Abstract
Older case series established diagnostic considerations for children meeting a priori definitions of fever of unknown origin (FUO). No recent study has examined the final diagnoses of children referred for unexplained fever.
This study was conducted with a retrospective chart review of patients referred to a pediatric infectious diseases clinic from 2008 to 2012 for unexplained fever.
Sixty-nine of 221 patients were referred for “prolonged” unexplained fever. Ten of these were not actually having fever, and 11 had diagnoses that were readily apparent at the initial visit. The remaining 48 were classified as having FUO. The median duration of reported fever for these patients was 30 days; 15 had a diagnosis made, 5 of which were serious. None of the serious FUO diagnoses were infections. Of 152 patients with “recurrent” unexplained fever, 92 had an “intermittent” fever pattern, and most of these had sequential, self-limited viral illnesses or no definitive diagnosis made. Twenty of the 60 patients with a “periodic” fever pattern were diagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome. Overall, 166 patients either were not having fever, had self-limited illnesses, or ultimately had no cause of fever discovered. Only 12 had a serious illness, 2 of which were infections (malaria and typhoid fever).
Most children referred with unexplained fever had either self-limited illnesses or no specific diagnosis established. Serious diagnoses were unusual, suggesting that these diagnoses rarely present with unexplained fever alone, or that, when they do, the diagnoses are made by primary care providers or other subspecialists.
Unexplained fever is a common reason for referral to pediatric infectious diseases (PID) specialists. The usual construct under which such children are evaluated is that of fever of unknown origin (FUO), first crystalized in adults by Petersdorf and Beeson in 1961 [ 1 ] but not addressed in children until the 1970s–1990s. In fact, our understanding of FUO in children is based primarily on 5 major papers published during that era [ 2–6 ]. Each of these was a retrospective case series from an academic medical center that used a different definition of “fever” and “FUO”, as follows: core temperature ≥100.5°F on at least 1 occasion every day for ≥14 days [ 6 ]; oral or rectal temperature ≥100.5°F on at least 2 occasions per week for ≥3 weeks [ 5 ]; temperature ≥101.1°F (method not specified) on multiple occasions for ≥3 weeks (outpatients) or ≥1 week (inpatients) [ 4 ]; rectal temperature ≥101.4°F on at least 5 occasions for ≥2 weeks [ 3 ]; rectal temperature ≥102.1°F on multiple occasions for ≥3 weeks (outpatients) or ≥1 week (inpatients) [ 2 ]. Even the Brighton Collaboration definition of fever (“the endogenous elevation of at least one measured body temperature of ≥38°C [100.4°F], irrespective of device used, anatomic site, age, or environmental conditions”) is, by Brighton's own admission, “to some extent arbitrary” [ 7 ].
There are many more children who are referred to academic medical centers with unexplained fever than who meet such definitions of fever and FUO—one might wonder who these children are and with what they are ultimately diagnosed. In addition, whereas the seminal papers established—in rank order—infectious, inflammatory, neoplastic, and “other” conditions as the diagnoses of concern in patients with FUO, those papers also made it clear that the causes of unexplained fever, as reported in the literature, change over time. For example, from the 1970s to the 1990s, infectious diseases became less common in case series of FUO, and “no diagnosis” became more common [ 8 ]. This is perhaps not surprising, given expansion of the diagnostic modalities available to primary care providers. Occult infections, for example, may now be diagnosed and treated by primary care providers, leaving fewer children with infectious diseases—and more with “no diagnosis”—to be referred to academic subspecialists.
Few studies have revisited the classic FUO construct in the United States since the late 1990s, and none, to our knowledge, has provided a broader view of the characteristics and diagnoses in children referred to PID specialists with unexplained fever. This case series was formulated to fill these gaps in the literature.
