Fever is one of the most common reasons that children visit a doctor. Most of the time fever is part of a self-limited viral infection; however, it can be a sign of a serious illness such as a life-threatening infection or malignancy. Rarely, the fever is prolonged or recurrent and the etiology is not readily apparent. The differential diagnosis of these unexplained fevers is broad, and the evaluation of such children requires a step-wise approach and often the help of subspecialists.
What Is Fever?
In 1992, Mackowiak et al.1 challenged the concept—axiomatic since 1869, when Wunderlich and Reeve2 said it was so—that 37°C (98.6°F) is the normal human body temperature. By measuring oral temperatures 3 times daily in 148 healthy volunteers, they determined that the average body temperature is different between people and fluctuates by the time of day within people. Other authors3,4 have shown that body temperature is affected by age, activity level, meals, and environmental conditions. Its measurement is also affected by anatomic site, be it forehead, tympanic membrane, sublingual space, axilla, or rectum. The number of different temperature-measuring devices (eg, glass-liquid, digital, color-change) only complicates matters. Contemporary authors and laypeople cannot seem to agree on what “normal” is—what number of degrees is normal, how and where temperature should be measured, and whether or not to use a “correction factor” to approximate core body temperature.
If clinicians cannot agree on what “normal” body temperature is, then it is even more difficult to agree about what body temperature constitutes “fever,” which is defined as the endogenous rise of core body temperature above normal (there is no debate that fever is a warning sign that something is wrong).5,6 The only “official” definition of fever, to our knowledge, comes from the Brighton Collaboration, whose working groups labor to create definitions of adverse events after vaccination. Based on expert opinion and literature review, Marcy et al.6 (writing for the Brighton Collaboration) suggest that fever is the endogenous elevation of at least one measured body temperature of ≥38°C (100.4°F), regardless of the intrinsic and extrinsic factors mentioned above (in other words, at any anatomic site, using any device, at any age, and under all environmental conditions).6 By the group's own admission, this definition is arbitrary; perhaps less arbitrarily, one could see the logic of adjusting the reading of an axillary temperature upward to more closely approximate core body temperature.7
Fever as Chief Complaint
Fever is one of the most common presenting complaints in children, representing about 35% of unscheduled visits to pediatric offices.8 Most children who present with fever have additional signs and symptoms that lead to a specific diagnosis. In this review, undifferentiated fever is present when a previously healthy child presents as an outpatient with fever as the chief complaint without signs, symptoms, or physical findings of a specific clinical illness.9 Not included, for example, would be the febrile 6-month-old infant with otitis media, or the 3-year-old toddler with an upper respiratory infection. Undifferentiated fever should not be confused with fever without source, which refers to the febrile 3- to 36-month old child who is at risk for occult bacterial infection.10
Self-limited undifferentiated febrile illnesses are common in a primary pediatric practice despite the paucity of literature on the topic. Pediatricians are experienced in testing and treating, or waiting out, these incidents. The challenge comes in undifferentiated fevers that are recurrent or prolonged. What testing should be done in the office? What is the natural history? What is the risk of a serious condition? What patient should be referred, and to whom?
Ironically, some children with “undifferentiated fever” are not experiencing a fever at all. Parents may be concerned that their child's temperature of 99.0°F is a fever because of their belief that the child's temperature usually runs “low,” and that anything above “normal” constitutes a fever. Kleiman11 described children like this as having “pseudo-fever of unknown origin.” The parents' belief that something is wrong is real, but manifestations of real disease are not found. Family stress, recent illness or death of a loved one, behavior problems, and school absences may be clues to the diagnosis.
