Pediatric Fever of Unknown Origin

Pediatricians often confuse fever without a source and fever of unknown origin.After completing this article, readers should be able to:Fever is a common complaint in children. In most cases, fevers are due to self-limited viral infections and require no more than symptomatic treatment. Sometimes fever is due to common bacterial infections that are diagnosed by history and physical examination and require antibiotic treatment without laboratory evaluation. In a few clinical situations, the cause of fever is not easily identified. Fever without a source (FWS) may need further evaluation that includes laboratory tests or imaging. Rarely, the fever is more prolonged, requires more intensive evaluation, and falls in the category of fever of unknown origin (FUO).There is often confusion about the terms FUO and FWS. Distinguishing between FUO and FWS is important and is based on duration of fever. FWS can progress to FUO if no cause is elicited after 1 week of fever.The current incidence and prevalence of pediatric FUO remain unclear. Several factors contribute to the difficulty in determining the epidemiology, including the lack of a standardized definition, clinical criteria, and coding using the International Classification of Diseases-9 code for the condition. Furthermore, the causes of FUO often have an overlapping collection of symptoms and insidious disease courses. The general direction of the evaluation varies based on patient presentation, geographic location, associated symptoms, environmental exposures, physician experience, and available testing techniques.Body temperature is primarily controlled by the hypothalamus via regulation of pulmonary, skin, and metabolic systems. A basic understanding of the physiologic factors regulating temperature can help distinguish between normal variance and fever. The mean basal temperature varies according to age, gender, body habitus, time of day, activity level, menstrual cycle, and other factors. (1)(2) Importantly, physiologic temperature exhibits a morning nadir and an early evening peak, which can vary by as much as 1ºC. Furthermore, infants and young children maintain higher temperatures than older children and adults, primarily because of increased metabolic rate and body surface-to-weight ratio. (1)(3) Of note, core body temperature is positively related to obesity, which should be taken into account with the growing number of obese children in the United States.Fever generally is defined as a core temperature of at least 38.0ºC (100.4ºF) and is the result of a complex series of signalling cascades initiated in response to specific biologic stimuli. (2) Fever is believed to provide an evolutionary advantage in fighting off infection. Bacteria and viruses are heat sensitive and exhibit temperature-dependent toxin production, growth, and response to antibiotics. (4)(5) The body’s mechanism of increasing core temperature in response to infection functions to ward off the offending microbes. Increased metabolic rate accelerates immune system mobilization, lymphocyte transformation, lysosome and neutrophil activity, and phagocytosis. Increases in lipolysis and proteolysis diminish the amount of free glucose that can be used by invading organisms. Similarly, the body transiently removes iron, zinc, and copper, critical cofactors in viral and bacterial replication, from the blood in response to the presence of fever. (6) Taken together, the fever response provides a natural defense mechanism against invading pathogens.One of the challenges in investigating and reviewing FUO is the lack of a standard definition. The number of fever days before considering FUO historically ranged from 5 to 21 and required some degree of medical evaluation. (7)(8) The original literature included a lengthy time course of up to 3 weeks, but the advent of improved and rapid laboratory techniques has led to a shortened number of fever days before considering FUO diagnoses. With the availability of rapid molecular diagnostic techniques for many infections, most of the common causes of FUO from the past can now be diagnosed or excluded rapidly, which has shortened the time that is required to move from FWS to FUO.FUO has more recently been defined as a temperature higher than 38.0°C (100.4°F) that lasts longer than at least 8 days without a clear source. (9) Although most children meeting the definition of FUO would have had some laboratory assessment, it is not currently a prerequisite. (10) However, any previous evaluation would help to broaden or narrow the differential diagnosis.FUO remains a diagnostic dilemma for many pediatricians because it is frequently difficult to distinguish clinically between benign and potentially life-threatening causes. The spectrum of FUO causes is broad and includes infectious, autoimmune, oncologic, neurologic, genetic, factitious, and iatrogenic (Fig 1). Pediatricians face the significant challenge of not missing the diagnosis of a serious illness or an easily treatable condition that can result in increased morbidity. Fortunately, FUO is usually an uncommon presentation of common diseases, most of which are easily treatable without increased morbidity.Relatively few studies document the cause of FUO in developed countries; most of the current knowledge is derived from three studies performed almost 4 decades ago. (11)(12)(13) Low patient numbers and narrow patient populations in more recent studies limit the value of conclusions. (14)(15)(16)(17) More recent studies conducted in adult patients indicate a clear shift to noninfectious causes of FUO, but few corresponding studies confirm this shift in