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Fever of unknown origin in children: Evaluation

Fever of unknown origin in children: Evaluation
Literature review current through: Jan 2024.
This topic last updated: Jan 23, 2023.

INTRODUCTION — Fever is a common presenting complaint in children. Most febrile illnesses either resolve before a diagnosis can be made or develop distinguishing characteristics that lead to a diagnosis. Fever of unknown origin (FUO) refers to a prolonged febrile illness without an established etiology despite thorough evaluation.

An approach to the evaluation of FUO in children will be reviewed here. Causes of FUO in children, fever without a source, and fever in specific pediatric populations are discussed separately:

(See "Fever of unknown origin in children: Etiology".)

(See "Fever without a source in children 3 to 36 months of age: Evaluation and management".)

(See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "The febrile infant (29 to 90 days of age): Management".)

(See "Fever in children with chemotherapy-induced neutropenia".)

(See "Management of children with non-chemotherapy-induced neutropenia and fever".)

DEFINITIONS — A consensus definition for FUO in children is lacking [1]. For clinical purposes, we define FUO in children as fever >38.3°C (101°F) at least once per day for ≥8 days with no apparent diagnosis after initial outpatient or hospital evaluation that includes a detailed history, thorough physical examination, and initial laboratory assessment. We use a duration of eight days because caregivers often seek medical care or consultation when fever persists for longer than one week; other experts may require a longer duration of fever.

Various definitions for FUO have been used in published studies of FUO in children [2-12]. The required duration of fever for inclusion in case series has ranged from five days to three weeks. Some series used different durations depending upon the setting (inpatient versus outpatient) [3,4,12]. Several made a distinction between FUO and "prolonged fever" [9,10]. Our definition is notably different from the standard definition of FUO for adults [13]. (See "Fever of unknown origin in adults: Evaluation and management", section on 'Definitions and categories of fuo'.)

FUO must be differentiated from fever without a source (FWS), which we define as fever for ≤1 week without adequate explanation after a thorough history and physical examination; FWS can progress to FUO if it lasts >1 week. The most common causes, differential diagnosis, evaluation, and management of FUO and FWS differ. FWS is discussed separately. (See "The febrile infant (29 to 90 days of age): Outpatient evaluation" and "Fever without a source in children 3 to 36 months of age: Evaluation and management".)

FUO also must be differentiated from "pseudoFUO," a term used to describe sequential febrile illnesses (usually viral), the first of which may be associated with a higher than normal fever and vague persistent symptoms [14].

CAUSES — Many infectious and noninfectious diseases can cause FUO in children (table 1). FUO is usually caused by common disorders, often with an unusual presentation (table 2) [3-10,15-17]. (See "Fever of unknown origin in children: Etiology".)

Infectious diseases are the most common identifiable cause of FUO in children, followed by rheumatologic diseases (eg, systemic lupus erythematosus [SLE], vasculitis) [18,19]. Neoplastic disorders are less common [3-10,15-17]. In systematic reviews of studies in adult patients, the types of diagnoses and proportions of cases in various etiologic categories (eg, infectious, rheumatologic) varied geographically [20,21].

In a 2011 systematic review of 18 studies of FUO including 1638 children (<18 years of age), most of the included studies required a minimum of two or three weeks of fever [18]. The most common causes of FUO were as follows [18]:

Infection – 51 percent of cases; 59 percent of infections were bacterial; the most common bacterial infections varied geographically:

Bartonellosis (eg, cat scratch disease) and urinary tract infections in resource-rich countries

Brucellosis, tuberculosis, and typhoid fever in resource-poor countries

No diagnosis or resolution before diagnosis – 23 percent of cases

Rheumatologic disease – 9 percent of cases, most commonly juvenile idiopathic arthritis and SLE

Neoplastic disorder – 6 percent of cases, most commonly leukemia and lymphoma

The remaining cases were caused by various conditions including Kawasaki disease, inflammatory bowel disease, factitious fever, hemophagocytic lymphohistiocytosis, immunodeficiency, familial Mediterranean fever, nonspecified autoimmune diseases, and drugs.

In a more recent single-center review, among 102 children hospitalized with FUO (defined as fever of ≥38°C for >7 days without an identifiable source on presentation), 41 percent were categorized as infectious, 27 percent as autoimmune, 19 percent as oncologic, and 14 percent as other or unknown [19].

The proportion of undiagnosed cases increased in case series published after the late 1990s [9,16,17]. With advances in diagnostic testing (eg, molecular assays) and increased awareness of certain conditions, children with diseases previously common in FUO case series are now diagnosed earlier in their course of illness (eg, infectious diseases, neoplastic disorders, rheumatologic diseases, periodic fever syndromes, etc), leaving increasing numbers of children with difficult-to-diagnose conditions in FUO series [16,17,22,23].

OVERVIEW OF EVALUATION

Setting — The evaluation of FUO usually begins in the outpatient setting. Children who require hospitalization generally have abnormal physical examination or initial laboratory findings. Potential indications for admission in children with FUO include [23]:

Ill-appearance

Progressive symptoms or clinical deterioration

Concern for medical child abuse (ie, Munchausen syndrome by proxy)

Need for observation of the child in a controlled setting

Need to perform studies or procedures best coordinated in the inpatient setting

Pace — The evaluation should proceed quickly if the child is ill-appearing or deteriorating clinically. Even though children with chronic medical conditions generally have been excluded from case series of FUO, the evaluation should also proceed quickly if the child has a chronic medical condition that increases susceptibility to infection (eg, human immunodeficiency virus [HIV] infection, sickle cell disease, or other immune deficiency; cystic fibrosis; disruption in barrier function [eg, tracheostomy tube, cochlear implant]) [14].