METHODS
The University of Louisville PID Clinic provides outpatient consultation in infectious diseases and immunology for children who live in the Louisville metro area, north-central and western Kentucky, and southern Indiana. The clinic has daily office hours and is staffed, on any given day, by a board-certified PID specialist and a nurse practitioner with over 10 years of experience in the subspecialty. During the study period, 6 different physician providers rotated for 2 weeks at a time through the clinic, and there were 900 visits (300 new patients) per year. The only requirement for being seen as a patient was to be referred by another provider, and patients were scheduled regardless of ability to pay.
This was a retrospective study of children referred to the PID Clinic for unexplained fever. To identify patients, a computerized database containing open text fields listing diagnoses and reasons for referral was queried for the terms “fever,” “febrile,” and “FUO” from January 1, 2008 through February 28, 2012. After implementation of an electronic health record (EHR) in March 2012, the database contained billable codes rather than text fields; therefore, from March 1, 2012 through December 31, 2012, the database was queried for the diagnosis of fever (International Classification of Diseases, Ninth Revision [ICD-9], code 780.60). Patients who were first evaluated as inpatients and subsequently seen as outpatients were not included. Also excluded were patients whose first outpatient visit occurred before January 1, 2008 and patients referred for a specific diagnosis containing the word fever (eg, “typhoid fever,” “scarlet fever,” or “fever blisters”). These and other exclusions are delineated in Figure 1 .
Derivation of the study population. FMF, familial Mediterranean fever; FUO, fever of unknown origin; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.
Derivation of the study population. FMF, familial Mediterranean fever; FUO, fever of unknown origin; PFAPA, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome.
Unique patients were identified and the medical records were reviewed (a complete waiver was granted by the University of Louisville Human Subjects Committee). To be included in the final study cohort, patients needed to have unexplained fever as determined by the PID provider and indicated in the medical record. A standardized data abstraction form and operations manual were used for the chart reviews, which were performed by a single investigator. Information pertaining to history, physical examination, diagnostic studies performed before referral, and final diagnosis was recorded. For purposes of analysis, diagnostic studies were considered discrete units if they were ordered as such; for example, a complete blood count, erythrocyte sedimentation rate, comprehensive metabolic panel, chest x-ray, tuberculin skin test, and Epstein-Barr virus (EBV) serology panel were each considered 1 diagnostic test.
Because there are no generally accepted schemes for classifying children referred with unexplained fever (see introduction section), a priori definitions were not used. Instead, patient characteristics derived from the medical record were used to develop categories of illness. Thus, children with prolonged unexplained fever (PUF) were operationally defined as follows: (1) the chief complaint was fever; (2) the infectious disease provider determined that the child was having fever; (3) the fever was perceived or documented by the parents and/or referring provider to be part of a continuous illness; (4) the fever was not attributed to a specific etiology before referral; and (5) the illness was sufficiently concerning to warrant direct involvement of a PID specialist. Children with recurrent unexplained fever (RUF) met the same criteria, except that the fever was perceived or documented to be part of a discontinuous illness. It is important to point out that the terms “PUF” and “RUF” apply to the reason for referral (for example, a patient might be referred for PUF but might not actually be having fever). Likewise, given the lack of agreement on what constitutes “fever” (see introduction section) and the variability in temperature-taking methods used at home, no a priori definition of fever was used—instead, patients were considered to have fever if that was the assessment of the PID provider.
Descriptive analyses were performed using Microsoft Excel for Mac 2011 version 14.3.9 (131030). Medians and interquartile ranges were used as measures of central tendency.
RESULTS
The derivation of the study population is shown in Figure 1 . Review of the 4586 visits to the PID Clinic from 2008 through 2012 yielded 221 unique patients who were referred for unexplained fever. The change in method for case identification (pre-EHR free-text field database versus post-EHR ICD-9 code database) did not affect the number of subjects identified per month, and there was no association between year or season and the number of cases identified. Males and females were equally represented, most patients were white, and the median age was 4.0 years (interquartile range [IQR], 2.1–7.5). The most common source of referral was pediatricians, followed by family physicians and nurse practitioners. Of the 221 unique patients, 211 were classified as having fever by the PID provider; their median maximum temperature was 104°F (IQR, 102°F–104°F).