One has to be careful not to label febrile illnesses as “undifferentiated” if there are clues in the history, physical examination, or simple laboratory tests that suggest a specific diagnosis at the index visit. Some children present with common manifestations of uncommon diseases. For example, fever, rash, and headache in the summertime could be caused by Rocky Mountain spotted fever, whereas fever, cough, and lymphadenopathy could be histoplasmosis; one can appreciate how geography influences the likelihood of each of these diagnoses. Fever and an erythematous papule over a healed scratch could be clues to the diagnosis of cat scratch disease; one can appreciate how pet exposure affects the prior probability here. A detailed history may give it away—typhoid fever, for example, suspected in the patient who has recently returned from traveling. Other patients may present with uncommon manifestations of common diseases. For example, bacterial pneumonia and pyelonephritis can present with fever alone. Providers must follow all leads and think of all possible causes before deciding that a child truly has undifferentiated fever.9
Undifferentiated fevers may be prolonged or recurrent (Figure 1). In one recent study, 31% of 221 children referred to an ambulatory pediatric infectious diseases practice for unexplained fever had a prolonged pattern, with a median duration of 30 days.12 In 71% of these children with unexplained fever, the fever had occurred on consecutive days without interruption. The remaining 69% of children in the study had recurrent fevers.12
Undifferentiated fever schematic. Asterisk indicates that consideration of a primary immune deficiency should be given to children with severe, unusual, or recurrent infections. ALL, acute lymphocytic leukemia; ARF, acute rheumatic fever; EBV, Epstein-Barr virus; FMF, familial Mediterranean fever; HIDS, hyper-immunoglobulin D syndrome; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; PFAPA, periodic fever, aphthous stomatis, pharyngitis, adenitis; SLE, systemic lupus erythematosus; TRAPS, tumor necrosis receptor-associated periodic syndrome.
Prolonged Unexplained Fever
Prolonged unexplained fever (PUF) refers to sequential daily fevers that last beyond the typical (viral) illness; in this regard, it is useful to remember that the fever from nearly all viral illnesses will resolve within 1 week. Most children will likely have seen their doctor before a fever becomes prolonged, and they may have been given the diagnosis of viral syndrome (not otherwise specified). PUF does not become an issue until the second or third visit for a given illness.
PUF used to be called fever of unknown origin (FUO) (PUF makes more sense, as the term FUO does not convey the fact that the problem is the length of time the fevers have persisted). The FUO concept in adults was introduced by Petersdorf and Beeson in 196113 but was not addressed in children until the 1970s. Between 1972 and 1998, five major articles about FUO were published. Each was a retrospective case series from an academic medical center, and each used a different definition of fever.14–18 These articles established the four etiologic categories for FUO that have been taught in pediatric training ever since: infectious diseases, inflammatory conditions, neoplasms, and miscellaneous causes (Figure 1).
In the earlier studies about FUO,14–16 infectious causes made up 29% to 52% of cases. Final diagnoses included viral syndrome, urinary tract infection, and osteomyelitis, as well as more specific infections like tuberculosis, typhoid fever, and malaria. However, fever as a presenting and predominant symptom occurs commonly in diseases other than infections. The early series found inflammatory disorders in 10% to 20% of children and malignancies in 4% to 13%. In these early case series, 12% to 20% of children never received a specific diagnosis made.14–16
The etiologies of PUF have changed over time. In more recent case series, specific infectious diseases like cat scratch disease, tularemia, and Epstein-Barr virus infection were more commonly reported. This does not mean that these diseases were necessarily emergent, but rather that the diagnoses were being made more often because of readily available specific diagnostic tests. These same diagnostic modalities have become more accessible, so more children with PUF are probably being diagnosed in the primary care setting and not being referred. Studies using magnetic resonance imaging or even lymph node biopsy are now performed in an ambulatory setting prior to subspecialty consultation. Polymerase chain reaction panels with rapid turnaround times, high sensitivity and specificity, and the ability to test for several etiologies at once have replaced less sensitive and laborious culture methods. Not surprisingly, then, diagnoses of infectious diseases have become less common, and “no diagnosis” more common among children with PUF referred to academic medical centers.17,18
The primary challenge represented by patients with PUF is differentiating life-threatening infections or malignancies from prolonged viral syndromes and other conditions that may not require treatment. The first step is to determine the fever pattern and catalog the diagnostic studies performed to date. Next comes a detailed history, which may lead the clinician down a specific diagnostic path. Certain exposures should trigger consideration of “exposure-disease pairs,” such as kittens and cat scratch disease, unpasteurized milk and brucellosis, and travel to Africa and malaria (Table 1). The review of systems may uncover clues to inflammatory syndromes: weight loss and diarrhea may indicate inflammatory bowel disease, whereas fleeting, salmon-colored rash may indicate systemic-onset juvenile idiopathic arthritis (JIA). Physical examination may reveal important findings: firm, rubbery, matted supraclavicular lymph node may indicate malignancy; whereas exudative tonsillitis and splenomegaly may indicate infectious mononucleosis. Table 1 is a list of possible infectious, inflammatory, and malignant etiologies, clues that should be sought, and targeted diagnostic studies that could confirm the diagnosis.
