Demam Tidak Tahu Penyebab FUO

CHAPTER 6 3

FEVER WITHOUT SOURCE AND FEVER OF

UNKNOWN ORIGINDebra L. Palazzi

Petersdorf and Beeson81 in 1961 proposed that the term fever of unknown origin (FUO) be reserved for persons with an illness persisting for 3 or more weeks and accompanied by temperatures higher than 38.4° C (101.2° F) on at least several occasions. They further specified that the cause of the fever should remain undetermined after at least 1 week of investigation in the hospital. Although this definition was arbitrary, it was useful at that time, when many of the diagnostic tests now in routine use were unknown. The purpose of their precise definition was to explore the cause of fever in this select group of adult patients and to permit comparison of data from different investigations. This exacting definition probably never was applied rigorously in pediatric practice. In children, the term fever of unknown origin should be reserved for fever of at least 8 days’ duration and for which no diagnosis is apparent after the initial workup in the hospital or as an outpatient.

Many investigators prefer using the term fever without source (FWS) for fever of recent onset with no adequate explanation determined by the history or physical examination. The distinction between FUO and FWS is of more than academic interest for several reasons. First, although overlap exists, the differential diagnoses of these clinical conditions are distinct, and the most frequent causes of one can be different from the most frequent causes of the other. Second, a child with fever of recent onset generally warrants more immediate evaluation than does a child with FUO. The latter usually does not occur as an emergency and requires timely, but not urgent, diagnostic or therapeutic intervention. Third, although expectant antibiotic treatment of children with FUO generally is not indicated, expectant treatment of infants with FWS is recommended in most cases.

FEVER WITHOUT SOURCE

A convenient definition of FWS is the occurrence of fever for 1 week or less in a child in whom a careful history and physical examination fail to reveal a probable cause of the fever. An estimated 14 to 40 percent of children with fever have no localizing signs or symptoms.9,13 Stein93 found that the peak incidence occurs during the second year of life. On

the basis of a review of private pediatric practices in upstate New York, Hoekelman and colleagues46

predicted that every 4 to 5 days a practicing pediatrician would see one child between 1 and 24 months of age with FWS.

83

Most children with fever of recent onset have acute infectious diseases, the majority of which are self-limited.108 A few of these patients have serious acute infectious diseases, including meningitis, bacteremia, and urinary tract infection, and a very few have acute noninfectious diseases or chronic disorders. For example, an occasional patient with FWS is discovered to have a disorder such as heat illness, drug poisoning, Kawasaki disease, malignancy, or connective tissue disease. However, these disorders occur infrequently. A physician faced with a child with FWS should consider the possibility of a noninfectious cause or the onset of a chronic disease, but unless a clinical clue suggests one of these entities, investigation in this direction is not warranted.

Many children with FWS are in the prodromal stages of an acute infectious illness, and evidence of a specific infection, such as pharyngitis, otitis media, or pneumo-nia, develops within hours to days of first being evaluated by a physician. Fever can precede the appearance of specific signs and symptoms by as long as 3 days, as in measles, Rocky Mountain spotted fever, and leptospiro-sis. In some infections, such as roseola, viral hepatitis, infectious mononucleosis, typhus, and typhoid fever, the interval between the onset of fever and the appearance of specific findings often is more than 3 days.

Occult BacteremiaOne major concern regarding a young child with FWS is the possibility that the child has occult bacteremia. The patient does not appear ill, is judged clinically well enough to be managed as an outpatient, and does not have an infection commonly associated with bacteremia, such as pneumonia, but the blood culture yields pathogenic bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Escherichia coli, Salmonella, group A streptococcus, or Staphylococcus aureus. Before introduction of the pneumococcal conjugate vaccines, the incidence of occult bacteremia in children with FWS was approximately 3 to 5 percent.* More recent data report an incidence of less than 1 percent, although this figure may vary depending on vaccine coverage rates in the population studied.† A large prospective study of 3571 febrile children younger than 3 years of age found that no patients who had received at least 1 vaccination of heptavalent pneumococcal vaccine had

*References 7, 16, 26, 49, 60, 65, 74, 97, 108.†References 2, 3, 32, 45, 84, 89, 95, 101, 106.

838 SECTION XII SYSTEMIC INFECTIOUS DISEASES

pneumococcal bacteremia.27

With the introduction of the 13-valent pneumococcal conjugate vaccine, further decreases in occult bacteremia caused by pneumococci are anticipated.28

Historically, occult bacteremia has been found to occur more commonly in children with FWS than in febrile children of the same age with infections such as pharyngitis, otitis media, or upper respiratory tract infection. In the 1970s, investigators65

reported the incidence of bacteremia in febrile children without an obvious source of infection to be 9.9 percent, as opposed to 3.3 percent in children with otitis media, upper respiratory tract infection, or a flulike syndrome. During the same era, Teele and colleagues97 found a 3.9 percent incidence of bacteremia in children with FWS and a 1.5 percent incidence in comparably febrile children with otitis media or pharyngitis.

The risk for occult bacteremia developing in a child with FWS is age-related, with the greatest risk occurring in the first few months of life. Numerous studies have demonstrated a higher risk for bacteremia or other serious bacterial infections in febrile infants younger than3 months old.62,65,88,97 In a group of children with clinically unsuspected meningococcemia, all 12 patients who initially looked well enough to be treated as outpatients were younger than 24 months of age.35 Bonadio and col-leagues22 found the incidence of positive bacterial cultures to be 12 percent in febrile infants younger than

4 weeks and 6 percent in those between 4 and 8 weeks of age.

The risk for having occult bacteremia and other serious bacterial infections increases with the severity of fever. In a prospective study of bacteremia in children seen in the outpatient department, McCarthy and col-leagues63 identified a small, but statistically significant, difference in the incidence of bacteremia between children with temperatures of 40° C (104° F) or higher and those with temperatures of 40.5° C (104.9° F) or higher. In a prospective study in which blood was obtained for culture from all febrile children younger than 2 years old seen in a walk-in clinic, no positive blood cultures were found in 44 children with FWS and rectal temperatures lower than 38.9° C (102° F), whereas five (3.9%) positive blood cultures were found in 129 children with FWS and rectal temperatures of 38.9° C (102° F) or higher.86,97

Other studies have reported similar findings.16,62,89

Several series of children with fevers of 41° C (105.8° F) or higher found a relatively high prevalence of bacteremia and other serious blood infections, especially meningitis and pneumonia.21,62,86 However, even in this group of children with very high fever, most of those older than 2 or 3 months of age who looked well did not have a serious bacterial infection.

The white blood cell (WBC) count has been studied extensively as a potential tool in the diagnosis of occult bacteremia. On the basis of a study of hospitalized chil-dren, Todd98 reported that the absolute number of poly-morphonuclear

leukocytes and the absolute number of nonsegmented polymorphonuclear leukocytes were more sensitive than was the total WBC count, the percentage of polymorphonuclear leukocytes, or the percentage of nonsegmented polymorphonuclear leukocytes. However,

whether information based on hospitalized children— presumably all of whom had serious localized infections or looked ill enough to warrant hospitalization—can be applied to children with FWS who look well enough to be treated on an ambulatory basis is questionable.

Considerable debate continues over the usefulness of the WBC count in febrile children evaluated in the outpatient setting. McCarthy and associates63 concluded that a WBC count of 15,000/mm3 or greater was helpful in identifying patients at greatest risk for the development of bacteremia. Dershewitz36

found a direct relationship between the total leukocyte count and the prevalence of bacteremia and stated that “knowledge of the count was a helpful but limited predictor of patients with positive blood cultures.” Other investigators reported that the incidence of bacteremia increased with an increased WBC count89

and that bacteremia most commonly occurred in patients with counts of 20,000/mm3 or higher.70

Other studies have examined the utility of the WBC count specifically in children with FWS who look well enough to be treated on an outpatient basis. One such study found a sensitivity of 1.0 and a positive predictive value of 0.11 for a total WBC count of 15,000/mm3.97 Using a white blood cell count of 20,000/mm3 would have decreased the sensitivity to 0.4 while increasing the positive predictive value to only 0.13. In another series, the sensitivity for a WBC count of 15,000/mm3

was 0.87, with a specificity of 0.73.16 Kline and coworkers54 found that a WBC count of 15,000/mm3

was more sensitive for S. pneumoniae bacteremia than for H. influenzae bactere-mia. Although a total WBC count of 15,000/mm3 does not accurately predict which child is or is not bacteremic, it is helpful in dividing the population of children with FWS into high- and low-risk groups.17,45 However, the value of the 15,000/mm3

level has been substantially reduced in the studies conducted since the pneumococcal conjugate vaccine was introduced.

Some investigators have found the erythrocyte sedi-mentation rate to be no more useful than the WBC count in predicting bacteremia in ambulatory febrile patients.63 Others have reported that the serum concentration of C-reactive protein may be more accurate than the complete blood count or erythrocyte sedimentation rate in distinguishing bacterial from viral infections.64,80 However, recent studies reported conflicting data regarding the utility of the C-reactive protein test in screening children 3 to 36 months old for occult bacteremia.47,87 An elevated serum procalcitonin level has been found by some investigators to be at least as sensitive and specific as is C-reactive protein in predicting serious bacterial infection in children with fever and no localizing signs.5,55,85

Other hematologic findings that suggest bacteremia include thrombocytopenia,31 Döhle inclusion bodies, toxic granulations, and vacuolization of neutrophils. In one study, peripheral blood smears of children younger than 24 months old with acute febrile illnesses were reviewed the following day by a single

investigator to determine whether vacuolization and toxic granulations were present; when both abnormalities were present, the positive predictive value for bacteremia was 0.76.57 The

63 FEVER WITHOUT SOURCE AND FEVER OF UNKNOWN ORIGIN 839

presence of these findings should be considered when estimating the risk for bacteremia.1,31,73

Several studies have examined the response to acet-aminophen and found no difference in the rate of reduction of temperature or improvement in clinical appearance between bacteremic and nonbacteremic children.11,99,110 Mazur and associates,61 however, found that febrile children aged 2 months to 6 years old who did not respond to a dose of acetaminophen by a reduction in temperature of at least 0.8° C in 2 hours had a statistically significant increased risk for having occult bacteremia in contrast to those who did respond.