Prolonged Unexplained Fever
Sixty-nine (31% of the total) patients were determined by the PID provider to have been referred for PUF. These children tended to be older (median age, 6.8 years; IQR, 2.2–12.3) than those referred for RUF (3.3 years; IQR, 2.1–6.1; see below and Table 1 ), but the children were similar in terms of other demographic characteristics. Ten (14%) of the 69 patients who were referred for PUF were actually not having fever. These children tended to be older than the others (median age, 9.3 years; IQR, 6.1–12.7) and most (7 of 10) were female. Three of these patients brought fever diaries to the first visit, none of which demonstrated repeatedly elevated temperatures ≥100.5°F.
Characteristics of Patients Referred for Unexplained Fever
| Characteristic | Illness Pattern | ||
|---|---|---|---|
| Prolonged Unexplained Fever (PUF) N = 69 | Recurrent Unexplained Fever (RUF) N = 152 | All Patients N = 221 | |
| Characteristics at Initial Visit | |||
| Median age at first visit (years, IQR) | 6.8 (2.2–12.3) | 3.3 (2.1–6.1) | 4 (2.1–7.5) |
| Male gender | 29 (42%) | 82 (54%) | 111 (50%) |
| White race a | 50 (94%) | 112 (88%) | 162 (90%) |
| Referral source | |||
| Pediatrician | 45 (65%) | 117 (77%) | 162 (73%) |
| Family practitioner | 11 (16%) | 14 (9%) | 25 (12%) |
| Nurse practitioner | 8 (12%) | 8 (5%) | 16 (7%) |
| Pediatric subspecialist | 3 (4%) | 6 (4%) | 9 (4%) |
| Self | 0 (0%) | 2 (2%) | 2 (1%) |
| Unknown | 2 (3%) | 5 (3%) | 7 (3%) |
| Final Diagnostic Category | |||
| No illness, self-limited illness, or no diagnosis made | 43 (62%) | 123 (81%) | 166 (75%) |
| Mild or moderate illness b | 18 (26%) | 25 (16%) | 43 (20%) |
| Serious illness c | 8 (12%) | 4 (3%) | 12 (5%) |
| Characteristic | Illness Pattern | ||
|---|---|---|---|
| Prolonged Unexplained Fever (PUF) N = 69 | Recurrent Unexplained Fever (RUF) N = 152 | All Patients N = 221 | |
| Characteristics at Initial Visit | |||
| Median age at first visit (years, IQR) | 6.8 (2.2–12.3) | 3.3 (2.1–6.1) | 4 (2.1–7.5) |
| Male gender | 29 (42%) | 82 (54%) | 111 (50%) |
| White race a | 50 (94%) | 112 (88%) | 162 (90%) |
| Referral source | |||
| Pediatrician | 45 (65%) | 117 (77%) | 162 (73%) |
| Family practitioner | 11 (16%) | 14 (9%) | 25 (12%) |
| Nurse practitioner | 8 (12%) | 8 (5%) | 16 (7%) |
| Pediatric subspecialist | 3 (4%) | 6 (4%) | 9 (4%) |
| Self | 0 (0%) | 2 (2%) | 2 (1%) |
| Unknown | 2 (3%) | 5 (3%) | 7 (3%) |
| Final Diagnostic Category | |||
| No illness, self-limited illness, or no diagnosis made | 43 (62%) | 123 (81%) | 166 (75%) |
| Mild or moderate illness b | 18 (26%) | 25 (16%) | 43 (20%) |
| Serious illness c | 8 (12%) | 4 (3%) | 12 (5%) |
Abbreviations: IQR, interquartile range; PUF, prolonged unexplained fever; RUF, recurrent unexplained fever.