Targeted Studies for Fever of Unknown Origin
Often there may be no clues to the diagnosis at the outset. In these cases, a good starting point would be to obtain serial standard laboratory studies that might eventually point you in the right direction. Inflammatory markers that remain normal or are down-trending are less worrisome than those that continue to rise, potentially signifying a more serious condition. Clinically ill children may warrant hospitalization or more extensive evaluation at the first visit. Well-appearing children may be given a fever/symptom diary and asked to return for follow-up at weekly intervals for repeated examinations and other diagnostic studies. To paraphrase Long and Edward,19 the pace of the illness determines the cadence of testing. Patients who are sicker or becoming sicker at a rapid pace require more extensive testing early on, whereas those who are clinically well and able to attend school or play with siblings may be evaluated in a step-wise fashion. After the third or fourth visit to the primary care provider without a diagnosis, an infectious disease consultation may be requested. Referral to oncology, rheumatology, or gastroenterology may also be warranted depending on the test results and symptoms.
Recurrent Unexplained Fever
Recurrent unexplained fever (RUF) may be intermittent or periodic (Figure 1). In the case series alluded to above,12 61% of children referred for RUF had an intermittent fever pattern and 39% had a periodic pattern. The majority of children with RUF will have intermittent fevers. Intermittent fevers are common in children and are usually due to sequential self-limited viral infections. In fact, children younger than age 2 years normally have five or six (or up to 12 for a child in daycare or with siblings in school or daycare) acute respiratory illnesses per year.20 So it is not unusual (albeit, a bit unlucky) for a child to have a febrile illness about every 6 weeks, especially in the winter; therefore, one need not always have to consider an underlying medical condition.
When does the number of febrile illnesses merit additional evaluations? Primary immunodeficiencies are rare in the United States, with a prevalence of 1 per 20,000.21 Conceivably, a child with an immune deficiency could present with intermittent fevers in the absence of defined specific infections. Several sets of criteria have been proposed for suspecting a primary immunodeficiency; the most publicly acknowledged are those from the Jeffrey Modell Foundation.22 Children with primary immune deficiencies are likely to have some combination of a positive family history, failure to thrive, and unusual or severe infections.23 A reasonable screen for immune deficiency is shown in Table 2, but testing should be tailored to the particular infectious disease history.
Immunology Tests Based on Type of Immune Deficit
A fever diary helps determine if the fever episodes are distinct or are part of a more threatening process. It is rare for a single infection to cause prolonged (as opposed to continuous) intermittent fevers, although an intermittent fever pattern may be seen with subacute bacterial endocarditis, deep-seated abdominal abscess, or osteomyelitis, especially if antibiotics, which could suppress the infection, were received during the illness. Cases of relapsing fever in the United States are usually caused by Borrelia hermseii or Borrelia recurrentis, which are transmitted by the bites of ticks or lice, respectively. Relapsing fever is characterized by sudden onset of high fever and chills that end spontaneously after a few days, followed by an afebrile period of days to weeks, then by one or more relapses, which are generally milder than the first episode. Malaria may cause paroxysms of fever that occur every other day (Plasmodium falciparum, Plasmodium vivax, and Plasmodium ovale) or every third day (Plasmodium malariae).