The most important aspects of assessment of a febrile child are a careful history and physical examination. Laboratory data are secondary and should be ordered on the basis of the clinical assessment. By definition, a child with FWS has no localizing signs to explain the fever or indicate a site of infection. Many physicians suggest that a general impression can indicate whether the child has occult bacteremia. Some physicians have suggested that careful clinical judgment, based on extensive experience, can identify most, if not all, children with serious illnesses.20,78 McCarthy and colleagues,65-68 in a series of carefully designed studies, elucidated the variables of history and observation that were most useful in assessing febrile children. They found that observation of the variable playfulness had the strongest correlation with overall assessment.67 However, they observed that even an experienced attending pediatrician could identify only 57 percent of seriously ill children by initial impression before performing a full physical examination. Dershewitz36 found that private pediatricians were no more accurate than pediatric residents in identifying children with occult bacteremia and that in

the private office, pediatricians were no better at predicting bacteremia in familiar patients than in first-time patients.

In a study of 292 consecutive febrile children seen in an emergency department, Waskerwitz and Berkelham-mer103 identified a subgroup of patients who had no localizing signs and who looked so well that they were predicted not to have bacteremia. The physicians were assisted in their assessment by a functional scale that gave 0 to 2 points for the child’s eating, drinking, sleeping, and play activities, with a best possible score of 8. The group of patients who had functional scores of 5 or greater, with no localized infection and predicted clinically not to have bacteremia, were free of bacteremia, whereas 14 of 202 patients with functional scores of 4 or less were bactere-mic. In this study, the physicians were not able to identify which patients had bacteremia and which did not; rather, they were able to identify one subgroup at high risk for having bacteremia and another at very low risk. Teach and Fleisher96 found that although Yale Observation Scale scores were higher in patients with bacteremia than in those without, the difference was not clinically useful in detecting bacteremia in well-looking febrile children without a discernible focus of infection. The clinician’s overall assessment of the degree of illness of the child appears to be a valuable, but not infallible, tool in estimating the risk for occult bacteremia in children with FWS.

Clinical Management of Fever Without SourceThe clinician should not be dogmatic about the management of children with FWS. One reasonable approach, based on a careful history, thorough physical examination, and overall clinical impression, is to classify these children as being at low or high risk for the presence of occult bacteremia and other serious bacterial infections. For the low-risk group, no laboratory investigation is required routinely. For the high-risk group, a complete blood count and blood culture should be obtained, especially in young infants and children who are incompletely immunized. Many studies have shown that the most common serious bacterial infection in children with FWS is urinary tract infection.4,101,104

Therefore, urinalysis and urine culture should be performed in febrile infants and children younger than 24 months of age. Lumbar puncture and chest radiography are considered on an individual basis. If the patient appears ill, admission to the hospital may be justified, even if all test results are nega-tive. When high-risk children look well enough to be sent home, they are reasonable candidates for expectant anti-biotic therapy, pending the outcome of blood and urine cultures. For patients clinically considered to be at moderate risk (not clearly high or low risk), the physician has the option of obtaining a WBC count and using the results to decide whether to obtain blood and urine for culture and prescribe antibiotics expectantly.

Table 63-1 lists risk factors for the development of occult bacteremia. Current information is not sufficient to warrant the use of scoring systems except as part of investigational series. In the final analysis, the clinician’s judgment, taking into account all available clinical and

laboratory data about each patient, is the guide to selecting which children require a diagnostic workup and expectant therapy with antibiotics.

If the physician elects to prescribe antibiotics while awaiting the results of blood culture, such antibiotic therapy should provide adequate coverage for S. pneu-moniae, N. meningitidis, and H. influenzae, although the frequency of H. influenzae and S. pneumoniae has decreased dramatically with current immunization practice and N. meningitidis is uncommon. A single injection of ceftriax-one 50 to 75 mg/kg given while awaiting the results of blood culture has been successful in resolving fever, clearing bacteremia, and preventing meningitis and was found to be superior to oral regimens in several series.14,18,41

Children with a positive blood culture should be recalled for reevaluation, even if they are afebrile.8 Children who have been immunized against both H. influenzae and S. pneumoniae should be considered to be at relatively low risk for the development of occult bacteremia and may require less workup, unless they appear ill or have a very high fever.

Infants younger than 90 days old pose a special problem because they have an increased risk for developing a serious bacterial infection, clinical evaluation is more difficult, and a broader spectrum of invading organisms (e.g., group B streptococcus, E. coli, and Listeria monocy-togenes) exists. Baker and coworkers10 showed the safety of managing selected low-risk infants (i.e., normal WBC


TABLE 63-1 Risk Factors for Occult Bacteremia

Factor High Risk Low Risk

Age ≤3 mo >3 moImmunization status* Incomplete CompleteMagnitude of fever ≥40° C (104° F) ≤39.4° C (103° F)White blood cell count ≥15,000/mm3 <15,000/mm3

Peripheral blood smear Toxic granulation or vacuolization of Unremarkablepolymorphonuclear leukocytes, thrombocytopenia

Underlying chronic disorder Sickle-cell disease, immunodeficiency, malnutrition NoneHistory of contact with Contact with Neisseria meningitidis or Haemophilus None

bacterial disease influenzaeClinical appearance Appears ill, toxic, or unhappy; inconsolable; irritable or Looks well, playful, eating normally,

lethargic; not eating or drinking enough not irritable

*Vaccination status is incomplete if the child has received fewer than 3 doses of Haemophilus influenzae vaccine and fewer than three doses of conjugated pneumococcal vaccine and is complete if the child received at least three doses of each vaccine.

count, urinalysis, lumbar puncture, and chest radiograph and, if diarrhea was present, negative smear for fecal leukocytes) 30 to 90 days of age on an outpatient basis without antibiotics. Jaskiewicz and coworkers51 found the Rochester criteria (WBC count of 5000 to 15,000/mm3, band count <1500/mm3, spun urine specimen <10 WBCs/ high-power field, stool specimen [if diarrhea] <5 WBCs/ high-power field) to have a 98.9 percent negative predictive value in well-appearing, previously healthy infants younger than 90 days old with no focal infections. One reasonable practice guideline for managing infants with FWS is to hospitalize and treat all who appear toxic and all younger than 28 days. Those between 28 and 90 days of age can be managed as outpatients if they look well and the blood count, urinalysis, and cerebrospinal fluid analysis are within normal limits.12,15

FEVER OF UNKNOWN ORIGIN

The exact definition of FUO is a subject of considerable disagreement, and series in the pediatric literature differ in their criteria for inclusion. Brewis23 defined FUO in children as a temperature of 38.3° C (101° F) or higher for 5 to 7 consecutive days without localizing signs or symptoms. In sharp contrast, McClung69 and Lohr and Hendley58 considered children with fever for at least 3 weeks on an outpatient basis or 1 week in the hospital to have FUO. Pizzo and associates,83 however, required only that the fever be present for 2 weeks, with no distinction made between outpatient or in-hospital status. A reason-able working definition of FUO for clinical purposes is the presence of fever for 8 or more days in a child for whom a careful and thorough history, physical examination, and preliminary laboratory data fail to reveal a probable cause of the fever.

Most cases of FUO in children are caused by relatively common diseases.39 In four series of FUO totaling 418 children, only 5 patients would be considered to have rare disorders (i.e., Behçet syndrome, ichthyosis, variant of “blue diaper” syndrome, diencephalic seizure disorder, and “possible chronic lead and/or arsenic intoxica-tion”).23,58,69,83

The adage that FUO is more likely to be caused by an unusual manifestation of a common

disorder than by a common manifestation of a rare dis-order certainly is true in pediatrics. The three most common discernible causes of FUO in children, in order of decreasing frequency, are infectious diseases, connec-tive tissue diseases, and neoplasms. In approximately 10 to 20 percent of cases, a definitive diagnosis never is established.

In the United States, the systemic infectious diseases diagnosed most frequently in children with FUO include tuberculosis, brucellosis, tularemia, salmonellosis, cat-scratch fever and infections caused by rickettsia, spirochetes (e.g., leptospirosis), Epstein-Barr virus, cytomegalic inclusion virus, human immunodeficiency virus (HIV), hepatitis viruses, and other viruses. The most common causes of localized infection are upper respiratory tract infections (e.g., sinusitis, otitis, tonsillitis), urinary tract infection, osteomyelitis, and occult abscesses, including hepatic and pelvic abscesses.

The connective tissue disease most commonly manifested as FUO in children is juvenile idiopathic arthritis, which accounts for more than 90 percent of connective tissue diseases in most series, followed by systemic lupus erythematosus, and then by undefined vasculitis.58,69,72,83

Frequently, a definitive diagnosis of juvenile idiopathic arthritis can be made only after an extended period of observation because physical examination may yield few findings and the results of specific serologic studies gen-erally are normal or negative.