a Race not available for 16 subjects with prolonged fever and 25 subjects with recurrent fever.
b Includes periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (N = 20); Epstein-Barr virus infection (4); cat scratch disease (4); sinusitis (3); histoplasmosis (2); recurrent urinary tract infections (2); viral upper respiratory tract infection (2); bacterial lymphadenitis (1); central fever (1); cytomegalovirus infection (1); idiopathic aphthous stomatitis (1); recurrent pneumonia (1); suppurative otitis media (1).
c See Table 3 for details. Includes inflammatory bowel disease (N = 3); juvenile idiopathic arthritis (2); acute lymphoblastic leukemia (1); familial Mediterranean fever (1); systemic lupus erythematosus (1); malaria (1); rheumatic fever (1); typhoid fever (1); Epstein-Barr virus infection complicated by hemophagocytic lymphohistiocytosis (1).
Of the 59 patients referred for PUF who were experiencing fever, 11 (19%) had a diagnosis that was apparent on the initial visit. Nine of these had infections: sinusitis (N = 2); viral respiratory infection (2); bacterial lymphadenitis (1); cat scratch disease (CSD) (1); suppurative otitis media (1); recent EBV infection (1); and typhoid fever (1). One of the remaining patients had inflammatory bowel disease (IBD), and 1 had acute rheumatic fever. These patients either had laboratory evidence of a specific disorder obtained before the initial PID visit or had clinical features that strongly suggested a specific diagnosis. For example, the patient with CSD was a 7-year-old female who had 27 days of reported daily fever with a maximum temperature of 102°F. On physical examination, she had a healed kitten scratch on her arm with an overlying red papule. Bartonella henselae immunoglobulin (Ig)G was positive at 1:256 (IgM was negative).
The remaining 48 patients referred for PUF who were having fever were classified as having FUO. Their median duration of reported fever before the initial visit was 30 days (IQR, 21–60). Thirty-four (71%) gave a history of sequential daily fevers (this was supported by a fever diary in 8 patients), and 14 (29%) had sequential daily fevers occasionally interrupted by afebrile days. On average, each of these 48 patients had 10 diagnostic studies performed before referral. Of the 15 (31%) patients with FUO who ultimately had a diagnosis made, 10 (67%) had confirmed infections: acute EBV or cytomegalovirus infection (N = 5; 1 of these patients developed hemophagocytic lymphohistiocytosis [HLH]); CSD (3); and histoplasmosis (2). The other 5 patients had inflammatory conditions (systemic juvenile idiopathic arthritis [JIA] [2]; IBD [1]), central fever (1), or malignancy (acute lymphoblastic leukemia [ALL] [1]). Five of the 15 FUO patients who had a diagnosis made were considered to have a serious condition (JIA, IBD, ALL, HLH), none of which was infectious in nature.
Despite extensive work-up, 33 (69%) of the 48 patients with FUO never had a definitive diagnosis made. Twenty-two of them had fevers that resolved by the last clinic visit or as reported by follow-up telephone call. Of the other 11 children, 4 were referred to other subspecialists (rheumatology [2], ophthalmology [1], gastroenterology [1]). A computer search of the local inpatient hospital and outpatient records systems did not reveal any hospitalizations or visits for serious diagnoses.
Recurrent Unexplained Fever
One hundred fifty-two (69% of the total) patients were referred for RUF. Ninety-two (61%) presented with a pattern of intermittent fevers, and 91% of these either had no specific diagnosis made or were thought to have experienced sequential, self-limited illnesses. A minority of patients with intermittent fevers had definitive diagnoses established; those were recurrent urinary tract infections (N = 2); right middle lobe syndrome with recurrent pneumonias (1); chronic sinusitis (1); malaria relapse (1); systemic lupus erythematosus (SLE; 1); IBD (1); and idiopathic aphthous stomatitis (1).