Intermittent fever can be a sign of an autoimmune disorder, like inflammatory bowel disease or JIA. Although clinicians may think of these diseases as presenting with organ-specific complaints, fever alone can be the prominent symptom, as it was in 83% of children diagnosed with Crohn's disease in one case series24 and in 98% to 100% of children with systemic onset JIA.25 Autoinflammatory disorders are rare but should be considered once infections, immune deficiencies, malignancies, and autoimmune disorders have been ruled out. These conditions are characterized by stereotypical episodes of inflammation caused by dysregulation of the innate immune system. Common symptoms include rash, serositis (abdominal pain, pericarditis, pleuritis), arthritis, aphthous ulcers, and elevated inflammatory markers. Whereas autoimmune disorders will worsen over time without treatment, autoinflammatory disorders, because the innate immune system does not exhibit memory, will continue to have distinct stereotypical episodes that are usually no different in magnitude than the previous episodes, although some of these disorders will lead to amyloidosis over time.26 Fever is a predominant symptom in familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and hyper-immunoglobulin D syndrome.
Periodic fevers occur with clockwork predictability, but cyclic neutropenia and PFAPA (periodic fever, aphthous stomatitis, pharyngitis, and adenitis) syndrome are the only causes. Cyclic neutropenia is characterized by fever, aphthous ulcers, malaise, and occasional bacterial infections every 21 days, coincident with a drop in blood neutrophil count. It is caused by a mutation in the neutrophil elastase gene, resulting in cyclical decreased production of myeloid progenitor cells in the bone marrow. The diagnosis can be made by obtaining serial complete blood counts 2 to 3 times weekly, looking for those nadirs that occur every 21 days.27
PFAPA syndrome is the most common recurrent fever syndrome in childhood. It appears to be autoinflammatory in nature, but specific genetic causes are currently lacking.28 One hallmark feature is its regularity—the fever episodes occur so regularly that a family can plan vacations around them. Another feature is stereotypy—the current episode is exactly like the previous one and will be similar to the next one. Onset usually occurs before age 5 years, with cycles every 3 to 8 weeks and episodes lasting 3 to 6 days.29 A prodrome of malaise and irritability often proceeds the fever, which itself can be accompanied by tonsilitis, enlarged cervical lymph nodes, red and sore throat, and aphthous ulcers. Additional symptoms vary and include headache, diarrhea, arthralgia, and abdominal pain. Some children may have all manifestations with each episode, whereas others may have only one or two signs. The white blood cell count and C-reactive protein are typically elevated during episodes but return to normal between episodes. Growth and development are normal.30 The diagnosis of PFAPA syndrome is based on clinical criteria and exclusion of other etiologies. A fever and symptom diary are crucial diagnostic tools. Elevated white blood cell counts and C-reactive protein levels during episodes is not surprising, and although originally recommended to help support the diagnosis, obtaining these tests may not be that helpful in differentiating PFAPA from other etiologies. Episodes can be aborted with oral steroids, and tonsillectomy appears to be curative in most patients.31
Children with PUF and RUF will continue to present to outpatient practices. Distinguishing between the two may help narrow the differential diagnosis. Taking a detailed history, performing a thorough physical examination, and reviewing a fever and symptom diary are crucial in recognizing clues that may ultimately lead to a diagnosis. Be prepared, however, for the possibility of no diagnosis, which is not a problem as long as the child looks healthy and the fever eventually resolves, which sometimes may take several weeks. Consider referral if it does not.
- Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6°F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA. 1992;268:1578–1580. doi:10.1001/jama.1992.03490120092034 [CrossRef]
- Wunderlich CA, Reeve JC. The course of the temperature in diseases: a guide to clinical thermometry. Am J Med Sci. 1869;57:425–447. doi:10.1097/00000441-186904000-00021 [CrossRef]
- Atkinson G, Coldwells A, Reilly T, Waterhouse J. A comparison of circadian rhythms in work performance between physically active and inactive subjects. Ergonomics. 1993;36:273–281. doi:. doi:10.1080/00140139308967882 [CrossRef]
- Newman BH, Martin CA. The effect o hot beverages, cold beverages, and chewing gum on oral temperature. Transfusion. 2001;41:1241–1243. doi:10.1046/j.1537-2995.2001.41101241.x [CrossRef]
- Merriam-Webster. Fever. https://www.merriam-webster.com/dictionary/fever. Accessed August 7, 2018.
- Marcy SM, Kohl KS, Dagan R, et al. Brighton Collaboration Fever Working Group. Fever as an adverse event following immunization: case definition and guidelines of data collection, analysis and presentation. Vaccine. 2004;22:551–556. doi:10.1016/j.vaccine.2003.09.007 [CrossRef]
- Rideout ME, First LR. Fever: measuring and managing a sizzling symptom. Contemp Pediatr. 2001;18:42–54.
- McGowan JE, Bratton L, Klein JO, Finland M. Bacteremia in children seen in a “walk-in” pediatric clinic. N Engl J Med. 1973;288:1309–1312. doi:10.1056/NEJM197306212882501 [CrossRef]
- Marshall G. Prolonged and recurrent fevers in children. J Infect. 2014;68:S83–S93. doi:. doi:10.1016/j.jinf.2013.09.017 [CrossRef]
- Baraff LJ. Management of infants and young children with fever without source. Pediatr Ann. 2008;37:673–679. doi:10.3928/00904481-20081001-01 [CrossRef]
- Kleiman MB. The complaint of persistent fever. Pediatr Clin North Am. 1982;29:201–208. doi:10.1016/S0031-3955(16)34117-7 [CrossRef]
- Statler VA, Marshall GS. Characteristics of patients referred to a pediatric infectious diseases clinic with unexplained fever. J Pediatric Infect Dis Soc. 2016;5:249–256. doi:. doi:10.1093/jpids/piv008 [CrossRef]
- Petersdorf RG, Beeson PB. Fever of unexplained origin: report on 100 cases. Medicine. 1961;40:1–30. doi:10.1097/00005792-196102000-00001 [CrossRef]
- McClung HJ. Prolonged fever of unknown origin in children. Am J Dis Child. 1972;124:544–550.
- Pizzo PA, Lovejoy FH, Smith DH. Prolonged fever in children: review of 100 cases. Pediatrics. 1975;55:468–473.
- Lohr JA, Hendley JO. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Clin Pediatr. 1977;16:768–773. doi:10.1177/000992287701600905 [CrossRef]
- Steele RW, Jones SM, Lowe BA, Glasier CM. Usefulness of scanning procedures for diagnosis of fever of unknown origin in children. J Pediatr. 1991;119:526–530. doi:10.1016/S0022-3476(05)82399-6 [CrossRef]
- Jacobs RF, Schutze GE. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis. 1998;26:80–84. doi:10.1086/516256 [CrossRef]
- Long SS, Edward KM. Prolonged, recurrent, and periodic fever syndromes. In: Long SS, ed. Principles and Practice of Pediatric Infectious Disease. 4th ed. Philadelphia, PA: Saunders Elsevier; 2012:117–127.
- Glezen WP, Denny FW. Epidemiology of acute lower respiratory disease in children. N Engl J Med. 1973;288:498–505. doi:10.1056/NEJM197303082881005 [CrossRef]
- Joshi AY, Iyer V, Hagan JB, St Sauver JL, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin Proc. 2009;84:16–22. doi:. doi:10.4065/84.1.16 [CrossRef]
- Jeffrey Modell Foundation. 10 Warning signs. http://www.info4pi.org/library/educational-materials/10-warning-signs. Accessed August 13, 2018.