The pace can be more deliberate if the child appears well. Sometimes the fever resolves without explanation before invasive diagnostic testing is undertaken. (See 'Outcome' below.)

Approach — The first step in the evaluation of FUO is verification of the height and duration of fever to distinguish FUO from fever without a source and sequential febrile infections. (See 'Fever history' below and 'Definitions' above.)

The initial evaluation includes a detailed history, physical examination, basic diagnostic tests for all patients, and additional testing targeted to clinical findings in individual patients [12,14,23-25].

A detailed and thorough history and physical examination are the most important components of the diagnostic evaluation. In case series of FUO, incomplete histories, overlooked physical findings, and failure to correctly interpret existing laboratory data delayed determination of the underlying cause [3-5].

The clinician must be prepared to repeat the clinical assessment on multiple occasions to reassess historical features or clinical findings that may have been missed or not reported previously. It may help to rephrase important questions. A patient or caregiver eventually may recall information that was omitted, forgotten, or thought to be unimportant when the initial history was obtained. New physical findings can appear, and subtle abnormalities not appreciated on the initial evaluation can become more apparent. In a retrospective series of 54 children with FUO, more than 25 percent developed clinically relevant physical findings after admission to the hospital [3].

INITIAL EVALUATION

History — The history in a child with FUO should include questions related to common disorders (often with an unusual presentation) as well as uncommon diseases (table 3). Virtually any historical finding may be relevant.

Fever history — It is essential to obtain as much detail about the fever as possible. Important aspects include:

How was the fever assessed (eg, by touch, forehead strip, or measured with a thermometer)? If measured with a thermometer, which type was used?

Temperature recorded with a rectal thermometer is most accurate; however, in an older child, temperature recorded with an oral thermometer is usually adequate. (See "Fever in infants and children: Pathophysiology and management", section on 'Temperature measurement'.)

Was the fever confirmed by someone other than the caregiver?

Lack of confirmation by someone other than the caregiver may be a clue to factitious fever.

What are the duration, height, and pattern of fever? These are best documented by asking the caregiver to keep a fever diary over days to weeks, depending upon the diagnoses being considered. The caregiver should document the date and time of fever, height and duration of fever, method of assessing the fever, and associated symptoms.

Normal variations in body temperature (eg, elevations after exercise or late in the afternoon) should not be mistaken for febrile episodes. (See "Fever in infants and children: Pathophysiology and management", section on 'Normal body temperature'.)

Although the pattern and duration of fever generally are not helpful in making a specific diagnosis in children with FUO [3,5], certain fever patterns may suggest a diagnosis (eg, malaria (table 4)).

Are there specific circumstances that precede the temperature elevation? For example, some children with periodic fever syndromes have a prodrome of fatigue before the febrile episode.

Does the child appear ill or develop any signs or symptoms during the febrile episode?

Absence of malaise or other generalized symptoms during febrile episodes may suggest factitious fever.

Children with juvenile idiopathic arthritis (JIA) are ill-appearing with fever and improve dramatically with defervescence. The rash of systemic JIA is characteristically evanescent and may be present only during fever (picture 1). (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Do other constitutional symptoms (eg, myalgias, headache, malaise, etc) persist when the fever abates?

The persistence of constitutional symptoms is more worrisome for a systemic disease.

Is there associated sweating?

Patients with fever, heat intolerance, and sweating may have hyperthyroidism. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

Patients with fever, heat intolerance, and absence of sweating may have ectodermal dysplasia. (See "The genodermatoses: An overview", section on 'Ectodermal dysplasias'.)

Lack of sweating with defervescence may indicate factitious fever.

Associated complaints — It is important to ask, and ask again, about past or current abnormalities or complaints. As examples:

Red eyes that resolved spontaneously may suggest Kawasaki disease. Other causes of FUO that may be associated with red eyes include leptospirosis, tuberculosis, infectious mononucleosis, and tularemia. (See "Kawasaki disease: Clinical features and diagnosis".)

Abdominal pain, diarrhea, rash, and shock in the weeks following severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection can suggest multisystem inflammatory syndrome in children (MIS-C), although the median duration of fever in MIS-C is less than seven days, making MIS-C less of a consideration in children with FUO [26]. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Nasal discharge may suggest rhinosinusitis. (See "Acute bacterial rhinosinusitis in children: Clinical features and diagnosis", section on 'Acute bacterial rhinosinusitis'.)

Recurrent pharyngitis with ulcerations may suggest periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. (See "Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA syndrome)".)

Gastrointestinal complaints may suggest salmonellosis, leptospirosis, tularemia, an intra-abdominal abscess, hepatosplenic cat scratch disease, or inflammatory bowel disease (IBD).