Malignancy is a less frequent cause of FUO in children than in adults and usually is the third-largest group, after infectious diseases and connective tissue diseases. Malig-nancy accounted for 7 percent of FUO cases in the series reported by Pizzo and associates83 and for 13 percent in the Lohr and Hendley58 series. Leukemia and lymphoma are responsible for most cases of cancer manifested as FUO in children. Other tumors less commonly reported as causing FUO include neuroblastoma, hepatoma, sarcoma, and atrial myxoma.

The prognosis for children with FUO is better than that for adults, and most children with FUO have treatable or self-limited disease. Historically, mortality rates for children with FUO were 6 to 9 percent.58,83 However, more contemporary studies indicate that mortality is quite low.79


Diagnostic Approach to a Child with Fever of Unknown OriginA child with FUO is admitted to the hospital for more than simply laboratory investigation. Hospitalization provides an opportunity to observe the child, repeat the history and physical examination, analyze all available data, and investigate every potential diagnostic lead. In the Lohr and Hendley58 series of 54 children with FUO, an incomplete history delayed establishing the diagnosis in 9 cases, and physical findings that were ignored delayed rendering the diagnosis in 4 cases. In McClung’s report69 of 99 pediatric cases of FUO, errors in the history or physical examination obscured the correct diagnosis for at least 10 patients. Failure to use existing laboratory data correctly is another common factor pre-venting early determination of the diagnosis in children with FUO.58,83

Clinical Evaluation

The first and most important step in the diagnostic workup of a child with FUO is obtaining a complete and detailed history and conducting a physical examination. The clinical evaluation must be thorough and careful, and it must be repeated frequently. Often, a patient or parent eventually recalls information that was omitted or forgotten when the initial history was obtained. Physical findings change, and abnormalities not originally present can appear subsequently. Lohr and Hendley58 noted that in more than 25 percent of children admitted to the hospital with FUO, significant physical findings developed that were not present at the time of admission.

A detailed history should be obtained regarding contact with infected or otherwise ill persons and any exposure to animals, including pets and wild animals. The number of children with zoonotic infections is increasing each year. History of a cat scratch or exposure to kittens may be a clue for Bartonella henselae. Immunization of domestic animals such as the dog against lepto-spirosis can prevent canine disease, but it does not prevent carriage, excretion, and transmission of this infection. A history of travel extending back to birth must be elicited. Reemergence of histoplasmosis, coccidioidomycosis, blastomycosis, leishmaniasis, or malaria years after visiting or living in an endemic area can occur. Inquiring about prophylactic immunizations, precautions taken against the ingestion of contaminated food or water, and malarial prophylaxis is important. Questioning should include the possibility that rocks, soil, or artifacts from geographically distant regions may have been brought into the home, as well as the possibility that contact with persons who have visited distant countries has occurred. Even contact with insects can be important. Tick bites can be a clue to Rocky Mountain spotted fever or tick-borne relapsing fever. North American mosquitoes and some ticks carry a variety of arboviruses.

The physician should determine whether the patient has eaten game meat, raw meat, or raw shellfish. A history of pica should be sought routinely. Ingestion of dirt can suggest a diagnosis of visceral larva migrans, toxo-plasmosis, or other infectious diseases. A detailed history

regarding all medications, including topical agents and nonprescription items, must be elicited carefully. Any history of surgical procedures should be explored.

Questions designed to determine the genetic or ethnic background of the patient can reveal information that specifically suggests or largely excludes diagnoses such as nephrogenic diabetes insipidus (found in Ulster Scots), familial Mediterranean fever (found in Armenians, Arabs, and Sephardic Jews), familial dysautonomia (found in Jews), and Kikuchi-Fujimoto disease, a benign and self-limited histiocytic necrotizing lymphadenitis (found mostly in young Asian females and characterized by fever, lymphadenopathy, and malaise).

The history should be exacting regarding the duration, height, and pattern of the fever, as well as the circumstances under which temperature elevation occurs, whether the child appears ill or any signs or symptoms develop, and how well the fever responds to antipyretic drugs. A history of “fever” occurring only after exercise or late in the afternoon can indicate parental concern about normal variations in body temperature. A history of high fever occurring in the absence of malaise or other generalized signs can be a clue to factitious fever. The physician also should obtain a careful history regarding how well the fever has been documented. Has a ther-mometer been used, by whom, and in whose presence? A history of sweating and heat intolerance can indicate hyperthyroidism, whereas a history of heat intolerance with the absence of sweating can be a clue to ectodermal dysplasia.

Several investigators found that neither the pattern of fever nor its duration was useful in pointing to or establishing a diagnosis in children with FUO.58,83 However, occasionally the character of the fever can be helpful. Intermittent fever is characterized by a return of temperature to normal at least once daily. If the peak of fever is high and the rate of

defervescence quick, this pattern often is referred to as hectic or spiking. Intermittent fevers suggest pyogenic infections but also occur with tuberculosis, lymphoma, and juvenile idiopathic arthritis. In remittent fever, the temperature fluctuates but does not return to normal. A sustained fever pattern is characterized by persistent fever with little or no fluctuation and can occur in typhoid fever or typhus. Antipyretic agents can make a remittent or sustained fever appear intermittent. Relapsing fever refers to a pattern in which the patient is afebrile for 1 or more days between episodes of fever and can be seen with malaria, rat-bite fever, infection with Borrelia, and lymphoma. Recurrent episodes of fever of more than a year’s duration can suggest metabolic defects, central nervous system abnormalities in temperature control, and immunodeficient states.

The general activity and appearance of the patient should be observed, vital signs checked, and growth parameters measured. Weight loss is an important, though nonspecific, finding. Impairment of linear growth or short stature can be a clue to inflammatory bowel disease, an intracranial lesion involving the pituitary gland, or a long-standing chronic disease. Examining the patient during an episode of fever to observe the presence or absence of sweating, the effect of the fever on the heart and respiratory rate, the presence or absence of malaise


or other symptoms, and the appearance of “toxicity” is helpful. The rash of juvenile idiopathic arthritis characteristically is evanescent and may be present only during periods of temperature elevation.

Some special aspects of the physical examination merit mention. Hypohidrosis, anomalous dentition, and sparse hair, particularly involving the eyebrows and eyelashes, suggest anhidrotic ectodermal dysplasia. Palpebral con-junctivitis can be a clue to the presence of infectious mononucleosis, Newcastle disease, or lupus erythemato-sus, whereas predominantly bulbar conjunctivitis can suggest leptospirosis or Kawasaki disease. Phlyctenular conjunctivitis can signal tuberculosis.

Absence of the pupillary constrictor response can be caused by a deficiency of the constrictor sphincter muscle of the eye. This muscle, derived from ectoderm rather than mesoderm, develops embryologically at the same time that hypothalamic structures and function are undergoing differentiation. Absence of this muscle can suggest that the elevation in temperature is the result of hypothalamic or autonomic dysfunction. Careful fundu-scopic examination can disclose evidence of miliary tuberculosis, vasculitis, or toxoplasmosis. Lack of tears, absence of corneal reflexes, and a smooth tongue with absence of the fungiform papillae suggest familial dysautonomia.

Purulent or persistent nasal discharge can be a sign of sinusitis. The physician should palpate for tenderness over the sinuses.

Hyperemia of the pharynx, even in the absence of exudate or specific symptoms, can be a clue to the diagnosis of infectious mononucleosis, cytomegalic inclusion disease, toxoplasmosis, tularemia, or leptospirosis. Gingival hypertrophy or inflammation and loosening or loss of teeth can indicate leukemia or Langerhans cell histiocytosis.

The bones and muscles should be palpated carefully. Tenderness over a bone can be found in cases of osteomyelitis or marrow invasion by neoplastic disease. The appreciation of a new heart murmur may result from infective endocarditis. Muscle tenderness can be associ-ated with trichinosis, dermatomyositis, polyarteritis, or various arboviral infections.

The search for skin lesions and rash must be careful, extensive, and repeated. Petechiae can indicate endocar-ditis or other sources of bacteremia but also can occur with viral and rickettsial infections. A seborrheic rash can be a sign of histiocytosis. A small papule present for over a week may be the inoculation site for cat-scratch disease.

A careful rectal examination can reveal pararectal tenderness or a mass indicative of a pelvic abscess or tumor. A test for occult blood should be performed on stool. Examination of the external genitalia should

be completed on patients of all ages, and sexually active adolescent females should undergo a pelvic examination.

Laboratory Evaluation

The extent of laboratory investigation depends on the age of the patient, duration of the fever, and history and physical examination findings. Laboratory studies should

be directed, as much as possible, toward the most likely diagnostic possibilities. The tempo of the diagnostic evaluation should be adjusted to the severity of the illness. In a critically ill child, speedy evaluation is important. If the patient is less severely ill, however, the evaluation can proceed more slowly; sometimes the fever can disappear without apparent explanation before a definitive diagnosis can be established and any invasive diagnostic proce-dures have been undertaken.

A complete blood count and careful examination of the peripheral smear are indicated for all patients. Anemia, thrombocytosis, and thrombocytopenia should be noted. Although mild or moderate changes in the total WBC or differential count usually are of no help, in some series, children with more than 10,000 polymorphonuclear leu-kocytes or 500 nonsegmented neutrophils/mm3 were found to have a greater likelihood of having a serious bacterial infection.93,98 Atypical lymphocytes generally indicate viral infection, whereas bizarre or immature forms can suggest leukemia. Although the erythrocyte sedimentation rate and C-reactive protein are of no specific diagnostic value, they are a general indicator of inflammation and can help in ruling out factitious fever, determining the need for further evaluation, and monitoring the progress of the disease process.