children. (10)(18)(19) Although numerous follow-up studies in developing countries catalogue the underlying causes of FUO, varying medical resources and endemic pathogens in these countries make it unclear whether such findings apply to the United States. (20)(21)(22)(23)(24)The sentinel studies on pediatric FUO in the United States found that approximately 90% of cases had an identifiable cause: approximately 50% infectious, 10% to 20% collagen-vascular, and 10% oncologic. (11)(12)(13) Smaller subsequent studies from the 1990s had highly variable results: 20% to 44% infectious, 0% to 7% collagen-vascular, 2% to 3% oncologic, and up to 67% undiagnosed. (14)(15) The reason for this seemingly paradoxic increase in undiagnosed cases of FUO in the setting of improved diagnostic techniques is unclear. However, the shift from infectious to unidentifiable causes of FUO correlates with advances in diagnostic testing, including wider availability and rapid turnaround time. The advent of polymerase chain reaction, improved culture techniques, and better understanding of atypical viral and bacterial pathogenesis and autoimmune processes likely contribute to earlier diagnosis of the cause of FWS and fewer children advancing to the category of FUO. This shift to unidentifiable causes due to laboratory advances is supported by recent studies from developing countries with significant laboratory limitations, which show primarily infectious causes of FUO, similar to those of older studies in developed countries. (20)(21)(22)(23)(24)Most cases of “undiagnosed” FUO appear to be benign, with many resolving spontaneously without a confirmed cause. These cases possibly consist of prolonged viral syndromes or difficult-to-confirm atypical bacterial infections. Substantially more evidence in the adult population supports the dynamic etiology of FUO over time, with multiple studies over several decades demonstrating an increasing trend toward undiagnosed cases. Some studies suggest that as many as 50% of adult FUO cases remain undiagnosed. (18)(19) These investigations also show decreased infectious and increased inflammatory diagnoses in the adult population over the same period of time. A better understanding of the current etiologic categories of FUO in children should improve the ability of medical practitioners to generate a differential diagnosis.Recent literature from developing countries indicates that the causes of FUO remain primarily infectious. (20)(21)(22)(23)(24)(25) Chow et al (20) reviewed FUO causes in several developing countries from 1990 to 2008. In published studies with greater than 49 patients, infection (36%–78%) was by far the most common cause compared to other causes such as malignancy (2%–12%), collagen-vascular (2%–21%), miscellaneous noninfectious (2%–50%), and unknown (12%–29%). Most of these infections were of bacterial or atypical bacterial origin in contrast to the more common viral causes in developed countries. A more recent report of FUO in Turkey revealed a similar composition, with infection being most common, followed by malignancy and collagen-vascular diseases. (23) A 2012 study of 95 pediatric patients in Iran demonstrated that collagen-vascular diseases were more common causes than malignancy, but there was a high rate of undiagnosed cases. (26)Interestingly, Chantada et al (25) reviewed 113 cases of FUO in Argentina according to three age categories: 0 to 11 months, 12 to 59 months, and older than 60 months. Infection was the most common cause across all age groups, but infectious causes were less common in those ages 12 to 59 months compared to the other two age groups. Children ages 12 to 59 months had a corresponding increase in neoplastic and miscellaneous noninfectious causes of FUO. These results differed from a study of 80 patients in Turkey, which suggested a decreased likelihood of infectious causes with increasing age. (21) As with recent studies in developed countries, small sample sizes and variation in endemic infections limit generalization of these findings.Several contributing and complicating factors are associated with the higher infectious burden of FUO in developing countries. The prevalence of certain infections known to cause FUO, such as human immunodeficiency virus (HIV), tuberculosis, leishmaniasis, and malaria, is higher in developing countries. Similarly, the rate of vaccine-preventable diseases is higher in developing compared to developed countries. Limited public health prevention programs and diminished access to health-care workers likely contribute to an increased incidence of infectious diseases as the cause for FUO, as does a decreased frequency of early recognition of infectious causes. Furthermore, limited awareness and ability to test for newly recognized causes of FUO, such as hemophagocytosis syndrome, may limit diagnosis of certain noninfectious causes.Initially distinguishing among infectious, autoimmune, malignancy, and miscellaneous causes of FUO may be difficult, but a thorough history and physical examination can often generate a directed differential diagnosis. We highly recommend a tiered approach to FUO to decrease overall costs and the use of invasive testing.Evaluation of FUO should be systematic and logically guided by history and physical examination findings. A detailed history, a thorough physical examination, and a proper interpretation of laboratory tests already performed are critical. The speed with which the evaluation should proceed and whether it should be outpatient or inpatient depends, in large part, on how ill the patient appears.The first step in evaluating FUO is documentation that fever is actually