Limb or bone pain may suggest:

Brucellosis (see "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Clinical manifestations')

Leukemia or lymphoma (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Overview of Hodgkin lymphoma in children and adolescents")

Osteomyelitis or septic arthritis (see "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Clinical features' and "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Clinical features')

Infantile cortical hyperostosis (see "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)')

Kikuchi-Fujimoto disease (see "Kikuchi disease", section on 'Clinical features')

Exposures — It is important to ask, and ask again, specifically about the following exposures:

Medications (including prescription, topical, and nonprescription drugs) and nutritional supplements (see "Drug fever")

History of surgical procedures:

Patients with a history of abdominal surgery have an increased risk of intra-abdominal abscess

The list of potential infectious pathogens may need to be expanded in children with tracheotomy tubes, gastric tubes, cochlear implants, or other implantable devices

Contact with infected or otherwise ill persons (FUO is usually caused by unusual presentations of common illnesses)

Exposure to animals, including household pets, domestic animals in the community, and wild animals (table 5) (see "Zoonoses: Cats" and "Zoonoses: Dogs" and "Zoonoses: Animals other than dogs and cats")

Travel history (including place of residence), extending back to birth; a number of diseases acquired in endemic areas can reemerge years after departure (eg, histoplasmosis, coccidioidomycosis, blastomycosis, leishmaniasis, malaria, tuberculosis); the travel history should include:

The site(s) of travel

Prophylactic medications and immunizations before travel

Exposure to mosquitos or other insects (eg, sandfly)

Measures taken to prevent exposure to contaminated food and water

Whether artifacts, rocks, or soil from other geographic areas were brought into the home

Exposure to other persons with a recent history of travel

Tick bites can be a clue to Rocky Mountain spotted fever, human ehrlichiosis or anaplasmosis, tularemia, tick-borne relapsing fever, or Lyme disease

North American mosquitoes and some ticks carry a variety of arboviruses (eg, West Nile Virus)

Consumption of game meat (toxoplasmosis, tularemia), raw meat (tularemia, brucellosis), or raw shellfish (hepatitis)

A history of pica, specifically eating dirt (visceral larva migrans, toxoplasmosis) [23]

Ethnic or genetic background — Certain conditions associated with fever tend to occur among members of certain ethnic groups. As examples:

Arginine vasopressin resistance (previously called nephrogenic diabetes insipidus) in Ulster Scots [27] (see "Evaluation of patients with polyuria")

Familial Mediterranean fever is most common in Turkish, Armenian, North African Jewish, and Arabian individuals but is not restricted to these groups (see "Familial Mediterranean fever: Epidemiology, genetics, and pathogenesis", section on 'Epidemiology' and "Clinical manifestations and diagnosis of familial Mediterranean fever")

Familial dysautonomia in Ashkenazi Jewish people (see "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)')

Examination — Performance of a complete and meticulous physical examination is necessary to identify clues to the underlying cause of FUO (table 6) [14,23]. Even subtle abnormalities may be relevant. The examination should be repeated because abnormal findings may develop or evolve over time.

The patient with FUO should be evaluated while febrile. This is necessary to assess how ill the patient appears; to determine the effect of fever on heart rate, respiratory rate, and sweating; and to document any accompanying symptoms (eg, malaise or myalgias) or signs. The rash of systemic JIA is characteristically evanescent and may be present only during fever (picture 1).

General assessment – The physical examination should begin with a general assessment of the patient's appearance, activity, vital signs, and growth parameters.

Patients ≥13 years of age with temperature ≥38.9°C (102°F) should be assessed for relative bradycardia: the failure of the pulse to increase as expected with fever (approximately 10 beats per minute for each 0.6°C [1°F]).

Relative bradycardia can be associated with several infectious diseases, including Legionella, psittacosis, Q fever, typhoid fever, typhus, babesiosis, malaria, leptospirosis, yellow fever, Dengue fever, viral hemorrhagic fever, and Rocky Mountain spotted fever [28].

Weight loss is a nonspecific finding but may be a clue to IBD, diabetes insipidus, malignancy, or other systemic illness/infection.

Short stature or deceleration of linear growth may suggest IBD or endocrine abnormalities (eg, pituitary lesion). (See "Causes of short stature", section on 'Systemic disorders or processes with secondary effects on growth'.)

Skin and scalp – A number of conditions that cause FUO are associated with dermatologic abnormalities. The skin should be examined repeatedly; dermatologic abnormalities may develop or evolve over time.

Relevant dermatologic abnormalities include:

Petechiae in infective endocarditis, bacteremia, and viral and rickettsial infections.

The rash of Rocky Mountain spotted fever, which typically begins on the ankles and wrists and spreads to the palms and soles and centrally (picture 2).

Papular lesions in cat scratch disease (picture 3).

Eschar at the site of tick bite in Mediterranean spotted fever, African tick bite fever, or rarely, tularemia (picture 4).

Erythema migrans or erythema migrans-like rashes in tick-borne diseases: Lyme disease (picture 5A-B) and Southern tick-associated rash illness (picture 6).

Rose spots in typhoid fever (picture 7).

Salmon-pink rash of systemic JIA (picture 1).

Malar erythema in systemic lupus erythematosus (SLE) (picture 8A-B).

Palpable purpura in vasculitis (eg, polyarteritis nodosa) (picture 9).

Urticarial and/or serpiginous macular lesions and band of erythema at the lateral aspects of the hands and feet (picture 10) in serum sickness.

Erythema nodosum (picture 11) in children with infection, JIA, SLE, malignancy, and IBD. (See "Erythema nodosum".)

Seborrheic lesions can indicate Langerhans cell histiocytosis (picture 12A-C).