Blood should be obtained from all patients for aerobic and anaerobic

culture. In select cases, media appropriate for the isolation of Francisella organisms, Leptospira, and Spirillum also should be used.

Urine analysis and culture should be completed for all patients. In one series of FUO in children, failure to perform urinalysis and failure to investigate pyuria adequately were the most common laboratory errors.69

Radiographic study of the urinary tract, however, should be performed only when indicated.

All patients should undergo radiographic examination of the chest. Diagnostic imaging of the nasal sinuses, mastoids, and gastrointestinal tract is performed initially only for specific indications but should be done eventually in all children whose fever persists without explanation for a long period. Persistent fever and elevation of the erythrocyte sedimentation rate or C-reactive protein, with or without anemia, abdominal complaints, anorexia, and weight loss, are sufficient indications for radiographic study to rule out inflammatory bowel disease.

All patients should have an intradermal tuberculin skin test. Control skin tests with antigens such as Candida are of limited value because the anergy may be specific for tuberculosis rather than universal for all skin-testing materials.59,71,75,76 A positive control test result and negative tuberculin test result do not rule out tuberculosis.

Bone marrow examination is most useful in diagnosing cancer (especially

leukemia), histiocytic disorders, and hemophagocytic disease. It is less useful in determining infection. Hayani and associates44

reviewed the results of 414 bone marrow examinations for FUO in children. In only one case was an organism (Salmonella group D) recovered from the marrow that also was not recovered from blood or another source. Noninfectious causes of FUO were found in 8 percent of specimens: malignancy (6.7%), hemophagocytic lymphohistiocytosis (0.7%), histiocytosis (0.5%), and hypoplastic anemia (0.2%). In


most of these cases, the diagnosis had been suspected clinically before the bone marrow was examined.

Patients should undergo a serum test for HIV infection. Other appropriate serologic tests can help establish a diagnosis of cat-scratch disease, brucellosis, tularemia, Epstein-Barr virus infection, cytomegalovirus infection, other viral infections, toxoplasmosis, and certain fungal infections.

Hepatic enzymes and serum chemistry, including electrolytes, urea nitrogen, and creatinine, should be determined in all patients. Serum antinuclear antibody should be measured in those older than 5 years if family history is significant or clinical suspicion warrants it. Serum hepatitis antigens, electrocardiography, electroencepha-lography, echocardiography, and stool culture and examination for ova and parasites generally should be performed in selected cases. Other tests to be considered for individual patients include ophthalmologic examination by slit lamp, radiographic bone survey, technetium bone scan, abdominal imaging by ultrasonography, computed tomography (CT), or magnetic resonance imaging (MRI).25,82 CT scanning and indium-111 scanning40 can detect inflammatory lesions and tumors. Such scanning procedures offer a relatively noninvasive technique for

screening patients with FUO for a variety of disorders. Although Steele and associates92 found that radionucleo-tide scans seldom led to unsuspected diagnoses in chil-dren and suggested that they not be used indiscriminately, gallium scanning has been helpful in diagnosing adult patients with FUO,43 but is not generally recommended in children. Lymph node biopsy, liver biopsy, and exploratory laparoscopy are reserved for patients with evidence of involvement of these organs.

In general, antibiotics or other medications should not be administered empirically as a diagnostic measure in children with FUO. Exceptions include the use of non-steroidal agents in children with presumed juvenile idiopathic arthritis and the use of antituberculosis drugs in critically ill children thought to have disseminated tuber-culosis. Empirical trials of broad-spectrum antibiotics generally do more to obscure than illuminate the etiology of FUO and can mask or delay establishing the diagnosis of infections such as meningitis, parameningeal infection, endocarditis, or osteomyelitis.

Examples of disorders that can be manifested as FUO in children are listed in Table 63-2. A few of these disorders are discussed briefly in the following sections.

TABLE 63-2 Causes of Fever of Unknown Origin in Children

Infectious Diseases

BacterialBacterial endocarditisBrucellosisCat-scratch diseaseLeptospirosis Liver abscessMastoiditis (chronic)Osteomyelitis Pelvic abscess Perinephric abscessPyelonephritis Salmonellosis SinusitisSubdiaphragmatic abscessTuberculosis Tularemia

ViralAdenovirusArbovirusesCytomegalovirusEpstein-Barr virus (infectious mononucleosis)Hepatitis viruses

ChlamydialLymphogranuloma venereumPsittacosis

RickettsialQ feverRocky Mountain spotted fever

FungalBlastomycosis (nonpulmonary) Histoplasmosis (disseminated)

Parasitic MalariaToxoplasmosisVisceral larva migrans

Unclassified Sarcoidosis

Collagen Vascular Diseases Juvenile rheumatoid arthritis Polyarteritis nodosaSystemic lupus erythematosus

MalignanciesHodgkin diseaseLeukemia and lymphomaNeuroblastomaMiscellaneousCentral diabetes insipidusDrug feverEctodermal dysplasiaFactitious feverFamilial dysautonomiaGranulomatous colitisHemophagocytic lymphohistiocytosisInfantile cortical hyperostosisKikuchi-Fujimoto diseaseNephrogenic diabetes insipidusPancreatitisPeriodic feverSerum sicknessThyrotoxicosisUlcerative colitis


Infectious Causes of Fever of Unknown OriginInfectious causes of FUO can be divided into systemic and localized. Immunodeficient states may be considered under the general classification of infections.

Generalized Infections

Brucellosis. The manifestation of this disease as FUO is explained by the nonspecific symptoms that it engenders and by the chronicity of untreated infection. Many physicians, particularly in urban areas, tend to ignore the possibility of this disease and neglect to inquire about a history of exposure to animals or animal products, espe-cially the consumption of unpasteurized goat’s milk cheese (see Chapter 128).

Cat-Scratch Disease. During recent years, many children with FUO have proved to be infected with B. hense-lae. Cat-scratch disease is one of the most common causes of FUO in patients seen at the infectious disease service at Texas Children’s Hospital in Houston.6

Most of the children with this manifestation of cat-

scratch disease have hepatosplenic involvement. Jacobs and Schutze48 reported that B. henselae infection was the cause of 4.8 percent of all cases of FUO at the Arkansas Children’s Hospital and 10.9 percent of the cases of FUO caused by infection. B. henselae infection is best diagnosed by serologic evaluation (i.e., immunofluorescence assay that detects serum antibody to B. henselae). Biopsy of lesions (e.g., lymph nodes, liver, bone marrow) may allow visu-alization of bacilli with the Warthin-Starry silver stain; however, this finding is not specific for B. henselae. Management of patients with cat-scratch disease is primarily symptomatic because the disease usually is self-limited. Antimicrobial therapy can be helpful in acutely or severely ill patients, especially those with hepato-splenic disease. Several oral antimicrobial regimens (rifampin, trimethoprim-sulfamethoxazole, and azithro-mycin) and parenteral gentamicin have been used suc-cessfully for the treatment of this disease. Specifically, rifampin 20 mg/kg/day in two divided doses for 14 days has been particularly efficacious.6

However, the optimal duration of therapy is not known.

Leptospirosis. Leptospirosis is caused by a single family of organisms composed of multiple serotypes; it is one of the most widespread zoonoses in the world. Transmission of infection from animal

to human can occur by direct contact with the blood, tissue, organs, or urine of infected animals or indirectly by exposure to an environment that has been contaminated by leptospires. The organism also can be acquired from soil or from fresh water after ingestion. Reports indicate that leptospirosis is not a rare disease, that many infections are not associated with occupational exposure, and that urban and suburban cases are becoming more prevalent.111 Clinical manifestations of leptospirosis usually are not specific. A variety of laboratory aids are available, but specimens must be collected and handled properly. In some cases, establishing

a definitive diagnosis may be impossible; negative cultures or failure to demonstrate a rise in antibody titer does not exclude the possibility that the patient has active infection because the organism may not be present in the specimens that have been cultured, the antibody titer may have peaked before an acute-phase specimen was collected, and antibiotic therapy may suppress the develop-ment of positive titers or delay their appearance (see Chapter 141).

Toxoplasmosis. Toxoplasmosis should be considered in any child with persistent fever. Cervical or supracla-vicular adenopathy is present in most cases, but occasionally fever is the only manifestation. The diagnosis is established by demonstration of a rising serologic titer; antibody to Toxoplasma gondii is so prevalent that demon-stration of a high titer alone is not diagnostic of acute infection. Demonstration of Toxoplasma in tissue sections or body fluid is highly suggestive, although the organism can persist in tissue for years. Isolation of the parasite is not absolutely diagnostic of recent infection (see Chapter 223).

Malaria. Malaria also should be considered in children with FUO. In addition to fever, splenomegaly usually is present. A history of travel to endemic areas should be sought, although malaria has occurred in patients who never traveled outside the United States.

Disease can occur even in persons who have taken antimalarial drugs when they visited the endemic region. A delay of several months can occur between the development of infection and the onset of symptoms. The infection can be transmitted from a person who has visited an endemic area to one who has not when an appropriate mosquito vector is present. Malaria also can be acquired by blood transfusion or by the use of needles and syringes contaminated by the parasite. Demonstration of malarial organisms on appropriately stained thin or thick smears of blood is diagnostic (see Chapter 219).