present. Parental perception of fever often varies from the medical definition. It is useful to determine what the parent defines as fever and whether this varies from the medical definition of 38.0°C (100.4ºF). In our experience, parents frequently report tactile or subjective fevers without actually measuring the patient’s temperature with an instrument. Parents should be asked if the temperature was checked using a thermometer.Pseudo-FUO has been defined as successive episodes of benign, self-limited infections with fever that the parents perceive as one prolonged fever episode. (27) This needs to be carefully ruled out before undertaking an expensive and unnecessary evaluation. Usually, pseudo-FUO starts with a well-defined infection (most often viral) that resolves but is followed by other febrile viral illnesses that may be less well defined. Diagnosis of pseudo-FUO usually requires a careful history, focusing on identifying afebrile periods between febrile episodes. Differentiating pseudo-FUO from real FUO can be challenging. If pseudo-FUO is suspected and the patient does not appear ill, keeping a fever diary can be helpful. In rare situations, a basic laboratory evaluation may be necessary.Any associated symptoms and the timing of antipyretic administration is particularly important. A detailed description of the patient’s fever pattern as intermittent (eg, tuberculosis), recurrent (periodic fever disorders), relapsing (rat bite fever), remittent (endocarditis, juvenile idiopathic arthritis [JIA]), or sustained (pyogenic abscess) can sometimes narrow the differential diagnosis. (12)(13) Information on the frequency and timing of fevers can be helpful in determining the fever curve and ability to document the fever in the medical setting. Periodicity of fever and the presence of other symptoms at the time fever is present can aid in making certain diagnoses, such as periodic fever, aphthous stomatitis, pharyngitis, and adenopathy (PFAPA) or other periodic fever disorders, without further expensive evaluation. (28)Fever can be the initial presentation of certain immunodeficiency syndromes, but many affected patients have a history of repeated infections, diarrhea, or abnormal physical findings, such as a rash. A history of atopy or autoimmune disease increases the likelihood of an autoimmune or rheumatologic cause. Furthermore, neutropenic fever in certain situations can be a medical emergency, and the presence of neutropenia may broaden the potential infectious sources of fever while narrowing the diagnostic possibility (eg, cyclic neutropenia). Determining the patient’s risk factors for neutropenic fever and any associated signs and symptoms is an important step in an evaluation of FUO.Information regarding the ethnicity, race, family history, and genetic background of the patient can be helpful. Periodic fever disorders often run in families and are more common in certain ethnicities. For example, familial dysautonomia is most common in the Ashkenazi Jewish population whereas familial Mediterranean fever is seen in those of Arab, Jewish, Armenian, and and corresponding endemic pathogens known to cause FUO should be taken into For example, is more common in the United States and of the cases of fever are from and to or in these is an important for making these diagnoses. A thorough history is critical in the evaluation of FUO and should to and if there is no history, should determine the patient’s overall to any or (eg, or than have any evaluating for a more of the of diseases by in the Similarly, a thorough history of any or (eg, recent to countries, the can help narrow the differential diagnosis based on causes of FUO are by associated A detailed of and timing in to fever can to a diagnosis. many patients with FUO have a of it is important to determine whether may have the disease or fever This is particularly important because fever is one of the causes of FUO and a may to fever most important of evaluation for FUO is repeated history and the patient and family to report any or signs or symptoms of how may Most cases of FUO are diagnosed because important the direction of further thorough physical examination should be performed that signs and any signs provide evidence of the underlying diagnosis physical should be and in a controlled inpatient setting may be because up to of significant physical findings may be at the time of the other normal physical examination findings at the time of the initial FUO evaluation are highly of a benign underlying cause. the evaluation, as the the of laboratory and assessment, repeated history and physical are may that aid in determining laboratory and number of basic laboratory studies may be used to determine the source of FUO. A blood with differential and can suggest an infectious or cause. and are with the understanding that may be If the patient has symptoms, studies are also should be before to and of in or may indicate atypical or causes. molecular testing for tuberculosis, or atypical bacterial pathogens and viral is expensive and results can be days to These tests should be performed based on specific risk factors or physical for such as rate and is common in the evaluation of FUO. These tests results are and not diagnostic of any the other should the physician to proceed with further evaluation. Of note, normal results not serious causes of is a of that is by the in response to of of the to a peak, and resolves of the of vary based on age, gender, obesity, and should the of from in the patient than on a initial can be in a of disease including infectious, and has been much in as a of serious bacterial and current evidence that a is required