Absence of sweating during fever may suggest ectodermal dysplasia, familial dysautonomia, or dehydration (eg, related to diabetes insipidus).

Sparse hair (picture 13), particularly of the eyebrows and eyelashes, and hypohidrosis may suggest hypohidrotic ectodermal dysplasia.

Patients with familial dysautonomia may have blotchy skin and multiple areas of skin trauma.

Eyes – The eye examination may provide a number of potential diagnostic clues, including:

Palpebral conjunctivitis – Infectious mononucleosis, coxsackievirus infection, measles, Newcastle disease (a viral infection associated with exposure to chickens or other birds).

Bulbar conjunctivitis – Leptospirosis (picture 14), Kawasaki disease (picture 15).

Phlyctenular conjunctivitis (with small, white, elevated lesions) – Tuberculosis.

Conjunctival hemorrhage – Infective endocarditis.

Ischemic retinopathy with hemorrhages and retinal detachment, ischemic optic neuropathy – Polyarteritis nodosa [29,30].

Absence of the pupillary constrictor response – Hypothalamic or autonomic dysfunction.

Absent tears and corneal reflexes – Familial dysautonomia (Riley-Day syndrome).

Abnormal funduscopic examination:

-Choroid tubercles (picture 16) – Miliary tuberculosis

-Chorioretinitis (eg, raised yellow-white, cottony lesions in a nonvascular distribution) (picture 17) – Toxoplasmosis

-Perivascular sheathing (picture 18) – Vasculitis

Sinuses – Sinus tenderness in patients with persistent nasal discharge may indicate rhinosinusitis.

Oropharynx – The oropharyngeal examination may provide a number of potential diagnostic clues, including:

Oral ulcers – IBD, Behçet syndrome, SLE. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Extraintestinal manifestations' and "Clinical manifestations and diagnosis of Behçet syndrome", section on 'Clinical manifestations' and "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Pharyngeal hyperemia without exudate – Infectious mononucleosis (caused by Epstein-Barr virus [EBV] or cytomegalovirus [CMV]), toxoplasmosis, tularemia, leptospirosis.

Dental abscess (picture 19) and other oral infections [31-34] (may be complicated by other infections [eg, sinusitis, brain abscess, mediastinal abscess]).

Anomalous dentition (hypodontia, adontia, or conical "peg teeth" (picture 20)) – Hypohidrotic ectodermal dysplasia. (See "The genodermatoses: An overview", section on 'Ectodermal dysplasias'.)

Smooth tongue (ie, without fungiform papillae) or excessive salivation – Familial dysautonomia. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)'.)

Gingival hypertrophy or inflammation and loosening or loss of teeth:

-Leukemia (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children")

-Langerhans cell histiocytosis (see "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis", section on 'Skin and oral mucosa')

Lymph nodes – Causes of lymph node enlargement are discussed separately. (See "Peripheral lymphadenopathy in children: Etiology", section on 'General classification'.)

Chest

Tachypnea, crackles (rales), decreased or bronchial breath sounds, bronchophony, whispered pectoriloquy, increased tactile fremitus, and/or dullness to percussion are suggestive of pneumonia. (See "Community-acquired pneumonia in children: Clinical features and diagnosis", section on 'History and examination'.)

Cardiac murmur, especially one of new onset, may suggest infective endocarditis. (See "Infective endocarditis in children", section on 'Clinical manifestations'.)

A pericardial rub is a sign of pericarditis, a manifestation of SLE and other disorders. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Clinical manifestations'.)

Abdomen

Hepatomegaly or splenomegaly – Some of the more common causes of hepatomegaly or splenomegaly in children with FUO include brucellosis, cat scratch disease, infectious mononucleosis, infective endocarditis, malaria, and salmonellosis. Splenomegaly may also be due to childhood leukemia (acute lymphoblastic leukemia and acute myeloid leukemia) or non-Hodgkin lymphoma.

Tenderness on palpation of the liver may indicate hepatitis, liver abscess, or cat scratch disease [35].

Abdominal mass – Malignancy (neuroblastoma, Wilms tumor, lymphoma, germ cell tumor).

Musculoskeletal

Bony tenderness can indicate:

-Osteomyelitis (see "Hematogenous osteomyelitis in children: Clinical features and complications", section on 'Clinical features')

-Malignant infiltration of the bone marrow (eg, acute lymphoblastic leukemia/lymphoma, primary bone tumors such as Ewing sarcoma and osteosarcoma, metastatic lesions from neuroblastoma or rhabdomyosarcoma)

-Infantile cortical hyperostosis (see "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)')

Joint tenderness/effusion can indicate joint infection, JIA, SLE, or IBD.

Muscle tenderness can be found in:

-Trichinellosis (see "Trichinellosis")

-Various arboviral and other viral infections

-Dermatomyositis (see "Juvenile dermatomyositis and other idiopathic inflammatory myopathies: Epidemiology, pathogenesis, and clinical manifestations")

-Polyarteritis nodosa (see "Vasculitis in children: Incidence and classification", section on 'Classification criteria')

-Subdiaphragmatic abscess (if the tenderness is over the trapezius muscle) [15]

Hyperactive deep tendon reflexes (DTR) may indicate hyperthyroidism. (See "Clinical manifestations and diagnosis of Graves disease in children and adolescents".)