Salmonellosis. Salmonella organisms are contaminants in many food products. In view of the nonspecific signs and symptoms with which salmonellosis can occur, its association with FUO in children is not surprising. Repetitive blood and stool cultures are most helpful in establishing a diagnosis (see Chapter 111).

Tuberculosis. Tuberculosis is an important cause of FUO in children, as well as in adults. Nonpulmonary tuberculosis is manifested as FUO more frequently than is pulmonary tuberculosis, which usually is evident on routine chest radiographs. FUO occurs most commonly with disseminated tuberculosis or infection of the liver, peritoneum, pericardium, or genitourinary tract. Active disseminated tuberculosis has been well documented in children with negative results on chest

radiography and tuberculin skin tests.76,94

Negative interferon-γ release assay results also may occur.33 A high index of suspicion and a careful history of possible contacts are important to make the diagnosis. Funduscopic examination can reveal choroid tubercles. Liver and bone marrow


frequently are involved in children with miliary tubercu-losis; liver biopsy specimens and bone marrow aspirates should be obtained and processed for morphologic evaluation and culture. If the chest radiograph yields abnormal results, cultures of gastric aspirates, sputum, or both should be obtained. Because nontuberculous mycobacte-ria (i.e., atypical organisms) are present in the gastric contents of normal individuals, demonstration of acid-fast organisms on smears of gastric secretion does not necessarily indicate disease. Rarely, a patient with tuber-culous pericarditis has fever, weight loss, and weakness but no precordial pain or other specific cardiac complaints. Disseminated infection with atypical mycobacte-ria generally is seen in patients infected with HIV (see Chapter 96) or those with other immunodeficiencies.

Tularemia. Generally, failure to consider tularemia in children with FUO may be attributed to a lack of appreciation of the many sources of infection and the various routes of inoculation. The organism can be acquired from contact with a variety of animal species, as well as from ticks, mosquitoes, lice, fleas, flies, and contaminated water. The organism can penetrate mucous membranes and broken or unbroken skin, or it can be inhaled or swallowed. Patients and parents should be questioned about animal contact and the ingestion of rabbit or squirrel meat (see Chapter 132).

Viral Infections. Infection by most viruses produces an illness that is relatively brief. Exceptions to this rule can include infections by adenovirus, cytomegalovirus, Epstein-Barr virus, hepatitis viruses, and certain arbovi-ruses. In all of these diseases, symptoms are extremely variable and signs and symptoms frequently are

nonspecific. The diagnosis can be established by appropriate cultures and serologic studies (see Chapter 252).

Immunodeficiency. A variety of congenital and acquired immunodeficiency states can be manifested as FUO. Patients with immunoglobulin deficiencies (e.g., Bruton agammaglobulinemia) may have a long history of recurrent fever, with or without evident infection, whereas patients with abnormalities in lymphocyte function are more likely to have prolonged fever caused by persistent viral or parasitic infection.

Localized Infections

Bacterial Endocarditis. Infective endocarditis is an infrequent cause of FUO in children. Acute bacterial endocarditis tends to be fulminant, but the subacute form begins insidiously, generally at the site of a preexisting cardiac lesion. Subacute bacterial endocarditis is a rare occurrence in infants and increases in frequency with advancing age. The organisms most commonly encountered are viridans streptococci, enterococci, S. aureus, and Staphylococcus epidermidis. The absence of a cardiac murmur does not exclude the possibility of endocarditis, especially when the infection is limited to the right side of the heart. Endocarditis also can occur in the absence of positive blood cultures, particularly in association with

the following factors: use of antibiotics for an undefined febrile illness, right-sided cardiac lesions, prolonged duration of disease, infection by unusual organisms such as Brucella or Coxiella burnetii, and inadequate culture methods for the detection of infection with anaerobic organisms. Frequently associated laboratory findings include anemia, leukocytosis, and an elevated erythrocyte sedimentation rate. Several blood cultures (aerobic and anaerobic) of adequate volume should be obtained before starting antibiotics. Echocardiography can reveal vegetations, but negative results do not rule out endocarditis (see Chapter 26).

Bone and Joint Infections. Infections of bones and joints usually can be diagnosed clinically but occasionally are manifested as FUO. This manifestation occurs commonly in young children who cannot explain where they hurt and is more likely to occur with osteomyelitis than with septic arthritis. Infection of the pelvic bones is implicated most often in this regard. Radioisotopic bone scan and MRI are more sensitive than are plain radio-graphs of the bones (see Chapters 55 and 56).

Intra-Abdominal Abscesses. Subphrenic, perinephric, and pelvic abscesses may be manifested as FUO. A history of previous intra-abdominal disease or abdominal surgery or a history of vague abdominal complaints should heighten suspicion of an intra-abdominal collection of pus. The organisms involved most commonly are S. aureus, streptococci, E. coli, and anaerobic flora. Fever may be the only sign of a pelvic, perinephric, or psoas abscess. Urinalysis generally yields normal results, but the mass can be demonstrated by ultrasound examination, CT, or MRI.

Liver Abscess and Other Hepatic Infections. Pyo-genic

liver abscesses are encountered most frequently in immunocompromised pediatric patients but can be seen in otherwise normal children.53 In some patients, persistent fever is the only finding. Blood cultures usually are sterile, and serum levels of liver enzymes generally are close to or within normal limits. Many patients have hepatomegaly and right upper quadrant abdominal tenderness. The diagnosis can be established by examination of the liver by ultrasonography, radioisotope scanning, CT, or MRI. Bacterial hepatitis and bacterial cholangitis can occur in the absence of jaundice and other specific signs of liver dysfunction.105,109

Granulomatous hepatitis is not a specific disease but rather a syndrome characterized by granuloma formation within the liver. A specific cause cannot be determined in every case. Although most reported cases have been in adults,90 pediatric cases do occur, particularly with Epstein-Barr virus infection and with cat-scratch disease. The diagnosis can be made by ultrasound or other diagnostic imaging (see Chapter 49).

Upper Respiratory Tract Infections. Frequently, infections of the upper respiratory tract and related organs are manifested as FUO.58,69,83 Although obvious signs or symptoms would be expected, the complaints


often appear trivial and may be ignored. Reported cases of FUO have occurred in children with mastoiditis, sinusitis, chronic or recurrent otitis media, chronic or recurrent pharyngitis, tonsillitis, peritonsillar abscess, and nonspecific upper respiratory tract infection. A para-pharyngeal inflammatory pseudotumor manifested as FUO has been reported in a 3-year-old girl in whom anemia and weight loss also developed. The cause never was discerned, but the symptoms resolved after surgical removal of the inflammatory mass.29

Noninfectious Causes of Fever of Unknown OriginCentral Nervous System Dysfunction

Children with severe brain damage can have dysfunctional thermoregulation, and body temperature in some of these patients can remain elevated for months. Cases of otherwise neurologically normal children who have had fever as a result of central dysfunction also have been reported. Berger19 discussed a 16-year-old child with recurrent episodes of fever that were thought to represent a form of epilepsy but disappeared when treatment with phenytoin was begun. Wolff and associates107

reported a 14-year-old child with cyclic episodes of fever,

nausea, vomiting, and emotional disturbance caused by a central nervous system lesion.

Diabetes Insipidus

Central and nephrogenic diabetes insipidus can cause FUO in infants and young children. Polyuria and poly-dipsia may not be appreciated during infancy. Hyperther-mia, weight loss, and peripheral vascular collapse can ensue. Signs of dehydration or an increased serum con-centration of sodium suggests the diagnosis. The diagnosis is established by simultaneous measurements of urine and serum electrolytes and osmolality during periods of normal hydration and after carefully controlled periods of water deprivation. Serum levels of antidiuretic hormone also can be measured by radioimmunoassay.

Drug Fever

Nearly any medication can be associated with an allergic reaction, including fever. The offending agent may be a prescribed drug, an over-the-counter preparation, or a street drug such as amphetamine or 1-[1-phenylcyclohexyl] piperidine (phencyclidine [PCP]). Atropine, whether taken systemically or used topically in the form of eye drops, can cause elevation of temperature. Phenothi-azines and anticholinergic drugs can inhibit sweating and impair regulation of temperature. Epinephrine and related compounds can affect thermoregulatory control

mechanisms and produce fever. Drug fever can be low-grade or high and spiking. Fever can be continuous or intermittent. Discontinuation of the drug generally is followed by disappearance of the fever within 48 to 72 hours, but it sometimes persists for as long as a month as a result of slow excretion of the offending agent.

Factitious Fever

A parent or patient may report the presence of fever that does not exist. The reading of the thermometer can be increased by immersing the bulb in hot liquid or by rinsing the mouth with hot liquid immediately before inserting the thermometer. Clues to factitious fever include absence of tachycardia, malaise, or discomfort despite a markedly elevated temperature; apparent rapid defervescence unaccompanied by diaphoresis; failure of the temperature curve to follow the normal diurnal variation of body temperature; hyperpyrexia; and normal temperature reading when the temperature is obtained rectally by someone who remains in attendance during the procedure. The presence of fever also can be con-firmed or excluded by measuring the temperature of a freshly voided urine specimen. The current use of elec-tronic thermometers in most hospitals decreases the possibility of factitious fever in that setting because the nurse or aide usually brings in the thermometer and stays in attendance during the relatively brief period of insertion. In more unusual cases, the patient or parent can induce fever by the injection of infective or foreign materials.

