A Clinical guide to pediatric infectious disease
Fever of Unknown Origin
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
- Respiratory.Sinusitis is often reported to be a cause of low-grade, prolonged fever. Because sinus aspiration is not done routinely, upper respiratory infection symptoms that last longer than 2 weeks provide the major clue for bacterial sinus infection.
- Dental. Careful examination should always be done, evaluating for dental caries and abscess formation.
- Urinary tract. This is a common cause of prolonged fever in children. Young children may not complain of dysuria but rather of abdominal pain and anorexia. Many children with prolonged fever receive a chest x-ray, numerous blood tests, and never have urinary tract infection considered. A certain percentage of urinary tract infections are missed on dipstick testing and even urinalysis. If urinary tract infection is considered, culture and sensitivity tests of an appropriately obtained urine specimen should be done.
- Pneumonia. Lower respiratory infection is common in children and may be associated with increased respiratory rate, increased work of breathing, and hypoxia. A chest radiograph is often considered a front-line study in patients with prolonged fever.
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
- Cat-scratch disease. Exposure to kittens or cats is frequently elicited. Classically described as causing lymphadenopathy, this infection is increasingly described as a cause of pediatric FUO. It can be associated with a granulomatous hepatitis, which can be seen by computed tomography. Diagnosis is by serology showing the causative agent, Bartonella henselae.
- Brucellosis. Brucellaspecies are gram-negative coccobacilli. Disease is caused by exposure to unpasteurized dairy products and in some areas is a major cause of prolonged fever. Travelers to endemic areas may not be aware of exposure through regional foods. Patients can present with fever, arthralgias, hepatosplenomegaly, and orchitis. Diagnosis is by serology and by culture of the bacteria from blood or bone marrow. If brucellosis is suspected, blood cultures must be held for at least 21 days due to slow growth of the organism.
- Tuberculosis. This is seen in patients traveling to endemic areas or who have family members visiting from endemic areas. Miliary disease can present with prolonged fever and weight loss. Early on, miliary disease on chest x-ray may not be readily appreciated, and sequential films may be required if the diagnosis is suspected. A tuberculin skin test should also be done in all patients suspected of having tuberculosis.
- Malaria.Patients present with spiking fevers, anemia, and splenomegaly. The diagnosis is made by examination of both thin and thick smears of the blood looking for malaria parasites. The thick smears are made by applying blood twice to a slide; these smears contain more red blood cells to examine for parasites. Identification of the actual species of malaria is often easier to determine on thin smears. Therapy for malaria depends on the infecting species.
- Salmonella.Enteric fever refers to invasive Salmonella species infection. The most common enteric fever is that caused by Salmonella typhi species. After ingestion, the invasive salmonella enters the bloodstream from the gastrointestinal tract. Diarrhea may not be a principal symptom because the organism does not reside long in the gastrointestinal tract. The diagnosis is suggested by high fevers, leukopenia, organomegaly, and an embolic rash (rose spots). Diagnosis is by blood culture. Because enteric fever is one of the major treatable forms of FUO, in the correct epidemiologic setting, it should always be considered (see Chapter 14).
- Rickettsial disease.This is a group of tick-borne illnesses, which are obligate intracellular pathogens. The major rickettsial disease is Rocky Mountain spotted fever (RMSF), characterized by fever, headache, and an extremity rash. Its cause is Rickettsia rickettsii.
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.
- Dengue.Dengue fever is an arboviral infection associated with fever, myalgia, leukopenia, and rash. Dengue virus is transmitted by mosquito vectors. Dengue is found primarily in tropical areas, particularly the Caribbean and Central and South America. Dengue hemorrhagic fever is considered the most severe of the spectrum, and it is thought to be caused by repeated infections by a variety of dengue serotypes. Diagnosis is by serology. Treatment is supportive.
- Leptospirosis.Leptospira are spirochetes typically found in animals. This illness results from exposure to water that has been contaminated with the urine of dogs, rats, and livestock. Exposure can occur by exposure to fresh water or to occupational work with animals. Patients who participate in freshwater sports while on vacation are at risk for the disease. Acute leptospirosis can manifest as fever, myalgias, jaundice, and conjunctival redness. Laboratory evaluation may reveal aseptic meningitis and elevation of the liver function tests. Diagnosis is by blood and cerebrospinal fluid cultures, although the organism is difficult to grow. Serology is available and is usually the method used for diagnosis.