Absent or hypoactive DTR may indicate familial dysautonomia. (See "Hereditary sensory and autonomic neuropathies", section on 'HSAN3 (Familial dysautonomia)'.)

Genitourinary – The genitourinary examination of patients with FUO should include a rectal examination, examination of the external genitalia, and pelvic examination (for sexually active female adolescents). Relevant findings include:

Perirectal tenderness or mass – Pelvic abscess or tumor.

Genital ulcers, urethral discharge – Sexually transmitted infections.

Perianal fistulae, skin tags, or fissures – IBD.

For sexually active females: Cervical motion, uterine, or adnexal tenderness – Pelvic inflammatory disease.

For males: Testicular tenderness – Brucellosis, vasculitis (polyarteritis nodosa, Henoch-Schönlein purpura).

Initial diagnostic testing

Basic tests for all patients — We obtain the tests listed below in all children with FUO; results of these tests may provide clues to the most common or serious causes (table 7). We do not routinely obtain procalcitonin levels; the utility of procalcitonin levels in children with FUO is unclear. Additional tests may be indicated if the history, examination, or initial diagnostic tests suggest a diagnosis or diagnoses. (See 'Additional targeted tests' below.)

Complete blood count (CBC), differential, and smear – Abnormal CBC or smear may provide clues to the underlying diagnosis. Examples include:

Anemia – Malaria, tuberculosis, infective endocarditis, JIA, SLE, IBD [36]

Cytopenia in more than one cell line and/or bizarre or immature forms – Leukemia, hemophagocytic lymphohistiocytosis, SLE, Kikuchi-Fujimoto disease (see "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children")

Leukocytosis (>10,000 polymorphonuclear leukocytes [PMN]/microL) or bandemia (>500 nonsegmented neutrophils/microL) – Increased risk of severe bacterial infection [37,38], JIA, drug fever, infantile cortical hyperostosis

Neutropenia – Tuberculosis; human granulocytic anaplasmosis; Dengue fever; infection with EBV, CMV, and HIV; SLE; leukemia (see "Overview of neutropenia in children and adolescents" and "Infectious causes of neutropenia")

Atypical lymphocytes – Viral infection (eg, EBV, CMV), Kikuchi-Fujimoto disease

Lymphocytosis – Cat scratch disease, EBV, toxoplasmosis (see "Approach to the child with lymphocytosis or lymphocytopenia")

Lymphocytopenia – Brucellosis, malaria, tuberculosis, typhoid fever, HIV, SLE, sarcoidosis (see "Approach to the child with lymphocytosis or lymphocytopenia")

Eosinophilia – Parasitic or fungal infection, allergic disorder, neoplasm, immunodeficiency, drug fever (see "Approach to the patient with unexplained eosinophilia" and "Drug fever")

Thrombocytosis – JIA, Kawasaki disease, nonspecific marker of inflammation

Thrombocytopenia – EBV, CMV, HIV, parvovirus, varicella, leptospirosis, tularemia, rickettsial infection, SLE, Kikuchi-Fujimoto disease (see "Causes of thrombocytopenia in children")

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) – ESR and CRP are nonspecific markers of inflammation. Elevation of ESR and CRP decrease the likelihood of factious fever. Elevated ESR and CRP can be used to monitor disease progress. ESR (but not CRP) may be raised artifactually in hypergammaglobulinemia.

Normal ESR and CRP decrease the likelihood of infectious and inflammatory causes of FUO and may justify slowing the pace of the evaluation. However, normal ESR and CRP do not exclude noninflammatory causes (eg, familial dysautonomia, ectodermal dysplasia, thalamic dysfunction, diabetes insipidus, drug fever, etc). ESR (but not CRP) may be lowered artifactually in conditions involving the consumption of fibrinogen (such as disseminated intravascular coagulopathy and hemophagocytic lymphohistiocytosis).

Aerobic and anaerobic blood cultures – Routine blood cultures may provide a diagnosis in children with bacteremia, infective endocarditis, typhoid fever, or brucellosis. Anaerobic blood cultures may be helpful in isolating fastidious organisms (eg, Streptobacillus moniliformis) and facultative aerobes.

Urinalysis and urine culture – Relevant findings on urinalysis and urine culture include:

Pyuria and bacteriuria – Urinary tract infection

Sterile pyuria – Kawasaki disease (the white blood cells are monocytic cells; because they are not polymorphonuclear neutrophils, they are not detected by dipstick tests for leukocyte esterase), adjacent intra-abdominal infection, genitourinary tuberculosis (see "Kawasaki disease: Clinical features and diagnosis" and "Urogenital tuberculosis")

Hematuria and/or proteinuria – SLE, infective endocarditis, leptospirosis

Low specific gravity or osmolality – Diabetes insipidus

Urinary tract infection is one of the most frequent causes of FUO in children in resource-rich countries [18]. In one pediatric FUO series, the two most frequent laboratory errors were failure to perform a urinalysis and failure to adequately pursue the finding of pyuria [4].

Chest radiograph – Abnormal findings on chest radiograph may suggest a diagnosis:

Infiltrate – Pneumonia

Lymphadenopathy – Tuberculosis, lymphoma

Mediastinal mass – Leukemia, lymphoma, neurogenic tumor, rhabdomyosarcoma

Small nodular densities – Leptospirosis

Serum electrolytes, blood urea nitrogen (BUN), creatinine, and hepatic aminotransferases – Serum electrolytes, BUN, creatinine, and hepatic aminotransferases are obtained to evaluate renal and/or hepatic involvement.