- Subbarayan A, Colarusso G, Hughes SM, et al. Clinical features that identify children with primary immunodeficiency diseases. Pediatrics. 2011;127:810–816. doi:. doi:10.1542/peds.2010-3680 [CrossRef]
- Burbidge EJ, Huang S, Bayless TM. Clinical manifestations of Crohn's disease in children and adolescents. Pediatrics. 1975;55:866–871.
- Behrens EM, Beukelman T, Gallo L, et al. Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR). J Rheumatol. 2008;35:343–348.
- Verbsky JW. When to suspect autoinflammatory/recurrent fever syndromes. Pediatr Clin North Am. 2017;64:111–125. doi:. doi:10.1016/j.pcl.2016.08.008 [CrossRef]
- Dale DC, Hammond WP 4th, . Cyclic neutropenia: a clinical review. Blood Rev. 1988;2:178–185. doi:10.1016/0268-960X(88)90023-9 [CrossRef]
- Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–668. doi:. doi:10.1146/annurev.immunol.25.022106.141627 [CrossRef]
- Harel L, Hashkes PJ, Lapidus S, et al. The first international conference on periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome. J Pediatr. 2018;193:265–274.e3. doi:. doi:10.1016/j.jpeds.2017.10.034 [CrossRef]
- Vigo G, Zulian F. Periodic fevers with aphthous stomatitis, pharyngitis, and adenitis (PFAPA). Autoimmun Rev. 2012;12:52–55. doi:. doi:10.1016/j.autrev.2012.07.021 [CrossRef]
- Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP. Tonsillectomy for periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA). Cochrane Database Syst Rev. 2014;9:CD008669. doi:10.1002/14651858.CD008669.pub2 [CrossRef].
Targeted Studies for Fever of Unknown Origin
||Reason for Suspicion
||Cat scratch disease
||Exposure to kittens, cat scratch with papule, regional adenopathy
| EBV serology
||Fatigue, lymphadenopathy, cytopenias, elevated LFTs
Histoplasma complement fixation and immunodiffusion
||Residence in Ohio or Mississippi River Valleys, bird exposures
Blastomyces complement fixation and immunodiffusion
||Skin lesion, exposure to beavers, creeks
||Consumption of unpasteurized milk products
||Exposure to cats or litter boxes, consumption of poorly cooked meat
||Tick bite with eschar, rabbit hunting
| Tuberculin skin test, IGRA
||Exposure to active case, homeless shelter, travel
| HIV Ab/Ag or PCR
||Sexually active, IVDU, mononucleosis-like syndrome, cytopenias
| Blood culture for Salmonella
||Travel, hepatosplenomegaly, rose spots
| Thick and thin smears
Chlamydophila psittaci complement fixation or microimmunofluorescence
||Exposure to domestic and wild birds
Coxiella burnetii serology
||Participation in animal births
||Adventure travel, participating in sporting events that involve swimming in rivers or lakes
| Stool calprotectin, fecal occult blood test
||Inflammatory bowel disease
||Anemia, fatigue, blood in stool, diarrhea, abdominal pain, weight loss
| ASO titer, anti-DNAse B titer
||Heart murmur, migratory polyarthritis, erythema marginatum
| ANA, RF, C3, C4
||Various rheumatologic disorders
||Arthritis, anemia, proteinuria, rash
| Bone marrow aspirate, lymph node biopsy, peripheral smear
||Cytopenias, weight loss, bleeding, bruising, lymphadenopathy, night sweats
| Free T4, TSH
||Weight loss, hair loss, nervousness, tremors
| Abdominal CT or U/S
||Abdominal pain, distension, history of surgery or IBD
| Sinus CT
Immunology Tests Based on Type of Immune Deficit
| IgG, IgA, IgM, IgE levels
| Antibody response to vaccine antigens (eg, diphtheria toxoid, pneumococcal polysaccharide)
| Immunophenotype (flow cytometry)
| HIV Ag/Ab (4th generation EIA) or HIV DNA PCR
| Lymphocyte proliferative response to mitogens
| Absolute neutrophil count
| Dihydrorhodamine (DHR) oxidative burst assay