Fever: A Pediatric Rheumatologist’s Perspective

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PEDIATRIC RHEUMATOLOGY FOR THE GENERALIST

Fever: A Pediatric Rheumatologist’s Perspective

http://www.pedrheumonlinejournal.org/October/fever.htm

Lynn Punaro

Department of Pediatrics, Texas ish Rite Hospital

Dallas, Texas

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

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 North America, Brucella is more commonly seen in Europe and

South America. It is associated with the ingestion of unpasteurized milk

and it’s products. Fever, arthralgia or arthritis, and

hepatosplenomegaly are the most common presenting features.(14) Younger

children most often have involvement of a hip or knee. Older adolescents

usually have spondylitis or sacroilitis (15).

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 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.

Kawasaki Disease

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 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.

Correspondence to:

Marilyn Punaro, MD

Texas ish Rite Hospital

2222 Welborn Dallas, TX 75219

Phone: 214-559-7855 fax: 214-559-7835

Email: mpunaro@...