Hypernatremia may suggest diabetes insipidus or dehydration.

Hyponatremia may suggest leptospirosis or tularemia.

Elevated BUN and creatinine may indicate renal impairment (eg, in SLE) or dehydration.

Elevated hepatic aminotransferases may be a clue to a viral infection without distinctive features (eg, adenovirus, EBV, CMV) brucellosis, tularemia, JIA, or Kikuchi-Fujimoto disease.

Additional targeted tests — Additional laboratory and imaging tests should be directed to causes of FUO suggested by the history (table 3), physical examination (table 6), or basic screening tests (table 7). In a review of 40 children with FUO referred to a pediatric rheumatology clinic (presumably after the more common causes of FUO had been ruled out), results of laboratory, radiologic, and pathologic studies were occasionally abnormal, but none of the tests resulted in a specific diagnosis [39].

Examples of additional targeted testing include:

Suspected generalized infection – Various generalized infections (table 2) may be suspected on the basis of the initial evaluation (table 3 and table 6 and table 7). Diagnosis of these infections is discussed separately.

Brucellosis (see "Brucellosis: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnosis')

Cat scratch disease (see "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Approach to diagnosis')

Leptospirosis (see "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnosis')

Malaria (see "Laboratory tools for diagnosis of malaria")

Tuberculosis (see "Tuberculosis disease in children: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis' and "Tuberculosis infection (latent tuberculosis) in children", section on 'How to test')

Salmonellosis (see "Nontyphoidal Salmonella bacteremia and extraintestinal infection" and "Nontyphoidal Salmonella: Gastrointestinal infection and asymptomatic carriage")

Toxoplasmosis (see "Toxoplasmosis: Ocular disease")

Tularemia (see "Tularemia: Clinical manifestations, diagnosis, treatment, and prevention", section on 'Diagnosis')

Typhoid fever (see "Enteric (typhoid and paratyphoid) fever: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis')

Children at risk for syphilis – Given the potential long-term consequences of undiagnosed syphilis, we perform serologic testing for syphilis in neonates, young infants, and adolescents with FUO with risk factors for syphilis. (See "Syphilis: Screening and diagnostic testing" and "Congenital syphilis: Clinical manifestations, evaluation, and diagnosis", section on 'Evaluation and diagnosis'.)

Suspected HIV infection – For children with suspected HIV infection (eg, risk factors, cytopenias), we perform combination antigen/antibody HIV immunoassay. (See "Screening and diagnostic testing for HIV infection".)

Suspected Kawasaki disease For children for whom Kawasaki disease is a diagnostic consideration, appropriate serologic testing (if necessary) should be performed prior to the administration intravenous immune globulin. (See "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Initial treatment and prognosis", section on 'Intravenous immune globulin'.)

For infants <6 months of age with unexplained fever for ≥7 days, echocardiogram is warranted to evaluate for incomplete Kawasaki disease. In young children, Kawasaki disease often presents without mucocutaneous findings, and echocardiographic changes may be the only indication of Kawasaki disease. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Typical versus incomplete KD'.)

Suspected endocarditis – Infective endocarditis may be suspected in children with a history of a preexisting cardiac lesion, compatible examination (eg, new onset murmur, petechiae), or laboratory findings (eg, anemia, elevated ESR/CRP, positive blood culture). Additional testing for children with suspected endocarditis includes multiple sets of blood cultures over 24 hours, electrocardiography, and echocardiography [40]. (See "Infective endocarditis in children".)

Loose stools or recent international travel – Additional testing for children with FUO and loose stools or recent international travel may include stool cultures and/or examination for ova and parasites. Testing for Clostridioides difficile infection may be indicated in children with recent history of antibiotic use or gastrointestinal tract surgery, underlying bowel disease, or impaired humoral immunity. (See "Travelers' diarrhea: Epidemiology, microbiology, clinical manifestations, and diagnosis" and "Clostridioides difficile infection in children: Clinical features and diagnosis", section on 'Approach to diagnosis'.)

Children with gastrointestinal complaints – A stool guaiac test should be performed in children with gastrointestinal complaints or poor weight gain. Positive stool guaiac may be a clue to enteric infection, IBD, or vasculitis.

Children with gastrointestinal complaints, particularly abdominal pain or abdominal masses, may warrant abdominal imaging for abscess, tumor, or lymphadenopathy. For children with suspected hepatosplenic cat scratch disease and stable patients with vague intra-abdominal complaints, we generally start with abdominal ultrasonography. For patients in whom malignancy is suspected or those requiring urgent evaluation for possible surgical intervention, computed tomography (CT) or magnetic resonance imaging (MRI) may be preferred. Contrast imaging is preferred if infection or abscess is suspected.

Children with bone and/or joint tenderness or swelling – Additional evaluation of children with bone and/or joint tenderness usually includes plain radiographs, though advanced imaging may be necessary. (See "Hematogenous osteomyelitis in children: Evaluation and diagnosis", section on 'Initial evaluation' and "Bacterial arthritis: Clinical features and diagnosis in infants and children", section on 'Imaging' and "Differential diagnosis of the orthopedic manifestations of child abuse", section on 'Infantile cortical hyperostosis (Caffey disease)'.)

