In the early 1960s, fever of unknown origin (FUO) was defined in adults as fever lasting longer than 3 weeks with no obvious diagnosis after 1 week of inpatient evaluation. A variety of definitions have subsequently been used to define FUO in children, ranging from 2 to 3 weeks of unexplained fever, with at least 1 week being an inpatient evaluation. Many investigators have settled on the following definition: a normal host with oral or rectal temperature greater than 38°C (100.4°F) at least twice a week for more than 3 weeks. It is important at the outset to make the distinction between FUO and the more common fever without localizing signs, defined as fever for less than 2 weeks' duration. The latter is relatively common in children and is usually caused by a viral illness.
Categories of Pediatric Fever of Unknown Origin
3. Rheumatologic disorders
Etiologies of pediatric FUO have changed during the past three decades. Recent studies suggest that as many as 50% of children who present with prolonged fever resolve their fever without determination of cause; this is in contrast to the 10% to 20% of patients who had resolution of fever without a diagnosis 20 to 30 years ago. It has been suggested that the increased percentage of undiagnosed cases is the result of advances in laboratory and radiographic testing that diagnose major infections and malignancies earlier. It is thought that most prolonged fevers in children that resolve without definitive diagnosis are the result of viral infections that are difficult to diagnose. The major issue in evaluating a child with FUO is to identify those children who have a potentially treatable infectious, malignant, or rheumatologic condition.
The evaluation of a child with FUO can be a considerable challenge given the extensive differential diagnosis involved. There are several recommended approaches; the first is to consider the specific organ systems often involved in prolonged fever.
Specific Areas associated with Pediatric Fever of Unknown Origin
Pediatric FUO can also be approached by considering not only specific areas of infection but also unusual bacteria associated with prolonged fever. The following list is a summary of some unusual pathogens involved in pediatric FUO.
Unusual Bacteria associated with Pediatric Fever of Unknown Origin
RMSF is found throughout the United States and is transmitted by a tick bite. The spring and summer months are the months of highest incidence. States with the highest incidence of RMSF include North Carolina and Oklahoma, although a large number of cases are reported in Arkansas, Tennessee, and Missouri. The rash of RMSF may begin as a macular exanthem, which then becomes petechial. Typical distribution is on the wrists and ankles, with spread to the trunk. The distribution of the exanthem on the palms and soles provides a major clue to the diagnosis.
The diagnosis of RMSF is established by serology, usually an indirect immunofluorescence antibody (IFA). Patients with an exposure history and clinical presentation compatible with RMSF should have empiric treatment given. The drug of choice is doxycycline, even though this drug is typically not given to children younger than 8 years of age.
Ehrlichiosis includes human monocytic ehrlichiosis (HME) and human granulocytic ehrlichiosis (HGE). HME occurs in the southeastern and south central United States, whereas HGE is reported in Wisconsin, Minnesota, Connecticut, and New York, as well as the West Coast. Ehrlichiosis is a febrile illness that is similar to RMSF but is less frequently associated with rash. Leukopenia, anemia, and hepatitis are frequent findings. Diagnosis is by serology. Doxycycline is
again the treatment of choice. The rickettsial diseases highlight the importance of a history regarding tick exposure and travel.
Viral Infections associated with Fever of Unknown Origin
will be made by organomegaly and elevation of the liver function tests. Diagnosis is by serology.
Kawasaki disease is an inflammatory condition of unknown etiology occurring predominantly in children younger than 5 years of age. Although an infectious cause is not proved, it should be considered in the differential diagnosis of prolonged fever in children.
Kawasaki disease is a clinical diagnosis in which the criteria are as follows:
Additional signs seen in Kawasaki disease include elevation of liver function tests, peripheral facial nerve palsy, sterile pyuria, aseptic meningitis, and hydrops of the gallbladder.
The major concern is that untreated Kawasaki disease will result in coronary artery aneurysms in about 20% of cases. Treatment is with intravenous immunoglobulin at a dose of 2 g/kg given over 10 to 12 hours. Additional treatment involves aspirin at high dose of 80 to 100 mg/kg in four divided doses for several days while fever resolves. Subsequently, aspirin is given at a dose of 3 to 5 mg/kg per day once a day for 6 to 8 weeks until the sedimentation rate and platelet count are normal.