Familial Dysautonomia

Familial dysautonomia (Riley-Day syndrome), an autoso-mal recessive disorder, is characterized by autonomic and peripheral sensory nerve dysfunction. Eighty

percent of patients are children of Jewish parentage, particularly Ashkenazi Jews. Defective regulation of temperature can result in hypothermia or hyperthermia.34

A careful history and physical examination can reveal poorly coordinated swallowing movements that lead to recurrent aspiration and pneumonia; recurrent episodes of vomiting; excessive salivation; excessive or diminished sweating; diminished formation of tears; periods of hypotension, hypertension, or both; and erythema or blanching of the skin. The fungiform papillae of the tongue are absent or diminished in number, and the sensation of taste is deficient.91 Self-mutilation or multiple sites of skin trauma can reflect diminished or absent pain sensation peripherally. Deep tendon reflexes are diminished; corneal reflexes are impaired; and mental deficiency, dysarthria, and emotional lability are common findings.

Excretion of vanillylmandelic acid in urine can be diminished, and excretion of homovanillic acid can be increased. Administration of histamine intradermally can produce a wheal but no flare or pain at the site of injection. Placement of methacholine (2.5%) into the conjunctival sac produces pupillary constriction in children with familial dysautonomia but no response in normal children. Intravenous infusion of norepinephrine is followed by an exaggerated pressor response, and the

hypotensive response to infusion of methacholine is increased.

Hemophagocytic LymphohistiocytosisHemophagocytic lymphohistiocytosis is characterized by prolonged fever, hepatosplenomegaly, cytopenia, and


hyperferritinemia and hemophagocytosis in the bone marrow, liver, spleen, or lymph nodes.50,77 It is a life-threatening and unusual disorder in which uncontrolled proliferation of activated lymphocytes and histiocytes results in unregulated hypersecretion of inflammatory cytokines. Hemophagocytic lymphohistiocytosis can be primarily a familial disease or can be manifested as a reactive process triggered by infection, malignancy, immunologic disease, or drugs.

The diagnosis of hemophagocytic lymphohistiocytosis is suggested by fever, hepatosplenomegaly, cytopenia in at least two cell lines, hypertriglyceridemia or hypofibri-nogenemia, and an elevated ferritin level. Other laboratory abnormalities associated with hemophagocytic lymphohistiocytosis can include low or absent natural killer cell activity or elevated soluble CD25 (α chain of the interleukin-2 receptor), but these studies take time for results to return from reference laboratories.52 Because this disorder can be manifested initially as FUO and progress to masquerade as overwhelming sepsis, a high index of suspicion is required for establishing the diagnosis. Further investigation should include evaluation of bone marrow or lymph nodes for the presence of hemo-phagocytosis. Therapy should include treatment of the underlying infection or trigger, if one exists, in addition to appropriate immune modulation therapies. A substantial proportion of hemophagocytic lymphohistiocytosis cases progress rapidly to death despite administration of appropriate chemotherapy.50,52,77

Inflammatory Bowel Disease

Fever is a prominent feature in many children with inflammatory bowel disease.30,56,102 A greater percentage of children than adults with regional enteritis

have fever. Appropriate contrast-enhanced radiographic studies of the intestines should be undertaken in children with pro-longed FUO, even in the absence of findings specifically referable to the gastrointestinal tract, especially if the erythrocyte sedimentation rate is elevated and if the patient has anemia, weight loss, failure of linear growth, or a positive stool guaiac test.

Ulcerative colitis can be manifested as FUO, though less commonly than with regional enteritis. In patients with ulcerative colitis, symptoms referable to the gastrointestinal tract generally are present at the time that the patient is febrile.

Infantile Cortical Hyperostosis

The cause of infantile cortical hyperostosis (i.e., Caffey disease) is unknown. The decreased incidence in recent years suggests an infectious, possibly a viral, cause. Spon-taneous hyperplasia of subperiosteal bone begins during infancy and is associated with swelling of the overlying tissues. The skull, mandible, clavicles, scapula, and ribs are affected most frequently, but in some children the long bones and even the metatarsal bones can be involved. Most patients have persistent fever, sometimes as high as 40° C (104° F). Tenderness over the affected regions, irritability, elevated erythrocyte sedimentation rate, and leukocytosis are common findings. The diagnosis is

established by the clinical picture in conjunction with radiographically demonstrated periosteal involvement.

Juvenile Idiopathic (Rheumatoid) Arthritis

Juvenile idiopathic arthritis is a chronic inflammatory disorder that usually is manifested as one of three distinct syndromes: the systemic form, characterized by high, spiking temperatures (generally once or twice each day), evanescent rash, and lymphadenopathy; a polyarticular form; and a monarticular or pauciarticular form. Fever is associated with all three manifestations but occurs most commonly in the systemic form, in which case it is present in nearly 100 percent of patients. This form also is the one most likely to be manifested as FUO.24 Arthritis may not develop for months to years after onset of the fever. The diagnosis often needs to be made by exclusion because no laboratory findings are specific for the diagnosis.

Periodic Fevers

The periodic fever disorders, also known as unprovoked inflammatory events that sometimes can occur without accompanying fever, are rare heritable disorders characterized by recurrent (periodic or irregular) attacks of fever and inflammation.100 Between attacks, patients feel well. These disorders include familial Mediterranean fever and hyperimmunoglobulinemia D with periodic fever syndrome, which are autosomal recessive diseases. Familial Mediterranean fever is the most common peri-odic fever syndrome and is caused by a mutation in the MEFV gene, which encodes the protein pyrin. The illness is characterized by fever for 1 to 3 days accompanied by abdominal pain, pleurisy, and arthritis or arthralgia. Laboratory findings include peripheral leukocytosis and elevation of acute-phase reactants. The episodes occur irregularly. Persistent inflammation can lead to

secondary amyloidosis. The disease occurs most commonly in Armenians, North Africans, Sephardic Jews, and Turks and sometimes Ashkenazi Jews, Italians, and Greeks or persons of other ethnicities. Hyperimmunoglobulinemia D with periodic fever syndrome is associated with mutations in the MVK gene that encodes mevalonate kinase. Disease commonly presents before the age of 1 year, with episodes of fever lasting 3 to 7 days accompanied by cervical lymphadenopathy, abdominal pain, and vomiting or diarrhea.37,42 Patients also can have aphthous ulcers, rash, splenomegaly, and arthritis or arthralgias. Attacks may occur at irregular intervals and can be triggered by stress, vaccination, and viral infections. Immunoglobulin (Ig) D levels are elevated, and most patients also have elevated IgA. Secondary amyloidosis is rare.

Other periodic fever syndromes include tumor necro-sis factor receptor–associated periodic syndrome; pyo-genic sterile arthritis, pyoderma gangrenosum syndrome, and acne; and Blau syndrome. These are rare disorders that are autosomal dominant in transmission. The genes associated with these disorders encode proteins that share domains involved in innate immunity and apoptosis. Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory


disorder are cryopyrin-associated periodic syndromes, a group of overlapping autoinflammatory disorders in which fever is an accompanying but not major feature of illness.

The syndrome of periodic fever with aphthous stoma-titis, pharyngitis, and adenitis is a relatively common periodic fever syndrome. Symptoms such as fever, phar-yngitis, cervical lymphadenopathy, and mild aphthous ulcers usually recur at 3- to 4-week intervals, generally beginning abruptly and resolving spontaneously in 3 to 5 days. Leukocytosis and elevation of inflammatory markers occur during the acute episode and normalize in between. The cause of this syndrome remains unknown.38

Acknowledgments

Debra L. Palazzi would like to acknowledge Martin I. Lorin and the late Ralph D. Feigin as the original authors of this chapter.

NEW REFERENCES SINCE THE SIXTH EDITION.4.American Academy of Pediatrics, Subcommittee on Urinary

Tract Infection, Steering Committee on Quality Improvement and Management. Clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595–610.

5.Andreola B, Bressan S, Callegaro S, et al. Procalcitonin and C-reactive protein as diagnostic markers of severe bacterial infec-tions in febrile infants and children in the emergency department. Pediatr Infect Dis J 2007;26:672–7.

27. Carstairs KL, Tanen DA, Johnson AS, et al. Pneumococcal bac-teremia in febrile infants presenting to the emergency department before and after the introduction of the heptavalent pneumococcal vaccine. Ann Emerg Med 2007;49:772–7.

28. Centers for Disease Control and Prevention, Advisory Committee on Immunization Practices. Licensure of a 13-valent pneumococ-cal conjugate vaccine (PCV13) and recommendations for use among children, 2010. MMWR Morb Mortal Wkly Rep 2010; 59:258–61.

32.Craig JC, Williams GJ, Jones M, et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ 2010;340:c1594.

33.Cruz AT, Geltemeyer AM, Starke JR, et al. Comparing the tuber-culin skin test and T-SPOT TB blood test in children. Pediatrics 2011;127:e31–8.

52. Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophago-cytic lymphohistiocytosis. Blood 2011;118:4041–52.

79. Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre experience. Acta Paediatr 2006;95:463–6.

100. Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr Drug Targets Inflamm Allergy 2005;4:77–80.

101. Waddle E, Jhaveri R. Outcomes of febrile children without localising signs after pneumococcal conjugate vaccine. Arch Dis Child 2009;94:144–7.

104. Watt K, Waddle E, Jhaveri R. Changing epidemiology of serious bacterial infections in febrile infants without localizing signs. PLoS One 2010;5:e12448.

106. Wilkinson M, Bulloch B, Smith M. Prevalence of occult bactere-mia in children aged 3 to 36 months presenting to the emergency department with fever in the postpneumococcal conjugate vaccine era. Acad Emerg Med 2009;16:220–5.