Sixty patients (39% of those with RUF) presented with a periodic fever pattern, defined as fevers that recurred at regular, predictable intervals. Twenty-one (35%) of these met criteria for a periodic fever syndrome; those were periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome (N = 20) and familial Mediterranean fever (FMF; 1). Characteristics of PFAPA patients are shown in Table 2 . The median age was 3.5 years (IQR, 2.3–5.9) and 70% were male. Most patients had symptoms for over 6 months, and the typical pattern was fevers lasting 3 to 5 days recurring every 2 to 4 weeks. The remaining 39 patients with a periodic fever pattern never had a specific diagnosis established. Of these, 24 (62%) were known to have resolution of fevers. Of the other 15 patients, 3 were referred to rheumatology and none had a definite diagnosis made. A computer search of the local inpatient hospital and outpatient records systems did not reveal any hospitalizations or visits for serious diagnoses for the other 12 children.
Characteristics of Patients With Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis Syndrome
| Characteristic | |
|---|---|
| Median age at first visit (years) | 3.5 (2.3–5.9 a ) |
| Male gender | 13 (70%) |
| White race | 15 (75%) |
| Referral source | |
| Pediatrician | 14 (70%) |
| Self | 2 (10%) |
| Family practitioner | 1 (5%) |
| Nurse practitioner | 1 (5%) |
| Pediatric subspecialist | 1 (5%) |
| Unknown | 1 (5%) |
| Median duration of condition at first visit (months) b | 10 (6–18 a ) |
| Episodes every 2–4 weeks | 16 (75%) |
| Episode duration 3–5 days b | 14 (68%) |
| Characteristic | |
|---|---|
| Median age at first visit (years) | 3.5 (2.3–5.9 a ) |
| Male gender | 13 (70%) |
| White race | 15 (75%) |
| Referral source | |
| Pediatrician | 14 (70%) |
| Self | 2 (10%) |
| Family practitioner | 1 (5%) |
| Nurse practitioner | 1 (5%) |
| Pediatric subspecialist | 1 (5%) |
| Unknown | 1 (5%) |
| Median duration of condition at first visit (months) b | 10 (6–18 a ) |
| Episodes every 2–4 weeks | 16 (75%) |
| Episode duration 3–5 days b | 14 (68%) |
a Interquartile range.
b Data not available for 1 patient.
Summary
Of the 221 patients referred for unexplained fever, 166 (75%) either were not actually having fever, had self-limited illnesses, or ultimately had no cause of fever discovered (Table 1 ). Two-thirds of these patients were seen in the PID Clinic only 1 time, and 64% had resolution of fever after their initial or last clinic visit or last telephone contact. As shown in Table 1 , only 5% of children in the entire cohort were ultimately diagnosed with a serious illness, although serious illness was more common among patients with PUF than RUF. Characteristics of the 12 children with serious illnesses are shown in Table 3 .