There is increasing appreciation that infants younger than 6 months of age may have Kawasaki disease without having all clinical criteria necessary for diagnosis. It is concerning because these same young infants have a high incidence of subsequent coronary artery aneurysm formation. The term “atypical” or “incomplete” Kawasaki disease is currently used to describe children, typically young infants, who fail to meet the criteria for Kawasaki disease but have no other explanation for their clinical course and laboratory findings. Infants usually have persistent fever, extremely high sedimentation rate and C-reactive protein, and increasing platelet counts.
Kawasaki disease is typically seen in the first 5 years of life and should always be considered in children with prolonged fever. Although some cases of Kawasaki disease have all criteria manifesting at once, in many cases, the clinical manifestations have sequential appearance. When taking a history in a child with FUO, one should always specifically ask about swollen hands, conjunctivitis, and the appearance of rashes (Table 18.1).
TABLE 18.1. Specific Infections associated with Pediatric Fever of Unknown Origin
In addition to the infectious differential diagnosis, the clinician should be aware of the major noninfectious causes of pediatric FUO.
Systemic Lupus Erythematosus
Systemic lupus erythematosus (SLE) is an inflammatory condition of unknown etiology. The inflammation can affect virtually any organ system, including the skin, kidneys, and central nervous system. Criteria for the diagnosis of SLE have been revised. Often, the presentation will include prolonged fever. Symptoms relating to SLE, such as alopecia, oral ulcers, and arthritis, should be part of the evaluation, particularly in high-risk populations such as teenaged girls.
Criteria for Diagnosis of SLE
Four of the following criteria are required for diagnosis:
1. Malar rash
3. Discoid rash
4. Antinuclear antibody (ANA)
1. Pericardial disease
2. Pleural effusion
6. Oral ulcers
7. Neurologic disorder (seizures, psychosis)
8. Leukopenia, thrombocytopenia, hemolytic anemia
9. Renal disease
11. Autoantibody (anti-DNA, anti-Sm, false-positive VDRL)
Systemic Juvenile Rheumatoid Arthritis
Although it is the least common form of juvenile rheumatoid arthritis, pediatricians often see children with the systemic form because they frequently present with prolonged fever. The classic presentation is twice-daily fevers in which baseline temperature rises then falls below normal. Extreme elevation of sedimentation rate, often greater than 100 mm/h, is common. Other laboratory findings include leukocytosis, increased liver function tests, and a decreased serum albumin. Polyarthritis may not be evident for weeks to months after disease onset.
Systemic juvenile rheumatoid arthritis is thought to be a diagnosis of exclusion and is considered only after a complete diagnostic examination, including bone marrow evaluation.
Always a concern in a patient with prolonged fever is the possibility of cancer. The major cancers in the pediatric population include leukemia, lymphomas, and neuroblastoma. Particular attention should be paid to the presence of pallor, bruising, progressive adenopathy (particularly in the supraclavicular area), and hepatosplenomegaly.
The possibility of an underlying malignancy causing prolonged fever is a source of great anxiety to both caretakers and clinicians. In addition to history and clinical exam, certain laboratory markers can be helpful in identifying those children with a
malignancy. In addition to marked elevation of the sedimentation rate, serum uric acid and lactate dehydrogenase levels are often elevated.
Diagnostic Evaluation of the Child with Fever of Unknown Origin
The medical evaluation begins with a precise determination of duration and character of the fever, travel history, animal exposure, and associated illness in family members.
Specifics of the history should include the following:
The physical examination should always be done keeping in mind the possible entities that were elicited from the history. Sequential examination may be necessary; one group of investigators found that repeated physical examinations led to the diagnosis in more than one half of cases. Each organ system should be examined as it relates to the particular processes that are possible in a child with pediatric FUO.
Skin: Presence of rashes, areas of desquamation, photosensitivity, and vasculitic lesions
Laboratory evaluation of the child with prolonged fever is often divided into several steps.
Step 1 often includes the following:
Step 2 of the evaluation is always dictated by the history and repeated physical examination. Step 2 is more invasive and can include the following:
Although a variety of scanning procedures, including computed tomography and radionucleotide scans, are often obtained in patients with FUO, it has been reported that these studies usually do not lead to a diagnosis not previously suspected by the history or physical examination. Indications for scanning for occult abscess, granuloma lesions, or infiltrative diseases should always be based on the history and clinical examination.