for for bacterial infection. evaluating FUO, particularly in the should not be used to in or out a disease are a more diagnostic and can be used to treatment response and treatment to similar to those but is to and has a longer is an of and physiologic vary based on age, gender, and other factors. may be in cases of abnormal including and In is to and and number of blood is useful in determining or but for the it should be used with as a diagnostic particularly in the setting of in is the of increased may indicate an infectious, autoimmune, oncologic, or inflammatory Some have suggested that may be helpful in evaluation of FUO to distinguish between infectious and noninfectious causes. We have found that can be particularly helpful in an recognized cause of pediatric FUO. have in the diagnosis of and a value greater than is 90% sensitive and specific for and may a in the evaluation of FUO, but that has limited should be performed if symptoms are present or if there is for atypical bacterial tuberculosis, or techniques, particularly and are associated with and should be performed are known to increase the risk of and particularly in the pediatric and is and often requires in young children. recommend with specific diagnoses in For example, in a patient with symptoms, and an may aid in the diagnosis of inflammatory or Of note, all patients with a potential malignancy should a to for a before or to while for such as blood or and have not been well in the diagnosis of pediatric FUO. Limited evidence in children and studies in suggest that these techniques have and in the evaluation of FUO and should be used if to a diagnosis. fever and laboratory studies and to the underlying invasive may be can be performed to for or or may also be to or for These should be performed as a in the recommend that the initial laboratory evaluation of pediatric FUO consist of a basic metabolic and blood and If the patient has symptoms, studies may be These tests should be performed before treatment to of evaluation of FUO should be if any findings on history, physical examination, or laboratory and evaluation toward an system or diagnosis. A patient with known and should evaluation for fever, or on the endemic or which laboratory tests to it is important to that uncommon of common diseases are more likely to cause FUO than uncommon or rare diseases. A with fever, and is more likely to have virus or infection than or In a out common causes of FUO before testing for uncommon causes or invasive testing can the likelihood of with or results for rare have an initial diagnostic based on the broad etiologic categories of FUO that may be performed if a is for a disease (Fig The evaluation provides diagnostic in the evaluation of these categories that may be performed before for or invasive This tiered approach to FUO can decrease overall costs and the use of invasive initial of FUO remains an of FUO is often because most cases are by benign or for serious illness or can to treatment before evaluation. may be to or for an unknown disease which can laboratory or treatment. cases of FUO without a diagnosis and treatment may the diagnosis of life-threatening oncologic, infectious, and autoimmune diseases. treatment should be initiated with and in with first step in the of FUO is to all including antipyretic fever can at any time after a with an overall incidence of up to fever is a common source of FUO and can be by any including and the is fever usually or two of the resolving to If fever is suspected and the patient is multiple one at a time may be helpful in identifying the offending However, other causes of fever should be based on history and physical examination findings, the to that fever is due to fever than of an with FUO, not recommend use of or can the diagnosis of common infectious causes of FUO, such as system or Pediatricians or for atypical bacterial infections in the of risk factors or clinical for these diseases. These have activity against some and have limited which can the or natural disease of causes of FUO. We recommend the use of these there is high clinical and after the diagnostic tests for the are to use is challenging. can a significant in certain causes of FUO, such as autoimmune is no for treatment in most autoimmune diseases, and treatment should be after the diagnosis is one a broad of physiologic including the immune can potentially increase the risk of an infection or an underlying and can the diagnostic of blood and in testing and the other immune should not be a for immune associated with use after to 21 days of We recommend the use of if there is high for serious autoimmune and inflammatory such as or but not have been between adult and pediatric FUO is The of pediatric FUO is likely compared to FUO in the adult population due to in causes. The original studies on pediatric FUO from the demonstrated a rate of to (12)(13) However, with the causes of pediatric FUO, further study is to in adult and pediatric increasing of “undiagnosed” causes of FUO has the pediatric evidence for undiagnosed pediatric FUO. and followed children with undiagnosed FUO for a of of children with undiagnosed FUO were afebrile and clinically at Of the three children febrile or were not clinically two were diagnosed with and the other with Similarly, et al children to a for evaluation of FUO. Of the were available at follow-up had of fevers and developed evidence of inflammatory disease Of note, of these studies was for or the rate of to found in previous studies to current cases of FUO is currently particularly the in underlying etiology over time. study is to determine the and overall associated with pediatric FUO.