- Rat-bite fever.Rat bite fever is caused by either of two organisms: Streptobacillus moniliformis or Spirillum minus. The disease is transmitted by the bite of rats, ingestion of contaminated food products, or contact with an infected animal. Patients present with high fever, a maculopapular or petechial rash (predominantly on the extremities), arthralgias, and arthritis. Diagnosis is by culture of the organism; anaerobic blood cultures or the use of special media may be required. Treatment is with intravenous penicillin.
- Relapsing fever.This illness is caused by the spirochete Borrelia recurrentis; patients present with high fever, arthralgia, and often a macular rash of the trunk. Infection is caused by tick exposure in western mountainous areas and national parks. The first febrile episode is followed by a period of wellness with one or more relapses, which become progressively shorter. Diagnosis is made by eliciting an exposure history and viewing a spirochete on a peripheral blood smear. Treatment is with penicillin, doxycycline, or erythromycin.
Viral Infections associated with Fever of Unknown Origin
- Adenovirus infectionis often associated with pharyngitis or conjunctivitis. The conjunctivitis can be hemorrhagic associated with a pseudomembrane. The diagnosis can be made by serology or by a viral culture of eyes or nasopharynx.
- Mononucleosis syndrome (Epstein-Barr virus and cytomegalovirus).These viral pathogens produce a syndrome often associated with elevated liver function tests, rash, and pharyngitis. Diagnosis is by serology.
- Hepatitis.Hepatitis viruses A, B, and occasionally C can present with prolonged fever. In the younger child, these conditions may be anicteric. Initial suspicion
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:
- Fever for longer than 5 days.
- Erythematous mouth with strawberry tongue and red, cracked lips.
- A polymorphous rash that can be morbilliform, maculopapular, or erythema multiforme.
- Swollen hands and feet.
- Unilateral cervical adenitis.
- Bulbar conjunctivitis without exudate.
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:
- Duration and characteristics of the fever (number of spikes per day, timing of the temperature elevation, whether the temperature returns to normal or below normal)
- Travel history or exposure to people who have traveled to regions endemic for particular diseases (typhoid, malaria, tuberculosis, RMSF)
- Exposure to any animals (cat-scratch disease, rat-bite fever, leptospirosis)
- Exposure to unpasteurized dairy products (brucellosis)
- Presence of rashes, conjunctivitis, mucous membrane changes, and arthritis (juvenile arthritis, Kawasaki syndrome, SLE)
- Presence of associated cough, weight loss, or lymphadenopathy (lymphoma, leukemia, neuroblastoma)
- Specific complaints (abdominal pain, arthritis, chronic headache)
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:
- Sedimentation rate
- Complete blood count with differential (evaluation for anemia, thrombocytopenia, presence of blasts)
- Metabolic panel, including BUN, creatinine, liver function tests, lactate dehydrogenase, and uric acid levels
- Urinalysis and urine culture
- Chest x-ray and tuberculin skin test
- Epstein-Barr virus and cytomegalovirus serology
- Viral culture of the nasopharynx and eyes (if clinically warranted)
- Specific serology as suggested by the history or risk factors
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:
- Echocardiogram.Evaluate for coronary artery brightness or aneurysms associated with Kawasaki disease and pericardial effusion associated with various rheumatologic conditions, including SLE.
- Abdominal or pelvic computed tomography.Detection of occult abscesses or granulomatous lesions
- Bone scan.Evaluation for occult osteomyelitis or discitis
- Serology.As clinically indicated by history or physical exam
- ANA, double-stranded DNA, compliment levels(if history or physical suggests SLE)
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:
- Bone marrow aspiration, looking for infiltrative process or to culture a variety of organisms (such as brucellosis, tuberculosis, or disseminated fungal infection).
- Biopsy of suspicious skin lesions or lymph nodes.
- Endoscopy and biopsy
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:
- Recurring fevers beginning before 5 years of age
- Symptoms occurring in the absence of upper respiratory tract infection with at least one of the following signs: aphthous ulcers, pharyngitis, cervical lymph node swelling
- Completely asymptomatic intervals between episodes with normal growth and development
- Exclusion of cyclic neutropenia
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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