Step 3 is considered the most invasive step and can include the following:
As many as one half of patients with prolonged FUO do not receive a definitive diagnosis. The clinician must decide, based on the individual patient, which treatable processes need to be considered. It has been suggested that, once this has been done, the patient may be monitored closely. A period of 4 to 5 weeks has been reported
as an acceptable duration for prolonged fever once serious pathology has been ruled out.
TABLE 18.2. Management of Major Infections Associated with Pediatric Fever of Unknown Origin
When taking a history for FUO, it is important to distinguish FUO from periodic fever.
Whereas FUO implies a more continuous process, periodic fever is defined as three or more episodes of fever in a 6-month period with an interval of at least 7 days between febrile episodes. There are several classic periodic fever syndromes with which the general pediatrician should be familiar.
PFAPA is the syndrome of periodic fever, aphthous ulcers, pharyngitis, and adenitis. This is the most common periodic fever syndrome in pediatrics. Its etiology remains unknown. It is usually found in children younger than 5 years of age.
The PFAPA syndrome is characterized by periodic episodes of high fevers lasting 3 to 6 days with recurrence every 21 to 28 days. Patients often have a red throat, enlarged cervical lymph nodes, and tiny aphthous ulcers on the tongue. Throat, blood, and urine cultures are negative. Complete blood counts are typically normal. Moderate elevation of the sedimentation rate may be seen during acute episodes. A hallmark is the predictable intervals of the fever; parents often call the pediatrician's office and make an appointment for the following week because they know from prior experience that the child will have the fever at that time.
PFAPA syndrome may be more common than previously documented. Diagnostic criteria for the PFAPA syndrome have been published and are as follows:
Treatment of children with the PFAPA syndrome consists of a single dose of prednisone, 2 mg/kg, which results in a dramatic cessation of fever. This abrupt resolution of fever following prednisone has been proposed as a possible criterion for diagnosis. It has been noted that administration of prednisone may cause febrile episodes to occur more frequently. Tonsillectomy has been reported to eliminate the periodic fever entirely up to 80% of children.
Cyclic neutropenia is characterized by recurrent episodes of neutropenia, usually every 21 to 28 days. Recent evidence points to autosomal-dominant genetics in most cases, often associated with a mutation of the gene for neutrophil elastase.
Patients usually become symptomatic in childhood. Affected children present with fever, mouth ulcers, and frequently bacterial infections. Fever in children with cyclic neutropenia can also be present in the absence of any identifiable infection. Neutropenia typically can be documented to last 3 to 6 days.
To make the diagnosis of cyclic neutropenia, serial white blood cell count with differential must be done two or three times per week for 6 weeks. The diagnosis of cyclic neutropenia is made if an absolute neutrophil count greater than 500/m3 is seen with subsequent recovery.
Lifelong treatment with granulocyte colony-stimulating factor (G-CSF) has been helpful in many cases.
Hyperimmunoglobulinemia D Syndrome
The hyperimmunoglobulinemia D syndrome was first described in the mid-1980s. Most described patients are of Dutch or French heritage. Hyperimmunoglobulinemia D syndrome is thought to be caused by a mutation in the gene encoding mevalonate kinase (MVK). Enzyme activity is diminished although not entirely reduced. It is thought that this mutation somehow causes a decrease in inflammatory cytokines.
The syndrome is characterized by recurrent attacks of fever, typically occurring every 4 to 8 weeks. Febrile episodes last about 5 days and can be associated with cervical lymphadenopathy, abdominal pain, and headache.
A hallmark is the high immunoglobulin D (IgD) levels, more than 100 IU/mL or 14 mg/dL. Increased levels of IgA, often in the 1,000- to 2,000-mg/dL range, are also reported.
Diagnosis is made by evaluation of the clinical history and serum immunoglobulins D levels. Mutation analysis of the MVK gene is available at certain reference laboratories.
Treatment is with prednisone at a dose of 1 mg/kg given at onset of fever and repeated 24 hours later. As in the case of PFAPA, this is often thought to abort attacks and cause a decrease in the number of febrile days.
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