Cytopenias in ≥1 cell line – We consider obtaining bone marrow aspirate and biopsy to evaluate for leukemia, hemophagocytic lymphohistiocytosis [41], and Kikuchi-Fujimoto disease. We also evaluate such children for SLE and HIV. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis", section on 'Diagnosis' and "Screening and diagnostic testing for HIV infection".)

In one review of 414 bone marrow examinations for the evaluation of FUO in children, bone marrow results established noninfectious diagnoses in 8 percent of cases, including malignancy (6.7 percent), hemophagocytic syndromes (0.7 percent), histiocytosis (0.5 percent), and hypoplastic anemia (0.2 percent) [42]. Most of these disorders were suspected from clinical or laboratory clues before the bone marrow examination was performed.

Peripheral lymphadenopathy and worrisome features – Children with peripheral lymphadenopathy and worrisome features (table 8) may warrant early lymph node biopsy. (See "Peripheral lymphadenopathy in children: Evaluation and diagnostic approach".)

Recurrent or persistent infections – We measure serum concentrations of immunoglobulin (Ig) G, IgA, and IgM in children with recurrent or persistent infections [15].

Low Ig concentrations may indicate immunodeficiency. (See "Primary humoral immunodeficiencies: An overview".)

Elevated IgG levels may indicate autoimmune conditions (eg, SLE, IBD) or infection [43].

Elevated IgM levels suggest hyper-IgM syndrome. (See "Hyperimmunoglobulin M syndromes", section on 'Clinical manifestations'.)

IgE levels are unlikely to be helpful unless there is evidence of allergy or infection, suggesting hyper-IgE syndrome (eg, eosinophilia). (See "Autosomal dominant hyperimmunoglobulin E syndrome".)

Suspected IBD – IBD may be suspected in children with persistent fever, elevated ESR or CRP, anorexia, weight loss, and/or short stature, particularly if they have abdominal complaints (with or without anemia). The evaluation for IBD is discussed separately. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children", section on 'Diagnostic evaluation'.)

Recurrent or episodic fevers – In children with recurrent or episodic fevers, we obtain serum IgD levels to evaluate hyper-IgD syndrome. Molecular genetic tests are available for other periodic fever disorders but should be obtained in consultation with an expert in these conditions. (See "Hyperimmunoglobulin D syndrome: Clinical manifestations and diagnosis" and "The autoinflammatory diseases: An overview".)

Diagnostic interventions

Discontinue medications — Nonessential medications should be discontinued in children with FUO; multiple medications can be discontinued individually [24]. Resolution of fever within two half-lives of the drug (usually within three to four days) supports the diagnosis of drug fever. (See "Drug fever", section on 'Drug cessation'.)

Therapeutic trials

Nonsteroidal anti-inflammatory agents – A therapeutic trial of a nonsteroidal anti-inflammatory drug (NSAID) is reasonable if JIA is suspected. Resolution of fever supports the diagnosis. However, in general, the response of fever to anti-inflammatory drugs does not help to distinguish between infectious and noninfectious causes of fever.

Empiric antimicrobials – We generally avoid empiric antimicrobial therapy as a diagnostic measure in children with FUO except in those in whom a potentially life-threatening infections is a consideration (eg, malaria, typhoid fever, disseminated tuberculosis). (See "Treatment of uncomplicated falciparum malaria in nonpregnant adults and children" and "Enteric (typhoid and paratyphoid) fever: Treatment and prevention", section on 'Empiric therapy' and "Tuberculosis disease in children: Treatment and prevention".)

Empiric trials of broad-spectrum antibiotics can mask or delay the diagnosis of serious infections (eg, meningitis, parameningeal infection, infective endocarditis, osteomyelitis) [12,23]. Empiric antibiotics also can interfere with isolation of an organism from the blood or other cultures.

Empiric glucocorticoids – Empiric trials of glucocorticoids should not be administered to children with unexplained fever unless the child is in extremis and infections and malignancies have been convincingly excluded. Glucocorticoids may worsen infections and mask malignancies.

SUBSEQUENT EVALUATION — Children with persistent FUO should undergo serial evaluation. For patients who can be evaluated in the outpatient setting, we generally have the caregiver keep a fever diary and request that the child return for evaluation of new complaints or a change in clinical status. The fever diary should include the date and time of fever, height and duration of fever, method of assessing the fever, and associated symptoms. For children in the inpatient setting, a thorough physical examination and interval history is performed daily with further evaluation directed by new findings.

If FUO resolves after three to seven days, we do not perform additional evaluation.

If the FUO persists and the child is well appearing, it is reasonable to perform serial evaluations and obtain additional diagnostic studies only as indicated by new (or newly identified) symptoms or signs [18].

For ill-appearing children with persistent fever and no diagnosis after the initial evaluation, the following tests may be warranted (if not performed previously) [15]:

Serum concentrations of immunoglobulin (Ig) G, IgA, and IgM (for humoral immunodeficiency). (See "Primary humoral immunodeficiencies: An overview".)

Combination antigen/antibody HIV immunoassay. (See "Screening and diagnostic testing for HIV infection".)

Imaging of the gastrointestinal tract (for occult abscess, tumor, or lymphadenopathy) in patients with gastrointestinal complaints. For children with suspected hepatosplenic cat scratch disease and stable patients with vague intra-abdominal complaints, we generally start with abdominal ultrasonography. For patients in whom malignancy is suspected or those requiring urgent evaluation for possible surgical intervention, CT or MRI may be preferred. Contrast imaging is preferred if infection or abscess is suspected.