111. Yoder JS, Hlavsa MC, Craun GF, et al. Centers for Disease Control and Prevention. Surveillance for waterborne disease and outbreaks associated with recreational water use and other aquatic facility-associated health events: United States, 2005–2006. MMWR Surveill Summ 2008;57:1–29.

The full reference list for this chapter is available at expertconsult.com.

63 FEVER WITHOUT SOURCE AND FEVER OF UNKNOWN ORIGIN 848.e1

REFERENCES1. Adams KC, Dixon JH, Eichner ER.

Clinical usefulness of poly-morphonuclear leukocyte vacuolization in predicting septicemia in febrile children. Pediatrics 1978;62:67–70.

2. Alpern ER, Alessandrini EA, Bell LM, et al. Occult bacteremia from a pediatric emergency department: current prevalence, time to detection and outcome. Pediatrics 2000;106:505–11.

3. Alpern ER, Alessandrini EA, McGowan KL, et al. Serotype prevalence of occult pneumococcal bacteremia. Pediatrics 2001; 108:e23.

4. American Academy of Pediatrics, Subcommittee on Urinary Tract Infection, Steering Committee on Quality Improvement and Management. Clinical practice guideline for the diagnosis and management of the initial UTI in febrile infants and children 2 to 24 months. Pediatrics 2011;128:595–610.

5. Andreola B, Bressan S, Callegaro S, et al. Procalcitonin and C-reactive protein as diagnostic markers of severe bacterial infec-tions in febrile infants and children in the emergency department. Pediatr Infect Dis J 2007;26:672–7.

6. Arisoy ES, Correa AG, Wagner ML, Kaplan SL. Hepatosplenic cat-scratch disease in children: selected clinical features and treat-ment. Clin Infect Dis 1999;28:778–84.

7. Ayus JC, Krothapalli RK, Arieff AI. Occult bacteremia in febrile children. N Engl J Med 1988;318:1338–9.

8. Bachur R, Harper M. Reevaluation of outpatients with Streptococ-cus pneumoniae bacteremia. Pediatrics 2000;105:502–9.

9. Baker MD, Bell LM, Avner JR. Outpatient management without antibiotics of fever in selected infants. N Engl J Med 1993;329: 1437–41.

10.Baker MD, Bell LM, Avner JR. The efficacy of routine outpatient management without antibiotics of fever in selected infants. Pedi-atrics 1999;103:627–31.

11.Baker RC, Tiller T, Bausher JC, et al. Severity of disease correlated with fever reduction in febrile infants. Pediatrics 1989;83: 1016–9.

12.Baraff LJ. Management of fever without source in infants and children. Ann Emerg Med 2000;36:602–14.

13.Baraff LJ, Lee SI. Fever without source: management of children 3 to 36 months of age. Pediatr Infect Dis J 1992;11:146–51.

14.Baraff LJ, Oslund S, Prather M. Effect of antibiotic therapy and etiologic microorganism on the risk of bacterial meningitis in children with occult bacteremia. Pediatrics 1993;92:140–3.

15.Baraff LJ, Bass JW, Fleisher GR, et al. Practice guidelines for the management of infants and children 0 to 36 months of age with fever without source. Pediatrics 1993;92:1–12.

16.Baron MA, Fink HD. Bacteremia in private pediatric practice. Pediatrics 1980;66:171–5.

17.Baron MA, Fink HD, Cicchetti DV. Blood cultures in private pediatric practice: An eleven-year experience. Pediatr Infect Dis 1989;8:2–7.

18.Bass JW, Steel RW, Wittler RR, et al. Antimicrobial treatment of occult bacteremia: a multicenter cooperative study. Pediatr Infect Dis J 1993;12:466–73.

19.Berger H. Fever: An unusual manifestation of epilepsy. Postgrad Med 1966;40:479–81.

20.Bloom HR. Must we teach clinical judgment? Pediatrics 1981; 67:745–6.

21.Bonadio WA. Systemic bacterial infections in children with fever greater than 41° C. Pediatr Infect Dis J 1989;8:120–1.

22.Bonadio WA, Webster H, Wolfe A, Gorecki D. Correlating infectious outcome with clinical parameters of 1130 consecutive febrile infants aged zero to eight weeks. Pediatr Emerg Care 1993;9:84–6.

23.Brewis EC. Undiagnosed fever. Br Med J 1965;1:107–10.

24.Calabro JJ, Marchesano JM. Juvenile rheumatoid arthritis. N Engl J Med 1967;277:746–9.

25.Carey BM, Williams CE, Arthur RJ. Ultrasound demonstration of pericardial empyema in an infant with pyrexia of undetermined origin. Pediatr Radiol 1988;18:349–50.

26.Carroll WL, Farrell MK, Singer JI, et al. Treatment of occult bacteremia: a prospective randomized clinical trial. Pediatrics 1983;72:608–11.

27.Carstairs KL, Tanen DA, Johnson AS, et al. Pneumococcal bac-teremia in febrile infants presenting to the emergency department

before and after the introduction of the heptavalent pneumococcal vaccine. Ann Emerg Med 2007;49:772–7.

28.Centers for Disease Control and Prevention, Advisory Committee on Immunization Practices. Licensure of a 13-valent pneumococ-cal conjugate vaccine (PCV13) and recommendations for use among children, 2010. MMWR Morb Mortal Wkly Rep 2010;59: 258–61.

29.Chan YF, Ma LT, Yeung LT, et al. Parapharyngeal inflammatory pseudotumor presenting as fever of unknown origin in a 3-year-old girl. Pediatr Pathol 1988;8:195–203.

30.Chron BB, Yarnis H. Continuous fever of intestinal origin. Ann Intern Med 1947;26:858–62.

31.Corrigan JJ. Thrombocytopenia: laboratory sign of septicemia in infants and children. J Pediatr 1974;85:219–23.

32.Craig JC, Williams GJ, Jones M, et al. The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses. BMJ 2010;340:c1594.

33.Cruz AT, Geltemeyer AM, Starke JR, et al. Comparing the tuber-culin skin test and T-SPOT TB blood test in children. Pediatrics 2011;127:e31–8.

34.Dancis J, Smith AA. Familial dysautonomia. N Engl J Med 1966;274:207–9.

35.Dashefsky B, Teele DW, Klein JO. Unsuspected meningococce-mia. J Pediatr 1983;102:69–72.

36.Dershewitz RA. A comparative study of the prevalence, outcome and prediction of bacteremia in children. J Pediatr 1983;103: 352–8.

37.Drenth JPH, Haagsma CJ, van Der Meer JWH. Hyperimmuno-globulinemia D and periodic fever syndrome. Medicine (Baltimore) 1994;73:133–44.

38.Feder HMJ, Bialecki CA. Periodic fever associated with aphthous stomatitis, pharyngitis and cervical adenitis. Pediatr Infect Dis 1989;8:186–9.

39.Feigin RD, Shearer WT. Fever of unknown origin in children. Curr Probl Pediatr 1976;6:2–57.

40.Fineman DS, Palestno CJ, Kim CK, et al. Detection of abnormalities in febrile AIDS patients with In-111–labelled leukocyte and Ga-67 scintigraphy. Radiology 1989;170:677–80.

41.Fleishner GR, Rosenberg N, Vinci R, et al. Intramuscular versus oral antibiotic therapy for the prevention of meningitis and other bacterial sequelae in young febrile children at risk for occult bac-teremia. J Pediatr 1994;124:504–12.

42.Gross C, Schnetzer JR, Ferrante A, Vladutiu AO. Children with

hyperimmunoglobulinemia D and periodic fever syndrome. Pediatr Infect Dis J 1996;15:72–7.

43.Habibian MR, Staab EV, Matthews HA. Gallium citrate Ga 67 scans in febrile patients. JAMA 1975;233:1073–6.

44.Hayani A, Mahoney DH, Fernback DJ. Role of bone marrow examination in the child with prolonged fever. J Pediatr 1990; 116:919–20.

45.Herz AM, Greenhow TL, Alcantara J, et al. Changing epidemiology of outpatient bacteremia in 3- to 30-month-old children after the introduction of the heptavalent-conjugated pneumococcal vaccine. Pediatr Infect Dis J 2006;25:293–300.

46.Hoekelman R, Lewin EB, Shapira MD, et al. Potential bacteremia in pediatric practice. Am J Dis Child 1979;133:1017–9.

47.Isaacman DJ, Burke DL. Utility of the serum C-reactive protein for detection of occult bacterial infection in children. Arch Pediatr Adolesc Med 2002;156:905–9.

48.Jacobs RF, Schutze GE. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis 1988;26:80–4.

49.Jaffe DM, Tanz RR, Davis T, et al. Antibiotic administration to treat possible occult bacteremia in febrile children. N Engl J Med 1987;317:1175–80.

50.Janka GE. Familial and acquired hemophagocytic lymphohistio-cytosis. Eur J Pediatr 2007;166:95–109.

51.Jaskiewicz JA, McCarthy CA, Richardson AC, et al. Febrile infants at low risk for serious bacterial infection: an appraisal of the Rochester criteria and implications of management. Pediatrics 1994;94:390–6.

52.Jordan MB, Allen CE, Weitzman S, et al. How I treat hemophago-cytic lymphohistiocytosis. Blood 2011;118:4041–52.

848.e2 SECTION XII SYSTEMIC INFECTIOUS DISEASES

53.Kaplan SL, Feigin RD. Pyogenic liver abscess in normal children with fever of unknown origin. Pediatrics 1976;58:614–6.