Clinical Features of Patients with a Serious Diagnosis
| Patient | Age (Years) | Gender | Presenting Features | Diagnostic Work-up | Fever Category | Final Diagnosis |
|---|---|---|---|---|---|---|
| 1 | 3.5 | Male | Travel to Senegal, history of other tropical diseases, abdominal pain | CBC, thick and thin smears | RUF Intermittent | Malaria due to Plasmodiumvivax |
| 2 | 4.2 | Male | History of anal fistula repair, weight loss, decreased appetite, fatigue, abdominal pain, constipation, wasting | CBC, CRP | RUF Intermittent | IBD |
| 3 | 3.5 | Male | Quotidian fever pattern, fatigue, joint pain, rash | CBC, ESR | PUF FUO | Systemic JIA |
| 4 | 4.8 | Female | Adopted from China, decreased appetite, mouth sores, abdominal pain, muscle pain, rash, headache, irritability | Periodic fever gene panel | RUF Periodic | Familial Mediterranean fever |
| 5 | 7.3 | Male | Fatigue, muscle pain, rash, headache, lymphadenopathy | CBC, CMP, bone marrow biopsy, lymph node biopsy, ferritin, abdominal x-ray | PUF FUO | Hemophagocytic lymphohistiocytosis |
| 6 | 11.1 | Male | Weight loss, decreased appetite, early satiety | None | PUF FUO | IBD |
| 7 | 19.4 | Female | Travel to India, exposure to raw sewage, vomiting, diarrhea, abdominal pain, muscle pain, rash, headache | None | PUF Diagnosis on first visit | Typhoid fever |
| 8 | 0.8 | Female | Rash, decreased appetite | ESR | PUF FUO | Systemic JIA |
| 9 | 2.8 | Female | Decreased appetite, fatigue, night sweats, lymphadenopathy, single enlarged lymph node | CBC, lymph node biopsy | PUF FUO | Acute lymphoblastic leukemia |
| 10 | 15.4 | Female | Fatigue, diarrhea, abdominal pain, bloody stools | Occult blood, colonoscopy | PUF Diagnosis on first visit | IBD |
| 11 | 10.9 | Male | Decreased appetite, joint pain, muscle pain, heart murmur | Echocardiogram, anti-DNAse-B, ASO titer | PUF Diagnosis on first visit | Rheumatic fever with rheumatic heart disease |
| 12 | 9.8 | Female | Family history of rheumatoid arthritis, joint pain, joint swelling, rash | ESR, U/A, ANA, RF | RUF Intermittent | Systemic lupus erythematosus |
| Patient | Age (Years) | Gender | Presenting Features | Diagnostic Work-up | Fever Category | Final Diagnosis |
|---|---|---|---|---|---|---|
| 1 | 3.5 | Male | Travel to Senegal, history of other tropical diseases, abdominal pain | CBC, thick and thin smears | RUF Intermittent | Malaria due to Plasmodiumvivax |
| 2 | 4.2 | Male | History of anal fistula repair, weight loss, decreased appetite, fatigue, abdominal pain, constipation, wasting | CBC, CRP | RUF Intermittent | IBD |
| 3 | 3.5 | Male | Quotidian fever pattern, fatigue, joint pain, rash | CBC, ESR | PUF FUO | Systemic JIA |
| 4 | 4.8 | Female | Adopted from China, decreased appetite, mouth sores, abdominal pain, muscle pain, rash, headache, irritability | Periodic fever gene panel | RUF Periodic | Familial Mediterranean fever |
| 5 | 7.3 | Male | Fatigue, muscle pain, rash, headache, lymphadenopathy | CBC, CMP, bone marrow biopsy, lymph node biopsy, ferritin, abdominal x-ray | PUF FUO | Hemophagocytic lymphohistiocytosis |
| 6 | 11.1 | Male | Weight loss, decreased appetite, early satiety | None | PUF FUO | IBD |
| 7 | 19.4 | Female | Travel to India, exposure to raw sewage, vomiting, diarrhea, abdominal pain, muscle pain, rash, headache | None | PUF Diagnosis on first visit | Typhoid fever |
| 8 | 0.8 | Female | Rash, decreased appetite | ESR | PUF FUO | Systemic JIA |
| 9 | 2.8 | Female | Decreased appetite, fatigue, night sweats, lymphadenopathy, single enlarged lymph node | CBC, lymph node biopsy | PUF FUO | Acute lymphoblastic leukemia |
| 10 | 15.4 | Female | Fatigue, diarrhea, abdominal pain, bloody stools | Occult blood, colonoscopy | PUF Diagnosis on first visit | IBD |
| 11 | 10.9 | Male | Decreased appetite, joint pain, muscle pain, heart murmur | Echocardiogram, anti-DNAse-B, ASO titer | PUF Diagnosis on first visit | Rheumatic fever with rheumatic heart disease |
| 12 | 9.8 | Female | Family history of rheumatoid arthritis, joint pain, joint swelling, rash | ESR, U/A, ANA, RF | RUF Intermittent | Systemic lupus erythematosus |
Abbreviations: ANA, antinuclear antibody; ASO, antistreptolysin O; CBC, complete blood count; CMP, complete metabolic panel; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; FUO, fever of unknown origin; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; PUF, prolonged unexplained fever; RF, rheumatoid factor; RUF, recurrent unexplained fever; U/A, urinalysis.
