
and painless with prominent tenosynovitis and minimal
limitation. Over time it may become more destructive and painful. Uveitis can be
severe and can result in blindness. The
presence of uveitis is a feature that helps
distinguish juvenile onset sarcoid from systemic
onset JA. Another distinguishing feature
is the rash, which is usually papular, or nodular in sarcoidosis, in contrast to the salmon pink macules seen in SOJA.
Pulmonary disease is seldom seen in the early onset patients. Angiotensin converting enzyme (ACE) levels are also less
likely to be positive (35-37). Diagnosis
is clinical and supported by histologic evidence of
non-caseating granulomas in
affected tissues.
Recurrent Episodic Fevers (see Diagnostic Considerations #4)
Some children with unexplained fever present with
a prolonged course of episodes of high grade fever lasting several days to
several weeks separated by fever free intervals of variable duration. Children
with this fever pattern tend to present at an earlier age and to have higher
maximal temperatures than those presenting as classic FUO (38). Although the term “periodic fever syndromes “
has been used to describe this presentation, most of the disorders classified
in this group have fevers that occur at irregular and unpredictable intervals
(39). An exception to this rule is the
PFAPA syndrome (periodic fever, apthous ulcers, pharyngitis and adenopathy) which
has episodes of high fever lasting an average of 3 days, and recurring at
regular intervals of 21-28 days, especially in the first year of disease. The
majority of cases occur in children less than 5 years of age. The most common
associated manifestations are cervical adenopathy, pharyngitis and apthous stomatitis. This condition is non-familial and diagnosis is
based on clinical criteria (40, 41).
Cyclic neutropenia also
exhibits regular intervals of fever and should be considered in the
differential diagnosis (40).
The identification and characterization of the
genes responsible for several of the familial periodic fever syndromes has
created an explosion of knowledge in this area. A brief overview of these
conditions is provided, and the interested reader is directed to several
excellent reviews (39-44).
Familial Mediterranean Fever (FMF) is an autosomal recessive disease occurring primarily in people
of eastern Mediterranean ancestry (40).
Most cases develop prior to the age of 20 years. The classic
presentation is fever with serositis, especially
peritonitis. Attacks typically last 1-3 days and are almost always associated
with pain in the abdomen, joints or chest (39).
Hyper IgD syndrome
(HIDS) is an autosomal recessive disease most
commonly seen in people of Dutch or French ancestry. The classic triad of
features is fever, cervical adenopathy and diarrhea.
A distinguishing feature of this condition is the early age of onset, usually
below the age of 1 year and it is frequently triggered by immunization. IgD levels are typically greater than 100 during attacks,
but diagnosis is based on genetic analysis (40, 43).
Tumor necrosis factor (TNF) receptor associated
periodic syndrome (TRAPS) is an autosomal dominant
disease. Distinguishing features of TRAPS include the longer duration of fever
episodes, some lasting weeks, periorbital edema, and
localized myalgias (39, 40).
Mutations in a single gene, CIAS1, appear to be
responsible for the auto-inflammatory syndromes of familial cold urticaria (FCU), Muckle-Wells
syndrome, and Chronic Infantile Neurological Cutaneous
and Articular Syndrome (CINCA)/Neonatal Onset Multisystem Inflammatory Disease (NOMID). FCU is characterized by cold induced episodes
of fever, urticaria, arthralgias,
and conjunctivis. Muckle-Wells
syndrome is similar, but is not triggered by cold, and patients eventually
develop sensorineural hearing loss (40). CINCA/NOMID is characterized by very early
onset of rash (often at birth), a characteristic arthropathy,
and involvement of the central nervous system including the sensory organs
accompanied by recurrent fever and inflammation. (44)
Both Bechet’s Disease
and Inflammatory Bowel Disease can present with a recurrent fever pattern (39,
40)
Evaluation
of the patient
History
A thorough history and physical are essential in
the evaluation of the patient with unexplained fever. Multiple pediatric FUO series indicate that the history and physical suggested the final diagnosis in
the vast majority of patients (1, 2, 5). A detailed history of the present illness
should be elicited including the duration, intensity, and pattern of the fever
as well as associated symptoms. A complete review of systems should be
performed with particular attention to musculoskeletal symptoms, mucocutaneous manifestations, ocular problems, and
gastrointestinal symptoms. A history of prior illness, particularly
streptococcal infection or a severe diarrhea before the onset of symptoms may
be an important clue. Travel history, exposure to pets, a complete list of
medications, family and social history may also provide pertinent information.