54.Kline MW, Smith EO, Kaplan SL, et al. Effects of causative organism and presence or absence of meningitis on white blood cell counts in children with bacteremia. J Emerg Med 1988;6: 33–5.

55.Lacour AG, Gervaix A, Zamora SA, et al. Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identifi-cators of serious bacterial infections in children with fever without localising signs. Eur J Pediatr 2001;160:95–100.

56.Lee FI, Davies DM. Crohn’s disease presenting as pyrexia of unknown origin. Lancet 1961;1:1205–6.

57.Liu C, Lehan C, Speer ME, et al. Early detection of bacteremia in an outpatient clinic. Pediatrics 1985;75:827–31.

58.Lohr JA, Hendley JO. Prolonged fever of unknown origin: record of experience with 54 childhood patients. Clin Pediatr (Phila) 1977;16:768–73.

59.Margolis MT. Specific anergy in tuberculosis. N Engl J Med 1983;309:1388.

60.Marshall R, Teele DW, Klein JO. Unsuspected bacteremia due to Haemophilus influenzae: outcome in children not initially admitted to hospital. J Pediatr 1979;95:690–5.

61.Mazur LJ, Jones T, Kozinetz CA. Temperature response to acetaminophen and risk of occult bacteremia: a case control study. J Pediatr 1989;115:888–91.

62.McCarthy PL, Dolan TF. Hyperpyrexia in children: eight-year emergency room experience. Am J Dis Child 1976;130:849–51.

63.McCarthy PL, Jekel JF, Dolan TF. Temperature greater than or equal to 40° C in children less than 24 months of age: a prospective study.

Pediatrics 1977;59:663–8.

64.McCarthy PL, Frank AL, Ablow RC, et al. Value of the C-reactive protein test in the differentiation of bacterial and viral pneumonia. J Pediatr 1978;92:454–9.

65.McCarthy PL, Grundy GW, Spiesel SZ, et al. Bacteremia in children: an outpatient review. Pediatrics 1976;57:861–8.

66.McCarthy PL, Jekel JF, Stashwick CA, et al. History and observation variables in assessing febrile children. Pediatrics 1980;65: 1090–5.

67.McCarthy PL, Jekel JF, Stashwick CA, et al. Further definition of history and observation variables in assessing febrile children. Pediatrics 1981;67:687–93.

68.McCarthy PL, Sharpe MR, Spiesel SZ, et al. Observation scales to identify serious illness in febrile children. Pediatrics 1982; 70:802–9.

69.McClung HJ. Prolonged fever of unknown origin in childhood. Am J Dis Child 1972;124:544–50.

70.McGowan JE, Bratton L, Klein JO, et al. Bacteremia in febrile children seen in a walk-in pediatric clinic. N Engl J Med 1973; 288:1309–12.

71.McMurray DN, Echeverri A. Cell-mediated immunity in anergic patients with pulmonary tuberculosis. Am Rev Respir Dis 1978; 118:827–34.

72.Miller ML, Szer I, Yogev R, Bernstein B. Fever of unknown origin. Pediatr Clin North Am 1995;42:999–1011.

73.Morens DW. WBC and differential: Value in predicting bacterial disease in children. Am J Dis Child 1979;133:25–7.

74. Murray DL, Zonana J, Seidel JS, et al. Relative importance of bacteremia and viremia in the course of acute fevers of unknown origin in outpatient children. Pediatrics 1981;68: 157–60.

75.Nash DR, Douglas JE. Anergy in active

pulmonary tuberculosis: a comparison between positive and negative reactors and an evaluation of 5 TU and 250 TU skin test doses. Chest 1980;77: 32–7.

76.Ostrow JH. Tuberculin negative tuberculosis. Am Rev Respir Dis 1973;107:882–3.

77.Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin. Clin Infect Dis 2003;36:306–12.

78.Pantell RH, Newman TB, Bernzweig J, et al. Management and outcomes of care of fever in early infancy. JAMA 2004;291: 1203–12.

79.Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre experience. Acta Paediatr 2006; 95:463–6.

80.Peltola H. C-reactive protein in rapid differentiation of acute epiglottitis from spasmodic croup and acute laryngotracheitis: preliminary report. J Pediatr 1983;102:713–5.

81.Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine (Baltimore) 1961;40:1–30.

82.Picus D, Siegel MJ, Balfe DM. Abdominal computed tomography in children with unexplained prolonged fever. J Comput Assist Tomogr 1984;8:851–6.

83.Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics 1975;55:468–73.

84.Poehling KA, Talbot TR, Griffin MR, et al. Invasive pneumococ-cal disease among infants before and after introduction of pneu-mococcal conjugate vaccine. JAMA 2006;295:1668–74.

85.Prat C, Dominguez J, Rodrigo C, et al. Use of quantitative and semiquantitative procalcitonin measurements to identify children with sepsis and meningitis. Eur J Clin Microbiol Infect Dis 2004;23: 136–8.

86.Press S. Association of hyperpyrexia with serious disease in chil-dren. Clin Pediatr (Phila) 1994;33:19–25.

87.Pulliam PN, Attia MW, Cronan KM. C-reactive protein in febrile children 1 to 36 months of age with clinically undetectable serious bacterial infection. Pediatrics 2001;108:1275–9.

88.Roberts KB, Borzy MS. Fever in the first eight weeks of life. Johns Hopkins Med J 1977;141:9–13.

89.Sard B, Bailey MC, Vinci R. An analysis of pediatric blood cultures in the postpneumococcal conjugate vaccine era in a community hospital emergency department. Pediatr Emerg Care 2006;22: 295–300.

90.Simon HB, Wolff SM. Granulomatous hepatitis and prolonged fever of unknown origin: A study of 13 patients. Medicine (Baltimore) 1973;52:1–21.

91.Smith AA, Farbman A, Dancis J. Tongue in familial dysautonomia. Am J Dis Child 1965;110:152–3.

92.Steele RW, Jones SM, Lowe BA, et al. Usefulness of scanning procedures for diagnosis of fever of unknown origin in children. J Pediatr 1991;119:526–30.

93.Stein RC. The white blood cell count in fevers of unknown origin. Am J Dis Child 1972;124:60–3.

94.Steiner P, Portuguleza C. Tuberculous meningitis in children. Am Rev Respir Dis 1973;107:22–9.

95.Stoll MJ, Rubin LG. Incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine. Arch Pediatr Adolesc Med 2004;158:671–5.

96.Teach SJ, Fleisher GR. Efficacy of an observation scale in detecting bacteremia in febrile children three to thirty six months of age, treated as outpatients. J Pediatr 1995;126:877–81.

97.Teele DW, Pelton SI, Grant MJ, et al. Bacteremia in febrile children under 2 years of age: results of cultures of blood of 600 consecutive febrile children in a “walk-in” clinic. J Pediatr 1975; 87:227–30.

98.Todd JK. Childhood infections: diagnostic value of peripheral white blood cell and differential cell counts. Am J Dis Child 1974;127:810–6.

99.Torrey SB, Henretig F, Fleisher G, et al. Temperature response to antipyretic therapy in children. Am J Emerg Med 1985;3:190–2.

100. Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr Drug Targets Inflamm Allergy 2005;4:77–80.

101. Waddle E, Jhaveri R. Outcomes of febrile children without localis-ing signs after pneumococcal conjugate vaccine. Arch Dis Child 2009;94:144–7.

102. Walker SH. Periodic fever in juvenile

regional enteritis. J Pediatr 1962;60:561–5.

103. Waskerwitz S, Berkelhammer JE. Outpatient bacteremia: clinical findings in children under two years with initial temperatures of 39.5° C or higher. J Pediatr 1981;99:231–3.

104. Watt K, Waddle E, Jhaveri R. Changing epidemiology of serious bacterial infections in febrile infants without localizing signs. PLoS One 2010;5:e12448.

105. Weinstein L. Bacterial hepatitis: a case report on an unrecognized cause of fever of unknown origin. N Engl J Med 1978;299:1052–4.

106. Wilkinson M, Bulloch B, Smith M. Prevalence of occult bactere-mia in children aged 3 to 36 months presenting to the emergency department with fever in the postpneumococcal conjugate vaccine era. Acad Emerg Med 2009;16:220–5.

63 FEVER WITHOUT SOURCE AND FEVER OF UNKNOWN ORIGIN 848.e3

107. Wolff SM, Ward SB, Landy M. A syndrome of periodic hypotha-lamic discharge. Am J Med 1964;36:956–66.

108. Wright PF, Thompson J, McKee KT, Jr, et al. Patterns of illness in the highly febrile young child: epidemiologic, clinical and labo-

ratory correlates. Pediatrics 1981;67:694–700.

109. Wyllie R, Fitzgerald JF. Bacterial cholangitis in a 10-week-old infant with fever of undetermined origin. Pediatrics 1980;65: 164–7.

110. Yamamoto LT, Wigder HN, Fligner DJ, et al. Relationship of bacteremia to antipyretic therapy in febrile children. Pediatr Emerg Care 1987;3:223–6.

111. Yoder JS, Hlavsa MC, Craun GF, et al; Centers for Disease Control and Prevention. Surveillance for waterborne disease and outbreaks associated with recreational water use and other aquatic facility-associated health events: United

States, 2005–2006. MMWR Surveill Summ 2008;57:1–29.

Demam Tidak Tahu Penyebab FUO

Documents

Transcript of Demam Tidak Tahu Penyebab FUO