DISCUSSION
The most important finding in this study is that the majority of patients referred to an active PID outpatient service for unexplained fevers did not have a serious illness. In fact, 95% of 221 patients had no fever, self-limited illnesses, conditions for which no specific diagnosis was made (but fevers resolved), or mild-to-moderate illnesses (which may or may not have warranted treatment). Only 2 patients of 221 had serious infectious diseases (1 had malaria and 1 had typhoid fever). Ten patients had serious noninfectious conditions (HLH, IBD, JIA, FMF, SLE, rheumatic fever, ALL); in as much as these diagnoses predominated among sick children, PID physicians should be familiar with their presentation and laboratory evaluation. This is not to say that serious diseases—infectious or otherwise—do not present with unexplained fever. Rather, those children whose serious illnesses present with fever are probably being diagnosed by primary care providers or are being referred by primary care providers to other specialists.
In general, the children with serious illnesses were not a mystery. The history and physical exam provided the necessary clues to diagnosis. Two children had travel history and clinical syndromes consistent with tropical diseases (malaria and typhoid). Three with IBD described gastrointestinal complaints with significant weight loss and/or bloody stools. Each child diagnosed with a hematologic/oncologic process (ALL, HLH) had significant lymphadenopathy, prompting biopsy, and all 3 children with autoimmune disorders (SLE or JIA) had a rash at the time of referral. Thus, children with serious illnesses had clinical features at the time of referral that prompted further evaluation and definitive diagnosis.
The paucity of children with serious infections in this series stands in contrast to previous case series [ 2–6 ]. Notably absent from the current cohort are patients with tuberculosis, brucellosis, meningitis, endocarditis, osteomyelitis, liver abscess, and tick-borne rickettsial infection, all of which featured prominently in earlier studies. Similarly, only 1 patient in the current study was diagnosed with a malignancy, in contrast to the number and variety of malignancies seen in earlier studies. The most obvious difference between the current study and previous ones is that most of the earlier studies were based exclusively on inpatient populations meeting a priori definitions of FUO (only 1 study [ 6 ] included outpatients). Because hospital admission for diagnostic work-up is unusual today (the result of insurance restrictions), the picture of prolonged fever painted by these earlier studies is no longer accurate, at least as it relates to outpatient PID practice. Other factors that may be operative here include the availability of sophisticated diagnostic tests (for example, serologies, computed tomography [CT], magnetic resonance imaging, etc) and the expansion of outpatient services for other subspecialties (for example, rheumatology and hematology/oncology). The present study updates what might be expected by PID specialists in the evaluation of outpatients referred for fever.
Forty-eight patients (70% of those referred with PUF) were considered to have FUO. Their median duration of reported fever (30 days) was longer than the criteria used in previous studies, most of which defined FUO as ≥14 days of fever. This suggests that primary care physicians are waiting longer before referring patients, which is consistent with the idea that they are pursuing more extensive work-ups before referral. In fact, these patients had an average of 10 diagnostic tests each before referral, ranging from point-of-care tests (eg, rapid strep screen, heterophile antibody) to studies for specific infectious diseases (eg, serology for EBV, B henselae , and West Nile virus) to more invasive studies (eg, lymph node biopsy, colonoscopy, and abdominal and pelvis CT scan). The majority of children with FUO never had a definitive diagnosis made; it is possible that by the time these patients reached the point of referral, many of the more easily diagnosable conditions had already been ruled out. These children obviously had a cause for fever—whatever that cause was, it was apparently self-limited. A definitive diagnosis was established in only 15 of the 48 FUO patients, 5 of which were considered serious. Thus, serious diagnoses were unusual even among the highly selected children with FUO.