Positron emission tomography (PET) scans – In a review of prospective adult studies, (18)F-2-deoxy-2-fluoro-D-glucose (FDG)-PET contributed to the diagnosis in 25 to 69 percent of cases of FUO [44]. FDG-PET was more sensitive than gallium citrate single photon emission CT in detecting tumors, infection, and inflammation.

PET scans appear to be promising in the evaluation of FUO in children, but studies are limited [45].

Other imaging techniques generally are not helpful if there are no localizing findings. These include central nervous system imaging (with or without electroencephalogram), labeled white blood cell scans [46-48], radiographic bone survey, technetium bone scan, and liver-spleen scan. Although whole-body MRI is used to evaluate the extent of multisystem disease in children with cancer and inflammatory disorders (eg, chronic recurrent multifocal osteomyelitis, JIA) [49], the utility of whole-body MRI in the routine evaluation of children with persistent FUO has not been established.

INDICATIONS FOR CONSULTATION — Indications for consultation may include:

Persistent fever and ill-appearance in children with no diagnosis after the initial evaluation (eg, consultation with an expert in pediatric infectious diseases, pediatric rheumatology, and/or pediatric hematology-oncology depending on the most likely diagnoses being considered). Multiple specialists may be consulted simultaneously if the child is very ill and prompt diagnosis is essential.

Guidance regarding testing for periodic fever disorders (consultation with an expert in these disorders [eg, pediatric rheumatologist or pediatric infectious diseases specialist]).

OUTCOME — Children with FUO usually have treatable or self-limiting diseases. The fever resolves over time in most cases, and a specific diagnosis eventually can be made in others [7,8,15,50]. However, the outcome is not necessarily benign. In two series from the 1970s, mortality rates were 6 and 9 percent [3,5]. Mortality is lower in more recent series [7,8].

Many patients without a definitive diagnosis appear to do well, although episodes of fever may recur [4,39,50]. In long-term follow-up (median 3.5 years, range 1.2 to 5.3 years) of 19 children with FUO for at least two weeks and in whom no diagnosis was established, 16 were afebrile and completely well [50]. Two patients were subsequently diagnosed with juvenile idiopathic arthritis, one shortly after discharge and one 1.5 years later. One child, who had presented with abdominal pain and fever, had two episodes of intussusception (8 and 14 months after discharge), and the authors speculate that the initial episode might have been intussusception that spontaneously reduced.

In another series of 40 children who were referred for pediatric rheumatology evaluation with FUO of at least one month's duration and in whom no diagnosis was established, 37 were available for follow-up at a mean of 60.5 months [39]. Two children developed inflammatory bowel disease (one 7 months and the other 3.5 years after the initial evaluation); in both children, fever resolved after initiation of appropriate therapy.

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Basics topic (see "Patient education: Fever in children (The Basics)")

Beyond the Basics topic (see "Patient education: Fever in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions – A consensus definition of fever of unknown origin (FUO) in children is lacking. For clinical purposes, we define FUO in children as fever >38.3°C (101°F) at least once per day for ≥8 days with no apparent diagnosis after initial outpatient or hospital evaluation. (See 'Definitions' above.)

Causes – Infections are the most common identifiable causes of FUO in children, followed by rheumatologic diseases and neoplastic disorders (table 1). However, in many cases, the fever resolves before a definitive diagnosis is established. FUO is usually caused by common disorders, often with an unusual presentation (table 2). (See 'Causes' above.)

Evaluation – A detailed history and physical examination are essential. These should be repeated on several occasions. (See 'Overview of evaluation' above.)

History – The history should include details about the fever, associated complaints, and exposures (eg, to ill contacts, animals, insects, travel, drugs) (table 3). (See 'History' above.)

Examination – The patient should be examined while febrile. Important aspects of the examination include vital signs, growth parameters, the skin, scalp, eyes, sinuses, oropharynx, chest, abdominal, and musculoskeletal and genitourinary systems (table 6). (See 'Examination' above.)

Initial diagnostic evaluation – We suggest the following tests as part of the initial evaluation (table 7) (see 'Basic tests for all patients' above):

-Complete blood count and peripheral smear

-Erythrocyte sedimentation rate and C-reactive protein

-Blood cultures

-Urinalysis and urine culture

-Chest radiograph

-Serum electrolytes, blood urea nitrogen, creatinine, and hepatic aminotransferases

Additional diagnostic tests – Additional diagnostic tests should be based upon the findings of the history, examination, and initial tests. Diagnostic imaging may be warranted eventually in ill-appearing children in whom FUO persists without explanation. (See 'Additional targeted tests' above and 'Subsequent evaluation' above.)

Therapeutic trials – Empiric treatment with anti-inflammatory medications or antimicrobial agents generally should be avoided in children with FUO. However, it may be reasonable to provide a trial of a nonsteroidal anti-inflammatory drug for children with suspected juvenile idiopathic arthritis or directed antimicrobial therapy for children in whom a potentially life-threatening infections is consideration (eg, malaria, typhoid fever, disseminated tuberculosis). Such decisions often are best made in consultation with an expert in these disorders. (See 'Diagnostic interventions' above.)

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References

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