Physical Examination
Physical examination should include vital signs,
including blood pressure, height and weight plotted on a growth curve and a general
gestalt of the patient (does the patient appear acutely or chronically ill?).
Although weight loss was not found to be either a differential or prognostic
feature in Pizzo’s FUO series (2), in cases of very
prolonged or periodic fevers its absence can be reassuring. Eyes should be
carefully checked. Formal ophthalmologic
evaluation, especially slit lamp, is non-invasive and may provide diagnostic
clues. The presence of palatal vasculitis or apthous ulcers of the nose, mouth, or genital area should be
noted. Lymphadenopathy and hepatosplenomegaly
are non-specific but suggest a systemic process. Localized findings such as a
new heart murmur may be extremely useful in directing further workup. The skin
should be carefully assessed for petechiae, purpura, nodules, and edema, as well as rashes including
those distributed on the hand or in photosensitive areas. Each peripheral joint
should be assessed for swelling, heat, redness, tenderness and range of motion.
The child’s gait should be observed and the spine checked for tenderness and
range of motion. Long bones should be palpated for areas of tenderness. Muscle
weakness is often mistaken for generalized debilitation. Formal muscle testing as well as observation
of the patient’s ability to get on the exam table or sit up from a supine
position may detect specific abnormalities.
Laboratory and Radiology
Complete Blood Count (CBC)
Although a CBC does not provide
diagnostically specific information, it is still a useful screening test in the
evaluation of a patient with fever and arthritis. Leucocytosis,
anemia, and thrombocytosis all may indicate systemic
inflammation, and are commonly present in patients acutely ill with collagen vascular diseases (CVD). The
exception to this is SLE, with which an active patient often has leucopoenia,
and thrombocytopenia. Differential counts are also helpful since most patients
with CVD will have a neutrophilic predominance
(2). Eosinophilia
is suggestive of Churg-Strauss vasculitis.
A low white blood cell count, or thrombocytopenia in a patient without lupus,
or neutropenia should prompt consideration of
leukemia.
Urinalysis
Urinalysis
should always be performed since evidence of nephritis is an important clue
suggesting SLE or other forms of vasculitis.
Erythrocyte Sedimentation Rate
(ESR)
An
elevated ESR is present in most CVD patients with fever (3). This is a highly
non-specific test, but a normal result in an acutely ill patient makes the
diagnosis of an inflammatory condition much less likely. If a patient has a
high ESR but a normal platelet count, leukemia should be considered.
Serum Protein Analysis
A
low albumin and elevated globulin are another non-specific indication of
inflammation and have been found to be of use in suggesting CVD in some FUO
series (2, 3).
Immunologic Serology
As
previously discussed, the diagnostic yield of autoantibody tests is low unless
drawn in the context of findings suggestive of a specific collagen
vascular disease (28). The ANA is very non-specific and can be positive both in
infections and in malignancy.
Other
Additional testing such as muscle
enzymes, LDH, uric acid, infectious antibody titers or additional cultures
should be directed by specific indications. Plain films of joints are rarely
helpful, and in one FUO series, all such studies were negative, including those
in patients with active juvenile arthritis (3). The diagnostic yield of
abdominal ultrasound, gallium scans, indium scans, and bone marrow biopsies
have been shown to be low, except when directed by specific indication (4, 45,
46).
Conclusion
Five to twenty percent of FUOs in childhood are ultimately determined to be caused by
a collagen vascular disease. The most
common rheumatic diseases to present with fever in childhood are systemic onset
juvenile arthritis, systemic lupus, and Kawasaki Disease. In evaluating unexplained fever in the
context of symptoms suggestive of a rheumatic disorder, detailed history and a
thorough physical examination yield the most significant information. Familiarity with the clinical presentation of
rheumatic diseases and recognition of typical disease patterns is essential in
guiding laboratory and radiographic investigation and in the interpretation of
serologic studies. Conditions which may mimic rheumatic disorders, such as
infection or malignancy, must be considered in the differential diagnosis. Close clinical follow-up and re-evaluation of
the patient over time may be necessary to establish the diagnosis.
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