The majority of patients in this study had RUF. Few previous studies have examined what to expect in such patients. Interestingly, none of these patients was diagnosed with an immune deficiency. This may be because children who are ultimately diagnosed with immune deficiencies are referred for treatment or evaluation of specific, unusual, or recurrent infections, as opposed to unexplained fever per se. This would imply that extensive immunological evaluation is unwarranted in patients with RUF in the absence of specific indications of immune deficiency.
Most of the patients with a periodic fever pattern who ultimately had a diagnosis made had PFAPA syndrome; three-quarters of these patients had at least 1 of the suggested clinical criteria [ 9 ] and were less than 5 years of age when they started having fevers. All had regularly recurring fevers, with more than two-thirds having episodes every 2 to 4 weeks lasting 3 to 5 days. These characteristics are in line with descriptions of PFAPA syndrome in the literature [ 10–12 ].
A small number of patients in this study were not actually having fevers, despite being referred for such. Some of these patients fit what Kleiman [ 13 ] described as having “pseudo-fever of unknown origin”—normal body temperature when it is measured accurately and normal physical exam. There are usually additional clues to this diagnosis, such as family stress or recent illness or death of a loved one. In these patients, the belief that “something is wrong” is real, but manifestations of real disease are not found. Oftentimes, the “second opinion” of the PID subspecialist aids in comforting the family's fear.
Another small group of children in this series were having fever but had evidence of a specific cause at their first visit. The diagnoses were made by suggestive history (eg, travel in a patient with typhoid fever), physical findings (eg, inflamed lymph nodes in a patient with bacterial lymphadenitis), or readily available serologic tests (eg, EBV antibody panel in a patient with symptoms of mononucleosis). Interestingly, the 2 patients with inflammatory processes (IBD and rheumatic fever) each had diagnostic studies that confirmed the disease concurrently with referral to the PID Clinic. In 1 case, the referring provider did not know the results; in the other case, the provider wanted a second opinion.
This study is limited by its reliance on the completeness and accuracy of the medical record. Loss to follow-up was rare, but some patients may have been seen at other referral centers after their visit to the PID Clinic. Another limitation was that at least 6 different providers saw the patients included in the study, and each may have had a different approach to the evaluation. On the other hand, weekly case conferences may have served to establish some degree of uniformity. Finally, information regarding guidance given to primary care providers over the phone before referral was not available. That being said, the overriding philosophy was to provide limited initial consultation by phone (for example, to recommend basic screening tests and limited targeted testing) and to encourage referral for evaluation beyond these basics. Therefore, the findings should be applicable to PID practices with similar philosophies, operating at analogous academic medical centers in comparable communities.
CONCLUSIONS
Assuming generalizability to other PID practice situations, most children referred for unexplained fever are likely to have nonserious or self-limited illnesses. It would appear that children with serious illnesses rarely present with fever alone, or that, when they do present with fever alone, their diagnoses are established by primary care providers or other specialists. The minority of patients who do have serious infections, autoimmune or autoinflammatory diseases, or malignancies are likely to have clues to those diagnoses at the time they are seen. Many children with unexplained fever who lack such “red flags” are likely to improve without having a specific diagnosis made. Well appearing children with PUF and RUF do not need an extensive diagnostic “fishing expedition.”
This study has implications for managing the expectations of patients being referred to PID specialists for unexplained fever. Assuming equivalent diagnostic strategies by the primary care physician before referral, patients could be counseled that a definitive diagnosis might be elusive, but that serious diagnoses are unlikely.
Acknowledgments
Financial support. This work was funded by the Children's Hospital Foundation, the philanthropic arm of Kosair Children's Hospital, Louisville, KY.
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
